This is page 18 of 19. Use http://codebase.md/genomoncology/biomcp?lines=true&page={x} to view the full context.
# Directory Structure
```
├── .github
│ ├── actions
│ │ └── setup-python-env
│ │ └── action.yml
│ ├── dependabot.yml
│ └── workflows
│ ├── ci.yml
│ ├── deploy-docs.yml
│ ├── main.yml.disabled
│ ├── on-release-main.yml
│ └── validate-codecov-config.yml
├── .gitignore
├── .pre-commit-config.yaml
├── BIOMCP_DATA_FLOW.md
├── CHANGELOG.md
├── CNAME
├── codecov.yaml
├── docker-compose.yml
├── Dockerfile
├── docs
│ ├── apis
│ │ ├── error-codes.md
│ │ ├── overview.md
│ │ └── python-sdk.md
│ ├── assets
│ │ ├── biomcp-cursor-locations.png
│ │ ├── favicon.ico
│ │ ├── icon.png
│ │ ├── logo.png
│ │ ├── mcp_architecture.txt
│ │ └── remote-connection
│ │ ├── 00_connectors.png
│ │ ├── 01_add_custom_connector.png
│ │ ├── 02_connector_enabled.png
│ │ ├── 03_connect_to_biomcp.png
│ │ ├── 04_select_google_oauth.png
│ │ └── 05_success_connect.png
│ ├── backend-services-reference
│ │ ├── 01-overview.md
│ │ ├── 02-biothings-suite.md
│ │ ├── 03-cbioportal.md
│ │ ├── 04-clinicaltrials-gov.md
│ │ ├── 05-nci-cts-api.md
│ │ ├── 06-pubtator3.md
│ │ └── 07-alphagenome.md
│ ├── blog
│ │ ├── ai-assisted-clinical-trial-search-analysis.md
│ │ ├── images
│ │ │ ├── deep-researcher-video.png
│ │ │ ├── researcher-announce.png
│ │ │ ├── researcher-drop-down.png
│ │ │ ├── researcher-prompt.png
│ │ │ ├── trial-search-assistant.png
│ │ │ └── what_is_biomcp_thumbnail.png
│ │ └── researcher-persona-resource.md
│ ├── changelog.md
│ ├── CNAME
│ ├── concepts
│ │ ├── 01-what-is-biomcp.md
│ │ ├── 02-the-deep-researcher-persona.md
│ │ └── 03-sequential-thinking-with-the-think-tool.md
│ ├── developer-guides
│ │ ├── 01-server-deployment.md
│ │ ├── 02-contributing-and-testing.md
│ │ ├── 03-third-party-endpoints.md
│ │ ├── 04-transport-protocol.md
│ │ ├── 05-error-handling.md
│ │ ├── 06-http-client-and-caching.md
│ │ ├── 07-performance-optimizations.md
│ │ └── generate_endpoints.py
│ ├── faq-condensed.md
│ ├── FDA_SECURITY.md
│ ├── genomoncology.md
│ ├── getting-started
│ │ ├── 01-quickstart-cli.md
│ │ ├── 02-claude-desktop-integration.md
│ │ └── 03-authentication-and-api-keys.md
│ ├── how-to-guides
│ │ ├── 01-find-articles-and-cbioportal-data.md
│ │ ├── 02-find-trials-with-nci-and-biothings.md
│ │ ├── 03-get-comprehensive-variant-annotations.md
│ │ ├── 04-predict-variant-effects-with-alphagenome.md
│ │ ├── 05-logging-and-monitoring-with-bigquery.md
│ │ └── 06-search-nci-organizations-and-interventions.md
│ ├── index.md
│ ├── policies.md
│ ├── reference
│ │ ├── architecture-diagrams.md
│ │ ├── quick-architecture.md
│ │ ├── quick-reference.md
│ │ └── visual-architecture.md
│ ├── robots.txt
│ ├── stylesheets
│ │ ├── announcement.css
│ │ └── extra.css
│ ├── troubleshooting.md
│ ├── tutorials
│ │ ├── biothings-prompts.md
│ │ ├── claude-code-biomcp-alphagenome.md
│ │ ├── nci-prompts.md
│ │ ├── openfda-integration.md
│ │ ├── openfda-prompts.md
│ │ ├── pydantic-ai-integration.md
│ │ └── remote-connection.md
│ ├── user-guides
│ │ ├── 01-command-line-interface.md
│ │ ├── 02-mcp-tools-reference.md
│ │ └── 03-integrating-with-ides-and-clients.md
│ └── workflows
│ └── all-workflows.md
├── example_scripts
│ ├── mcp_integration.py
│ └── python_sdk.py
├── glama.json
├── LICENSE
├── lzyank.toml
├── Makefile
├── mkdocs.yml
├── package-lock.json
├── package.json
├── pyproject.toml
├── README.md
├── scripts
│ ├── check_docs_in_mkdocs.py
│ ├── check_http_imports.py
│ └── generate_endpoints_doc.py
├── smithery.yaml
├── src
│ └── biomcp
│ ├── __init__.py
│ ├── __main__.py
│ ├── articles
│ │ ├── __init__.py
│ │ ├── autocomplete.py
│ │ ├── fetch.py
│ │ ├── preprints.py
│ │ ├── search_optimized.py
│ │ ├── search.py
│ │ └── unified.py
│ ├── biomarkers
│ │ ├── __init__.py
│ │ └── search.py
│ ├── cbioportal_helper.py
│ ├── circuit_breaker.py
│ ├── cli
│ │ ├── __init__.py
│ │ ├── articles.py
│ │ ├── biomarkers.py
│ │ ├── diseases.py
│ │ ├── health.py
│ │ ├── interventions.py
│ │ ├── main.py
│ │ ├── openfda.py
│ │ ├── organizations.py
│ │ ├── server.py
│ │ ├── trials.py
│ │ └── variants.py
│ ├── connection_pool.py
│ ├── constants.py
│ ├── core.py
│ ├── diseases
│ │ ├── __init__.py
│ │ ├── getter.py
│ │ └── search.py
│ ├── domain_handlers.py
│ ├── drugs
│ │ ├── __init__.py
│ │ └── getter.py
│ ├── exceptions.py
│ ├── genes
│ │ ├── __init__.py
│ │ └── getter.py
│ ├── http_client_simple.py
│ ├── http_client.py
│ ├── individual_tools.py
│ ├── integrations
│ │ ├── __init__.py
│ │ ├── biothings_client.py
│ │ └── cts_api.py
│ ├── interventions
│ │ ├── __init__.py
│ │ ├── getter.py
│ │ └── search.py
│ ├── logging_filter.py
│ ├── metrics_handler.py
│ ├── metrics.py
│ ├── openfda
│ │ ├── __init__.py
│ │ ├── adverse_events_helpers.py
│ │ ├── adverse_events.py
│ │ ├── cache.py
│ │ ├── constants.py
│ │ ├── device_events_helpers.py
│ │ ├── device_events.py
│ │ ├── drug_approvals.py
│ │ ├── drug_labels_helpers.py
│ │ ├── drug_labels.py
│ │ ├── drug_recalls_helpers.py
│ │ ├── drug_recalls.py
│ │ ├── drug_shortages_detail_helpers.py
│ │ ├── drug_shortages_helpers.py
│ │ ├── drug_shortages.py
│ │ ├── exceptions.py
│ │ ├── input_validation.py
│ │ ├── rate_limiter.py
│ │ ├── utils.py
│ │ └── validation.py
│ ├── organizations
│ │ ├── __init__.py
│ │ ├── getter.py
│ │ └── search.py
│ ├── parameter_parser.py
│ ├── prefetch.py
│ ├── query_parser.py
│ ├── query_router.py
│ ├── rate_limiter.py
│ ├── render.py
│ ├── request_batcher.py
│ ├── resources
│ │ ├── __init__.py
│ │ ├── getter.py
│ │ ├── instructions.md
│ │ └── researcher.md
│ ├── retry.py
│ ├── router_handlers.py
│ ├── router.py
│ ├── shared_context.py
│ ├── thinking
│ │ ├── __init__.py
│ │ ├── sequential.py
│ │ └── session.py
│ ├── thinking_tool.py
│ ├── thinking_tracker.py
│ ├── trials
│ │ ├── __init__.py
│ │ ├── getter.py
│ │ ├── nci_getter.py
│ │ ├── nci_search.py
│ │ └── search.py
│ ├── utils
│ │ ├── __init__.py
│ │ ├── cancer_types_api.py
│ │ ├── cbio_http_adapter.py
│ │ ├── endpoint_registry.py
│ │ ├── gene_validator.py
│ │ ├── metrics.py
│ │ ├── mutation_filter.py
│ │ ├── query_utils.py
│ │ ├── rate_limiter.py
│ │ └── request_cache.py
│ ├── variants
│ │ ├── __init__.py
│ │ ├── alphagenome.py
│ │ ├── cancer_types.py
│ │ ├── cbio_external_client.py
│ │ ├── cbioportal_mutations.py
│ │ ├── cbioportal_search_helpers.py
│ │ ├── cbioportal_search.py
│ │ ├── constants.py
│ │ ├── external.py
│ │ ├── filters.py
│ │ ├── getter.py
│ │ ├── links.py
│ │ └── search.py
│ └── workers
│ ├── __init__.py
│ ├── worker_entry_stytch.js
│ ├── worker_entry.js
│ └── worker.py
├── tests
│ ├── bdd
│ │ ├── cli_help
│ │ │ ├── help.feature
│ │ │ └── test_help.py
│ │ ├── conftest.py
│ │ ├── features
│ │ │ └── alphagenome_integration.feature
│ │ ├── fetch_articles
│ │ │ ├── fetch.feature
│ │ │ └── test_fetch.py
│ │ ├── get_trials
│ │ │ ├── get.feature
│ │ │ └── test_get.py
│ │ ├── get_variants
│ │ │ ├── get.feature
│ │ │ └── test_get.py
│ │ ├── search_articles
│ │ │ ├── autocomplete.feature
│ │ │ ├── search.feature
│ │ │ ├── test_autocomplete.py
│ │ │ └── test_search.py
│ │ ├── search_trials
│ │ │ ├── search.feature
│ │ │ └── test_search.py
│ │ ├── search_variants
│ │ │ ├── search.feature
│ │ │ └── test_search.py
│ │ └── steps
│ │ └── test_alphagenome_steps.py
│ ├── config
│ │ └── test_smithery_config.py
│ ├── conftest.py
│ ├── data
│ │ ├── ct_gov
│ │ │ ├── clinical_trials_api_v2.yaml
│ │ │ ├── trials_NCT04280705.json
│ │ │ └── trials_NCT04280705.txt
│ │ ├── myvariant
│ │ │ ├── myvariant_api.yaml
│ │ │ ├── myvariant_field_descriptions.csv
│ │ │ ├── variants_full_braf_v600e.json
│ │ │ ├── variants_full_braf_v600e.txt
│ │ │ └── variants_part_braf_v600_multiple.json
│ │ ├── openfda
│ │ │ ├── drugsfda_detail.json
│ │ │ ├── drugsfda_search.json
│ │ │ ├── enforcement_detail.json
│ │ │ └── enforcement_search.json
│ │ └── pubtator
│ │ ├── pubtator_autocomplete.json
│ │ └── pubtator3_paper.txt
│ ├── integration
│ │ ├── test_openfda_integration.py
│ │ ├── test_preprints_integration.py
│ │ ├── test_simple.py
│ │ └── test_variants_integration.py
│ ├── tdd
│ │ ├── articles
│ │ │ ├── test_autocomplete.py
│ │ │ ├── test_cbioportal_integration.py
│ │ │ ├── test_fetch.py
│ │ │ ├── test_preprints.py
│ │ │ ├── test_search.py
│ │ │ └── test_unified.py
│ │ ├── conftest.py
│ │ ├── drugs
│ │ │ ├── __init__.py
│ │ │ └── test_drug_getter.py
│ │ ├── openfda
│ │ │ ├── __init__.py
│ │ │ ├── test_adverse_events.py
│ │ │ ├── test_device_events.py
│ │ │ ├── test_drug_approvals.py
│ │ │ ├── test_drug_labels.py
│ │ │ ├── test_drug_recalls.py
│ │ │ ├── test_drug_shortages.py
│ │ │ └── test_security.py
│ │ ├── test_biothings_integration_real.py
│ │ ├── test_biothings_integration.py
│ │ ├── test_circuit_breaker.py
│ │ ├── test_concurrent_requests.py
│ │ ├── test_connection_pool.py
│ │ ├── test_domain_handlers.py
│ │ ├── test_drug_approvals.py
│ │ ├── test_drug_recalls.py
│ │ ├── test_drug_shortages.py
│ │ ├── test_endpoint_documentation.py
│ │ ├── test_error_scenarios.py
│ │ ├── test_europe_pmc_fetch.py
│ │ ├── test_mcp_integration.py
│ │ ├── test_mcp_tools.py
│ │ ├── test_metrics.py
│ │ ├── test_nci_integration.py
│ │ ├── test_nci_mcp_tools.py
│ │ ├── test_network_policies.py
│ │ ├── test_offline_mode.py
│ │ ├── test_openfda_unified.py
│ │ ├── test_pten_r173_search.py
│ │ ├── test_render.py
│ │ ├── test_request_batcher.py.disabled
│ │ ├── test_retry.py
│ │ ├── test_router.py
│ │ ├── test_shared_context.py.disabled
│ │ ├── test_unified_biothings.py
│ │ ├── thinking
│ │ │ ├── __init__.py
│ │ │ └── test_sequential.py
│ │ ├── trials
│ │ │ ├── test_backward_compatibility.py
│ │ │ ├── test_getter.py
│ │ │ └── test_search.py
│ │ ├── utils
│ │ │ ├── test_gene_validator.py
│ │ │ ├── test_mutation_filter.py
│ │ │ ├── test_rate_limiter.py
│ │ │ └── test_request_cache.py
│ │ ├── variants
│ │ │ ├── constants.py
│ │ │ ├── test_alphagenome_api_key.py
│ │ │ ├── test_alphagenome_comprehensive.py
│ │ │ ├── test_alphagenome.py
│ │ │ ├── test_cbioportal_mutations.py
│ │ │ ├── test_cbioportal_search.py
│ │ │ ├── test_external_integration.py
│ │ │ ├── test_external.py
│ │ │ ├── test_extract_gene_aa_change.py
│ │ │ ├── test_filters.py
│ │ │ ├── test_getter.py
│ │ │ ├── test_links.py
│ │ │ └── test_search.py
│ │ └── workers
│ │ └── test_worker_sanitization.js
│ └── test_pydantic_ai_integration.py
├── THIRD_PARTY_ENDPOINTS.md
├── tox.ini
├── uv.lock
└── wrangler.toml
```
# Files
--------------------------------------------------------------------------------
/tests/data/myvariant/variants_full_braf_v600e.txt:
--------------------------------------------------------------------------------
```
1 | Took: 4
2 | Total: 1
3 | Max Score: 26.326775
4 |
5 | # Hits
6 | Id: chr7:g.140453136A>T
7 | Score: 26.326775
8 | Chrom: 7
9 | Observed: True
10 |
11 | ## Cadd
12 | License: http://bit.ly/2TIuab9
13 | Alt: T
14 | Anc: A
15 | Annotype: CodingTranscript
16 | Bstatistic: 570
17 | Chrom: 7
18 | Consdetail: missense
19 | Consequence: NON_SYNONYMOUS
20 | Consscore: 7
21 | Cpg: 0.01
22 | Exon: 15/18
23 | Fitcons: 0.666978
24 | Gc: 0.4
25 | Grantham: 121
26 | Isderived: TRUE
27 | Isknownvariant: FALSE
28 | Istv: TRUE
29 | Length: 0
30 | Min Dist Tse: 18739
31 | Min Dist Tss: 876
32 | Mutindex: -13
33 | Naa: E
34 | Oaa: V
35 | Phred: 32
36 | Pos: 140453136
37 | Rawscore: 6.641785
38 | Ref: A
39 | Segway: GE1
40 | Type: SNV
41 |
42 | ### Chmm
43 | Bivflnk: 0.0
44 | Enh: 0.0
45 | Enhbiv: 0.0
46 | Het: 0.0
47 | Quies: 0.102
48 | Reprpc: 0.0
49 | Reprpcwk: 0.0
50 | Tssa: 0.0
51 | Tssaflnk: 0.0
52 | Tssbiv: 0.0
53 | Tx: 0.11
54 | Txflnk: 0.0
55 | Txwk: 0.78
56 | Znfrpts: 0.0
57 |
58 | ### Dna
59 | Helt: -0.55
60 | Mgw: 0.7
61 | Prot: 3.19
62 | Roll: 8.98
63 |
64 | ### Encode
65 | Exp: 21.94
66 | H3k27ac: 6.0
67 | H3k4me1: 17.72
68 | H3k4me3: 4.08
69 | Nucleo: 1.6
70 |
71 | ### Gene
72 | Ccds Id: CCDS5863.1
73 | Feature Id: ENST00000288602
74 | Gene Id: ENSG00000157764
75 | Genename: BRAF
76 |
77 | #### Cds
78 | Cdna Pos: 1860
79 | Cds Pos: 1799
80 | Rel Cdna Pos: 0.75
81 | Rel Cds Pos: 0.78
82 |
83 | #### Prot
84 | Domain: ndomain
85 | Protpos: 600
86 | Rel Prot Pos: 0.78
87 |
88 | ### Gerp
89 | N: 5.65
90 | Rs: 771
91 | Rs Pval: 4.53805e-225
92 | S: 5.65
93 |
94 | ### Mapability
95 | 20bp: 1
96 | 35bp: 1
97 |
98 | ### Phast Cons
99 | Mammalian: 1.0
100 | Primate: 0.998
101 | Vertebrate: 1.0
102 |
103 | ### Phylop
104 | Mammalian: 2.167
105 | Primate: 0.525
106 | Vertebrate: 5.101
107 |
108 | ### Polyphen
109 | Cat: probably_damaging
110 | Val: 0.967
111 |
112 | ### Sift
113 | Cat: deleterious
114 | Val: 0
115 |
116 | ## Civic
117 | License: http://bit.ly/2FqS871
118 | Allele Registry Id: CA123643
119 | Deprecated: False
120 | Id: 12
121 | Mane Select Transcript: ENST00000646891.2:c.1799T>A
122 | Name: V600E
123 | Open Cravat Url:
124 | https://run.opencravat.org/webapps/variantreport/index.html?alt_base=T&c
125 | hrom=chr7&pos=140753336&ref_base=A
126 | Open Revision Count: 0
127 |
128 | ### Comments
129 | Total Count: 1
130 |
131 | ### Contributors
132 |
133 | #### Curators
134 | Last Action Date: 2015-09-08T19:54:43Z
135 | Total Action Count: 1
136 |
137 | ##### User
138 | Id: 70
139 |
140 | ##### Unique Actions
141 | Action: REVISION_SUGGESTED
142 | Count: 1
143 |
144 | #### Curators
145 | Last Action Date: 2016-02-18T22:19:46Z
146 | Total Action Count: 3
147 |
148 | ##### User
149 | Id: 41
150 |
151 | ##### Unique Actions
152 | Action: REVISION_SUGGESTED
153 | Count: 3
154 |
155 | #### Curators
156 | Last Action Date: 2016-03-24T02:17:27Z
157 | Total Action Count: 2
158 |
159 | ##### User
160 | Id: 3
161 |
162 | ##### Unique Actions
163 | Action: REVISION_SUGGESTED
164 | Count: 2
165 |
166 | #### Curators
167 | Last Action Date: 2019-05-17T00:23:44Z
168 | Total Action Count: 3
169 |
170 | ##### User
171 | Id: 6
172 |
173 | ##### Unique Actions
174 | Action: REVISION_SUGGESTED
175 | Count: 2
176 |
177 | ##### Unique Actions
178 | Action: VARIANT_CREATED
179 | Count: 1
180 |
181 | #### Curators
182 | Last Action Date: 2017-04-29T15:22:52Z
183 | Total Action Count: 4
184 |
185 | ##### User
186 | Id: 83
187 |
188 | ##### Unique Actions
189 | Action: REVISION_SUGGESTED
190 | Count: 4
191 |
192 | #### Curators
193 | Last Action Date: 2022-01-13T05:40:29Z
194 | Total Action Count: 1
195 |
196 | ##### User
197 | Id: 110
198 |
199 | ##### Unique Actions
200 | Action: COMMENTED
201 | Count: 1
202 |
203 | #### Curators
204 | Last Action Date: 2022-01-10T19:43:00Z
205 | Total Action Count: 3
206 |
207 | ##### User
208 | Id: 15
209 |
210 | ##### Unique Actions
211 | Action: REVISION_SUGGESTED
212 | Count: 3
213 |
214 | #### Editors
215 | Last Action Date: 2017-04-02T01:41:36Z
216 | Total Action Count: 5
217 |
218 | ##### User
219 | Id: 15
220 |
221 | ##### Unique Actions
222 | Action: REVISION_ACCEPTED
223 | Count: 5
224 |
225 | #### Editors
226 | Last Action Date: 2016-02-18T22:20:12Z
227 | Total Action Count: 3
228 |
229 | ##### User
230 | Id: 41
231 |
232 | ##### Unique Actions
233 | Action: REVISION_ACCEPTED
234 | Count: 3
235 |
236 | #### Editors
237 | Last Action Date: 2017-05-12T03:16:45Z
238 | Total Action Count: 4
239 |
240 | ##### User
241 | Id: 6
242 |
243 | ##### Unique Actions
244 | Action: REVISION_ACCEPTED
245 | Count: 3
246 |
247 | ##### Unique Actions
248 | Action: REVISION_REJECTED
249 | Count: 1
250 |
251 | #### Editors
252 | Last Action Date: 2017-05-14T03:50:30Z
253 | Total Action Count: 4
254 |
255 | ##### User
256 | Id: 3
257 |
258 | ##### Unique Actions
259 | Action: REVISION_ACCEPTED
260 | Count: 4
261 |
262 | #### Editors
263 | Last Action Date: 2020-05-30T00:13:47Z
264 | Total Action Count: 1
265 |
266 | ##### User
267 | Id: 968
268 |
269 | ##### Unique Actions
270 | Action: REVISION_ACCEPTED
271 | Count: 1
272 |
273 | #### Editors
274 | Last Action Date: 2022-01-13T05:39:29Z
275 | Total Action Count: 1
276 |
277 | ##### User
278 | Id: 110
279 |
280 | ##### Unique Actions
281 | Action: REVISION_ACCEPTED
282 | Count: 1
283 |
284 | ### Coordinates
285 | Chromosome: 7
286 | Coordinate Type: GENE_VARIANT_COORDINATE
287 | Ensembl Version: 75
288 | Reference Bases: A
289 | Reference Build: GRCH37
290 | Representative Transcript: ENST00000288602.6
291 | Start: 140453136
292 | Stop: 140453136
293 | Variant Bases: T
294 |
295 | ### Creation Activity
296 | Created At: 2015-06-21T16:49:42Z
297 |
298 | #### User
299 | Display Name: kkrysiak
300 | Id: 6
301 | Role: ADMIN
302 |
303 | ### Feature
304 | Deprecated: False
305 | Flagged: False
306 | Id: 5
307 | Link: /features/5
308 | Name: BRAF
309 |
310 | ### Flags
311 | Total Count: 0
312 |
313 | ### Last Accepted Revision Event
314 |
315 | #### Originating User
316 | Display Name: CamGrisdale
317 | Id: 968
318 | Role: EDITOR
319 |
320 | ### Last Submitted Revision Event
321 |
322 | #### Originating User
323 | Display Name: LynzeyKujan
324 | Id: 83
325 | Role: CURATOR
326 |
327 | ### Revisions
328 | Total Count: 0
329 |
330 | ### Variant Types
331 | Id: 47
332 | Link: /variant-types/47
333 | Name: Missense Variant
334 | Soid: SO:0001583
335 | Clinvar Ids: 13961, 376069
336 | Hgvs Descriptions:
337 | - NM_004333.4:c.1799T>A
338 | - NP_004324.2:p.Val600Glu
339 | - NC_000007.13:g.140453136A>T
340 | - ENST00000288602.6:c.1799T>A
341 |
342 | ### Molecular Profiles
343 | Id: 12
344 | Molecular Profile Score: 1378.5
345 | Name: BRAF V600E
346 |
347 | #### Evidence Items
348 | Description:
349 | BRAF V600E is shown to be associated with the tall-cell variant of
350 | papillary thyroid cancer.
351 | Evidence Direction: SUPPORTS
352 | Evidence Level: B
353 | Evidence Rating: 3
354 | Evidence Type: DIAGNOSTIC
355 | Flagged: False
356 | Id: 79
357 | Name: EID79
358 | Significance: POSITIVE
359 | Variant Origin: SOMATIC
360 |
361 | ##### Disease
362 | Disease Url: https://www.disease-ontology.org/?id=DOID:1781
363 | Display Name: Thyroid Cancer
364 | Doid: 1781
365 | Id: 16
366 | Link: /diseases/16
367 | Name: Thyroid Cancer
368 |
369 | ##### My Disease Info
370 | Do Def:
371 | An endocrine gland cancer located in the thyroid gland located in the
372 | neck below the thyroid cartilage.
373 | Icd10: C73
374 | Mesh: D013964
375 | Mondo Id: MONDO:0002108
376 | Ncit: C3414, C7510
377 | Disease Aliases:
378 | - Malignant Neoplasm Of Thyroid Gland
379 | - Malignant Tumour Of Thyroid Gland
380 | - Neoplasm Of Thyroid Gland
381 | - Thyroid Gland Cancer
382 | - Thyroid Gland Neoplasm
383 | - Thyroid Neoplasm
384 |
385 | ##### Molecular Profile
386 | Id: 12
387 |
388 | ##### Source
389 | Abstract:
390 | This study was designed to examine the aggressive features of BRAF-
391 | positive papillary thyroid cancer (PTC) and association with age.We
392 | compared the clinicopathologic parameters and BRAF V600E mutation status
393 | of 121 elderly (age ≥65 years) PTC patients who underwent thyroidectomy
394 | from January 2007 to December 2009 to a consecutive cohort of 98 younger
395 | (age <65 years) PTC patients.Younger and elderly PTC patients had
396 | similar incidences of BRAF-positive tumors (41% vs. 38%; p = 0.67). The
397 | elderly cohort was more likely to have smaller tumors (mean 1.6 vs. 2.1
398 | cm; p = 0.001), present with advanced TNM stage (36% vs. 19%; p =
399 | 0.008), and have persistent/recurrent disease (10% vs. 1%; p = 0.006).
400 | BRAF-positive status was associated with PTC that were tall cell variant
401 | (p < 0.001), had extrathyroidal extension (p < 0.001), lymph node
402 | involvement (p = 0.008), advanced (III/IV) TNM stage (p < 0.001), and
403 | disease recurrence (p < 0.001). Except for lymph node involvement, the
404 | association between aggressive histology characteristics at presentation
405 | and BRAF-positive PTC also was observed within the age-defined cohorts.
406 | In short-term follow-up (mean, 18 months), persistent/recurrent PTC was
407 | much more likely to occur in patients who were both BRAF-positive and
408 | elderly (22%).BRAF mutations are equally present in younger and older
409 | patients. Aggressive histology characteristics at presentation are
410 | associated with BRAF-positive PTC, irrespective of age. However, the
411 | well-established association of BRAF with recurrence is limited to older
412 | (age ≥65 years) patients.
413 | Author String:
414 | Gina M Howell, Sally E Carty, Michaele J Armstrong, Shane O Lebeau,
415 | Steven P Hodak, Christopher Coyne, Michael T Stang, Kelly L McCoy,
416 | Marina N Nikiforova, Yuri E Nikiforov, Linwah Yip
417 | Citation: Howell et al., 2011
418 | Citation Id: 21594703
419 | Id: 93
420 | Journal: Ann Surg Oncol
421 | Link: /sources/93
422 | Name: PubMed: Howell et al., 2011
423 | Open Access: False
424 | Publication Date: 2011-12
425 | Retracted: False
426 | Source Type: PUBMED
427 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21594703
428 | Title:
429 | Both BRAF V600E mutation and older age (≥ 65 years) are associated with
430 | recurrent papillary thyroid cancer.
431 |
432 | #### Evidence Items
433 | Description:
434 | Dabrafenib with trametinib provides higher response rate and lower
435 | toxicity (as compared to chemotherapy) in patients with melanoma.
436 | Evidence Direction: SUPPORTS
437 | Evidence Level: B
438 | Evidence Rating: 5
439 | Evidence Type: PREDICTIVE
440 | Flagged: False
441 | Id: 95
442 | Name: EID95
443 | Significance: SENSITIVITYRESPONSE
444 | Variant Origin: SOMATIC
445 |
446 | ##### Disease
447 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
448 | Display Name: Melanoma
449 | Doid: 1909
450 | Id: 7
451 | Link: /diseases/7
452 | Name: Melanoma
453 |
454 | ##### My Disease Info
455 | Do Def:
456 | A cell type cancer that has_material_basis_in abnormally proliferating
457 | cells derives_from melanocytes which are found in skin, the bowel and
458 | the eye.
459 | Icdo: 8720/3
460 | Mesh: D008545
461 | Mondo Id: MONDO:0005105
462 | Ncit: C3224
463 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
464 |
465 | ##### Molecular Profile
466 | Id: 12
467 |
468 | ##### Source
469 | Abstract:
470 | Dabrafenib and trametinib were approved for use as monotherapies in
471 | BRAF-mutant metastatic melanoma by the U.S. Food and Drug Administration
472 | (FDA) in 2013, and most recently, their use in combination has received
473 | accelerated FDA approval. Both drugs target the mitogen-activated
474 | protein kinase (MAPK) pathway: dabrafenib selectively inhibits mutant
475 | BRAF that constitutively activates the pathway, and trametinib
476 | selectively inhibits MEK1 and MEK2 proteins activated by RAF kinases.
477 | The phase III study of dabrafenib in BRAF(V600E) metastatic melanoma
478 | reported rapid tumor regression in most patients and a 59% objective
479 | RECIST response rate. The median progression-free survival (PFS) and
480 | overall survival (OS) were improved compared with dacarbazine.
481 | Toxicities were well tolerated and different from those reported for
482 | vemurafenib, the first FDA-approved BRAF inhibitor. Efficacy has been
483 | demonstrated in other BRAF-mutant genotypes. The phase III study of
484 | trametinib in BRAF inhibitor-naïve patients with BRAF(V600E) or
485 | BRAF(V600K) also showed benefit with a prolonged median PFS and OS
486 | compared with chemotherapy. Trametinib is ineffective in patients who
487 | have progressed on BRAF inhibitors. A phase II trial of combined
488 | dabrafenib and trametinib demonstrated higher response rates and longer
489 | median PFS than dabrafenib monotherapy, with less cutaneous toxicity.
490 | Here, we review the clinical development of both drugs as monotherapies
491 | and in combination, and discuss their role in the management of BRAF-
492 | mutant melanoma.
493 | Author String: Alexander M Menzies, Georgina V Long
494 | Citation: Menzies et al., 2014
495 | Citation Id: 24583796
496 | Id: 105
497 | Journal: Clin Cancer Res
498 | Link: /sources/105
499 | Name: PubMed: Menzies et al., 2014
500 | Open Access: False
501 | Publication Date: 2014-4-15
502 | Retracted: False
503 | Source Type: PUBMED
504 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24583796
505 | Title:
506 | Dabrafenib and trametinib, alone and in combination for BRAF-mutant
507 | metastatic melanoma.
508 |
509 | ##### Therapies
510 | Deprecated: False
511 | Id: 22
512 | Link: /therapies/22
513 | Name: Dabrafenib
514 |
515 | ##### Therapies
516 | Deprecated: False
517 | Id: 19
518 | Link: /therapies/19
519 | Name: Trametinib
520 |
521 | #### Evidence Items
522 | Description:
523 | BRAF V600E is correlated with shorter disease-free and overall Survival
524 | in a Spanish cohort of melanoma patients.
525 | Evidence Direction: SUPPORTS
526 | Evidence Level: B
527 | Evidence Rating: 3
528 | Evidence Type: PROGNOSTIC
529 | Flagged: False
530 | Id: 104
531 | Name: EID104
532 | Significance: POOR_OUTCOME
533 | Variant Origin: SOMATIC
534 |
535 | ##### Disease
536 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
537 | Display Name: Melanoma
538 | Doid: 1909
539 | Id: 7
540 | Link: /diseases/7
541 | Name: Melanoma
542 |
543 | ##### My Disease Info
544 | Do Def:
545 | A cell type cancer that has_material_basis_in abnormally proliferating
546 | cells derives_from melanocytes which are found in skin, the bowel and
547 | the eye.
548 | Icdo: 8720/3
549 | Mesh: D008545
550 | Mondo Id: MONDO:0005105
551 | Ncit: C3224
552 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
553 |
554 | ##### Molecular Profile
555 | Id: 12
556 |
557 | ##### Source
558 | Abstract:
559 | BRAF mutations are frequent in melanoma but their prognostic
560 | significance remains unclear.We sought to further evaluate the
561 | prognostic value of BRAF mutations in localized cutaneous melanoma.We
562 | undertook an observational retrospective study of 147 patients with
563 | localized invasive (stages I and II) cutaneous melanomas to determine
564 | the prognostic value of BRAF mutation status.After a median follow-up of
565 | 48 months, patients with localized melanomas with BRAF-mutant melanomas
566 | exhibited poorer disease-free survival than those with BRAF-wt genotype
567 | (hazard ratio 2.2, 95% confidence interval 1.1-4.3) even after
568 | adjustment for Breslow thickness, tumor ulceration, location, age, sex,
569 | and tumor mitotic rate.The retrospective design and the small number of
570 | events are limitations.Our findings suggest that reappraisal of clinical
571 | treatment approaches for patients with localized melanoma harboring
572 | tumors with BRAF mutation might be warranted.
573 | Author String:
574 | Eduardo Nagore, Celia Requena, Víctor Traves, Carlos Guillen, Nicholas K
575 | Hayward, David C Whiteman, Elke Hacker
576 | Citation: Nagore et al., 2014
577 | Citation Id: 24388723
578 | Id: 111
579 | Journal: J Am Acad Dermatol
580 | Link: /sources/111
581 | Name: PubMed: Nagore et al., 2014
582 | Open Access: False
583 | Publication Date: 2014-5
584 | Retracted: False
585 | Source Type: PUBMED
586 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24388723
587 | Title: Prognostic value of BRAF mutations in localized cutaneous melanoma.
588 |
589 | #### Evidence Items
590 | Description:
591 | In the setting of BRAF(V600E), NF1 loss resulted in elevated activation
592 | of RAS-GTP and resistance to RAF inhibitors.
593 | Evidence Direction: SUPPORTS
594 | Evidence Level: D
595 | Evidence Rating: 3
596 | Evidence Type: PREDICTIVE
597 | Flagged: False
598 | Id: 90
599 | Name: EID90
600 | Significance: RESISTANCE
601 | Variant Origin: SOMATIC
602 |
603 | ##### Disease
604 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
605 | Display Name: Melanoma
606 | Doid: 1909
607 | Id: 7
608 | Link: /diseases/7
609 | Name: Melanoma
610 |
611 | ##### My Disease Info
612 | Do Def:
613 | A cell type cancer that has_material_basis_in abnormally proliferating
614 | cells derives_from melanocytes which are found in skin, the bowel and
615 | the eye.
616 | Icdo: 8720/3
617 | Mesh: D008545
618 | Mondo Id: MONDO:0005105
619 | Ncit: C3224
620 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
621 |
622 | ##### Molecular Profile
623 | Id: 12
624 |
625 | ##### Source
626 | Abstract:
627 | Melanoma is a disease characterized by lesions that activate ERK.
628 | Although 70% of cutaneous melanomas harbor activating mutations in the
629 | BRAF and NRAS genes, the alterations that drive tumor progression in the
630 | remaining 30% are largely undefined. Vemurafenib, a selective inhibitor
631 | of RAF kinases, has clinical utility restricted to BRAF-mutant tumors.
632 | MEK inhibitors, which have shown clinical activity in NRAS-mutant
633 | melanoma, may be effective in other ERK pathway-dependent settings.
634 | Here, we investigated a panel of melanoma cell lines wild type for BRAF
635 | and NRAS to determine the genetic alteration driving their
636 | transformation and their dependence on ERK signaling in order to
637 | elucidate a candidate set for MEK inhibitor treatment. A cohort of the
638 | BRAF/RAS wild type cell lines with high levels of RAS-GTP had loss of
639 | NF1, a RAS GTPase activating protein. In these cell lines, the MEK
640 | inhibitor PD0325901 inhibited ERK phosphorylation, but also relieved
641 | feedback inhibition of RAS, resulting in induction of pMEK and a rapid
642 | rebound in ERK signaling. In contrast, the MEK inhibitor trametinib
643 | impaired the adaptive response of cells to ERK inhibition, leading to
644 | sustained suppression of ERK signaling and significant antitumor
645 | effects. Notably, alterations in NF1 frequently co-occurred with RAS and
646 | BRAF alterations in melanoma. In the setting of BRAF(V600E), NF1 loss
647 | abrogated negative feedback on RAS activation, resulting in elevated
648 | activation of RAS-GTP and resistance to RAF, but not MEK, inhibitors. We
649 | conclude that loss of NF1 is common in cutaneous melanoma and is
650 | associated with RAS activation, MEK-dependence, and resistance to RAF
651 | inhibition.
652 | Author String:
653 | Moriah H Nissan, Christine A Pratilas, Alexis M Jones, Ricardo Ramirez,
654 | Helen Won, Cailian Liu, Shakuntala Tiwari, Li Kong, Aphrothiti J
655 | Hanrahan, Zhan Yao, Taha Merghoub, Antoni Ribas, Paul B Chapman, Rona
656 | Yaeger, Barry S Taylor, Nikolaus Schultz, Michael F Berger, Neal Rosen,
657 | David B Solit
658 | Citation: Nissan et al., 2014
659 | Citation Id: 24576830
660 | Id: 98
661 | Journal: Cancer Res
662 | Link: /sources/98
663 | Name: PubMed: Nissan et al., 2014
664 | Open Access: True
665 | Pmc Id: PMC4005042
666 | Publication Date: 2014-4-15
667 | Retracted: False
668 | Source Type: PUBMED
669 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24576830
670 | Title:
671 | Loss of NF1 in cutaneous melanoma is associated with RAS activation and
672 | MEK dependence.
673 |
674 | ##### Therapies
675 | Deprecated: False
676 | Id: 4
677 | Link: /therapies/4
678 | Name: Vemurafenib
679 |
680 | #### Evidence Items
681 | Description:
682 | BRAF V600E is correlated with poor prognosis in papillary thyroid cancer
683 | in a study of 187 patients with PTC and other thyroid diseases.
684 | Evidence Direction: SUPPORTS
685 | Evidence Level: B
686 | Evidence Rating: 3
687 | Evidence Type: PROGNOSTIC
688 | Flagged: False
689 | Id: 106
690 | Name: EID106
691 | Significance: POOR_OUTCOME
692 | Variant Origin: SOMATIC
693 |
694 | ##### Disease
695 | Disease Url: https://www.disease-ontology.org/?id=DOID:3969
696 | Display Name: Papillary Thyroid Carcinoma
697 | Doid: 3969
698 | Id: 156
699 | Link: /diseases/156
700 | Name: Papillary Thyroid Carcinoma
701 |
702 | ##### My Disease Info
703 | Do Def:
704 | A differentiated thyroid gland carcinoma that is characterized by the
705 | small mushroom shape of the tumor which has a stem attached to the
706 | epithelial layer and arises from the follicular cells of the thyroid
707 | gland.
708 | Icdo: 8260/3
709 | Mesh: D000077273
710 | Mondo Id: MONDO:0005075
711 | Ncit: C4035
712 | Disease Aliases:
713 | - Papillary Carcinoma Of The Thyroid Gland
714 | - Papillary Carcinoma Of Thyroid
715 | - Thyroid Gland Papillary Carcinoma
716 |
717 | ##### Molecular Profile
718 | Id: 12
719 |
720 | ##### Source
721 | Abstract:
722 | The aim of the present study was to investigate the prevalence of the
723 | BRAF V600E mutation in papillary thyroid carcinoma (PTC) and to
724 | determine the correlation between this mutation and indicators of poor
725 | prognosis and outcome in patients with PTC. The BRAF V600E mutation
726 | status was analyzed in 187 tumor samples using the multiplex allele-
727 | specific PCR method. Univariate and multivariate analyses were performed
728 | to investigate the association of the BRAF V600E mutation with clinical
729 | features and patient outcome. The sensitivity of the multiplex allele-
730 | specific PCR combined with denaturing high-performance liquid
731 | chromatography reached ~1%. The BRAF V600E mutation was observed in
732 | 63.6% (119/187) of tumor tissues, predominantly in PTC specimens, and no
733 | BRAF mutation was identified in other benign-type thyroid diseases. The
734 | univariate analysis indicated that the BRAF V600E mutation was
735 | associated with age, tumor stage and prognosis (P<0.05). In addition,
736 | the frequency of the BRAF V600E mutation was significantly different in
737 | the central (75.3%) and lateral neck (49.3%) lymph nodes of patients
738 | with lymph node metastasis. Multivariate logistic regression analysis
739 | showed that the BRAF V600E mutation (HR, 2.471; 95% CI, 1.149-5.312) and
740 | lymph node metastasis (HR, 3.003; 95% CI, 1.027-8.771) are independent
741 | factors that predict tumor prognosis. Thus, the BRAF V600E mutation is
742 | an independent risk factor that may be used to predict thyroid cancer
743 | persistence/recurrence.
744 | Author String: Guoping He, Baojian Zhao, Xu Zhang, Rixiang Gong
745 | Citation: He et al., 2014
746 | Citation Id: 24396464
747 | Id: 112
748 | Journal: Oncol Lett
749 | Link: /sources/112
750 | Name: PubMed: He et al., 2014
751 | Open Access: True
752 | Pmc Id: PMC3881916
753 | Publication Date: 2014-2
754 | Retracted: False
755 | Source Type: PUBMED
756 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24396464
757 | Title:
758 | Prognostic value of the BRAF V600E mutation in papillary thyroid
759 | carcinoma.
760 |
761 | #### Evidence Items
762 | Description:
763 | V600E is correlated with disease recurrence in both age cohorts (>65 and
764 | <65 yo).
765 | Evidence Direction: SUPPORTS
766 | Evidence Level: B
767 | Evidence Rating: 3
768 | Evidence Type: PROGNOSTIC
769 | Flagged: False
770 | Id: 107
771 | Name: EID107
772 | Significance: POOR_OUTCOME
773 | Variant Origin: SOMATIC
774 |
775 | ##### Disease
776 | Disease Url: https://www.disease-ontology.org/?id=DOID:3969
777 | Display Name: Papillary Thyroid Carcinoma
778 | Doid: 3969
779 | Id: 156
780 | Link: /diseases/156
781 | Name: Papillary Thyroid Carcinoma
782 |
783 | ##### My Disease Info
784 | Do Def:
785 | A differentiated thyroid gland carcinoma that is characterized by the
786 | small mushroom shape of the tumor which has a stem attached to the
787 | epithelial layer and arises from the follicular cells of the thyroid
788 | gland.
789 | Icdo: 8260/3
790 | Mesh: D000077273
791 | Mondo Id: MONDO:0005075
792 | Ncit: C4035
793 | Disease Aliases:
794 | - Papillary Carcinoma Of The Thyroid Gland
795 | - Papillary Carcinoma Of Thyroid
796 | - Thyroid Gland Papillary Carcinoma
797 |
798 | ##### Molecular Profile
799 | Id: 12
800 |
801 | ##### Source
802 | Abstract:
803 | This study was designed to examine the aggressive features of BRAF-
804 | positive papillary thyroid cancer (PTC) and association with age.We
805 | compared the clinicopathologic parameters and BRAF V600E mutation status
806 | of 121 elderly (age ≥65 years) PTC patients who underwent thyroidectomy
807 | from January 2007 to December 2009 to a consecutive cohort of 98 younger
808 | (age <65 years) PTC patients.Younger and elderly PTC patients had
809 | similar incidences of BRAF-positive tumors (41% vs. 38%; p = 0.67). The
810 | elderly cohort was more likely to have smaller tumors (mean 1.6 vs. 2.1
811 | cm; p = 0.001), present with advanced TNM stage (36% vs. 19%; p =
812 | 0.008), and have persistent/recurrent disease (10% vs. 1%; p = 0.006).
813 | BRAF-positive status was associated with PTC that were tall cell variant
814 | (p < 0.001), had extrathyroidal extension (p < 0.001), lymph node
815 | involvement (p = 0.008), advanced (III/IV) TNM stage (p < 0.001), and
816 | disease recurrence (p < 0.001). Except for lymph node involvement, the
817 | association between aggressive histology characteristics at presentation
818 | and BRAF-positive PTC also was observed within the age-defined cohorts.
819 | In short-term follow-up (mean, 18 months), persistent/recurrent PTC was
820 | much more likely to occur in patients who were both BRAF-positive and
821 | elderly (22%).BRAF mutations are equally present in younger and older
822 | patients. Aggressive histology characteristics at presentation are
823 | associated with BRAF-positive PTC, irrespective of age. However, the
824 | well-established association of BRAF with recurrence is limited to older
825 | (age ≥65 years) patients.
826 | Author String:
827 | Gina M Howell, Sally E Carty, Michaele J Armstrong, Shane O Lebeau,
828 | Steven P Hodak, Christopher Coyne, Michael T Stang, Kelly L McCoy,
829 | Marina N Nikiforova, Yuri E Nikiforov, Linwah Yip
830 | Citation: Howell et al., 2011
831 | Citation Id: 21594703
832 | Id: 93
833 | Journal: Ann Surg Oncol
834 | Link: /sources/93
835 | Name: PubMed: Howell et al., 2011
836 | Open Access: False
837 | Publication Date: 2011-12
838 | Retracted: False
839 | Source Type: PUBMED
840 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21594703
841 | Title:
842 | Both BRAF V600E mutation and older age (≥ 65 years) are associated with
843 | recurrent papillary thyroid cancer.
844 |
845 | #### Evidence Items
846 | Description:
847 | BRAF mutation correlated with poor prognosis in papillary thyroid cancer
848 | in both older (>65 yo) and younger (<65 yo) cohorts.
849 | Evidence Direction: SUPPORTS
850 | Evidence Level: B
851 | Evidence Rating: 3
852 | Evidence Type: PROGNOSTIC
853 | Flagged: False
854 | Id: 105
855 | Name: EID105
856 | Significance: POOR_OUTCOME
857 | Variant Origin: SOMATIC
858 |
859 | ##### Disease
860 | Disease Url: https://www.disease-ontology.org/?id=DOID:3969
861 | Display Name: Papillary Thyroid Carcinoma
862 | Doid: 3969
863 | Id: 156
864 | Link: /diseases/156
865 | Name: Papillary Thyroid Carcinoma
866 |
867 | ##### My Disease Info
868 | Do Def:
869 | A differentiated thyroid gland carcinoma that is characterized by the
870 | small mushroom shape of the tumor which has a stem attached to the
871 | epithelial layer and arises from the follicular cells of the thyroid
872 | gland.
873 | Icdo: 8260/3
874 | Mesh: D000077273
875 | Mondo Id: MONDO:0005075
876 | Ncit: C4035
877 | Disease Aliases:
878 | - Papillary Carcinoma Of The Thyroid Gland
879 | - Papillary Carcinoma Of Thyroid
880 | - Thyroid Gland Papillary Carcinoma
881 |
882 | ##### Molecular Profile
883 | Id: 12
884 |
885 | ##### Source
886 | Abstract:
887 | This study was designed to examine the aggressive features of BRAF-
888 | positive papillary thyroid cancer (PTC) and association with age.We
889 | compared the clinicopathologic parameters and BRAF V600E mutation status
890 | of 121 elderly (age ≥65 years) PTC patients who underwent thyroidectomy
891 | from January 2007 to December 2009 to a consecutive cohort of 98 younger
892 | (age <65 years) PTC patients.Younger and elderly PTC patients had
893 | similar incidences of BRAF-positive tumors (41% vs. 38%; p = 0.67). The
894 | elderly cohort was more likely to have smaller tumors (mean 1.6 vs. 2.1
895 | cm; p = 0.001), present with advanced TNM stage (36% vs. 19%; p =
896 | 0.008), and have persistent/recurrent disease (10% vs. 1%; p = 0.006).
897 | BRAF-positive status was associated with PTC that were tall cell variant
898 | (p < 0.001), had extrathyroidal extension (p < 0.001), lymph node
899 | involvement (p = 0.008), advanced (III/IV) TNM stage (p < 0.001), and
900 | disease recurrence (p < 0.001). Except for lymph node involvement, the
901 | association between aggressive histology characteristics at presentation
902 | and BRAF-positive PTC also was observed within the age-defined cohorts.
903 | In short-term follow-up (mean, 18 months), persistent/recurrent PTC was
904 | much more likely to occur in patients who were both BRAF-positive and
905 | elderly (22%).BRAF mutations are equally present in younger and older
906 | patients. Aggressive histology characteristics at presentation are
907 | associated with BRAF-positive PTC, irrespective of age. However, the
908 | well-established association of BRAF with recurrence is limited to older
909 | (age ≥65 years) patients.
910 | Author String:
911 | Gina M Howell, Sally E Carty, Michaele J Armstrong, Shane O Lebeau,
912 | Steven P Hodak, Christopher Coyne, Michael T Stang, Kelly L McCoy,
913 | Marina N Nikiforova, Yuri E Nikiforov, Linwah Yip
914 | Citation: Howell et al., 2011
915 | Citation Id: 21594703
916 | Id: 93
917 | Journal: Ann Surg Oncol
918 | Link: /sources/93
919 | Name: PubMed: Howell et al., 2011
920 | Open Access: False
921 | Publication Date: 2011-12
922 | Retracted: False
923 | Source Type: PUBMED
924 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21594703
925 | Title:
926 | Both BRAF V600E mutation and older age (≥ 65 years) are associated with
927 | recurrent papillary thyroid cancer.
928 |
929 | #### Evidence Items
930 | Description:
931 | In patients with multiple myeloma, those with BRAF V600E had shorter
932 | overall survival than wild-type.
933 | Evidence Direction: SUPPORTS
934 | Evidence Level: B
935 | Evidence Rating: 3
936 | Evidence Type: PROGNOSTIC
937 | Flagged: False
938 | Id: 463
939 | Name: EID463
940 | Significance: POOR_OUTCOME
941 | Variant Origin: SOMATIC
942 |
943 | ##### Disease
944 | Disease Url: https://www.disease-ontology.org/?id=DOID:9538
945 | Display Name: Multiple Myeloma
946 | Doid: 9538
947 | Id: 41
948 | Link: /diseases/41
949 | Name: Multiple Myeloma
950 |
951 | ##### My Disease Info
952 | Do Def: A myeloid neoplasm that is located_in the plasma cells in bone marrow.
953 | Icd10: C90.0
954 | Mesh: D009101
955 | Mondo Id: MONDO:0009693
956 | Ncit: C3242
957 | Disease Aliases: Myeloma
958 |
959 | ##### Molecular Profile
960 | Id: 12
961 |
962 | ##### Source
963 | Abstract:
964 | In multiple myeloma, there has been little progress in the specific
965 | therapeutic targeting of oncogenic mutations. Whole-genome sequencing
966 | data have recently revealed that a subset of patients carry an
967 | activating mutation (V600E) in the BRAF kinase. To uncover the clinical
968 | relevance of this mutation in multiple myeloma, we correlated the
969 | mutation status in primary tumor samples from 379 patients with myeloma
970 | with disease outcome. We found a significantly higher incidence of
971 | extramedullary disease and a shorter overall survival in mutation
972 | carriers when compared with controls. Most importantly, we report on a
973 | patient with confirmed BRAF V600E mutation and relapsed myeloma with
974 | extensive extramedullary disease, refractory to all approved therapeutic
975 | options, who has rapidly and durably responded to low doses of the
976 | mutation-specific BRAF inhibitor vermurafenib. Collectively, we provide
977 | evidence for the development of the BRAF V600E mutation in the context
978 | of clonal evolution and describe the prognostic and therapeutic
979 | relevance of this targetable mutation.
980 | Author String:
981 | Mindaugas Andrulis, Nicola Lehners, David Capper, Roland Penzel,
982 | Christoph Heining, Jennifer Huellein, Thorsten Zenz, Andreas von
983 | Deimling, Peter Schirmacher, Anthony D Ho, Hartmut Goldschmidt, Kai
984 | Neben, Marc S Raab
985 | Citation: Andrulis et al., 2013
986 | Citation Id: 23612012
987 | Id: 278
988 | Journal: Cancer Discov
989 | Link: /sources/278
990 | Name: PubMed: Andrulis et al., 2013
991 | Open Access: False
992 | Publication Date: 2013-8
993 | Retracted: False
994 | Source Type: PUBMED
995 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23612012
996 | Title: Targeting the BRAF V600E mutation in multiple myeloma.
997 |
998 | #### Evidence Items
999 | Description:
1000 | An inducible BRAF-V600E mouse melanoma model has shown a tight
1001 | correlation between activated BRAF and disease progression.
1002 | Evidence Direction: SUPPORTS
1003 | Evidence Level: D
1004 | Evidence Type: PREDICTIVE
1005 | Flagged: False
1006 | Id: 2123
1007 | Name: EID2123
1008 | Significance: SENSITIVITYRESPONSE
1009 | Variant Origin: SOMATIC
1010 |
1011 | ##### Disease
1012 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
1013 | Display Name: Melanoma
1014 | Doid: 1909
1015 | Id: 7
1016 | Link: /diseases/7
1017 | Name: Melanoma
1018 |
1019 | ##### My Disease Info
1020 | Do Def:
1021 | A cell type cancer that has_material_basis_in abnormally proliferating
1022 | cells derives_from melanocytes which are found in skin, the bowel and
1023 | the eye.
1024 | Icdo: 8720/3
1025 | Mesh: D008545
1026 | Mondo Id: MONDO:0005105
1027 | Ncit: C3224
1028 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
1029 |
1030 | ##### Molecular Profile
1031 | Id: 12
1032 |
1033 | ##### Source
1034 | Abstract:
1035 | The usual paradigm for developing kinase inhibitors in oncology is to
1036 | use a high-affinity proof-of-concept inhibitor with acceptable metabolic
1037 | properties for key target validation experiments. This approach requires
1038 | substantial medicinal chemistry and can be confounded by drug toxicity
1039 | and off-target activities of the test molecule. As a better alternative,
1040 | we have developed inducible short-hairpin RNA xenograft models to
1041 | examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results
1042 | show that tumor regression resulting from BRAF suppression is inducible,
1043 | reversible, and tightly regulated in these models. Analysis of
1044 | regressing tumors showed the primary mechanism of action for BRAF to be
1045 | increased tumor cell proliferation and survival. In a metastatic
1046 | melanoma model, conditional BRAF suppression slowed systemic tumor
1047 | growth as determined by in vivo bioluminescence imaging. Taken together,
1048 | gain-of-function BRAF signaling is strongly associated with in vivo
1049 | tumorigenicity, confirming BRAF as an important target for small-
1050 | molecule and RNA interference-based therapeutics.
1051 | Author String:
1052 | Klaus P Hoeflich, Daniel C Gray, Michael T Eby, Janet Y Tien, Leo Wong,
1053 | Janeko Bower, Alvin Gogineni, Jiping Zha, Mary J Cole, Howard M Stern,
1054 | Lesley J Murray, David P Davis, Somasekar Seshagiri
1055 | Citation: Hoeflich et al., 2006
1056 | Citation Id: 16424035
1057 | Id: 1485
1058 | Journal: Cancer Res
1059 | Link: /sources/1485
1060 | Name: PubMed: Hoeflich et al., 2006
1061 | Open Access: False
1062 | Publication Date: 2006-1-15
1063 | Retracted: False
1064 | Source Type: PUBMED
1065 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16424035
1066 | Title:
1067 | Oncogenic BRAF is required for tumor growth and maintenance in melanoma
1068 | models.
1069 |
1070 | ##### Therapies
1071 | Deprecated: False
1072 | Id: 6
1073 | Link: /therapies/6
1074 | Name: Sorafenib
1075 |
1076 | #### Evidence Items
1077 | Description:
1078 | An inducible BRAF-V600E mouse melanoma model shows a tight correlation
1079 | between activated BRAF and disease progression.
1080 | Evidence Direction: SUPPORTS
1081 | Evidence Level: D
1082 | Evidence Type: PREDICTIVE
1083 | Flagged: False
1084 | Id: 2128
1085 | Name: EID2128
1086 | Significance: SENSITIVITYRESPONSE
1087 | Variant Origin: SOMATIC
1088 |
1089 | ##### Disease
1090 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
1091 | Display Name: Melanoma
1092 | Doid: 1909
1093 | Id: 7
1094 | Link: /diseases/7
1095 | Name: Melanoma
1096 |
1097 | ##### My Disease Info
1098 | Do Def:
1099 | A cell type cancer that has_material_basis_in abnormally proliferating
1100 | cells derives_from melanocytes which are found in skin, the bowel and
1101 | the eye.
1102 | Icdo: 8720/3
1103 | Mesh: D008545
1104 | Mondo Id: MONDO:0005105
1105 | Ncit: C3224
1106 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
1107 |
1108 | ##### Molecular Profile
1109 | Id: 12
1110 |
1111 | ##### Source
1112 | Abstract:
1113 | The usual paradigm for developing kinase inhibitors in oncology is to
1114 | use a high-affinity proof-of-concept inhibitor with acceptable metabolic
1115 | properties for key target validation experiments. This approach requires
1116 | substantial medicinal chemistry and can be confounded by drug toxicity
1117 | and off-target activities of the test molecule. As a better alternative,
1118 | we have developed inducible short-hairpin RNA xenograft models to
1119 | examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results
1120 | show that tumor regression resulting from BRAF suppression is inducible,
1121 | reversible, and tightly regulated in these models. Analysis of
1122 | regressing tumors showed the primary mechanism of action for BRAF to be
1123 | increased tumor cell proliferation and survival. In a metastatic
1124 | melanoma model, conditional BRAF suppression slowed systemic tumor
1125 | growth as determined by in vivo bioluminescence imaging. Taken together,
1126 | gain-of-function BRAF signaling is strongly associated with in vivo
1127 | tumorigenicity, confirming BRAF as an important target for small-
1128 | molecule and RNA interference-based therapeutics.
1129 | Author String:
1130 | Klaus P Hoeflich, Daniel C Gray, Michael T Eby, Janet Y Tien, Leo Wong,
1131 | Janeko Bower, Alvin Gogineni, Jiping Zha, Mary J Cole, Howard M Stern,
1132 | Lesley J Murray, David P Davis, Somasekar Seshagiri
1133 | Citation: Hoeflich et al., 2006
1134 | Citation Id: 16424035
1135 | Id: 1485
1136 | Journal: Cancer Res
1137 | Link: /sources/1485
1138 | Name: PubMed: Hoeflich et al., 2006
1139 | Open Access: False
1140 | Publication Date: 2006-1-15
1141 | Retracted: False
1142 | Source Type: PUBMED
1143 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16424035
1144 | Title:
1145 | Oncogenic BRAF is required for tumor growth and maintenance in melanoma
1146 | models.
1147 |
1148 | ##### Therapies
1149 | Deprecated: False
1150 | Id: 22
1151 | Link: /therapies/22
1152 | Name: Dabrafenib
1153 |
1154 | #### Evidence Items
1155 | Description:
1156 | In the setting of BRAF(V600E), NF1 loss resulted in elevated activation
1157 | of RAS-GTP but does not show resistance to MEK inhibitors.
1158 | Evidence Direction: DOES_NOT_SUPPORT
1159 | Evidence Level: D
1160 | Evidence Rating: 3
1161 | Evidence Type: PREDICTIVE
1162 | Flagged: False
1163 | Id: 86
1164 | Name: EID86
1165 | Significance: RESISTANCE
1166 | Variant Origin: SOMATIC
1167 |
1168 | ##### Disease
1169 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
1170 | Display Name: Melanoma
1171 | Doid: 1909
1172 | Id: 7
1173 | Link: /diseases/7
1174 | Name: Melanoma
1175 |
1176 | ##### My Disease Info
1177 | Do Def:
1178 | A cell type cancer that has_material_basis_in abnormally proliferating
1179 | cells derives_from melanocytes which are found in skin, the bowel and
1180 | the eye.
1181 | Icdo: 8720/3
1182 | Mesh: D008545
1183 | Mondo Id: MONDO:0005105
1184 | Ncit: C3224
1185 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
1186 |
1187 | ##### Molecular Profile
1188 | Id: 12
1189 |
1190 | ##### Source
1191 | Abstract:
1192 | Melanoma is a disease characterized by lesions that activate ERK.
1193 | Although 70% of cutaneous melanomas harbor activating mutations in the
1194 | BRAF and NRAS genes, the alterations that drive tumor progression in the
1195 | remaining 30% are largely undefined. Vemurafenib, a selective inhibitor
1196 | of RAF kinases, has clinical utility restricted to BRAF-mutant tumors.
1197 | MEK inhibitors, which have shown clinical activity in NRAS-mutant
1198 | melanoma, may be effective in other ERK pathway-dependent settings.
1199 | Here, we investigated a panel of melanoma cell lines wild type for BRAF
1200 | and NRAS to determine the genetic alteration driving their
1201 | transformation and their dependence on ERK signaling in order to
1202 | elucidate a candidate set for MEK inhibitor treatment. A cohort of the
1203 | BRAF/RAS wild type cell lines with high levels of RAS-GTP had loss of
1204 | NF1, a RAS GTPase activating protein. In these cell lines, the MEK
1205 | inhibitor PD0325901 inhibited ERK phosphorylation, but also relieved
1206 | feedback inhibition of RAS, resulting in induction of pMEK and a rapid
1207 | rebound in ERK signaling. In contrast, the MEK inhibitor trametinib
1208 | impaired the adaptive response of cells to ERK inhibition, leading to
1209 | sustained suppression of ERK signaling and significant antitumor
1210 | effects. Notably, alterations in NF1 frequently co-occurred with RAS and
1211 | BRAF alterations in melanoma. In the setting of BRAF(V600E), NF1 loss
1212 | abrogated negative feedback on RAS activation, resulting in elevated
1213 | activation of RAS-GTP and resistance to RAF, but not MEK, inhibitors. We
1214 | conclude that loss of NF1 is common in cutaneous melanoma and is
1215 | associated with RAS activation, MEK-dependence, and resistance to RAF
1216 | inhibition.
1217 | Author String:
1218 | Moriah H Nissan, Christine A Pratilas, Alexis M Jones, Ricardo Ramirez,
1219 | Helen Won, Cailian Liu, Shakuntala Tiwari, Li Kong, Aphrothiti J
1220 | Hanrahan, Zhan Yao, Taha Merghoub, Antoni Ribas, Paul B Chapman, Rona
1221 | Yaeger, Barry S Taylor, Nikolaus Schultz, Michael F Berger, Neal Rosen,
1222 | David B Solit
1223 | Citation: Nissan et al., 2014
1224 | Citation Id: 24576830
1225 | Id: 98
1226 | Journal: Cancer Res
1227 | Link: /sources/98
1228 | Name: PubMed: Nissan et al., 2014
1229 | Open Access: True
1230 | Pmc Id: PMC4005042
1231 | Publication Date: 2014-4-15
1232 | Retracted: False
1233 | Source Type: PUBMED
1234 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24576830
1235 | Title:
1236 | Loss of NF1 in cutaneous melanoma is associated with RAS activation and
1237 | MEK dependence.
1238 |
1239 | ##### Therapies
1240 | Deprecated: False
1241 | Id: 19
1242 | Link: /therapies/19
1243 | Name: Trametinib
1244 |
1245 | ##### Therapies
1246 | Deprecated: False
1247 | Id: 29
1248 | Link: /therapies/29
1249 | Name: Mirdametinib
1250 |
1251 | #### Evidence Items
1252 | Description:
1253 | In a mouse in vivo study of MEK protein inhibitor, PD-0325901, was able
1254 | to suppress growth of SKMEL28 BRAF-V600E xenograft tumors (P<0.01). The
1255 | reduction of growth was associated with loss of D-cyclin expression and
1256 | induction of p27.
1257 | Evidence Direction: SUPPORTS
1258 | Evidence Level: D
1259 | Evidence Type: PREDICTIVE
1260 | Flagged: False
1261 | Id: 2124
1262 | Name: EID2124
1263 | Significance: SENSITIVITYRESPONSE
1264 | Variant Origin: SOMATIC
1265 |
1266 | ##### Disease
1267 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
1268 | Display Name: Melanoma
1269 | Doid: 1909
1270 | Id: 7
1271 | Link: /diseases/7
1272 | Name: Melanoma
1273 |
1274 | ##### My Disease Info
1275 | Do Def:
1276 | A cell type cancer that has_material_basis_in abnormally proliferating
1277 | cells derives_from melanocytes which are found in skin, the bowel and
1278 | the eye.
1279 | Icdo: 8720/3
1280 | Mesh: D008545
1281 | Mondo Id: MONDO:0005105
1282 | Ncit: C3224
1283 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
1284 |
1285 | ##### Molecular Profile
1286 | Id: 12
1287 |
1288 | ##### Source
1289 | Abstract:
1290 | The kinase pathway comprising RAS, RAF, mitogen-activated protein kinase
1291 | kinase (MEK) and extracellular signal regulated kinase (ERK) is
1292 | activated in most human tumours, often through gain-of-function
1293 | mutations of RAS and RAF family members. Using small-molecule inhibitors
1294 | of MEK and an integrated genetic and pharmacologic analysis, we find
1295 | that mutation of BRAF is associated with enhanced and selective
1296 | sensitivity to MEK inhibition when compared to either 'wild-type' cells
1297 | or cells harbouring a RAS mutation. This MEK dependency was observed in
1298 | BRAF mutant cells regardless of tissue lineage, and correlated with both
1299 | downregulation of cyclin D1 protein expression and the induction of G1
1300 | arrest. Pharmacological MEK inhibition completely abrogated tumour
1301 | growth in BRAF mutant xenografts, whereas RAS mutant tumours were only
1302 | partially inhibited. These data suggest an exquisite dependency on MEK
1303 | activity in BRAF mutant tumours, and offer a rational therapeutic
1304 | strategy for this genetically defined tumour subtype.
1305 | Author String:
1306 | David B Solit, Levi A Garraway, Christine A Pratilas, Ayana Sawai, Gad
1307 | Getz, Andrea Basso, Qing Ye, Jose M Lobo, Yuhong She, Iman Osman, Todd R
1308 | Golub, Judith Sebolt-Leopold, William R Sellers, Neal Rosen
1309 | Citation: Solit et al., 2006
1310 | Citation Id: 16273091
1311 | Id: 1487
1312 | Journal: Nature
1313 | Link: /sources/1487
1314 | Name: PubMed: Solit et al., 2006
1315 | Open Access: True
1316 | Pmc Id: PMC3306236
1317 | Publication Date: 2006-1-19
1318 | Retracted: False
1319 | Source Type: PUBMED
1320 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16273091
1321 | Title: BRAF mutation predicts sensitivity to MEK inhibition.
1322 |
1323 | ##### Therapies
1324 | Deprecated: False
1325 | Id: 29
1326 | Link: /therapies/29
1327 | Name: Mirdametinib
1328 |
1329 | #### Evidence Items
1330 | Description:
1331 | An inducible BRAF-V600E mouse melanoma model shows a tight correlation
1332 | between activated BRAF and disease progression.
1333 | Evidence Direction: SUPPORTS
1334 | Evidence Level: D
1335 | Evidence Type: PREDICTIVE
1336 | Flagged: False
1337 | Id: 2125
1338 | Name: EID2125
1339 | Significance: SENSITIVITYRESPONSE
1340 | Variant Origin: SOMATIC
1341 |
1342 | ##### Disease
1343 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
1344 | Display Name: Melanoma
1345 | Doid: 1909
1346 | Id: 7
1347 | Link: /diseases/7
1348 | Name: Melanoma
1349 |
1350 | ##### My Disease Info
1351 | Do Def:
1352 | A cell type cancer that has_material_basis_in abnormally proliferating
1353 | cells derives_from melanocytes which are found in skin, the bowel and
1354 | the eye.
1355 | Icdo: 8720/3
1356 | Mesh: D008545
1357 | Mondo Id: MONDO:0005105
1358 | Ncit: C3224
1359 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
1360 |
1361 | ##### Molecular Profile
1362 | Id: 12
1363 |
1364 | ##### Source
1365 | Abstract:
1366 | The usual paradigm for developing kinase inhibitors in oncology is to
1367 | use a high-affinity proof-of-concept inhibitor with acceptable metabolic
1368 | properties for key target validation experiments. This approach requires
1369 | substantial medicinal chemistry and can be confounded by drug toxicity
1370 | and off-target activities of the test molecule. As a better alternative,
1371 | we have developed inducible short-hairpin RNA xenograft models to
1372 | examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results
1373 | show that tumor regression resulting from BRAF suppression is inducible,
1374 | reversible, and tightly regulated in these models. Analysis of
1375 | regressing tumors showed the primary mechanism of action for BRAF to be
1376 | increased tumor cell proliferation and survival. In a metastatic
1377 | melanoma model, conditional BRAF suppression slowed systemic tumor
1378 | growth as determined by in vivo bioluminescence imaging. Taken together,
1379 | gain-of-function BRAF signaling is strongly associated with in vivo
1380 | tumorigenicity, confirming BRAF as an important target for small-
1381 | molecule and RNA interference-based therapeutics.
1382 | Author String:
1383 | Klaus P Hoeflich, Daniel C Gray, Michael T Eby, Janet Y Tien, Leo Wong,
1384 | Janeko Bower, Alvin Gogineni, Jiping Zha, Mary J Cole, Howard M Stern,
1385 | Lesley J Murray, David P Davis, Somasekar Seshagiri
1386 | Citation: Hoeflich et al., 2006
1387 | Citation Id: 16424035
1388 | Id: 1485
1389 | Journal: Cancer Res
1390 | Link: /sources/1485
1391 | Name: PubMed: Hoeflich et al., 2006
1392 | Open Access: False
1393 | Publication Date: 2006-1-15
1394 | Retracted: False
1395 | Source Type: PUBMED
1396 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16424035
1397 | Title:
1398 | Oncogenic BRAF is required for tumor growth and maintenance in melanoma
1399 | models.
1400 |
1401 | ##### Therapies
1402 | Deprecated: False
1403 | Id: 29
1404 | Link: /therapies/29
1405 | Name: Mirdametinib
1406 |
1407 | #### Evidence Items
1408 | Description:
1409 | Acquired resistance to vemurafenib in BRAF-V600E positive melanomas
1410 | frequently confound vemurafenib therapy.
1411 | Evidence Direction: SUPPORTS
1412 | Evidence Level: D
1413 | Evidence Type: PREDICTIVE
1414 | Flagged: False
1415 | Id: 2127
1416 | Name: EID2127
1417 | Significance: SENSITIVITYRESPONSE
1418 | Variant Origin: SOMATIC
1419 |
1420 | ##### Disease
1421 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
1422 | Display Name: Melanoma
1423 | Doid: 1909
1424 | Id: 7
1425 | Link: /diseases/7
1426 | Name: Melanoma
1427 |
1428 | ##### My Disease Info
1429 | Do Def:
1430 | A cell type cancer that has_material_basis_in abnormally proliferating
1431 | cells derives_from melanocytes which are found in skin, the bowel and
1432 | the eye.
1433 | Icdo: 8720/3
1434 | Mesh: D008545
1435 | Mondo Id: MONDO:0005105
1436 | Ncit: C3224
1437 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
1438 |
1439 | ##### Molecular Profile
1440 | Id: 12
1441 |
1442 | ##### Source
1443 | Abstract:
1444 | The identification of somatic mutations in the gene encoding the serine-
1445 | threonine protein kinase B-RAF (BRAF) in the majority of melanomas
1446 | offers an opportunity to test oncogene-targeted therapy for this
1447 | disease.We conducted a multicenter, phase 1, dose-escalation trial of
1448 | PLX4032 (also known as RG7204), an orally available inhibitor of mutated
1449 | BRAF, followed by an extension phase involving the maximum dose that
1450 | could be administered without adverse effects (the recommended phase 2
1451 | dose). Patients received PLX4032 twice daily until they had disease
1452 | progression. Pharmacokinetic analysis and tumor-response assessments
1453 | were conducted in all patients. In selected patients, tumor biopsy was
1454 | performed before and during treatment to validate BRAF inhibition.A
1455 | total of 55 patients (49 of whom had melanoma) were enrolled in the
1456 | dose-escalation phase, and 32 additional patients with metastatic
1457 | melanoma who had BRAF with the V600E mutation were enrolled in the
1458 | extension phase. The recommended phase 2 dose was 960 mg twice daily,
1459 | with increases in the dose limited by grade 2 or 3 rash, fatigue, and
1460 | arthralgia. In the dose-escalation cohort, among the 16 patients with
1461 | melanoma whose tumors carried the V600E BRAF mutation and who were
1462 | receiving 240 mg or more of PLX4032 twice daily, 10 had a partial
1463 | response and 1 had a complete response. Among the 32 patients in the
1464 | extension cohort, 24 had a partial response and 2 had a complete
1465 | response. The estimated median progression-free survival among all
1466 | patients was more than 7 months.Treatment of metastatic melanoma with
1467 | PLX4032 in patients with tumors that carry the V600E BRAF mutation
1468 | resulted in complete or partial tumor regression in the majority of
1469 | patients. (Funded by Plexxikon and Roche Pharmaceuticals.)
1470 | Author String:
1471 | Keith T Flaherty, Igor Puzanov, Kevin B Kim, Antoni Ribas, Grant A
1472 | McArthur, Jeffrey A Sosman, Peter J O'Dwyer, Richard J Lee, Joseph F
1473 | Grippo, Keith Nolop, Paul B Chapman
1474 | Citation: Flaherty et al., 2010
1475 | Citation Id: 20818844
1476 | Id: 352
1477 | Journal: N Engl J Med
1478 | Link: /sources/352
1479 | Name: PubMed: Flaherty et al., 2010
1480 | Open Access: True
1481 | Pmc Id: PMC3724529
1482 | Publication Date: 2010-8-26
1483 | Retracted: False
1484 | Source Type: PUBMED
1485 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/20818844
1486 | Title: Inhibition of mutated, activated BRAF in metastatic melanoma.
1487 |
1488 | ##### Therapies
1489 | Deprecated: False
1490 | Id: 22
1491 | Link: /therapies/22
1492 | Name: Dabrafenib
1493 |
1494 | #### Evidence Items
1495 | Description:
1496 | Acquired resistance to vemurafenib in BRAF-V600E positive melanomas
1497 | frequently confound vemurafenib therapy.
1498 | Evidence Direction: SUPPORTS
1499 | Evidence Level: D
1500 | Evidence Type: PREDICTIVE
1501 | Flagged: False
1502 | Id: 2133
1503 | Name: EID2133
1504 | Significance: SENSITIVITYRESPONSE
1505 | Variant Origin: SOMATIC
1506 |
1507 | ##### Disease
1508 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
1509 | Display Name: Melanoma
1510 | Doid: 1909
1511 | Id: 7
1512 | Link: /diseases/7
1513 | Name: Melanoma
1514 |
1515 | ##### My Disease Info
1516 | Do Def:
1517 | A cell type cancer that has_material_basis_in abnormally proliferating
1518 | cells derives_from melanocytes which are found in skin, the bowel and
1519 | the eye.
1520 | Icdo: 8720/3
1521 | Mesh: D008545
1522 | Mondo Id: MONDO:0005105
1523 | Ncit: C3224
1524 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
1525 |
1526 | ##### Molecular Profile
1527 | Id: 12
1528 |
1529 | ##### Source
1530 | Abstract:
1531 | Oncogenic mutations in the serine/threonine kinase B-RAF (also known as
1532 | BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies
1533 | have demonstrated that the B-RAF(V600E) mutation predicts a dependency
1534 | on the mitogen-activated protein kinase (MAPK) signalling cascade in
1535 | melanoma-an observation that has been validated by the success of RAF
1536 | and MEK inhibitors in clinical trials. However, clinical responses to
1537 | targeted anticancer therapeutics are frequently confounded by de novo or
1538 | acquired resistance. Identification of resistance mechanisms in a manner
1539 | that elucidates alternative 'druggable' targets may inform effective
1540 | long-term treatment strategies. Here we expressed ∼600 kinase and
1541 | kinase-related open reading frames (ORFs) in parallel to interrogate
1542 | resistance to a selective RAF kinase inhibitor. We identified MAP3K8
1543 | (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives
1544 | resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates
1545 | ERK primarily through MEK-dependent mechanisms that do not require RAF
1546 | signalling. Moreover, COT expression is associated with de novo
1547 | resistance in B-RAF(V600E) cultured cell lines and acquired resistance
1548 | in melanoma cells and tissue obtained from relapsing patients following
1549 | treatment with MEK or RAF inhibitors. We further identify combinatorial
1550 | MAPK pathway inhibition or targeting of COT kinase activity as possible
1551 | therapeutic strategies for reducing MAPK pathway activation in this
1552 | setting. Together, these results provide new insights into resistance
1553 | mechanisms involving the MAPK pathway and articulate an integrative
1554 | approach through which high-throughput functional screens may inform the
1555 | development of novel therapeutic strategies.
1556 | Author String:
1557 | Cory M Johannessen, Jesse S Boehm, So Young Kim, Sapana R Thomas, Leslie
1558 | Wardwell, Laura A Johnson, Caroline M Emery, Nicolas Stransky,
1559 | Alexandria P Cogdill, Jordi Barretina, Giordano Caponigro, Haley
1560 | Hieronymus, Ryan R Murray, Kourosh Salehi-Ashtiani, David E Hill, Marc
1561 | Vidal, Jean J Zhao, Xiaoping Yang, Ozan Alkan, Sungjoon Kim, Jennifer L
1562 | Harris, Christopher J Wilson, Vic E Myer, Peter M Finan, David E Root,
1563 | Thomas M Roberts, Todd Golub, Keith T Flaherty, Reinhard Dummer, Barbara
1564 | L Weber, William R Sellers, Robert Schlegel, Jennifer A Wargo, William C
1565 | Hahn, Levi A Garraway
1566 | Citation: Johannessen et al., 2010
1567 | Citation Id: 21107320
1568 | Id: 1492
1569 | Journal: Nature
1570 | Link: /sources/1492
1571 | Name: PubMed: Johannessen et al., 2010
1572 | Open Access: True
1573 | Pmc Id: PMC3058384
1574 | Publication Date: 2010-12-16
1575 | Retracted: False
1576 | Source Type: PUBMED
1577 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21107320
1578 | Title:
1579 | COT drives resistance to RAF inhibition through MAP kinase pathway
1580 | reactivation.
1581 |
1582 | ##### Therapies
1583 | Deprecated: False
1584 | Id: 22
1585 | Link: /therapies/22
1586 | Name: Dabrafenib
1587 |
1588 | #### Evidence Items
1589 | Description:
1590 | In a mouse in vivo study, the MEK protein inhibitor selumetinib
1591 | suppressed the growth of 1205Lu xenograft tumors, which contains the
1592 | BRAF-V600Emutation (0.91 +/- 0.10-fold volume increase vs. 9.47 +/-
1593 | 2.14-fold for non-treated mice). These tumors had a concomitant
1594 | reduction of BrdU positive cells (P=0.009) but no increase in apoptosis.
1595 | Selumetinib, in combination with docetaxel, a chemotherapeutic agent,
1596 | produced cycle arrest and elevated apoptosis.
1597 | Evidence Direction: SUPPORTS
1598 | Evidence Level: D
1599 | Evidence Type: PREDICTIVE
1600 | Flagged: False
1601 | Id: 2129
1602 | Name: EID2129
1603 | Significance: SENSITIVITYRESPONSE
1604 | Variant Origin: SOMATIC
1605 |
1606 | ##### Disease
1607 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
1608 | Display Name: Melanoma
1609 | Doid: 1909
1610 | Id: 7
1611 | Link: /diseases/7
1612 | Name: Melanoma
1613 |
1614 | ##### My Disease Info
1615 | Do Def:
1616 | A cell type cancer that has_material_basis_in abnormally proliferating
1617 | cells derives_from melanocytes which are found in skin, the bowel and
1618 | the eye.
1619 | Icdo: 8720/3
1620 | Mesh: D008545
1621 | Mondo Id: MONDO:0005105
1622 | Ncit: C3224
1623 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
1624 |
1625 | ##### Molecular Profile
1626 | Id: 12
1627 |
1628 | ##### Source
1629 | Abstract:
1630 | Disseminated melanoma is highly therapy resistant. The finding that 66%
1631 | of melanomas harbor the activating BRAF(V600E) mutation has raised
1632 | expectations for targeting the Ras/RAF/mitogen-activated protein
1633 | (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK
1634 | pathway in melanoma. This study addresses the anti-melanoma activity of
1635 | the MEK inhibitor AZD6244 (ARRY-142886).We recently have shown that
1636 | growing melanoma cells as three-dimensional collagen-implanted spheroids
1637 | enhances resistance to the MEK inhibitor U0126. Here, we investigated
1638 | the anti-melanoma activity of AZD6244 in two-dimensional cell culture,
1639 | the three-dimensional spheroid model, and an in vivo model.In two-
1640 | dimensional cell culture, AZD6244 was cytostatic and reduced the growth
1641 | of melanoma cells in a concentration-dependent fashion through the
1642 | induction of G(1)-phase cell cycle arrest. In our three-dimensional
1643 | spheroid model, the effects of AZD6244 were largely cytostatic and
1644 | reversible, with drug washout leading to spheroid regrowth. Finally,
1645 | 1205Lu cells were grown as tumor xenografts in severe combined
1646 | immunodeficient mice. After tumor establishment, mice were dosed twice
1647 | daily with 0, 10, or 30 mg/kg AZD6244 p.o. AZD6244 treatment decreased
1648 | phospho-ERK in the tumors and significantly suppressed tumor growth. The
1649 | original tumors remained viable, suggesting that AZD6244 monotherapy was
1650 | largely cytostatic, and not proapoptotic in this model. Further studies
1651 | showed that co-administration of AZD6244 (30 mg/kg) with docetaxel (15
1652 | mg/kg) led to tumor regression, indicating the potential for MEK
1653 | inhibitor/chemotherapy drug combinations.Inhibition of MEK is cytostatic
1654 | as a monotherapy in melanoma, but cytotoxic when combined with
1655 | docetaxel.
1656 | Author String:
1657 | Nikolas K Haass, Katrin Sproesser, Thiennga K Nguyen, Rooha Contractor,
1658 | C Angelica Medina, Katherine L Nathanson, Meenhard Herlyn, Keiran S M
1659 | Smalley
1660 | Citation: Haass et al., 2008
1661 | Citation Id: 18172275
1662 | Id: 1489
1663 | Journal: Clin Cancer Res
1664 | Link: /sources/1489
1665 | Name: PubMed: Haass et al., 2008
1666 | Open Access: False
1667 | Publication Date: 2008-1-1
1668 | Retracted: False
1669 | Source Type: PUBMED
1670 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/18172275
1671 | Title:
1672 | The mitogen-activated protein/extracellular signal-regulated kinase
1673 | kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma
1674 | cells and tumor regression when combined with docetaxel.
1675 |
1676 | ##### Therapies
1677 | Deprecated: False
1678 | Id: 63
1679 | Link: /therapies/63
1680 | Name: Selumetinib
1681 |
1682 | #### Evidence Items
1683 | Description:
1684 | In this Phase II pilot study (NCT00405587) of BRAF V600 inhibitor
1685 | vemurafenib in 21 metastatic colorectal cancer (CRC) patients with BRAF
1686 | V600E, one patient had a durable 21 week partial response, and seven
1687 | patients had 8 week stable disease as best response. Median progression
1688 | free survival was 2.1 months and median overall survival was 7.7 months.
1689 | The authors conclude that single agent vemurafenib did not show
1690 | meaningful activity in V600E CRC, in contrast to the significant
1691 | vemurafenib activity against V600 in melanoma.
1692 | Evidence Direction: DOES_NOT_SUPPORT
1693 | Evidence Level: B
1694 | Evidence Rating: 4
1695 | Evidence Type: PREDICTIVE
1696 | Flagged: False
1697 | Id: 1405
1698 | Name: EID1405
1699 | Significance: SENSITIVITYRESPONSE
1700 | Variant Origin: SOMATIC
1701 |
1702 | ##### Disease
1703 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
1704 | Display Name: Colorectal Cancer
1705 | Doid: 9256
1706 | Id: 11
1707 | Link: /diseases/11
1708 | Name: Colorectal Cancer
1709 |
1710 | ##### My Disease Info
1711 | Do Def:
1712 | An intestinal cancer that effects the long, tube-like organ that is
1713 | connected to the small intestine at one end and the anus at the other.
1714 | Icd10: C18.9
1715 | Mondo Id: MONDO:0005575
1716 | Ncit: C4978
1717 |
1718 | ##### Molecular Profile
1719 | Id: 12
1720 |
1721 | ##### Source
1722 | Abstract:
1723 | BRAF V600E mutation is seen in 5% to 8% of patients with metastatic
1724 | colorectal cancer (CRC) and is associated with poor prognosis.
1725 | Vemurafenib, an oral BRAF V600 inhibitor, has pronounced activity in
1726 | patients with metastatic melanoma, but its activity in patients with
1727 | BRAF V600E-positive metastatic CRC was unknown.In this multi-
1728 | institutional, open-label study, patients with metastatic CRC with BRAF
1729 | V600 mutations were recruited to an expansion cohort at the previously
1730 | determined maximum-tolerated dose of 960 mg orally twice a day.Twenty-
1731 | one patients were enrolled, of whom 20 had received at least one prior
1732 | metastatic chemotherapy regimen. Grade 3 toxicities included
1733 | keratoacanthomas, rash, fatigue, and arthralgia. Of the 21 patients
1734 | treated, one patient had a confirmed partial response (5%; 95% CI, 1% to
1735 | 24%) and seven other patients had stable disease by RECIST criteria.
1736 | Median progression-free survival was 2.1 months. Patterns of concurrent
1737 | mutations, microsatellite instability status, CpG island methylation
1738 | status, PTEN loss, EGFR expression, and copy number alterations were not
1739 | associated with clinical benefit. In contrast to prior expectations,
1740 | concurrent KRAS and NRAS mutations were detected at low allele frequency
1741 | in a subset of the patients' tumors (median, 0.21% allele frequency) and
1742 | were apparent mechanisms of acquired resistance in vemurafenib-sensitive
1743 | patient-derived xenograft models.In marked contrast to the results seen
1744 | in patients with BRAF V600E-mutant melanoma, single-agent vemurafenib
1745 | did not show meaningful clinical activity in patients with BRAF V600E
1746 | mutant CRC. Combination strategies are now under development and may be
1747 | informed by the presence of intratumor heterogeneity of KRAS and NRAS
1748 | mutations.
1749 | Author String:
1750 | Scott Kopetz, Jayesh Desai, Emily Chan, Joel Randolph Hecht, Peter J
1751 | O'Dwyer, Dipen Maru, Van Morris, Filip Janku, Arvind Dasari, Woonbook
1752 | Chung, Jean-Pierre J Issa, Peter Gibbs, Brian James, Garth Powis, Keith
1753 | B Nolop, Suman Bhattacharya, Leonard Saltz
1754 | Citation: Kopetz et al., 2015
1755 | Citation Id: 26460303
1756 | Id: 953
1757 | Journal: J Clin Oncol
1758 | Link: /sources/953
1759 | Name: PubMed: Kopetz et al., 2015
1760 | Open Access: True
1761 | Pmc Id: PMC4669589
1762 | Publication Date: 2015-12-1
1763 | Retracted: False
1764 | Source Type: PUBMED
1765 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26460303
1766 | Title:
1767 | Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-
1768 | Mutated Colorectal Cancer.
1769 |
1770 | ##### Therapies
1771 | Deprecated: False
1772 | Id: 4
1773 | Link: /therapies/4
1774 | Name: Vemurafenib
1775 |
1776 | #### Evidence Items
1777 | Description:
1778 | An inducible BRAF-V600E mouse melanoma model shows a tight correlation
1779 | between activated BRAF and disease progression.
1780 | Evidence Direction: SUPPORTS
1781 | Evidence Level: D
1782 | Evidence Type: PREDICTIVE
1783 | Flagged: False
1784 | Id: 2131
1785 | Name: EID2131
1786 | Significance: SENSITIVITYRESPONSE
1787 | Variant Origin: SOMATIC
1788 |
1789 | ##### Disease
1790 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
1791 | Display Name: Melanoma
1792 | Doid: 1909
1793 | Id: 7
1794 | Link: /diseases/7
1795 | Name: Melanoma
1796 |
1797 | ##### My Disease Info
1798 | Do Def:
1799 | A cell type cancer that has_material_basis_in abnormally proliferating
1800 | cells derives_from melanocytes which are found in skin, the bowel and
1801 | the eye.
1802 | Icdo: 8720/3
1803 | Mesh: D008545
1804 | Mondo Id: MONDO:0005105
1805 | Ncit: C3224
1806 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
1807 |
1808 | ##### Molecular Profile
1809 | Id: 12
1810 |
1811 | ##### Source
1812 | Abstract:
1813 | The usual paradigm for developing kinase inhibitors in oncology is to
1814 | use a high-affinity proof-of-concept inhibitor with acceptable metabolic
1815 | properties for key target validation experiments. This approach requires
1816 | substantial medicinal chemistry and can be confounded by drug toxicity
1817 | and off-target activities of the test molecule. As a better alternative,
1818 | we have developed inducible short-hairpin RNA xenograft models to
1819 | examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results
1820 | show that tumor regression resulting from BRAF suppression is inducible,
1821 | reversible, and tightly regulated in these models. Analysis of
1822 | regressing tumors showed the primary mechanism of action for BRAF to be
1823 | increased tumor cell proliferation and survival. In a metastatic
1824 | melanoma model, conditional BRAF suppression slowed systemic tumor
1825 | growth as determined by in vivo bioluminescence imaging. Taken together,
1826 | gain-of-function BRAF signaling is strongly associated with in vivo
1827 | tumorigenicity, confirming BRAF as an important target for small-
1828 | molecule and RNA interference-based therapeutics.
1829 | Author String:
1830 | Klaus P Hoeflich, Daniel C Gray, Michael T Eby, Janet Y Tien, Leo Wong,
1831 | Janeko Bower, Alvin Gogineni, Jiping Zha, Mary J Cole, Howard M Stern,
1832 | Lesley J Murray, David P Davis, Somasekar Seshagiri
1833 | Citation: Hoeflich et al., 2006
1834 | Citation Id: 16424035
1835 | Id: 1485
1836 | Journal: Cancer Res
1837 | Link: /sources/1485
1838 | Name: PubMed: Hoeflich et al., 2006
1839 | Open Access: False
1840 | Publication Date: 2006-1-15
1841 | Retracted: False
1842 | Source Type: PUBMED
1843 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16424035
1844 | Title:
1845 | Oncogenic BRAF is required for tumor growth and maintenance in melanoma
1846 | models.
1847 |
1848 | ##### Therapies
1849 | Deprecated: False
1850 | Id: 19
1851 | Link: /therapies/19
1852 | Name: Trametinib
1853 |
1854 | #### Evidence Items
1855 | Description:
1856 | Proposed resistance mechanisms include PDGFRB upregulation or NRAS
1857 | mutations resulting in MAPK pathway reactivation, but not secondary
1858 | mutations in BRAF. MEK inhibitors may demonstrate clinical benefit in
1859 | vemurafenib-resistant melanoma patients.
1860 | Evidence Direction: SUPPORTS
1861 | Evidence Level: D
1862 | Evidence Type: PREDICTIVE
1863 | Flagged: False
1864 | Id: 2132
1865 | Name: EID2132
1866 | Significance: SENSITIVITYRESPONSE
1867 | Variant Origin: SOMATIC
1868 |
1869 | ##### Disease
1870 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
1871 | Display Name: Melanoma
1872 | Doid: 1909
1873 | Id: 7
1874 | Link: /diseases/7
1875 | Name: Melanoma
1876 |
1877 | ##### My Disease Info
1878 | Do Def:
1879 | A cell type cancer that has_material_basis_in abnormally proliferating
1880 | cells derives_from melanocytes which are found in skin, the bowel and
1881 | the eye.
1882 | Icdo: 8720/3
1883 | Mesh: D008545
1884 | Mondo Id: MONDO:0005105
1885 | Ncit: C3224
1886 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
1887 |
1888 | ##### Molecular Profile
1889 | Id: 12
1890 |
1891 | ##### Source
1892 | Abstract:
1893 | Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in
1894 | ∼7% of human malignancies and ∼60% of melanomas. Early clinical
1895 | experience with a novel class I RAF-selective inhibitor, PLX4032,
1896 | demonstrated an unprecedented 80% anti-tumour response rate among
1897 | patients with B-RAF(V600E)-positive melanomas, but acquired drug
1898 | resistance frequently develops after initial responses. Hypotheses for
1899 | mechanisms of acquired resistance to B-RAF inhibition include secondary
1900 | mutations in B-RAF(V600E), MAPK reactivation, and activation of
1901 | alternative survival pathways. Here we show that acquired resistance to
1902 | PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB)
1903 | upregulation or N-RAS (also known as NRAS) mutations but not through
1904 | secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines
1905 | artificially derived from B-RAF(V600E)-positive melanoma cell lines and
1906 | validated key findings in PLX4032-resistant tumours and tumour-matched,
1907 | short-term cultures from clinical trial patients. Induction of PDGFRβ
1908 | RNA, protein and tyrosine phosphorylation emerged as a dominant feature
1909 | of acquired PLX4032 resistance in a subset of melanoma sub-lines,
1910 | patient-derived biopsies and short-term cultures. PDGFRβ-upregulated
1911 | tumour cells have low activated RAS levels and, when treated with
1912 | PLX4032, do not reactivate the MAPK pathway significantly. In another
1913 | subset, high levels of activated N-RAS resulting from mutations lead to
1914 | significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown
1915 | of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant
1916 | subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032
1917 | resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK
1918 | reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape
1919 | B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but
1920 | via receptor tyrosine kinase (RTK)-mediated activation of alternative
1921 | survival pathway(s) or activated RAS-mediated reactivation of the MAPK
1922 | pathway, suggesting additional therapeutic strategies.
1923 | Author String:
1924 | Ramin Nazarian, Hubing Shi, Qi Wang, Xiangju Kong, Richard C Koya, Hane
1925 | Lee, Zugen Chen, Mi-Kyung Lee, Narsis Attar, Hooman Sazegar, Thinle
1926 | Chodon, Stanley F Nelson, Grant McArthur, Jeffrey A Sosman, Antoni
1927 | Ribas, Roger S Lo
1928 | Citation: Nazarian et al., 2010
1929 | Citation Id: 21107323
1930 | Id: 1491
1931 | Journal: Nature
1932 | Link: /sources/1491
1933 | Name: PubMed: Nazarian et al., 2010
1934 | Open Access: True
1935 | Pmc Id: PMC3143360
1936 | Publication Date: 2010-12-16
1937 | Retracted: False
1938 | Source Type: PUBMED
1939 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21107323
1940 | Title:
1941 | Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS
1942 | upregulation.
1943 |
1944 | ##### Therapies
1945 | Deprecated: False
1946 | Id: 22
1947 | Link: /therapies/22
1948 | Name: Dabrafenib
1949 |
1950 | #### Evidence Items
1951 | Description:
1952 | V600E is associated with adverse pathological features of colorectal
1953 | cancer. This can be concluded as a marker of poor prognosis.
1954 | Evidence Direction: SUPPORTS
1955 | Evidence Level: B
1956 | Evidence Rating: 5
1957 | Evidence Type: PROGNOSTIC
1958 | Flagged: False
1959 | Id: 103
1960 | Name: EID103
1961 | Significance: POOR_OUTCOME
1962 | Variant Origin: SOMATIC
1963 |
1964 | ##### Disease
1965 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
1966 | Display Name: Colorectal Cancer
1967 | Doid: 9256
1968 | Id: 11
1969 | Link: /diseases/11
1970 | Name: Colorectal Cancer
1971 |
1972 | ##### My Disease Info
1973 | Do Def:
1974 | An intestinal cancer that effects the long, tube-like organ that is
1975 | connected to the small intestine at one end and the anus at the other.
1976 | Icd10: C18.9
1977 | Mondo Id: MONDO:0005575
1978 | Ncit: C4978
1979 |
1980 | ##### Molecular Profile
1981 | Id: 12
1982 |
1983 | ##### Source
1984 | Abstract:
1985 | Colorectal cancer (CRC) is a heterogeneous disease with multiple
1986 | underlying causative genetic mutations. The B-type Raf proto-oncogene
1987 | (BRAF) plays an important role in the mitogen-activated protein kinase
1988 | (MAPK) signaling cascade during CRC. The presence of BRAFV600E mutation
1989 | can determine the response of a tumor to chemotherapy. However, the
1990 | association between the BRAFV600E mutation and the clinicopathological
1991 | features of CRC remains controversial. We performed a systematic review
1992 | and meta-analysis to estimate the effect of BRAFV600E mutation on the
1993 | clinicopathological characteristics of CRC.We identified studies that
1994 | examined the effect of BRAFV600E mutation on CRC within the PubMed, ISI
1995 | Science Citation Index, and Embase databases. The effect of BRAFV600E on
1996 | outcome parameters was estimated by odds ratios (ORs) with 95%
1997 | confidence intervals (CIs) for each study using a fixed effects or
1998 | random effects model.25 studies with a total of 11,955 CRC patients met
1999 | inclusion criteria. The rate of BRAFV600 was 10.8% (1288/11955). The
2000 | BRAFV600E mutation in CRC was associated with advanced TNM stage, poor
2001 | differentiation, mucinous histology, microsatellite instability (MSI),
2002 | CpG island methylator phenotype (CIMP). This mutation was also
2003 | associated with female gender, older age, proximal colon, and mutL
2004 | homolog 1 (MLH1) methylation.This meta-analysis demonstrated that
2005 | BRAFV600E mutation was significantly correlated with adverse
2006 | pathological features of CRC and distinct clinical characteristics.
2007 | These data suggest that BRAFV600E mutation could be used to supplement
2008 | standard clinical and pathological staging for the better management of
2009 | individual CRC patients, and could be considered as a poor prognostic
2010 | marker for CRC.
2011 | Author String:
2012 | Dong Chen, Jun-Fu Huang, Kai Liu, Li-Qun Zhang, Zhao Yang, Zheng-Ran
2013 | Chuai, Yun-Xia Wang, Da-Chuan Shi, Qing Huang, Wei-Ling Fu
2014 | Citation: Chen et al., 2014
2015 | Citation Id: 24594804
2016 | Id: 110
2017 | Journal: PLoS One
2018 | Link: /sources/110
2019 | Name: PubMed: Chen et al., 2014
2020 | Open Access: True
2021 | Pmc Id: PMC3940924
2022 | Publication Date: 2014
2023 | Retracted: False
2024 | Source Type: PUBMED
2025 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24594804
2026 | Title:
2027 | BRAFV600E mutation and its association with clinicopathological features
2028 | of colorectal cancer: a systematic review and meta-analysis.
2029 |
2030 | #### Evidence Items
2031 | Description:
2032 | BRAF mutations were identified in 9% of 108 cases of high-grade
2033 | colorectal neuroendocrine tumors (80% V600E). Two patients were treated
2034 | with a combination of BRAF and MEK inhibition and exhibited durable
2035 | response (beyond 7 and 9 months, respectively). Urinary BRAF V600E tumor
2036 | DNA correlated with disease response in one of the patients. BRAF and
2037 | MEK inhibition was either dabrafenib+trametinib (case 1) or
2038 | vemurafenib+trametinib (case 2).
2039 | Evidence Direction: SUPPORTS
2040 | Evidence Level: C
2041 | Evidence Rating: 3
2042 | Evidence Type: PREDICTIVE
2043 | Flagged: False
2044 | Id: 1430
2045 | Name: EID1430
2046 | Significance: SENSITIVITYRESPONSE
2047 | Variant Origin: SOMATIC
2048 |
2049 | ##### Disease
2050 | Disease Url: https://www.disease-ontology.org/?id=DOID:0050626
2051 | Display Name: Gastrointestinal Neuroendocrine Tumor
2052 | Doid: 0050626
2053 | Id: 53
2054 | Link: /diseases/53
2055 | Name: Gastrointestinal Neuroendocrine Tumor
2056 |
2057 | ##### My Disease Info
2058 | Do Def:
2059 | A gastrointestinal system cancer that has_material_basis_in
2060 | neuroendocrine cells.
2061 | Mondo Id: MONDO:0000386
2062 | Disease Aliases:
2063 | - Gastrointestinal Neuroendocrine Tumour
2064 | - Malignant Gastrointestinal Neuroendocrine Tumor
2065 | - Malignant Gastrointestinal Neuroendocrine Tumour
2066 |
2067 | ##### Molecular Profile
2068 | Id: 12
2069 |
2070 | ##### Source
2071 | Abstract:
2072 | Neuroendocrine tumors comprise a heterogeneous group of malignancies
2073 | with a broad spectrum of clinical behavior. Poorly differentiated tumors
2074 | follow an aggressive course with limited treatment options, and new
2075 | approaches are needed. Oncogenic BRAF V600E (BRAF(V600E)) substitutions
2076 | are observed primarily in melanoma, colon cancer, and non-small cell
2077 | lung cancer, but have been identified in multiple tumor types. Here, we
2078 | describe the first reported recurrent BRAF(V600E) mutations in advanced
2079 | high-grade colorectal neuroendocrine tumors and identify a BRAF
2080 | alteration frequency of 9% in 108 cases. Among these BRAF alterations,
2081 | 80% were BRAF(V600E) Dramatic response to BRAF-MEK combination therapy
2082 | occurred in two cases of metastatic high-grade rectal neuroendocrine
2083 | carcinoma refractory to standard therapy. Urinary BRAF(V600E)
2084 | circulating tumor DNA monitoring paralleled disease response. Our series
2085 | represents the largest study of genomic profiling in colorectal
2086 | neuroendocrine tumors and provides strong evidence that BRAF(V600E) is
2087 | an oncogenic driver responsive to BRAF-MEK combination therapy in this
2088 | molecular subset.BRAF(V600E) is an established oncogenic driver, but
2089 | significant disparities in response exist among tumor types. Two
2090 | patients with treatment-refractory high-grade colorectal neuroendocrine
2091 | tumors harboring BRAF(V600E) exhibited rapid and durable response to
2092 | combined BRAF-MEK inhibition, providing the first clinical evidence of
2093 | efficacy in this aggressive tumor type. Cancer Discov; 6(6); 594-600.
2094 | ©2016 AACR.This article is highlighted in the In This Issue feature, p.
2095 | 561.
2096 | Author String:
2097 | Samuel J Klempner, Bruce Gershenhorn, Phu Tran, Thomas K Lee, Mark G
2098 | Erlander, Kyle Gowen, Alexa B Schrock, Deborah Morosini, Jeffrey S Ross,
2099 | Vincent A Miller, Philip J Stephens, Sai-Hong Ignatius Ou, Siraj M Ali
2100 | Citation: Klempner et al., 2016
2101 | Citation Id: 27048246
2102 | Id: 969
2103 | Journal: Cancer Discov
2104 | Link: /sources/969
2105 | Name: PubMed: Klempner et al., 2016
2106 | Open Access: True
2107 | Pmc Id: PMC5008024
2108 | Publication Date: 2016-6
2109 | Retracted: False
2110 | Source Type: PUBMED
2111 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/27048246
2112 | Title:
2113 | BRAFV600E Mutations in High-Grade Colorectal Neuroendocrine Tumors May
2114 | Predict Responsiveness to BRAF-MEK Combination Therapy.
2115 |
2116 | ##### Therapies
2117 | Deprecated: False
2118 | Id: 22
2119 | Link: /therapies/22
2120 | Name: Dabrafenib
2121 |
2122 | ##### Therapies
2123 | Deprecated: False
2124 | Id: 19
2125 | Link: /therapies/19
2126 | Name: Trametinib
2127 |
2128 | ##### Therapies
2129 | Deprecated: False
2130 | Id: 4
2131 | Link: /therapies/4
2132 | Name: Vemurafenib
2133 |
2134 | #### Evidence Items
2135 | Description:
2136 | The BRIM-3 Phase III trial NCT01006980 assessed BRAF inhibitor
2137 | vemurafenib versus dacarbazine in 598 patients with treatment naive
2138 | metastatic melanoma and confirmed V600E mutation. Significant
2139 | differences were seen in overall survival (13.3 months with vemurafenib
2140 | vs. 10.0 months with dacarbazine) and median progression free survival
2141 | (6.9 months with vemurafenib vs. 1.6 months with dacarbazine)
2142 | Evidence Direction: SUPPORTS
2143 | Evidence Level: B
2144 | Evidence Rating: 5
2145 | Evidence Type: PREDICTIVE
2146 | Flagged: False
2147 | Id: 1398
2148 | Name: EID1398
2149 | Significance: SENSITIVITYRESPONSE
2150 | Variant Origin: SOMATIC
2151 |
2152 | ##### Disease
2153 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
2154 | Display Name: Melanoma
2155 | Doid: 1909
2156 | Id: 7
2157 | Link: /diseases/7
2158 | Name: Melanoma
2159 |
2160 | ##### My Disease Info
2161 | Do Def:
2162 | A cell type cancer that has_material_basis_in abnormally proliferating
2163 | cells derives_from melanocytes which are found in skin, the bowel and
2164 | the eye.
2165 | Icdo: 8720/3
2166 | Mesh: D008545
2167 | Mondo Id: MONDO:0005105
2168 | Ncit: C3224
2169 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
2170 |
2171 | ##### Molecular Profile
2172 | Id: 12
2173 |
2174 | ##### Source
2175 | Abstract:
2176 | In the BRIM-3 trial, vemurafenib was associated with risk reduction
2177 | versus dacarbazine of both death and progression in patients with
2178 | advanced BRAF(V600) mutation-positive melanoma. We present an extended
2179 | follow-up analysis of the total population and in the BRAF(V600E) and
2180 | BRAF(V600K) mutation subgroups.Patients older than 18 years, with
2181 | treatment-naive metastatic melanoma and whose tumour tissue was positive
2182 | for BRAF(V600) mutations were eligible. Patients also had to have a life
2183 | expectancy of at least 3 months, an Eastern Cooperative Oncology Group
2184 | (ECOG) performance status of 0 or 1, and adequate haematological,
2185 | hepatic, and renal function. Patients were randomly assigned by
2186 | interactive voice recognition system to receive either vemurafenib (960
2187 | mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area
2188 | intravenously every 3 weeks). Coprimary endpoints were overall survival
2189 | and progression-free survival, analysed in the intention-to-treat
2190 | population (n=675), with data censored at crossover. A sensitivity
2191 | analysis was done. This trial is registered with ClinicalTrials.gov,
2192 | NCT01006980.675 eligible patients were enrolled from 104 centres in 12
2193 | countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were
2194 | randomly assigned to receive vemurafenib and 338 to receive dacarbazine.
2195 | Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5
2196 | months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially
2197 | randomly assigned to dacarbazine crossed over from dacarbazine to
2198 | vemurafenib. Median overall survival was significantly longer in the
2199 | vemurafenib group than in the dacarbazine group (13·6 months [95% CI
2200 | 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI
2201 | 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9
2202 | months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI
2203 | 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E)
2204 | disease, median overall survival in the vemurafenib group was 13·3
2205 | months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the
2206 | dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median
2207 | progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months
2208 | (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the
2209 | 57 (9%) patients with BRAF(V600K) disease, median overall survival in
2210 | the vemurafenib group was 14·5 months (95% CI 11·2-not estimable)
2211 | compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43
2212 | [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9
2213 | months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30
2214 | [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were
2215 | cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and
2216 | keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function
2217 | tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of
2218 | 287 patients) in the dacarbazine group. Eight (2%) patients in the
2219 | vemurafenib group and seven (2%) in the dacarbazine group had grade 5
2220 | events.Inhibition of BRAF with vemurafenib improves survival in patients
2221 | with the most common BRAF(V600E) mutation and in patients with the less
2222 | common BRAF(V600K) mutation.F Hoffmann-La Roche-Genentech.
2223 | Author String:
2224 | Grant A McArthur, Paul B Chapman, Caroline Robert, James Larkin, John B
2225 | Haanen, Reinhard Dummer, Antoni Ribas, David Hogg, Omid Hamid, Paolo A
2226 | Ascierto, Claus Garbe, Alessandro Testori, Michele Maio, Paul Lorigan,
2227 | Celeste Lebbé, Thomas Jouary, Dirk Schadendorf, Stephen J O'Day, John M
2228 | Kirkwood, Alexander M Eggermont, Brigitte Dréno, Jeffrey A Sosman, Keith
2229 | T Flaherty, Ming Yin, Ivor Caro, Suzanne Cheng, Kerstin Trunzer, Axel
2230 | Hauschild
2231 | Citation: McArthur et al., 2014
2232 | Citation Id: 24508103
2233 | Id: 947
2234 | Journal: Lancet Oncol
2235 | Link: /sources/947
2236 | Name: PubMed: McArthur et al., 2014
2237 | Open Access: True
2238 | Pmc Id: PMC4382632
2239 | Publication Date: 2014-3
2240 | Retracted: False
2241 | Source Type: PUBMED
2242 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24508103
2243 | Title:
2244 | Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K)
2245 | mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3,
2246 | randomised, open-label study.
2247 |
2248 | ##### Therapies
2249 | Deprecated: False
2250 | Id: 4
2251 | Link: /therapies/4
2252 | Name: Vemurafenib
2253 |
2254 | #### Evidence Items
2255 | Description:
2256 | Phase 2 trial in 132 patients with previously treated metastatic
2257 | melanoma with BRAF V600E mutation.
2258 | Confirmed overall response rate was 53% (95% confidence interval [CI],
2259 | 44 to 62; 6% with a complete response and 47% with a partial response),
2260 | median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and
2261 | median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1).
2262 | Median overall survival was 15.9 months (95% CI, 11.6 to 18.3).
2263 | Evidence Direction: SUPPORTS
2264 | Evidence Level: B
2265 | Evidence Rating: 3
2266 | Evidence Type: PREDICTIVE
2267 | Flagged: False
2268 | Id: 1410
2269 | Name: EID1410
2270 | Significance: SENSITIVITYRESPONSE
2271 | Variant Origin: SOMATIC
2272 |
2273 | ##### Disease
2274 | Disease Url: https://www.disease-ontology.org/?id=DOID:8923
2275 | Display Name: Skin Melanoma
2276 | Doid: 8923
2277 | Id: 206
2278 | Link: /diseases/206
2279 | Name: Skin Melanoma
2280 |
2281 | ##### My Disease Info
2282 | Do Def: A skin cancer that has_material_basis_in melanocytes.
2283 | Icd10: C43.9
2284 | Mesh: C562393
2285 | Mondo Id: MONDO:0005012
2286 | Ncit: C3510
2287 | Disease Aliases:
2288 | - Cutaneous Melanoma
2289 | - Malignant Ear Melanoma
2290 | - Malignant Lip Melanoma
2291 | - Malignant Lower Limb Melanoma
2292 | - Malignant Melanoma Of Ear And/or External Auricular Canal
2293 | - Malignant Melanoma Of Skin Of Lower Limb
2294 | - Malignant Melanoma Of Skin Of Trunk Except Scrotum
2295 | - Malignant Melanoma Of Skin Of Upper Limb
2296 | - Malignant Neck Melanoma
2297 | - Malignant Scalp Melanoma
2298 | - Malignant Trunk Melanoma
2299 | - Malignant Upper Limb Melanoma
2300 |
2301 | ##### Molecular Profile
2302 | Id: 12
2303 |
2304 | ##### Source
2305 | Abstract:
2306 | Approximately 50% of melanomas harbor activating (V600) mutations in the
2307 | serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor
2308 | vemurafenib (PLX4032) frequently produced tumor regressions in patients
2309 | with BRAF V600-mutant metastatic melanoma in a phase 1 trial and
2310 | improved overall survival in a phase 3 trial.We designed a multicenter
2311 | phase 2 trial of vemurafenib in patients with previously treated BRAF
2312 | V600-mutant metastatic melanoma to investigate the efficacy of
2313 | vemurafenib with respect to overall response rate (percentage of treated
2314 | patients with a tumor response), duration of response, and overall
2315 | survival. The primary end point was the overall response rate as
2316 | ascertained by the independent review committee; overall survival was a
2317 | secondary end point.A total of 132 patients had a median follow-up of
2318 | 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate
2319 | was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete
2320 | response and 47% with a partial response), the median duration of
2321 | response was 6.7 months (95% CI, 5.6 to 8.6), and the median
2322 | progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary
2323 | progression was observed in only 14% of patients. Some patients had a
2324 | response after receiving vemurafenib for more than 6 months. The median
2325 | overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common
2326 | adverse events were grade 1 or 2 arthralgia, rash, photosensitivity,
2327 | fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority,
2328 | keratoacanthoma type) were diagnosed in 26% of patients.Vemurafenib
2329 | induces clinical responses in more than half of patients with previously
2330 | treated BRAF V600-mutant metastatic melanoma. In this study with a long
2331 | follow-up, the median overall survival was approximately 16 months.
2332 | (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.).
2333 | Author String:
2334 | Jeffrey A Sosman, Kevin B Kim, Lynn Schuchter, Rene Gonzalez, Anna C
2335 | Pavlick, Jeffrey S Weber, Grant A McArthur, Thomas E Hutson, Stergios J
2336 | Moschos, Keith T Flaherty, Peter Hersey, Richard Kefford, Donald
2337 | Lawrence, Igor Puzanov, Karl D Lewis, Ravi K Amaravadi, Bartosz
2338 | Chmielowski, H Jeffrey Lawrence, Yu Shyr, Fei Ye, Jiang Li, Keith B
2339 | Nolop, Richard J Lee, Andrew K Joe, Antoni Ribas
2340 | Citation: Sosman et al., 2012
2341 | Citation Id: 22356324
2342 | Id: 354
2343 | Journal: N Engl J Med
2344 | Link: /sources/354
2345 | Name: PubMed: Sosman et al., 2012
2346 | Open Access: True
2347 | Pmc Id: PMC3724515
2348 | Publication Date: 2012-2-23
2349 | Retracted: False
2350 | Source Type: PUBMED
2351 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22356324
2352 | Title: Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib.
2353 |
2354 | ##### Therapies
2355 | Deprecated: False
2356 | Id: 4
2357 | Link: /therapies/4
2358 | Name: Vemurafenib
2359 |
2360 | #### Evidence Items
2361 | Description:
2362 | Thyroid cancer cell lines with BRAF V600E mutations were more sensitive
2363 | to the MEK inhibitor RDEA119 than those with wildtype BRAF (IC50:
2364 | 0.034-0.217 uM vs. 1.413-34.120 uM).
2365 | Evidence Direction: SUPPORTS
2366 | Evidence Level: D
2367 | Evidence Type: PREDICTIVE
2368 | Flagged: False
2369 | Id: 2139
2370 | Name: EID2139
2371 | Significance: SENSITIVITYRESPONSE
2372 | Variant Origin: SOMATIC
2373 |
2374 | ##### Disease
2375 | Disease Url: https://www.disease-ontology.org/?id=DOID:1781
2376 | Display Name: Thyroid Cancer
2377 | Doid: 1781
2378 | Id: 16
2379 | Link: /diseases/16
2380 | Name: Thyroid Cancer
2381 |
2382 | ##### My Disease Info
2383 | Do Def:
2384 | An endocrine gland cancer located in the thyroid gland located in the
2385 | neck below the thyroid cartilage.
2386 | Icd10: C73
2387 | Mesh: D013964
2388 | Mondo Id: MONDO:0002108
2389 | Ncit: C3414, C7510
2390 | Disease Aliases:
2391 | - Malignant Neoplasm Of Thyroid Gland
2392 | - Malignant Tumour Of Thyroid Gland
2393 | - Neoplasm Of Thyroid Gland
2394 | - Thyroid Gland Cancer
2395 | - Thyroid Gland Neoplasm
2396 | - Thyroid Neoplasm
2397 |
2398 | ##### Molecular Profile
2399 | Id: 12
2400 |
2401 | ##### Source
2402 | Abstract:
2403 | We examined the therapeutic potential of a novel MEK inhibitor, RDEA119,
2404 | and its synergism with the mTOR inhibitor, temsirolimus, in thyroid
2405 | cancer cell lines. RDEA119 potently inhibited the proliferation of the 4
2406 | cell lines that harbored BRAF mutation but had no or modest effects on
2407 | the other 4 cells that harbored wild-type BRAF (IC(50) of 0.034-0.217 μM
2408 | vs. 1.413-34.120 μM). This inhibitory effect of RDEA119 in selected cell
2409 | lines OCUT1 (BRAF V600E(+), PIK3CA H1047R(+)) and SW1376 (BRAF V600E(+))
2410 | was enhanced by combination with the mTOR inhibitor, temsirolimus. The
2411 | PTEN-deficient cell FTC133 was highly sensitive to temsirolimus but
2412 | insensitive to RDEA119, and simultaneous treatment with the latter
2413 | enhanced the sensitivity of the cell to the former. The KAT18 (wild-
2414 | type) cell was not sensitive to either drug alone but became sensitive
2415 | to the combination of the 2 drugs. The drug synergy was confirmed by
2416 | combination index and isobologram analyses. RDEA119 and temsirolimus
2417 | also showed synergistic effects on autophagic death of OCUT1 and KAT18
2418 | cells selectively tested. Dramatic synergistic effects of the 2 drugs
2419 | were also seen on the growth of FTC133 xenograft tumors in nude mice.
2420 | Overall, the effects of the 2 drugs on cell proliferation or autophagic
2421 | death, either alone or in combination, were more pronounced in cells
2422 | that harbored genetic alterations in the MAP kinase and PI3K/Akt
2423 | pathways. Thus, these results demonstrated the important therapeutic
2424 | potential of the novel MEK inhibitor RDEA119 and its synergism with
2425 | temsirolimus in thyroid cancer.
2426 | Author String: Dingxie Liu, Joanna Xing, Barry Trink, Mingzhao Xing
2427 | Citation: Liu et al., 2010
2428 | Citation Id: 21351275
2429 | Id: 1496
2430 | Journal: Int J Cancer
2431 | Link: /sources/1496
2432 | Name: PubMed: Liu et al., 2010
2433 | Open Access: True
2434 | Pmc Id: PMC2916062
2435 | Publication Date: 2010-12-15
2436 | Retracted: False
2437 | Source Type: PUBMED
2438 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21351275
2439 | Title:
2440 | BRAF mutation-selective inhibition of thyroid cancer cells by the novel
2441 | MEK inhibitor RDEA119 and genetic-potentiated synergism with the mTOR
2442 | inhibitor temsirolimus.
2443 |
2444 | ##### Therapies
2445 | Deprecated: False
2446 | Id: 463
2447 | Link: /therapies/463
2448 | Name: RDEA 119
2449 |
2450 | #### Evidence Items
2451 | Description:
2452 | Two clinical trials evaluated the effects of vemurafenib in 54 patients
2453 | with BRAF (V600E) positive hairy-cell leukemia. The overall response
2454 | rate was 98% with 19/54 having a complete response and 34/54 having a
2455 | partial response. In the Italian study (n=25), the median relapse-free
2456 | survival was 9 months and in the U.S. study (n=24), rate of progression-
2457 | free survival was 73% with overall survival rate of 91%.
2458 | Evidence Direction: SUPPORTS
2459 | Evidence Level: B
2460 | Evidence Rating: 2
2461 | Evidence Type: PREDICTIVE
2462 | Flagged: False
2463 | Id: 1579
2464 | Name: EID1579
2465 | Significance: SENSITIVITYRESPONSE
2466 | Variant Origin: SOMATIC
2467 |
2468 | ##### Disease
2469 | Disease Url: https://www.disease-ontology.org/?id=DOID:285
2470 | Display Name: Hairy Cell Leukemia
2471 | Doid: 285
2472 | Id: 665
2473 | Link: /diseases/665
2474 | Name: Hairy Cell Leukemia
2475 |
2476 | ##### My Disease Info
2477 | Do Def:
2478 | A chronic lymphocytic leukemia that is characterized by over production
2479 | of B cells (lymphocytes) by the bone marrow where the B cells appear
2480 | hairy under a microscope.
2481 | Icd10: C91.4
2482 | Icdo: 9940/3
2483 | Mesh: D007943
2484 | Mondo Id: MONDO:0018935
2485 | Ncit: C7402
2486 |
2487 | ##### Molecular Profile
2488 | Id: 12
2489 |
2490 | ##### Source
2491 | Abstract:
2492 | BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We
2493 | assessed the safety and activity of the oral BRAF inhibitor vemurafenib
2494 | in patients with hairy-cell leukemia that had relapsed after treatment
2495 | with a purine analogue or who had disease that was refractory to purine
2496 | analogues.We conducted two phase 2, single-group, multicenter studies of
2497 | vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in
2498 | the United States. The therapy was administered for a median of 16 weeks
2499 | in the Italian study and 18 weeks in the U.S. study. Primary end points
2500 | were the complete response rate (in the Italian trial) and the overall
2501 | response rate (in the U.S. trial). Enrollment was completed (28
2502 | patients) in the Italian trial in April 2013 and is still open (26 of 36
2503 | planned patients) in the U.S. trial.The overall response rates were 96%
2504 | (25 of 26 patients who could be evaluated) after a median of 8 weeks in
2505 | the Italian study and 100% (24 of 24) after a median of 12 weeks in the
2506 | U.S. study. The rates of complete response were 35% (9 of 26 patients)
2507 | and 42% (10 of 24) in the two trials, respectively. In the Italian
2508 | trial, after a median follow-up of 23 months, the median relapse-free
2509 | survival was 19 months among patients with a complete response and 6
2510 | months among those with a partial response; the median treatment-free
2511 | survival was 25 months and 18 months, respectively. In the U.S. trial,
2512 | at 1 year, the progression-free survival rate was 73% and the overall
2513 | survival rate was 91%. Drug-related adverse events were usually of grade
2514 | 1 or 2, and the events most frequently leading to dose reductions were
2515 | rash and arthralgia or arthritis. Secondary cutaneous tumors (treated
2516 | with simple excision) developed in 7 of 50 patients. The frequent
2517 | persistence of phosphorylated ERK-positive leukemic cells in bone marrow
2518 | at the end of treatment suggests bypass reactivation of MEK and ERK as a
2519 | resistance mechanism.A short oral course of vemurafenib was highly
2520 | effective in patients with relapsed or refractory hairy-cell leukemia.
2521 | (Funded by the Associazione Italiana per la Ricerca sul Cancro and
2522 | others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number
2523 | NCT01711632.).
2524 | Author String:
2525 | Enrico Tiacci, Jae H Park, Luca De Carolis, Stephen S Chung, Alessandro
2526 | Broccoli, Sasinya Scott, Francesco Zaja, Sean Devlin, Alessandro
2527 | Pulsoni, Young R Chung, Michele Cimminiello, Eunhee Kim, Davide Rossi,
2528 | Richard M Stone, Giovanna Motta, Alan Saven, Marzia Varettoni, Jessica K
2529 | Altman, Antonella Anastasia, Michael R Grever, Achille Ambrosetti, Kanti
2530 | R Rai, Vincenzo Fraticelli, Mario E Lacouture, Angelo M Carella, Ross L
2531 | Levine, Pietro Leoni, Alessandro Rambaldi, Franca Falzetti, Stefano
2532 | Ascani, Monia Capponi, Maria P Martelli, Christopher Y Park, Stefano A
2533 | Pileri, Neal Rosen, Robin Foà, Michael F Berger, Pier L Zinzani, Omar
2534 | Abdel-Wahab, Brunangelo Falini, Martin S Tallman
2535 | Citation: Tiacci et al., 2015
2536 | Citation Id: 26352686
2537 | Id: 1043
2538 | Journal: N Engl J Med
2539 | Link: /sources/1043
2540 | Name: PubMed: Tiacci et al., 2015
2541 | Open Access: True
2542 | Pmc Id: PMC4811324
2543 | Publication Date: 2015-10-29
2544 | Retracted: False
2545 | Source Type: PUBMED
2546 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26352686
2547 | Title: Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.
2548 |
2549 | ##### Therapies
2550 | Deprecated: False
2551 | Id: 4
2552 | Link: /therapies/4
2553 | Name: Vemurafenib
2554 |
2555 | #### Evidence Items
2556 | Description:
2557 | A 65-year-old man presented with stage II myeloma. He was initially
2558 | treated with chemotherapy and he received an autologous stem cell
2559 | transplant. Sequencing of the recurrent tumor harbored BRAF V600E
2560 | mutation and he was treated with vemurafenib. After 7 weeks of
2561 | treatment, the patient relapsed and died.
2562 | Evidence Direction: SUPPORTS
2563 | Evidence Level: C
2564 | Evidence Rating: 3
2565 | Evidence Type: PREDICTIVE
2566 | Flagged: False
2567 | Id: 1698
2568 | Name: EID1698
2569 | Significance: SENSITIVITYRESPONSE
2570 | Variant Origin: SOMATIC
2571 |
2572 | ##### Disease
2573 | Disease Url: https://www.disease-ontology.org/?id=DOID:9538
2574 | Display Name: Multiple Myeloma
2575 | Doid: 9538
2576 | Id: 41
2577 | Link: /diseases/41
2578 | Name: Multiple Myeloma
2579 |
2580 | ##### My Disease Info
2581 | Do Def: A myeloid neoplasm that is located_in the plasma cells in bone marrow.
2582 | Icd10: C90.0
2583 | Mesh: D009101
2584 | Mondo Id: MONDO:0009693
2585 | Ncit: C3242
2586 | Disease Aliases: Myeloma
2587 |
2588 | ##### Molecular Profile
2589 | Id: 12
2590 |
2591 | ##### Source
2592 | Author String:
2593 | J P Sharman, J Chmielecki, D Morosini, G A Palmer, J S Ross, P J
2594 | Stephens, J Stafl, V A Miller, S M Ali
2595 | Citation: Sharman et al., 2014
2596 | Citation Id: 24997557
2597 | Id: 1147
2598 | Journal: Clin Lymphoma Myeloma Leuk
2599 | Link: /sources/1147
2600 | Name: PubMed: Sharman et al., 2014
2601 | Open Access: False
2602 | Publication Date: 2014-10
2603 | Retracted: False
2604 | Source Type: PUBMED
2605 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24997557
2606 | Title:
2607 | Vemurafenib response in 2 patients with posttransplant refractory BRAF
2608 | V600E-mutated multiple myeloma.
2609 |
2610 | ##### Therapies
2611 | Deprecated: False
2612 | Id: 4
2613 | Link: /therapies/4
2614 | Name: Vemurafenib
2615 |
2616 | #### Evidence Items
2617 | Description:
2618 | Phase 1b study of vemurafenib, cetuximab and irinotecan in 19 patients
2619 | with colorectal cancer (1 with appendiceal cancer). Six of 17 evaluable
2620 | patients achieved an objective response, 15 patients total had either
2621 | stable disease or radiographic response (the patient with appendiceal
2622 | cancer had disease progression). Estimated median PFS was 7.7 months.
2623 | Effect of the combined treatment was also observed in xenograft and cell
2624 | line studies.
2625 | Evidence Direction: SUPPORTS
2626 | Evidence Level: B
2627 | Evidence Rating: 4
2628 | Evidence Type: PREDICTIVE
2629 | Flagged: False
2630 | Id: 1902
2631 | Name: EID1902
2632 | Significance: SENSITIVITYRESPONSE
2633 | Variant Origin: SOMATIC
2634 |
2635 | ##### Disease
2636 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
2637 | Display Name: Colorectal Cancer
2638 | Doid: 9256
2639 | Id: 11
2640 | Link: /diseases/11
2641 | Name: Colorectal Cancer
2642 |
2643 | ##### My Disease Info
2644 | Do Def:
2645 | An intestinal cancer that effects the long, tube-like organ that is
2646 | connected to the small intestine at one end and the anus at the other.
2647 | Icd10: C18.9
2648 | Mondo Id: MONDO:0005575
2649 | Ncit: C4978
2650 |
2651 | ##### Molecular Profile
2652 | Id: 12
2653 |
2654 | ##### Source
2655 | Abstract:
2656 | In vitro, EGFR inhibition, combined with the BRAF inhibitor vemurafenib,
2657 | causes synergistic cytotoxicity for BRAFV600E metastatic colorectal
2658 | cancer, further augmented by irinotecan. The safety and efficacy of
2659 | vemurafenib, irinotecan, and cetuximab in BRAF-mutated malignancies are
2660 | not defined. In this 3+3 phase I study, patients with BRAFV600E-advanced
2661 | solid cancers received cetuximab and irinotecan with escalating doses of
2662 | vemurafenib. Nineteen patients (18 with metastatic colorectal cancer and
2663 | 1 with appendiceal cancer) were enrolled. Three patients experienced
2664 | dose-limiting toxicities. The MTD of vemurafenib was 960 mg twice daily.
2665 | Six of 17 evaluable patients (35%) achieved a radiographic response by
2666 | Response Evaluation Criteria in Solid Tumors 1.1 criteria, consistent
2667 | with in vivo models demonstrating tumor regressions with the triplet
2668 | regimen. Median progression-free survival was 7.7 months. BRAFV600E
2669 | circulating cell-free DNA (cfDNA) trends correlated with radiographic
2670 | changes, and acquired mutations from cfDNA in genes reactivating MAPK
2671 | signaling were observed at progression.Vemurafenib, in combination with
2672 | irinotecan and cetuximab, was well tolerated in patients with
2673 | refractory, BRAF-mutated metastatic colorectal cancer, and both survival
2674 | outcomes and response rates exceeded prior reports for vemurafenib and
2675 | for irinotecan plus cetuximab in BRAFV600E metastatic colorectal cancer.
2676 | In vivo models demonstrated regressions with the triplet, in contrast
2677 | with vemurafenib and cetuximab alone. cfDNA predicted radiographic
2678 | response and identified mutations reactivating the MAPK pathway upon
2679 | progression. Cancer Discov; 6(12); 1352-65. ©2016 AACR.This article is
2680 | highlighted in the In This Issue feature, p. 1293.
2681 | Author String:
2682 | David S Hong, Van K Morris, Badi El Osta, Alexey V Sorokin, Filip Janku,
2683 | Siqing Fu, Michael J Overman, Sarina Piha-Paul, Vivek Subbiah, Bryan
2684 | Kee, Apostolia M Tsimberidou, David Fogelman, Jorge Bellido, Imad
2685 | Shureiqi, Helen Huang, Johnique Atkins, Gabi Tarcic, Nicolas Sommer,
2686 | Richard Lanman, Funda Meric-Bernstam, Scott Kopetz
2687 | Citation: Hong et al., 2016
2688 | Citation Id: 27729313
2689 | Id: 1336
2690 | Journal: Cancer Discov
2691 | Link: /sources/1336
2692 | Name: PubMed: Hong et al., 2016
2693 | Open Access: True
2694 | Pmc Id: PMC5562357
2695 | Publication Date: 2016-12
2696 | Retracted: False
2697 | Source Type: PUBMED
2698 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/27729313
2699 | Title:
2700 | Phase IB Study of Vemurafenib in Combination with Irinotecan and
2701 | Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E
2702 | Mutation.
2703 |
2704 | ##### Therapies
2705 | Deprecated: False
2706 | Id: 4
2707 | Link: /therapies/4
2708 | Name: Vemurafenib
2709 |
2710 | ##### Therapies
2711 | Deprecated: False
2712 | Id: 16
2713 | Link: /therapies/16
2714 | Name: Cetuximab
2715 |
2716 | ##### Therapies
2717 | Deprecated: False
2718 | Id: 101
2719 | Link: /therapies/101
2720 | Name: Irinotecan
2721 |
2722 | #### Evidence Items
2723 | Description:
2724 | Cetuximab or panitumumab may be ineffective in patients with BRAF
2725 | mutation unless BRAF inhibitor such as Sorafenib is introduced.
2726 | Evidence Direction: SUPPORTS
2727 | Evidence Level: D
2728 | Evidence Rating: 3
2729 | Evidence Type: PREDICTIVE
2730 | Flagged: False
2731 | Id: 2894
2732 | Name: EID2894
2733 | Significance: SENSITIVITYRESPONSE
2734 | Variant Origin: SOMATIC
2735 |
2736 | ##### Disease
2737 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
2738 | Display Name: Colorectal Cancer
2739 | Doid: 9256
2740 | Id: 11
2741 | Link: /diseases/11
2742 | Name: Colorectal Cancer
2743 |
2744 | ##### My Disease Info
2745 | Do Def:
2746 | An intestinal cancer that effects the long, tube-like organ that is
2747 | connected to the small intestine at one end and the anus at the other.
2748 | Icd10: C18.9
2749 | Mondo Id: MONDO:0005575
2750 | Ncit: C4978
2751 |
2752 | ##### Molecular Profile
2753 | Id: 12
2754 |
2755 | ##### Source
2756 | Abstract:
2757 | PURPOSE Cetuximab or panitumumab are effective in 10% to 20% unselected
2758 | metastatic colorectal cancer (CRC) patients. KRAS mutations account for
2759 | approximately 30% to 40% patients who are not responsive. The serine-
2760 | threonine kinase BRAF is the principal effector of KRAS. We hypothesized
2761 | that, in KRAS wild-type patients, BRAF mutations could have a
2762 | predictive/prognostic value. PATIENTS AND METHODS We retrospectively
2763 | analyzed objective tumor responses, time to progression, overall
2764 | survival (OS), and the mutational status of KRAS and BRAF in 113 tumors
2765 | from cetuximab- or panitumumab-treated metastatic CRC patients. The
2766 | effect of the BRAF V600E mutation on cetuximab or panitumumab response
2767 | was also assessed using cellular models of CRC. Results KRAS mutations
2768 | were present in 30% of the patients and were associated with resistance
2769 | to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was
2770 | detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-
2771 | mutated patients responded to treatment, whereas none of the responders
2772 | carried BRAF mutations (P = .029). BRAF-mutated patients had
2773 | significantly shorter progression-free survival (P = .011) and OS (P <
2774 | .0001) than wild-type patients. In CRC cells, the introduction of BRAF
2775 | V600E allele impaired the therapeutic effect of cetuximab or
2776 | panitumumab. Treatment with the BRAF inhibitor sorafenib restored
2777 | sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E
2778 | allele. CONCLUSION BRAF wild-type is required for response to
2779 | panitumumab or cetuximab and could be used to select patients who are
2780 | eligible for the treatment. Double-hit therapies aimed at simultaneous
2781 | inhibition of epidermal growth factor receptor and BRAF warrant
2782 | exploration in CRC patients carrying the V600E oncogenic mutation.
2783 | Author String:
2784 | Federica Di Nicolantonio, Miriam Martini, Francesca Molinari, Andrea
2785 | Sartore-Bianchi, Sabrina Arena, Piercarlo Saletti, Sara De Dosso, Luca
2786 | Mazzucchelli, Milo Frattini, Salvatore Siena, Alberto Bardelli
2787 | Citation: Di Nicolantonio et al., 2008
2788 | Citation Id: 19001320
2789 | Id: 100
2790 | Journal: J Clin Oncol
2791 | Link: /sources/100
2792 | Name: PubMed: Di Nicolantonio et al., 2008
2793 | Open Access: False
2794 | Publication Date: 2008-12-10
2795 | Retracted: False
2796 | Source Type: PUBMED
2797 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19001320
2798 | Title:
2799 | Wild-type BRAF is required for response to panitumumab or cetuximab in
2800 | metastatic colorectal cancer.
2801 |
2802 | ##### Therapies
2803 | Deprecated: False
2804 | Id: 6
2805 | Link: /therapies/6
2806 | Name: Sorafenib
2807 |
2808 | ##### Therapies
2809 | Deprecated: False
2810 | Id: 16
2811 | Link: /therapies/16
2812 | Name: Cetuximab
2813 |
2814 | #### Evidence Items
2815 | Description:
2816 | In a clinical study of 122 cancer patients, including 37 previously
2817 | treated colorectal cancer patients harboring BRAF V600 (V600E=32; V600
2818 | unknown=5) mutations, stable disease and progressive disease were
2819 | reported in 50% of patients (n=5/10) treated with vemurafenib
2820 | monotherapy, respectively.
2821 | Evidence Direction: SUPPORTS
2822 | Evidence Level: C
2823 | Evidence Type: PREDICTIVE
2824 | Flagged: False
2825 | Id: 3742
2826 | Name: EID3742
2827 | Significance: SENSITIVITYRESPONSE
2828 | Variant Origin: SOMATIC
2829 |
2830 | ##### Disease
2831 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
2832 | Display Name: Colorectal Cancer
2833 | Doid: 9256
2834 | Id: 11
2835 | Link: /diseases/11
2836 | Name: Colorectal Cancer
2837 |
2838 | ##### My Disease Info
2839 | Do Def:
2840 | An intestinal cancer that effects the long, tube-like organ that is
2841 | connected to the small intestine at one end and the anus at the other.
2842 | Icd10: C18.9
2843 | Mondo Id: MONDO:0005575
2844 | Ncit: C4978
2845 |
2846 | ##### Molecular Profile
2847 | Id: 12
2848 |
2849 | ##### Source
2850 | Abstract:
2851 | BRAF V600 mutations occur in various nonmelanoma cancers. We undertook a
2852 | histology-independent phase 2 "basket" study of vemurafenib in BRAF V600
2853 | mutation-positive nonmelanoma cancers.We enrolled patients in six
2854 | prespecified cancer cohorts; patients with all other tumor types were
2855 | enrolled in a seventh cohort. A total of 122 patients with BRAF V600
2856 | mutation-positive cancer were treated, including 27 patients with
2857 | colorectal cancer who received vemurafenib and cetuximab. The primary
2858 | end point was the response rate; secondary end points included
2859 | progression-free and overall survival.In the cohort with non-small-cell
2860 | lung cancer, the response rate was 42% (95% confidence interval [CI], 20
2861 | to 67) and median progression-free survival was 7.3 months (95% CI, 3.5
2862 | to 10.8). In the cohort with Erdheim-Chester disease or Langerhans'-cell
2863 | histiocytosis, the response rate was 43% (95% CI, 18 to 71); the median
2864 | treatment duration was 5.9 months (range, 0.6 to 18.6), and no patients
2865 | had disease progression during therapy. There were anecdotal responses
2866 | among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid
2867 | cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and
2868 | clear-cell sarcoma and among patients with colorectal cancer who
2869 | received vemurafenib and cetuximab. Safety was similar to that in prior
2870 | studies of vemurafenib for melanoma.BRAF V600 appears to be a targetable
2871 | oncogene in some, but not all, nonmelanoma cancers. Preliminary
2872 | vemurafenib activity was observed in non-small-cell lung cancer and in
2873 | Erdheim-Chester disease and Langerhans'-cell histiocytosis. The
2874 | histologic context is an important determinant of response in BRAF
2875 | V600-mutated cancers. (Funded by F. Hoffmann-La Roche/Genentech;
2876 | ClinicalTrials.gov number, NCT01524978.).
2877 | Author String:
2878 | David M Hyman, Igor Puzanov, Vivek Subbiah, Jason E Faris, Ian Chau,
2879 | Jean-Yves Blay, Jürgen Wolf, Noopur S Raje, Eli L Diamond, Antoine
2880 | Hollebecque, Radj Gervais, Maria Elena Elez-Fernandez, Antoine Italiano,
2881 | Ralf-Dieter Hofheinz, Manuel Hidalgo, Emily Chan, Martin Schuler, Susan
2882 | Frances Lasserre, Martina Makrutzki, Florin Sirzen, Maria Luisa
2883 | Veronese, Josep Tabernero, José Baselga
2884 | Citation: Hyman et al., 2015
2885 | Citation Id: 26287849
2886 | Id: 1040
2887 | Journal: N Engl J Med
2888 | Link: /sources/1040
2889 | Name: PubMed: Hyman et al., 2015
2890 | Open Access: True
2891 | Pmc Id: PMC4971773
2892 | Publication Date: 2015-8-20
2893 | Retracted: True
2894 | Retraction Date: 2018-10-18T00:00:00Z
2895 | Retraction Nature: Correction
2896 | Retraction Reasons: +Conflict of Interest;
2897 | Source Type: PUBMED
2898 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26287849
2899 | Title: Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.
2900 |
2901 | ##### Therapies
2902 | Deprecated: False
2903 | Id: 4
2904 | Link: /therapies/4
2905 | Name: Vemurafenib
2906 |
2907 | #### Evidence Items
2908 | Description:
2909 | In a retrospective study of 53, KRAS exon 2 wild-type, metastatic
2910 | colorectal cancer patients, patients harboring BRAF G466A (n=1), G469A
2911 | (n=2), D594G (n=1), or V600E (n=2) mutations were reported to be non-
2912 | responders to cetuximab in combination with irinotecan, (BRAF mutation
2913 | positive: responders vs. non-responders = 0 vs. 6; BRAF wild-type:
2914 | responders vs. non-responders 30 vs. 17; P=0.004), as compared to
2915 | patients with wild-type BRAF.
2916 | Evidence Direction: SUPPORTS
2917 | Evidence Level: C
2918 | Evidence Type: PREDICTIVE
2919 | Flagged: False
2920 | Id: 3740
2921 | Name: EID3740
2922 | Significance: RESISTANCE
2923 | Variant Origin: SOMATIC
2924 |
2925 | ##### Disease
2926 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
2927 | Display Name: Colorectal Cancer
2928 | Doid: 9256
2929 | Id: 11
2930 | Link: /diseases/11
2931 | Name: Colorectal Cancer
2932 |
2933 | ##### My Disease Info
2934 | Do Def:
2935 | An intestinal cancer that effects the long, tube-like organ that is
2936 | connected to the small intestine at one end and the anus at the other.
2937 | Icd10: C18.9
2938 | Mondo Id: MONDO:0005575
2939 | Ncit: C4978
2940 |
2941 | ##### Molecular Profile
2942 | Id: 12
2943 |
2944 | ##### Source
2945 | Abstract:
2946 | Approximately 45% of metastatic colorectal cancer (mCRC) patients with
2947 | wild-type KRAS exon 2 are resistant to cetuximab treatment. We set out
2948 | to identify additional genetic markers that might predict the response
2949 | to cetuximab treatment. Fifty-three wild-type KRAS exon 2 mCRC patients
2950 | were treated with cetuximab/irinotecan-based chemotherapy as a first- or
2951 | third-line therapy. The mutational statuses of 10 EGFR pathway genes
2952 | were analyzed in primary tumors using next-generation sequencing. BRAF,
2953 | PIK3CA, KRAS (exons 3 and 4), NRAS, PTEN, and AKT1 mutations were
2954 | detected in 6, 6, 5, 4, 1, and 1 patient, respectively. Four of the BRAF
2955 | mutations were non-V600 variants. Four tumors harbored multiple co-
2956 | existing (complex) mutations. All patients with BRAF mutations or
2957 | complex mutation patterns were cetuximab non-responders. All patients
2958 | but one harboring KRAS, NRAS, or BRAF mutations were non-responders.
2959 | Mutations in any one of these three genes were associated with a poor
2960 | response rate (7.1%) and reduced survival (PFS = 8.0 months) compared to
2961 | wild-type patients (74.4% and 11.6 months). Our data suggest that KRAS,
2962 | NRAS, and BRAF mutations predict response to cetuximab treatment in mCRC
2963 | patients.
2964 | Author String:
2965 | Hung-Chih Hsu, Tan Kien Thiam, Yen-Jung Lu, Chien Yuh Yeh, Wen-Sy Tsai,
2966 | Jeng Fu You, Hsin Yuan Hung, Chi-Neu Tsai, An Hsu, Hua-Chien Chen, Shu-
2967 | Jen Chen, Tsai-Sheng Yang
2968 | Citation: Hsu et al., 2016
2969 | Citation Id: 26989027
2970 | Id: 1946
2971 | Journal: Oncotarget
2972 | Link: /sources/1946
2973 | Name: PubMed: Hsu et al., 2016
2974 | Open Access: True
2975 | Pmc Id: PMC5008360
2976 | Publication Date: 2016-4-19
2977 | Retracted: False
2978 | Source Type: PUBMED
2979 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26989027
2980 | Title:
2981 | Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic
2982 | colorectal cancer patients.
2983 |
2984 | ##### Therapies
2985 | Deprecated: False
2986 | Id: 16
2987 | Link: /therapies/16
2988 | Name: Cetuximab
2989 |
2990 | #### Evidence Items
2991 | Description:
2992 | Acquired resistance to vemurafenib in BRAF V600E-positive melanomas
2993 | frequently confound vemurafenib therapy. Proposed resistance mechanisms
2994 | include PDGFRB upregulation or NRAS mutations resulting in MAPK pathway
2995 | reactivation but not secondary mutations in BRAF. MEK inhibitors may
2996 | demonstrate clinical benefit in vemurafenib resistant melanoma patients.
2997 | Evidence Direction: SUPPORTS
2998 | Evidence Level: D
2999 | Evidence Type: PREDICTIVE
3000 | Flagged: False
3001 | Id: 3745
3002 | Name: EID3745
3003 | Significance: SENSITIVITYRESPONSE
3004 | Variant Origin: SOMATIC
3005 |
3006 | ##### Disease
3007 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
3008 | Display Name: Melanoma
3009 | Doid: 1909
3010 | Id: 7
3011 | Link: /diseases/7
3012 | Name: Melanoma
3013 |
3014 | ##### My Disease Info
3015 | Do Def:
3016 | A cell type cancer that has_material_basis_in abnormally proliferating
3017 | cells derives_from melanocytes which are found in skin, the bowel and
3018 | the eye.
3019 | Icdo: 8720/3
3020 | Mesh: D008545
3021 | Mondo Id: MONDO:0005105
3022 | Ncit: C3224
3023 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
3024 |
3025 | ##### Molecular Profile
3026 | Id: 12
3027 |
3028 | ##### Source
3029 | Abstract:
3030 | Oncogenic mutations in the serine/threonine kinase B-RAF (also known as
3031 | BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies
3032 | have demonstrated that the B-RAF(V600E) mutation predicts a dependency
3033 | on the mitogen-activated protein kinase (MAPK) signalling cascade in
3034 | melanoma-an observation that has been validated by the success of RAF
3035 | and MEK inhibitors in clinical trials. However, clinical responses to
3036 | targeted anticancer therapeutics are frequently confounded by de novo or
3037 | acquired resistance. Identification of resistance mechanisms in a manner
3038 | that elucidates alternative 'druggable' targets may inform effective
3039 | long-term treatment strategies. Here we expressed ∼600 kinase and
3040 | kinase-related open reading frames (ORFs) in parallel to interrogate
3041 | resistance to a selective RAF kinase inhibitor. We identified MAP3K8
3042 | (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives
3043 | resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates
3044 | ERK primarily through MEK-dependent mechanisms that do not require RAF
3045 | signalling. Moreover, COT expression is associated with de novo
3046 | resistance in B-RAF(V600E) cultured cell lines and acquired resistance
3047 | in melanoma cells and tissue obtained from relapsing patients following
3048 | treatment with MEK or RAF inhibitors. We further identify combinatorial
3049 | MAPK pathway inhibition or targeting of COT kinase activity as possible
3050 | therapeutic strategies for reducing MAPK pathway activation in this
3051 | setting. Together, these results provide new insights into resistance
3052 | mechanisms involving the MAPK pathway and articulate an integrative
3053 | approach through which high-throughput functional screens may inform the
3054 | development of novel therapeutic strategies.
3055 | Author String:
3056 | Cory M Johannessen, Jesse S Boehm, So Young Kim, Sapana R Thomas, Leslie
3057 | Wardwell, Laura A Johnson, Caroline M Emery, Nicolas Stransky,
3058 | Alexandria P Cogdill, Jordi Barretina, Giordano Caponigro, Haley
3059 | Hieronymus, Ryan R Murray, Kourosh Salehi-Ashtiani, David E Hill, Marc
3060 | Vidal, Jean J Zhao, Xiaoping Yang, Ozan Alkan, Sungjoon Kim, Jennifer L
3061 | Harris, Christopher J Wilson, Vic E Myer, Peter M Finan, David E Root,
3062 | Thomas M Roberts, Todd Golub, Keith T Flaherty, Reinhard Dummer, Barbara
3063 | L Weber, William R Sellers, Robert Schlegel, Jennifer A Wargo, William C
3064 | Hahn, Levi A Garraway
3065 | Citation: Johannessen et al., 2010
3066 | Citation Id: 21107320
3067 | Id: 1492
3068 | Journal: Nature
3069 | Link: /sources/1492
3070 | Name: PubMed: Johannessen et al., 2010
3071 | Open Access: True
3072 | Pmc Id: PMC3058384
3073 | Publication Date: 2010-12-16
3074 | Retracted: False
3075 | Source Type: PUBMED
3076 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21107320
3077 | Title:
3078 | COT drives resistance to RAF inhibition through MAP kinase pathway
3079 | reactivation.
3080 |
3081 | ##### Therapies
3082 | Deprecated: False
3083 | Id: 4
3084 | Link: /therapies/4
3085 | Name: Vemurafenib
3086 |
3087 | #### Evidence Items
3088 | Description:
3089 | In an in vitro study, cell lines (including YUHUY and YUSAC2) expressing
3090 | BRAF V600E were associated with increased sensitivity to vemurafenib
3091 | (PLX4032) treatment, as compared to cell lines expressing wild-type
3092 | BRAF. Sensitive was determined by assessing cellular proliferation, and
3093 | ERK and MEK phosphorylation.
3094 | Evidence Direction: SUPPORTS
3095 | Evidence Level: D
3096 | Evidence Type: PREDICTIVE
3097 | Flagged: False
3098 | Id: 3747
3099 | Name: EID3747
3100 | Significance: SENSITIVITYRESPONSE
3101 | Variant Origin: SOMATIC
3102 |
3103 | ##### Disease
3104 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
3105 | Display Name: Melanoma
3106 | Doid: 1909
3107 | Id: 7
3108 | Link: /diseases/7
3109 | Name: Melanoma
3110 |
3111 | ##### My Disease Info
3112 | Do Def:
3113 | A cell type cancer that has_material_basis_in abnormally proliferating
3114 | cells derives_from melanocytes which are found in skin, the bowel and
3115 | the eye.
3116 | Icdo: 8720/3
3117 | Mesh: D008545
3118 | Mondo Id: MONDO:0005105
3119 | Ncit: C3224
3120 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
3121 |
3122 | ##### Molecular Profile
3123 | Id: 12
3124 |
3125 | ##### Source
3126 | Abstract:
3127 | BRAF(V600E/K) is a frequent mutationally active tumor-specific kinase in
3128 | melanomas that is currently targeted for therapy by the specific
3129 | inhibitor PLX4032. Our studies with melanoma tumor cells that are
3130 | BRAF(V600E/K) and BRAF(WT) showed that, paradoxically, while PLX4032
3131 | inhibited ERK1/2 in the highly sensitive BRAF(V600E/K), it activated the
3132 | pathway in the resistant BRAF(WT) cells, via RAF1 activation, regardless
3133 | of the status of mutations in NRAS or PTEN. The persistently active
3134 | ERK1/2 triggered downstream effectors in BRAF(WT) melanoma cells and
3135 | induced changes in the expression of a wide-spectrum of genes associated
3136 | with cell cycle control. Furthermore, PLX4032 increased the rate of
3137 | proliferation of growth factor-dependent NRAS Q61L mutant primary
3138 | melanoma cells, reduced cell adherence and increased mobility of cells
3139 | from advanced lesions. The results suggest that the drug can confer an
3140 | advantage to BRAF(WT) primary and metastatic tumor cells in vivo and
3141 | provide markers for monitoring clinical responses.
3142 | Author String:
3143 | Ruth Halaban, Wengeng Zhang, Antonella Bacchiocchi, Elaine Cheng, Fabio
3144 | Parisi, Stephan Ariyan, Michael Krauthammer, James P McCusker, Yuval
3145 | Kluger, Mario Sznol
3146 | Citation: Halaban et al., 2010
3147 | Citation Id: 20149136
3148 | Id: 1482
3149 | Journal: Pigment Cell Melanoma Res
3150 | Link: /sources/1482
3151 | Name: PubMed: Halaban et al., 2010
3152 | Open Access: True
3153 | Pmc Id: PMC2848976
3154 | Publication Date: 2010-4
3155 | Retracted: False
3156 | Source Type: PUBMED
3157 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/20149136
3158 | Title:
3159 | PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK
3160 | pathway and enhances cell migration and proliferation of BRAF melanoma
3161 | cells.
3162 |
3163 | ##### Therapies
3164 | Deprecated: False
3165 | Id: 4
3166 | Link: /therapies/4
3167 | Name: Vemurafenib
3168 |
3169 | #### Evidence Items
3170 | Description:
3171 | In NCI-MATCH trial, patients with advanced solid tumors, lymphoma or
3172 | multiple myeloma harboring BRAF V600E mutation were treated with
3173 | dabrafenib and trametinib.
3174 | Patients with melanoma, thyroid carcinoma, colorectal cancer or NSCLC
3175 | were excluded.
3176 | The response rate was 100% (4/4) in patients cholangiocarcinoma and 83%
3177 | (5/6) in patients with low-grade papillary serous adenocarcinoma of the
3178 | ovary or mucinous-papillary serous adenocarcinoma of the peritoneum.
3179 | Evidence Direction: SUPPORTS
3180 | Evidence Level: B
3181 | Evidence Rating: 3
3182 | Evidence Type: PREDICTIVE
3183 | Flagged: False
3184 | Id: 7454
3185 | Name: EID7454
3186 | Significance: SENSITIVITYRESPONSE
3187 | Variant Origin: SOMATIC
3188 |
3189 | ##### Disease
3190 | Disease Url: https://www.disease-ontology.org/?id=DOID:2394
3191 | Display Name: Ovarian Cancer
3192 | Doid: 2394
3193 | Id: 20
3194 | Link: /diseases/20
3195 | Name: Ovarian Cancer
3196 |
3197 | ##### My Disease Info
3198 | Do Def: A female reproductive organ cancer that is located_in the ovary.
3199 | Icd10: C56
3200 | Mesh: D010051
3201 | Mondo Id: MONDO:0008170
3202 | Ncit: C4984, C7431
3203 | Disease Aliases:
3204 | - Malignant Ovarian Tumor
3205 | - Malignant Tumour Of Ovary
3206 | - Ovarian Neoplasm
3207 | - Ovary Neoplasm
3208 | - Primary Ovarian Cancer
3209 | - Tumor Of The Ovary
3210 |
3211 | ##### Molecular Profile
3212 | Id: 12
3213 |
3214 | ##### Source
3215 | Abstract:
3216 | Background: The NCI-MATCH precision medicine trial assigns patients
3217 | (pts) with solid tumors, lymphomas, or multiple myeloma with progression
3218 | on prior treatment to a targeted therapy based on genetic alterations
3219 | identified in pre-treatment biopsies. Arm H (EAY131-H) evaluated the
3220 | combination of the BRAF inhibitor (inh) dabrafenib (DAB), and the MEK
3221 | inh, trametinib (TRM), in pts with BRAF V600E/K mutations. Methods: Pts
3222 | with melanoma, thyroid, or colorectal cancer were excluded. Pts with
3223 | NSCLC were excluded after the U.S. Food and Drug Administration (FDA)
3224 | approved DAB/TRM for this indication. Pts received DAB 150 mg po BID and
3225 | TRM 2 mg PO daily on 28 day cycles until disease progression or
3226 | intolerable toxicity; restaging was performed every 2 cycles. The
3227 | primary endpoint was objective response rate (ORR); secondary endpoints
3228 | included progression-free survival (PFS), 6-month PFS, and overall
3229 | survival (OS). Results: A total of 35 pts were enrolled from
3230 | 1/2016-2/2018; 2 were ineligible (CrCl below criteria; labs out of
3231 | window). Over 17 distinct tumor histologies were represented. 58% of pts
3232 | were female, median age was 63 (range 21-85), 94% were Caucasian, and
3233 | 48% of pts had received at least 3 prior therapies (range 1- 8). The
3234 | confirmed ORR was 33.3% (90% CI 19.9%, 49.1%), with a median duration of
3235 | response (DoR) of 12 months (mon). Varied histologies had a DoR of > 12
3236 | mon: histiocytic sarcoma, cholangiocarcinoma and mixed
3237 | adenoneuroendocrine carcinoma of unknown primary, among others. Median
3238 | PFS was 9.4 mon; the 6 mon PFS rate was 70.6% (90% CI 58.2%-85.5%), and
3239 | an additional 10 pts had a PFS > 5.5 mon. Median OS has not been
3240 | reached. At the time of data cutoff (12/2018) 11 pts continue on
3241 | treatment. Adverse events (AE) were comparable to previously reported
3242 | profiles of DAB/TRM; no new AEs were identified. The most frequent grade
3243 | 3 AEs were fatigue, neutropenia, hyponatremia, hypophosphatemia, and
3244 | urinary tract infection; there was 1 grade 4 sepsis; no grade 5 AEs.
3245 | Conclusions: In this pre-treated, mixed histology cohort, DAB and TRM
3246 | showed promising activity outside of currently approved FDA indications
3247 | warranting further investigations. Correlative analyses are planned.
3248 | Clinical trial information: NCT02465060
3249 | Author String: April K.S. Salama
3250 | Citation: April K.S. Salama, 2019, ASCO Annual Meeting, Abstract 3002
3251 | Citation Id: 172039
3252 | Id: 2954
3253 | Journal: J Clin Oncol 37, 2019 (suppl; abstr 3002)
3254 | Link: /sources/2954
3255 | Name: ASCO: April K.S. Salama, 2019, ASCO Annual Meeting, Abstract 3002
3256 | Open Access: False
3257 | Publication Date: 2019-6
3258 | Retracted: False
3259 | Source Type: ASCO
3260 | Source Url: https://meetinglibrary.asco.org/record/172039/abstract
3261 | Title:
3262 | Dabrafenib and trametinib in patients with tumors with BRAF V600E/K
3263 | mutations: Results from the molecular analysis for therapy choice
3264 | (MATCH) Arm H.
3265 |
3266 | ##### Therapies
3267 | Deprecated: False
3268 | Id: 22
3269 | Link: /therapies/22
3270 | Name: Dabrafenib
3271 |
3272 | ##### Therapies
3273 | Deprecated: False
3274 | Id: 19
3275 | Link: /therapies/19
3276 | Name: Trametinib
3277 |
3278 | #### Evidence Items
3279 | Description:
3280 | An inducible BRAF-V600E mouse melanoma model shows a tight correlation
3281 | between activated BRAF and disease progression.
3282 | Evidence Direction: SUPPORTS
3283 | Evidence Level: D
3284 | Evidence Type: PREDICTIVE
3285 | Flagged: False
3286 | Id: 3748
3287 | Name: EID3748
3288 | Significance: SENSITIVITYRESPONSE
3289 | Variant Origin: SOMATIC
3290 |
3291 | ##### Disease
3292 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
3293 | Display Name: Melanoma
3294 | Doid: 1909
3295 | Id: 7
3296 | Link: /diseases/7
3297 | Name: Melanoma
3298 |
3299 | ##### My Disease Info
3300 | Do Def:
3301 | A cell type cancer that has_material_basis_in abnormally proliferating
3302 | cells derives_from melanocytes which are found in skin, the bowel and
3303 | the eye.
3304 | Icdo: 8720/3
3305 | Mesh: D008545
3306 | Mondo Id: MONDO:0005105
3307 | Ncit: C3224
3308 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
3309 |
3310 | ##### Molecular Profile
3311 | Id: 12
3312 |
3313 | ##### Source
3314 | Abstract:
3315 | The usual paradigm for developing kinase inhibitors in oncology is to
3316 | use a high-affinity proof-of-concept inhibitor with acceptable metabolic
3317 | properties for key target validation experiments. This approach requires
3318 | substantial medicinal chemistry and can be confounded by drug toxicity
3319 | and off-target activities of the test molecule. As a better alternative,
3320 | we have developed inducible short-hairpin RNA xenograft models to
3321 | examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results
3322 | show that tumor regression resulting from BRAF suppression is inducible,
3323 | reversible, and tightly regulated in these models. Analysis of
3324 | regressing tumors showed the primary mechanism of action for BRAF to be
3325 | increased tumor cell proliferation and survival. In a metastatic
3326 | melanoma model, conditional BRAF suppression slowed systemic tumor
3327 | growth as determined by in vivo bioluminescence imaging. Taken together,
3328 | gain-of-function BRAF signaling is strongly associated with in vivo
3329 | tumorigenicity, confirming BRAF as an important target for small-
3330 | molecule and RNA interference-based therapeutics.
3331 | Author String:
3332 | Klaus P Hoeflich, Daniel C Gray, Michael T Eby, Janet Y Tien, Leo Wong,
3333 | Janeko Bower, Alvin Gogineni, Jiping Zha, Mary J Cole, Howard M Stern,
3334 | Lesley J Murray, David P Davis, Somasekar Seshagiri
3335 | Citation: Hoeflich et al., 2006
3336 | Citation Id: 16424035
3337 | Id: 1485
3338 | Journal: Cancer Res
3339 | Link: /sources/1485
3340 | Name: PubMed: Hoeflich et al., 2006
3341 | Open Access: False
3342 | Publication Date: 2006-1-15
3343 | Retracted: False
3344 | Source Type: PUBMED
3345 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16424035
3346 | Title:
3347 | Oncogenic BRAF is required for tumor growth and maintenance in melanoma
3348 | models.
3349 |
3350 | ##### Therapies
3351 | Deprecated: False
3352 | Id: 4
3353 | Link: /therapies/4
3354 | Name: Vemurafenib
3355 |
3356 | #### Evidence Items
3357 | Description:
3358 | In a retrospective study of 30 metastatic melanoma patients with
3359 | progressing metastases, patients with BRAF V600E mutation (n=8) treated
3360 | with vemurafenib monotherapy achieved a partial response (n=5) and
3361 | stable disease (n=1).
3362 | Evidence Direction: SUPPORTS
3363 | Evidence Level: C
3364 | Evidence Type: PREDICTIVE
3365 | Flagged: False
3366 | Id: 3749
3367 | Name: EID3749
3368 | Significance: SENSITIVITYRESPONSE
3369 | Variant Origin: SOMATIC
3370 |
3371 | ##### Disease
3372 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
3373 | Display Name: Melanoma
3374 | Doid: 1909
3375 | Id: 7
3376 | Link: /diseases/7
3377 | Name: Melanoma
3378 |
3379 | ##### My Disease Info
3380 | Do Def:
3381 | A cell type cancer that has_material_basis_in abnormally proliferating
3382 | cells derives_from melanocytes which are found in skin, the bowel and
3383 | the eye.
3384 | Icdo: 8720/3
3385 | Mesh: D008545
3386 | Mondo Id: MONDO:0005105
3387 | Ncit: C3224
3388 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
3389 |
3390 | ##### Molecular Profile
3391 | Id: 12
3392 |
3393 | ##### Source
3394 | Abstract:
3395 | Multiple BRAF inhibitor resistance mechanisms have been described,
3396 | however, their relative frequency, clinical correlates, and effect on
3397 | subsequent therapy have not been assessed in patients with metastatic
3398 | melanoma.Fifty-nine BRAF(V600)-mutant melanoma metastases from patients
3399 | treated with dabrafenib or vemurafenib were analyzed. The genetic
3400 | profile of resistance mechanisms and tumor signaling pathway activity
3401 | was correlated with clinicopathologic features and therapeutic
3402 | outcomes.Resistance mechanisms were identified in 58% progressing tumors
3403 | and BRAF alterations were common. Gene expression analysis revealed that
3404 | mitogen-activated protein kinase (MAPK) activity remained inhibited in
3405 | 21% of resistant tumors, and the outcomes of patients with these tumors
3406 | were poor. Resistance mechanisms also occurred in pretreatment biopsies
3407 | and heterogeneity of resistance mechanisms occurred within patients and
3408 | within tumors. There were no responses to subsequent targeted therapy,
3409 | even when a progressing tumor had a resistance mechanism predicted to be
3410 | responsive.Selecting sequential drugs based on the molecular
3411 | characteristics of a single progressing biopsy is unlikely to provide
3412 | improved responses, and first-line therapies targeting multiple pathways
3413 | will be required.
3414 | Author String:
3415 | Helen Rizos, Alexander M Menzies, Gulietta M Pupo, Matteo S Carlino,
3416 | Carina Fung, Jessica Hyman, Lauren E Haydu, Branka Mijatov, Therese M
3417 | Becker, Suzanah C Boyd, Julie Howle, Robyn Saw, John F Thompson, Richard
3418 | F Kefford, Richard A Scolyer, Georgina V Long
3419 | Citation: Rizos et al., 2014
3420 | Citation Id: 24463458
3421 | Id: 1951
3422 | Journal: Clin Cancer Res
3423 | Link: /sources/1951
3424 | Name: PubMed: Rizos et al., 2014
3425 | Open Access: False
3426 | Publication Date: 2014-4-1
3427 | Retracted: False
3428 | Source Type: PUBMED
3429 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24463458
3430 | Title:
3431 | BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum
3432 | and clinical impact.
3433 |
3434 | ##### Therapies
3435 | Deprecated: False
3436 | Id: 4
3437 | Link: /therapies/4
3438 | Name: Vemurafenib
3439 |
3440 | #### Evidence Items
3441 | Description:
3442 | In an in vitro study, BRAF V600E expressing cell lines (COLO205, A375
3443 | and COLO829) demonstrated improved sensitivity to vemurafenib treatment,
3444 | compared to BRAF wild-type expressing cells. Sensitivity was determined
3445 | by assessing cell proliferation (COLO205, GI50: 0.31uM; A375, GI50: 0.50
3446 | uM; COLO829, GI50: 1.7 uM vs. BRAF expressing cells (n=9) GI50: 10-41uM)
3447 | and ERK phosphorylation.
3448 | Evidence Direction: SUPPORTS
3449 | Evidence Level: D
3450 | Evidence Type: PREDICTIVE
3451 | Flagged: False
3452 | Id: 3751
3453 | Name: EID3751
3454 | Significance: SENSITIVITYRESPONSE
3455 | Variant Origin: SOMATIC
3456 |
3457 | ##### Disease
3458 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
3459 | Display Name: Melanoma
3460 | Doid: 1909
3461 | Id: 7
3462 | Link: /diseases/7
3463 | Name: Melanoma
3464 |
3465 | ##### My Disease Info
3466 | Do Def:
3467 | A cell type cancer that has_material_basis_in abnormally proliferating
3468 | cells derives_from melanocytes which are found in skin, the bowel and
3469 | the eye.
3470 | Icdo: 8720/3
3471 | Mesh: D008545
3472 | Mondo Id: MONDO:0005105
3473 | Ncit: C3224
3474 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
3475 |
3476 | ##### Molecular Profile
3477 | Id: 12
3478 |
3479 | ##### Source
3480 | Abstract:
3481 | BRAF(V600E) is the most frequent oncogenic protein kinase mutation
3482 | known. Furthermore, inhibitors targeting "active" protein kinases have
3483 | demonstrated significant utility in the therapeutic repertoire against
3484 | cancer. Therefore, we pursued the development of specific kinase
3485 | inhibitors targeting B-Raf, and the V600E allele in particular. By using
3486 | a structure-guided discovery approach, a potent and selective inhibitor
3487 | of active B-Raf has been discovered. PLX4720, a 7-azaindole derivative
3488 | that inhibits B-Raf(V600E) with an IC(50) of 13 nM, defines a class of
3489 | kinase inhibitor with marked selectivity in both biochemical and
3490 | cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E)
3491 | kinase compared with a broad spectrum of other kinases, and potent
3492 | cytotoxic effects are also exclusive to cells bearing the V600E allele.
3493 | Consistent with the high degree of selectivity, ERK phosphorylation is
3494 | potently inhibited by PLX4720 in B-Raf(V600E)-bearing tumor cell lines
3495 | but not in cells lacking oncogenic B-Raf. In melanoma models, PLX4720
3496 | induces cell cycle arrest and apoptosis exclusively in
3497 | B-Raf(V600E)-positive cells. In B-Raf(V600E)-dependent tumor xenograft
3498 | models, orally dosed PLX4720 causes significant tumor growth delays,
3499 | including tumor regressions, without evidence of toxicity. The work
3500 | described here represents the entire discovery process, from initial
3501 | identification through structural and biological studies in animal
3502 | models to a promising therapeutic for testing in cancer patients bearing
3503 | B-Raf(V600E)-driven tumors.
3504 | Author String:
3505 | James Tsai, John T Lee, Weiru Wang, Jiazhong Zhang, Hanna Cho, Shumeye
3506 | Mamo, Ryan Bremer, Sam Gillette, Jun Kong, Nikolas K Haass, Katrin
3507 | Sproesser, Ling Li, Keiran S M Smalley, Daniel Fong, Yong-Liang Zhu,
3508 | Adhirai Marimuthu, Hoa Nguyen, Billy Lam, Jennifer Liu, Ivana Cheung,
3509 | Julie Rice, Yoshihisa Suzuki, Catherine Luu, Calvin Settachatgul, Rafe
3510 | Shellooe, John Cantwell, Sung-Hou Kim, Joseph Schlessinger, Kam Y J
3511 | Zhang, Brian L West, Ben Powell, Gaston Habets, Chao Zhang, Prabha N
3512 | Ibrahim, Peter Hirth, Dean R Artis, Meenhard Herlyn, Gideon Bollag
3513 | Citation: Tsai et al., 2008
3514 | Citation Id: 18287029
3515 | Id: 1952
3516 | Journal: Proc Natl Acad Sci U S A
3517 | Link: /sources/1952
3518 | Name: PubMed: Tsai et al., 2008
3519 | Open Access: True
3520 | Pmc Id: PMC2268581
3521 | Publication Date: 2008-2-26
3522 | Retracted: False
3523 | Source Type: PUBMED
3524 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/18287029
3525 | Title:
3526 | Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent
3527 | antimelanoma activity.
3528 |
3529 | ##### Therapies
3530 | Deprecated: False
3531 | Id: 4
3532 | Link: /therapies/4
3533 | Name: Vemurafenib
3534 |
3535 | #### Evidence Items
3536 | Description:
3537 | In an in vitro study, a MBA72 cell line expressing BRAF V600E
3538 | demonstrated improved sensitivity to vemurafenib treatment, compared to
3539 | LND-1 cells expression BRAF wild-type. Sensitivity was determined by
3540 | assessing cell proliferation (MBA72, IC50: 3.2uM; vs. LND-1, IC50: 32.2
3541 | uM).
3542 | Evidence Direction: SUPPORTS
3543 | Evidence Level: D
3544 | Evidence Type: PREDICTIVE
3545 | Flagged: False
3546 | Id: 3752
3547 | Name: EID3752
3548 | Significance: SENSITIVITYRESPONSE
3549 | Variant Origin: SOMATIC
3550 |
3551 | ##### Disease
3552 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
3553 | Display Name: Melanoma
3554 | Doid: 1909
3555 | Id: 7
3556 | Link: /diseases/7
3557 | Name: Melanoma
3558 |
3559 | ##### My Disease Info
3560 | Do Def:
3561 | A cell type cancer that has_material_basis_in abnormally proliferating
3562 | cells derives_from melanocytes which are found in skin, the bowel and
3563 | the eye.
3564 | Icdo: 8720/3
3565 | Mesh: D008545
3566 | Mondo Id: MONDO:0005105
3567 | Ncit: C3224
3568 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
3569 |
3570 | ##### Molecular Profile
3571 | Id: 12
3572 |
3573 | ##### Source
3574 | Abstract:
3575 | BRAF G469A is a missense mutation within exon 11 of the BRAF gene
3576 | resulting in a constitutively activated enzyme frequently associated
3577 | with MAP kinase cascade signaling activation. No evidence currently
3578 | exists about its role in determining sensitivity/resistance to BRAF
3579 | inhibitors, utilized in the treatment of patients carrying BRAF V600
3580 | mutations, and to chemotherapy. The newly established metastatic
3581 | melanoma (MM) cell line MO-1 was characterized for its sensitivity to
3582 | vemurafenib and nab-paclitaxel, both already utilized for the treatment
3583 | of MM.All analyses were carried out by comparing results with those
3584 | found in MM cells wild type for BRAF or mutated in V600. In addition,
3585 | cellular effectors were investigated by ELISA kits, western blotting and
3586 | flow cytometry.The exposure to vemurafenib inhibited MO-1 cell
3587 | proliferation at concentrations similar to those obtained in
3588 | vemurafenib-resistant melanoma models, and an explanation of this
3589 | sensitivity is the strong activation of Erk1/2 and the low expression of
3590 | MITF. Nab-paclitaxel strongly reduced proliferation of MO-1 cells
3591 | perhaps for the very low expression level of PMEL17, transcriptionally
3592 | regulated by MITF and negatively involved in determining sensitivity to
3593 | taxanes.Thus, the mutation BRAF G469A in MM might be related to a weak
3594 | effectiveness of therapy with BRAF inhibitors and a promising
3595 | therapeutic approach may be with nab-paclitaxel.
3596 | Author String:
3597 | Letizia Porcelli, Gabriella Guida, Stefania Tommasi, Michele Guida,
3598 | Amalia Azzariti
3599 | Citation: Porcelli et al., 2015
3600 | Citation Id: 26070258
3601 | Id: 1953
3602 | Journal: Cancer Chemother Pharmacol
3603 | Link: /sources/1953
3604 | Name: PubMed: Porcelli et al., 2015
3605 | Open Access: False
3606 | Publication Date: 2015-8
3607 | Retracted: False
3608 | Source Type: PUBMED
3609 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26070258
3610 | Title:
3611 | Metastatic melanoma cells with BRAF G469A mutation: nab-paclitaxel
3612 | better than vemurafenib?
3613 |
3614 | ##### Therapies
3615 | Deprecated: False
3616 | Id: 4
3617 | Link: /therapies/4
3618 | Name: Vemurafenib
3619 |
3620 | #### Evidence Items
3621 | Description:
3622 | In a meta-analysis of 8 studies, papillary thyroid cancer patients with
3623 | BRAF V600E mutation had a higher frequency of recurrence and persistent
3624 | disease compared to those with wildtype BRAF (28.5% vs. 12.8% , Risk
3625 | ratio:2.14, 95%CI:1.67-2.74, P<0.00001).
3626 | Evidence Direction: SUPPORTS
3627 | Evidence Level: B
3628 | Evidence Rating: 3
3629 | Evidence Type: PROGNOSTIC
3630 | Flagged: False
3631 | Id: 2503
3632 | Name: EID2503
3633 | Significance: POOR_OUTCOME
3634 | Variant Origin: SOMATIC
3635 |
3636 | ##### Disease
3637 | Disease Url: https://www.disease-ontology.org/?id=DOID:3969
3638 | Display Name: Papillary Thyroid Carcinoma
3639 | Doid: 3969
3640 | Id: 156
3641 | Link: /diseases/156
3642 | Name: Papillary Thyroid Carcinoma
3643 |
3644 | ##### My Disease Info
3645 | Do Def:
3646 | A differentiated thyroid gland carcinoma that is characterized by the
3647 | small mushroom shape of the tumor which has a stem attached to the
3648 | epithelial layer and arises from the follicular cells of the thyroid
3649 | gland.
3650 | Icdo: 8260/3
3651 | Mesh: D000077273
3652 | Mondo Id: MONDO:0005075
3653 | Ncit: C4035
3654 | Disease Aliases:
3655 | - Papillary Carcinoma Of The Thyroid Gland
3656 | - Papillary Carcinoma Of Thyroid
3657 | - Thyroid Gland Papillary Carcinoma
3658 |
3659 | ##### Molecular Profile
3660 | Id: 12
3661 |
3662 | ##### Source
3663 | Abstract:
3664 | The effects of the BRAF(V600E) mutation on prognostic factors and poor
3665 | clinical outcomes in papillary thyroid cancer (PTC) have not been fully
3666 | quantified. The authors performed comprehensive meta-analysis to assess
3667 | the strength of associations between these conditions and the
3668 | BRAF(V600E) mutation.The authors identified the clinical studies that
3669 | examined the association of the BRAF(V600E) mutation in surgical
3670 | specimens with clinicopathologic outcomes between January 2003 and
3671 | October 2010 using the Medline database. One hundred thirty-one relevant
3672 | studies were hand-searched. The authors selected 27 studies that
3673 | included 5655 PTC patients. They calculated the pooled odds ratios (ORs)
3674 | or risk ratios with 95% confidence intervals (CIs) for each study using
3675 | a random effect model.The average prevalence rate of the BRAF(V600E)
3676 | mutation was 49.4%. In 26 studies, compared with the patients who had
3677 | the wild-type BRAF genes, the PTC patients with the BRAF(V600E) mutation
3678 | had increased ORs of an extrathyroidal invasion (OR, 2.14; 95% CI,
3679 | 1.68-2.73), a lymph node metastasis (OR, 1.54; 95% CI, 1.21-1.97), and
3680 | an advanced TNM stage (OR, 2.00; 95% CI, 1.61-2.49). In 8 studies,
3681 | patients with the mutation had 2.14-fold increased risk of recurrent and
3682 | persistent disease (95% CI, 1.67-2.74). The associations were generally
3683 | consistent across the different study populations.This meta-analysis
3684 | demonstrates that the BRAF(V600E) mutation is closely related to the
3685 | high-risk clinicopathological factors and poorer outcome of PTC. The
3686 | results obtained here suggest that the BRAF(V600E) mutation should be
3687 | considered as a poor prognostic marker in PTC and may lead to better
3688 | management for individual patients.
3689 | Author String:
3690 | Tae Hyuk Kim, Young Joo Park, Jung Ah Lim, Hwa Young Ahn, Eun Kyung Lee,
3691 | You Jin Lee, Kyung Won Kim, Seo Kyung Hahn, Yeo Kyu Youn, Kwang Hyun
3692 | Kim, Bo Youn Cho, Do Joon Park
3693 | Citation: Kim et al., 2012
3694 | Citation Id: 21882184
3695 | Id: 1495
3696 | Journal: Cancer
3697 | Link: /sources/1495
3698 | Name: PubMed: Kim et al., 2012
3699 | Open Access: False
3700 | Publication Date: 2012-4-1
3701 | Retracted: False
3702 | Source Type: PUBMED
3703 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21882184
3704 | Title:
3705 | The association of the BRAF(V600E) mutation with prognostic factors and
3706 | poor clinical outcome in papillary thyroid cancer: a meta-analysis.
3707 |
3708 | #### Evidence Items
3709 | Description:
3710 | In an in vitro study, several cell lines (including MALME-3M, Colo829,
3711 | Colo38, A375 and SK-MEK28) expressing BRAF V600E were associated with
3712 | increased sensitivity to vemurafenib (RG7204) treatment, as compared to
3713 | cell lines expressing BRAF wild-type. Sensitivity was determined by
3714 | proliferation assay and by assessing MEK1/2 phosphorylation. Further, in
3715 | an in vivo study, LOX, Colo829 and A375 xenografts were reportedly
3716 | sensitive to vemurafenib treatment as assessed by tumor volume.
3717 | Evidence Direction: SUPPORTS
3718 | Evidence Level: D
3719 | Evidence Type: PREDICTIVE
3720 | Flagged: False
3721 | Id: 3753
3722 | Name: EID3753
3723 | Significance: SENSITIVITYRESPONSE
3724 | Variant Origin: SOMATIC
3725 |
3726 | ##### Disease
3727 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
3728 | Display Name: Melanoma
3729 | Doid: 1909
3730 | Id: 7
3731 | Link: /diseases/7
3732 | Name: Melanoma
3733 |
3734 | ##### My Disease Info
3735 | Do Def:
3736 | A cell type cancer that has_material_basis_in abnormally proliferating
3737 | cells derives_from melanocytes which are found in skin, the bowel and
3738 | the eye.
3739 | Icdo: 8720/3
3740 | Mesh: D008545
3741 | Mondo Id: MONDO:0005105
3742 | Ncit: C3224
3743 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
3744 |
3745 | ##### Molecular Profile
3746 | Id: 12
3747 |
3748 | ##### Source
3749 | Abstract:
3750 | The BRAF(V600E) mutation is common in several human cancers, especially
3751 | melanoma. RG7204 (PLX4032) is a small-molecule inhibitor of BRAF(V600E)
3752 | kinase activity that is in phase II and phase III clinical testing.
3753 | Here, we report a preclinical characterization of the antitumor activity
3754 | of RG7204 using established in vitro and in vivo models of malignant
3755 | melanoma. RG7204 potently inhibited proliferation and mitogen-activated
3756 | protein/extracellular signal-regulated kinase (ERK) kinase and ERK
3757 | phosphorylation in a panel of tumor cell lines, including melanoma cell
3758 | lines expressing BRAF(V600E) or other mutant BRAF proteins altered at
3759 | codon 600. In contrast, RG7204 lacked activity in cell lines that
3760 | express wild-type BRAF or non-V600 mutations. In several tumor xenograft
3761 | models of BRAF(V600E)-expressing melanoma, we found that RG7204
3762 | treatment caused partial or complete tumor regressions and improved
3763 | animal survival, in a dose-dependent manner. There was no toxicity
3764 | observed in any dose group in any of the in vivo models tested. Our
3765 | findings offer evidence of the potent antitumor activity of RG7204
3766 | against melanomas harboring the mutant BRAF(V600E) gene.
3767 | Author String:
3768 | Hong Yang, Brian Higgins, Kenneth Kolinsky, Kathryn Packman, Zenaida Go,
3769 | Raman Iyer, Stanley Kolis, Sylvia Zhao, Richard Lee, Joseph F Grippo,
3770 | Kathleen Schostack, Mary Ellen Simcox, David Heimbrook, Gideon Bollag,
3771 | Fei Su
3772 | Citation: Yang et al., 2010
3773 | Citation Id: 20551065
3774 | Id: 351
3775 | Journal: Cancer Res
3776 | Link: /sources/351
3777 | Name: PubMed: Yang et al., 2010
3778 | Open Access: False
3779 | Publication Date: 2010-7-1
3780 | Retracted: False
3781 | Source Type: PUBMED
3782 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/20551065
3783 | Title:
3784 | RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent
3785 | antitumor activity in preclinical melanoma models.
3786 |
3787 | ##### Therapies
3788 | Deprecated: False
3789 | Id: 4
3790 | Link: /therapies/4
3791 | Name: Vemurafenib
3792 |
3793 | #### Evidence Items
3794 | Description:
3795 | In an in vitro study of 27 melanoma cell lines, 18 out of 20 cell lines
3796 | expressing BRAF V600E mutation were associated with sensitivity to
3797 | vemurafenib treatment (IC50: 0.01-1�M). Sensitivity was determined by
3798 | assessing growth inhibition.
3799 | Evidence Direction: SUPPORTS
3800 | Evidence Level: D
3801 | Evidence Type: PREDICTIVE
3802 | Flagged: False
3803 | Id: 3756
3804 | Name: EID3756
3805 | Significance: SENSITIVITYRESPONSE
3806 | Variant Origin: SOMATIC
3807 |
3808 | ##### Disease
3809 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
3810 | Display Name: Melanoma
3811 | Doid: 1909
3812 | Id: 7
3813 | Link: /diseases/7
3814 | Name: Melanoma
3815 |
3816 | ##### My Disease Info
3817 | Do Def:
3818 | A cell type cancer that has_material_basis_in abnormally proliferating
3819 | cells derives_from melanocytes which are found in skin, the bowel and
3820 | the eye.
3821 | Icdo: 8720/3
3822 | Mesh: D008545
3823 | Mondo Id: MONDO:0005105
3824 | Ncit: C3224
3825 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
3826 |
3827 | ##### Molecular Profile
3828 | Id: 12
3829 |
3830 | ##### Source
3831 | Abstract:
3832 | PLX4032/vemurafenib is a first-in-class small-molecule BRAF(V600E)
3833 | inhibitor with clinical activity in patients with BRAF mutant melanoma.
3834 | Nevertheless, drug resistance develops in treated patients, and
3835 | strategies to overcome primary and acquired resistance are required. To
3836 | explore the molecular mechanisms involved in primary resistance to
3837 | PLX4032, we investigated its effects on cell proliferation and signaling
3838 | in a panel of 27 genetically characterized patient-derived melanoma cell
3839 | lines. Cell sensitivity to PLX4032 was dependent on BRAF(V600E) and
3840 | independent from other gene alterations that commonly occur in melanoma
3841 | such as PTEN loss, BRAF, and MITF gene amplification. Two cell lines
3842 | lacking sensitivity to PLX4032 and harboring a different set of genetic
3843 | alterations were studied as models of primary resistance. Treatment with
3844 | the MEK inhibitor UO126 but not with PLX4032 inhibited cell growth and
3845 | ERK activation. Resistance to PLX4032 was maintained after CRAF down-
3846 | regulation by siRNA indicating alternative activation of MEK-ERK
3847 | signaling. Genetic characterization by multiplex ligation-dependent
3848 | probe amplification and analysis of phosphotyrosine signaling by MALDI-
3849 | TOF mass spectrometry analysis revealed the activation of MET and SRC
3850 | signaling, associated with the amplification of MET and of CTNNB1 and
3851 | CCND1 genes, respectively. The combination of PLX4032 with drugs or
3852 | siRNA targeting MET was effective in inhibiting cell growth and reducing
3853 | cell invasion and migration in melanoma cells with MET amplification;
3854 | similar effects were observed after targeting SRC in the other cell
3855 | line, indicating a role for MET and SRC signaling in primary resistance
3856 | to PLX4032. Our results support the development of classification of
3857 | melanoma in molecular subtypes for more effective therapies.
3858 | Author String:
3859 | Elisabetta Vergani, Viviana Vallacchi, Simona Frigerio, Paola Deho,
3860 | Piera Mondellini, Paola Perego, Giuliana Cassinelli, Cinzia Lanzi, Maria
3861 | Adele Testi, Licia Rivoltini, Italia Bongarzone, Monica Rodolfo
3862 | Citation: Vergani et al., 2011
3863 | Citation Id: 22241959
3864 | Id: 1956
3865 | Journal: Neoplasia
3866 | Link: /sources/1956
3867 | Name: PubMed: Vergani et al., 2011
3868 | Open Access: True
3869 | Pmc Id: PMC3257188
3870 | Publication Date: 2011-12
3871 | Retracted: False
3872 | Source Type: PUBMED
3873 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22241959
3874 | Title:
3875 | Identification of MET and SRC activation in melanoma cell lines showing
3876 | primary resistance to PLX4032.
3877 |
3878 | ##### Therapies
3879 | Deprecated: False
3880 | Id: 4
3881 | Link: /therapies/4
3882 | Name: Vemurafenib
3883 |
3884 | #### Evidence Items
3885 | Description:
3886 | In an in vitro study, a melanoma cell line, A375, expressing the BRAF
3887 | V600E mutation was associated with resistance to dasatinib treatment,
3888 | comparable to melanoma MEWO cells expressing wild-type BRAF. Resistance
3889 | was determined by assessing cell viability.
3890 | Evidence Direction: SUPPORTS
3891 | Evidence Level: D
3892 | Evidence Type: PREDICTIVE
3893 | Flagged: False
3894 | Id: 3759
3895 | Name: EID3759
3896 | Significance: RESISTANCE
3897 | Variant Origin: SOMATIC
3898 |
3899 | ##### Disease
3900 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
3901 | Display Name: Melanoma
3902 | Doid: 1909
3903 | Id: 7
3904 | Link: /diseases/7
3905 | Name: Melanoma
3906 |
3907 | ##### My Disease Info
3908 | Do Def:
3909 | A cell type cancer that has_material_basis_in abnormally proliferating
3910 | cells derives_from melanocytes which are found in skin, the bowel and
3911 | the eye.
3912 | Icdo: 8720/3
3913 | Mesh: D008545
3914 | Mondo Id: MONDO:0005105
3915 | Ncit: C3224
3916 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
3917 |
3918 | ##### Molecular Profile
3919 | Id: 12
3920 |
3921 | ##### Source
3922 | Abstract:
3923 | Point mutations in the KIT receptor tyrosine kinase gene have recently
3924 | been identified in mucosal, acral lentiginous, and chronically sun-
3925 | damaged melanomas. We have identified the first human melanoma cell line
3926 | with an endogenous L576P mutation, the most common KIT mutation in
3927 | melanoma ( approximately 30-40%). In vitro testing showed that the cell
3928 | viability of the L576P mutant cell line was not reduced by imatinib,
3929 | nilotinib, or sorafenib small molecule KIT inhibitors effective in
3930 | nonmelanoma cells with other KIT mutations. However, the viability of
3931 | the mutant cells was reduced by dasatinib at concentrations as low as 10
3932 | nM (P = 0.004). Molecular modeling studies found that the L576P mutation
3933 | induces structural changes in KIT that reduce the affinity for imatinib
3934 | (DeltaDeltaGbind = -2.52 kcal/mol) but not for dasatinib
3935 | (DeltaDeltaGbind = +0.32 kcal/mol). Two metastatic melanoma patients
3936 | with the L576P KIT mutation were treated with dasatinib, including one
3937 | patient previously treated with imatinib. Both patients had marked
3938 | reduction (>50%) and elimination of tumor F18-fluorodeoxyglucose
3939 | (FDG)-avidity by positron emission tomography (PET) imaging after
3940 | dasatinib treatment. These data support the selective inhibitory effect
3941 | of dasatinib against cells harboring the most common KIT mutation in
3942 | melanoma, and thus has therapeutic implications for acrallentiginous,
3943 | chronic sun-damaged, and mucosal melanomas.
3944 | Author String:
3945 | Scott E Woodman, Jonathan C Trent, Katherine Stemke-Hale, Alexander J
3946 | Lazar, Sabrina Pricl, Giovanni M Pavan, Maurizio Fermeglia, Y N Vashisht
3947 | Gopal, Dan Yang, Donald A Podoloff, Doina Ivan, Kevin B Kim, Nicholas
3948 | Papadopoulos, Patrick Hwu, Gordon B Mills, Michael A Davies
3949 | Citation: Woodman et al., 2009
3950 | Citation Id: 19671763
3951 | Id: 74
3952 | Journal: Mol Cancer Ther
3953 | Link: /sources/74
3954 | Name: PubMed: Woodman et al., 2009
3955 | Open Access: True
3956 | Pmc Id: PMC3346953
3957 | Publication Date: 2009-8
3958 | Retracted: False
3959 | Source Type: PUBMED
3960 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19671763
3961 | Title:
3962 | Activity of dasatinib against L576P KIT mutant melanoma: molecular,
3963 | cellular, and clinical correlates.
3964 |
3965 | ##### Therapies
3966 | Deprecated: False
3967 | Id: 20
3968 | Link: /therapies/20
3969 | Name: Dasatinib
3970 |
3971 | #### Evidence Items
3972 | Description:
3973 | In a hairy cell leukemia patient harboring BRAF V600E mutation, BRAF
3974 | V600E mutation was associated with improved response to vemurafenib
3975 | treatment. The patient was treated with 3 lines of chemotherapy,
3976 | including 6 cycles of pentostatin and rituximab combination therapy, but
3977 | experience progressive disease; subsequently, the patient was treated
3978 | with vemurafenib monotherapy for 58 days and achieved a partial
3979 | response.
3980 | Evidence Direction: SUPPORTS
3981 | Evidence Level: C
3982 | Evidence Type: PREDICTIVE
3983 | Flagged: False
3984 | Id: 3768
3985 | Name: EID3768
3986 | Significance: SENSITIVITYRESPONSE
3987 | Variant Origin: SOMATIC
3988 |
3989 | ##### Disease
3990 | Disease Url: https://www.disease-ontology.org/?id=DOID:285
3991 | Display Name: Hairy Cell Leukemia
3992 | Doid: 285
3993 | Id: 665
3994 | Link: /diseases/665
3995 | Name: Hairy Cell Leukemia
3996 |
3997 | ##### My Disease Info
3998 | Do Def:
3999 | A chronic lymphocytic leukemia that is characterized by over production
4000 | of B cells (lymphocytes) by the bone marrow where the B cells appear
4001 | hairy under a microscope.
4002 | Icd10: C91.4
4003 | Icdo: 9940/3
4004 | Mesh: D007943
4005 | Mondo Id: MONDO:0018935
4006 | Ncit: C7402
4007 |
4008 | ##### Molecular Profile
4009 | Id: 12
4010 |
4011 | ##### Source
4012 | Author String:
4013 | George A Follows, Hannah Sims, David M Bloxham, Thorsten Zenz, Melanie A
4014 | Hopper, Hongxiang Liu, Anthony Bench, Penny Wright, Mars B Van't Veer,
4015 | Mike A Scott
4016 | Citation: Follows et al., 2013
4017 | Citation Id: 23278307
4018 | Id: 1965
4019 | Journal: Br J Haematol
4020 | Link: /sources/1965
4021 | Name: PubMed: Follows et al., 2013
4022 | Open Access: False
4023 | Publication Date: 2013-4
4024 | Retracted: False
4025 | Source Type: PUBMED
4026 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23278307
4027 | Title:
4028 | Rapid response of biallelic BRAF V600E mutated hairy cell leukaemia to
4029 | low dose vemurafenib.
4030 |
4031 | ##### Therapies
4032 | Deprecated: False
4033 | Id: 4
4034 | Link: /therapies/4
4035 | Name: Vemurafenib
4036 |
4037 | #### Evidence Items
4038 | Description:
4039 | As a follow-up to a previous study (23300174), a hairy cell leukemia
4040 | patient harboring BRAF V600E mutation was associated with response to
4041 | vemurafenib monotherapy. The patient was previously treated with
4042 | vemurafenib and obtained a complete response, but then experienced
4043 | disease progression. Subsequently, the patient was re-treated with
4044 | vemurafenib and again achieved a complete hematological response.
4045 | Evidence Direction: SUPPORTS
4046 | Evidence Level: C
4047 | Evidence Type: PREDICTIVE
4048 | Flagged: False
4049 | Id: 3769
4050 | Name: EID3769
4051 | Significance: SENSITIVITYRESPONSE
4052 | Variant Origin: SOMATIC
4053 |
4054 | ##### Disease
4055 | Disease Url: https://www.disease-ontology.org/?id=DOID:285
4056 | Display Name: Hairy Cell Leukemia
4057 | Doid: 285
4058 | Id: 665
4059 | Link: /diseases/665
4060 | Name: Hairy Cell Leukemia
4061 |
4062 | ##### My Disease Info
4063 | Do Def:
4064 | A chronic lymphocytic leukemia that is characterized by over production
4065 | of B cells (lymphocytes) by the bone marrow where the B cells appear
4066 | hairy under a microscope.
4067 | Icd10: C91.4
4068 | Icdo: 9940/3
4069 | Mesh: D007943
4070 | Mondo Id: MONDO:0018935
4071 | Ncit: C7402
4072 |
4073 | ##### Molecular Profile
4074 | Id: 12
4075 |
4076 | ##### Source
4077 | Abstract:
4078 | Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative
4079 | disorder that accounts for 2% of all leukemia. Recent identification of
4080 | the recurrent V600E BRAF mutation in a majority of HCL patients has led
4081 | some teams to evaluate the clinical potential of vemurafenib, a BRAF
4082 | V600 specific inhibitor in a limited number of refractory HCL patients.
4083 | Recently, we published the case of an HCL patient successfully treated
4084 | with a low dose of vemurafenib. Eight months after the ending of
4085 | treatment this patient relapsed. We present here the successful
4086 | retreatment of this patient with a second line of vemurafenib. Our data
4087 | suggest for the first time that vemurafenib at the dose of 240 mg once a
4088 | day could be sufficient to maintain a complete hematological remission
4089 | after an initial induction treatment with low-dose vemurafenib (2 × 240
4090 | mg) daily without inducing major toxicity.
4091 | Author String:
4092 | Caroline Bailleux, Guillaume Robert, Clémence Ginet, Daniel Re, Antoine
4093 | Thyss, Isabelle Sudaka, Isabelle Peyrottes, Paul Hofman, Patrick
4094 | Auberger, Frederic Peyrade
4095 | Citation: Bailleux et al., 2015
4096 | Citation Id: 25815361
4097 | Id: 1966
4098 | Journal: Oncoscience
4099 | Link: /sources/1966
4100 | Name: PubMed: Bailleux et al., 2015
4101 | Open Access: True
4102 | Pmc Id: PMC4341463
4103 | Publication Date: 2015
4104 | Retracted: False
4105 | Source Type: PUBMED
4106 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25815361
4107 | Title:
4108 | Successful re-treatment of a relapsed V600E mutated HCL patient with
4109 | low-dose vemurafenib.
4110 |
4111 | ##### Therapies
4112 | Deprecated: False
4113 | Id: 4
4114 | Link: /therapies/4
4115 | Name: Vemurafenib
4116 |
4117 | #### Evidence Items
4118 | Description:
4119 | A hairy cell leukemia patient with extensive CNS involvement patient
4120 | harboring BRAF V600E mutation was associated with complete response to
4121 | vemurafenib monotherapy. Upon identification of the BRAF V600E mutation,
4122 | the patient was treated with cytarabine, rituximab and methotrexate but
4123 | quickly progressed; subsequently, the patient was treated with 2 rounds
4124 | of vemurafenib and achieved complete response.
4125 | Evidence Direction: SUPPORTS
4126 | Evidence Level: C
4127 | Evidence Type: PREDICTIVE
4128 | Flagged: False
4129 | Id: 3770
4130 | Name: EID3770
4131 | Significance: SENSITIVITYRESPONSE
4132 | Variant Origin: SOMATIC
4133 |
4134 | ##### Disease
4135 | Disease Url: https://www.disease-ontology.org/?id=DOID:285
4136 | Display Name: Hairy Cell Leukemia
4137 | Doid: 285
4138 | Id: 665
4139 | Link: /diseases/665
4140 | Name: Hairy Cell Leukemia
4141 |
4142 | ##### My Disease Info
4143 | Do Def:
4144 | A chronic lymphocytic leukemia that is characterized by over production
4145 | of B cells (lymphocytes) by the bone marrow where the B cells appear
4146 | hairy under a microscope.
4147 | Icd10: C91.4
4148 | Icdo: 9940/3
4149 | Mesh: D007943
4150 | Mondo Id: MONDO:0018935
4151 | Ncit: C7402
4152 |
4153 | ##### Molecular Profile
4154 | Id: 12
4155 |
4156 | ##### Source
4157 | Author String:
4158 | Michael M McDowell, Xiao Zhu, Nitin Agarwal, Marina N Nikiforova, Frank
4159 | S Lieberman, Jan Drappatz
4160 | Citation: McDowell et al., 2016
4161 | Citation Id: 27116997
4162 | Id: 1967
4163 | Journal: Leuk Lymphoma
4164 | Link: /sources/1967
4165 | Name: PubMed: McDowell et al., 2016
4166 | Open Access: False
4167 | Publication Date: 2016-12
4168 | Retracted: False
4169 | Source Type: PUBMED
4170 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/27116997
4171 | Title:
4172 | Response of relapsed central nervous system hairy cell leukemia to
4173 | vemurafenib.
4174 |
4175 | ##### Therapies
4176 | Deprecated: False
4177 | Id: 4
4178 | Link: /therapies/4
4179 | Name: Vemurafenib
4180 |
4181 | #### Evidence Items
4182 | Description:
4183 | In a retrospective study of 17 papillary thyroid cancer patients,
4184 | patients with BRAF V600E mutation (n=6) were associated with a 47%
4185 | (7/15) partial response rate and a 53% (8/15) stable disease rate.
4186 | Evidence Direction: SUPPORTS
4187 | Evidence Level: C
4188 | Evidence Type: PREDICTIVE
4189 | Flagged: False
4190 | Id: 3773
4191 | Name: EID3773
4192 | Significance: SENSITIVITYRESPONSE
4193 | Variant Origin: SOMATIC
4194 |
4195 | ##### Disease
4196 | Disease Url: https://www.disease-ontology.org/?id=DOID:3969
4197 | Display Name: Papillary Thyroid Carcinoma
4198 | Doid: 3969
4199 | Id: 156
4200 | Link: /diseases/156
4201 | Name: Papillary Thyroid Carcinoma
4202 |
4203 | ##### My Disease Info
4204 | Do Def:
4205 | A differentiated thyroid gland carcinoma that is characterized by the
4206 | small mushroom shape of the tumor which has a stem attached to the
4207 | epithelial layer and arises from the follicular cells of the thyroid
4208 | gland.
4209 | Icdo: 8260/3
4210 | Mesh: D000077273
4211 | Mondo Id: MONDO:0005075
4212 | Ncit: C4035
4213 | Disease Aliases:
4214 | - Papillary Carcinoma Of The Thyroid Gland
4215 | - Papillary Carcinoma Of Thyroid
4216 | - Thyroid Gland Papillary Carcinoma
4217 |
4218 | ##### Molecular Profile
4219 | Id: 12
4220 |
4221 | ##### Source
4222 | Abstract:
4223 | Vemurafenib, a selective BRAF inhibitor, appears to have promising
4224 | clinical activity in patients with papillary thyroid cancer (PTC)
4225 | harboring the BRAF(V600E) mutation.To determine the efficacy and safety
4226 | of vemurafenib when used outside of a clinical trial.A retrospective
4227 | review at MD Anderson Cancer Center.The best responses were evaluated
4228 | using RECIST v1.1. A single radiologist reviewed all images. Adverse
4229 | events (AEs) were evaluated using CTCAE v.4.0.We identified 17 patients
4230 | with advanced PTC harboring the BRAF(V600E) mutation who were treated
4231 | with vemurafenib outside of a clinical trial. Median age at diagnosis
4232 | was 63 years, and 53% were male. At vemurafenib start, 3 (18%) patients
4233 | had disease confined to the neck, and 14 (72%) had distant metastases.
4234 | Tyrosine kinase inhibitors had been previously administered to 4 (24%)
4235 | patients. Two (12%) patients discontinued vemurafenib because of AEs
4236 | before restaging. Best response: partial response (PR) in 7/15 (47%) and
4237 | stable disease (SD) in 8/15(53%) patients. The rate of durable response
4238 | (PR plus SD ≥ 6 months) was 67%. Median time to treatment failure was 13
4239 | months. There was no association between change in thyroglobulin and
4240 | tumor size. Drug discontinuation, drug interruptions, and dose
4241 | reductions were needed in 5 (29%), 13 (76%), and 10 (59%) patients,
4242 | respectively. Most common AEs were fatigue (71%), weight loss (71%),
4243 | anorexia (65%), arthralgias (59%), hair loss (59%), rash (59%), hand-
4244 | foot syndrome (53%), calluses (47%), diarrhea (47%), fever (41%), dry
4245 | mouth (35%), nausea (35%), and verrucous keratosis (35%). Grade ≥ 3 AEs
4246 | were present in 8 (47%) patients.Vemurafenib is a potentially effective
4247 | and well-tolerated treatment strategy in patients with advanced PTC
4248 | harboring the BRAF(V600E) mutation. Our results are similar to those
4249 | reported in a phase II clinical trial and support the potential role of
4250 | vemurafenib in this patient population.
4251 | Author String:
4252 | Ramona Dadu, Komal Shah, Naifa L Busaidy, Steven G Waguespack, Mouhammad
4253 | A Habra, Anita K Ying, Mimi I Hu, Roland Bassett, Camilo Jimenez, Steven
4254 | I Sherman, Maria E Cabanillas
4255 | Citation: Dadu et al., 2015
4256 | Citation Id: 25353071
4257 | Id: 1970
4258 | Journal: J Clin Endocrinol Metab
4259 | Link: /sources/1970
4260 | Name: PubMed: Dadu et al., 2015
4261 | Open Access: True
4262 | Pmc Id: PMC4283003
4263 | Publication Date: 2015-1
4264 | Retracted: False
4265 | Source Type: PUBMED
4266 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25353071
4267 | Title:
4268 | Efficacy and tolerability of vemurafenib in patients with BRAF(V600E)
4269 | -positive papillary thyroid cancer: M.D. Anderson Cancer Center off
4270 | label experience.
4271 |
4272 | ##### Therapies
4273 | Deprecated: False
4274 | Id: 4
4275 | Link: /therapies/4
4276 | Name: Vemurafenib
4277 |
4278 | #### Evidence Items
4279 | Description:
4280 | In a clinical trial (NCT01286753) of 55 cancer patients with BRAF V600E
4281 | mutation, patients with metastatic papillary thyroid cancer (n=3) were
4282 | associated with sensitivity to vemurafenib treatment. One patient
4283 | achieved partial response (31% reduction by RECIST) and two patients
4284 | achieved stable disease (9% and 16% reduction by RECIST criteria), the
4285 | time to progression for these three patients was 11.7, 13.2 and 11.4
4286 | months, and the overall survival was 15 months (patient was subsequently
4287 | treated with radiation therapy), at least 31.7 months (patient
4288 | subsequently underwent laryngectomy) and 24.9 months (patient was
4289 | subsequently treated with sorafenib, followed by sunitinib monotherapy),
4290 | respectively.
4291 | Evidence Direction: SUPPORTS
4292 | Evidence Level: C
4293 | Evidence Type: PREDICTIVE
4294 | Flagged: False
4295 | Id: 3774
4296 | Name: EID3774
4297 | Significance: SENSITIVITYRESPONSE
4298 | Variant Origin: SOMATIC
4299 |
4300 | ##### Disease
4301 | Disease Url: https://www.disease-ontology.org/?id=DOID:3969
4302 | Display Name: Papillary Thyroid Carcinoma
4303 | Doid: 3969
4304 | Id: 156
4305 | Link: /diseases/156
4306 | Name: Papillary Thyroid Carcinoma
4307 |
4308 | ##### My Disease Info
4309 | Do Def:
4310 | A differentiated thyroid gland carcinoma that is characterized by the
4311 | small mushroom shape of the tumor which has a stem attached to the
4312 | epithelial layer and arises from the follicular cells of the thyroid
4313 | gland.
4314 | Icdo: 8260/3
4315 | Mesh: D000077273
4316 | Mondo Id: MONDO:0005075
4317 | Ncit: C4035
4318 | Disease Aliases:
4319 | - Papillary Carcinoma Of The Thyroid Gland
4320 | - Papillary Carcinoma Of Thyroid
4321 | - Thyroid Gland Papillary Carcinoma
4322 |
4323 | ##### Molecular Profile
4324 | Id: 12
4325 |
4326 | ##### Source
4327 | Abstract:
4328 | Clinical benefit from cytotoxic chemotherapy for metastatic papillary
4329 | thyroid carcinoma (PTC) is disappointing, and effective therapeutic
4330 | approaches for these patients are urgently needed. Because kinase-
4331 | activating mutations in the BRAF proto-oncogene commonly occur in
4332 | advanced PTC, and inhibition of BRAF(V600E) has shown promising clinical
4333 | activity in melanoma, BRAF inhibitor therapy may be an effective
4334 | strategy to treat metastatic PTC.The dose escalation portion of a first-
4335 | in-human, phase I study of vemurafenib, a selective RAF inhibitor,
4336 | included three patients with metastatic PTC harboring the BRAF(V600E)
4337 | mutation. Vemurafenib was initially dosed at 240-360 mg twice a day,
4338 | later escalated to 720 mg twice a day. Response evaluation was performed
4339 | every 8 weeks per Response Evaluation Criteria in Solid Tumors
4340 | (RECIST).Among the three patients, one had a confirmed partial response
4341 | with reduction of pulmonary target lesions by 31%, and the duration of
4342 | response was 7.6 months before the disease progressed in the lungs and
4343 | the bones. The time to progression was 11.7 months. The other two
4344 | patients had stable disease, and the time to progression was 13.2 and
4345 | 11.4 months, respectively.Vemurafenib appears to have a promising
4346 | clinical activity in patients with metastatic PTC, and our data suggest
4347 | that the BRAF(V600E) mutant kinase is a relevant target for therapy in
4348 | this patient population. Further investigation of inhibitors of mutated
4349 | BRAF kinase in patients with PTC in a phase II study is warranted.
4350 | Author String:
4351 | Kevin B Kim, Maria E Cabanillas, Alexander J Lazar, Michelle D Williams,
4352 | Deborah L Sanders, Joseph L Ilagan, Keith Nolop, Richard J Lee, Steven I
4353 | Sherman
4354 | Citation: Kim et al., 2013
4355 | Citation Id: 23489023
4356 | Id: 1971
4357 | Journal: Thyroid
4358 | Link: /sources/1971
4359 | Name: PubMed: Kim et al., 2013
4360 | Open Access: True
4361 | Pmc Id: PMC3967415
4362 | Publication Date: 2013-10
4363 | Retracted: False
4364 | Source Type: PUBMED
4365 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23489023
4366 | Title:
4367 | Clinical responses to vemurafenib in patients with metastatic papillary
4368 | thyroid cancer harboring BRAF(V600E) mutation.
4369 |
4370 | ##### Therapies
4371 | Deprecated: False
4372 | Id: 4
4373 | Link: /therapies/4
4374 | Name: Vemurafenib
4375 |
4376 | #### Evidence Items
4377 | Description:
4378 | In an in vitro study, K2, a papillary thyroid carcinoma cell line
4379 | expressing the BRAFV600E mutation, was associated with sensitivity to
4380 | dasatinib treatment. Sensitivity was determined by assessing cell growth
4381 | inhibition. In an in vivo experiment, dasatinib also inhibited the
4382 | growth of K2 thyroid carcinoma xenografts in 7 of 13 mice.
4383 | Evidence Direction: SUPPORTS
4384 | Evidence Level: D
4385 | Evidence Type: PREDICTIVE
4386 | Flagged: False
4387 | Id: 3775
4388 | Name: EID3775
4389 | Significance: SENSITIVITYRESPONSE
4390 | Variant Origin: SOMATIC
4391 |
4392 | ##### Disease
4393 | Disease Url: https://www.disease-ontology.org/?id=DOID:3969
4394 | Display Name: Papillary Thyroid Carcinoma
4395 | Doid: 3969
4396 | Id: 156
4397 | Link: /diseases/156
4398 | Name: Papillary Thyroid Carcinoma
4399 |
4400 | ##### My Disease Info
4401 | Do Def:
4402 | A differentiated thyroid gland carcinoma that is characterized by the
4403 | small mushroom shape of the tumor which has a stem attached to the
4404 | epithelial layer and arises from the follicular cells of the thyroid
4405 | gland.
4406 | Icdo: 8260/3
4407 | Mesh: D000077273
4408 | Mondo Id: MONDO:0005075
4409 | Ncit: C4035
4410 | Disease Aliases:
4411 | - Papillary Carcinoma Of The Thyroid Gland
4412 | - Papillary Carcinoma Of Thyroid
4413 | - Thyroid Gland Papillary Carcinoma
4414 |
4415 | ##### Molecular Profile
4416 | Id: 12
4417 |
4418 | ##### Source
4419 | Abstract:
4420 | Papillary thyroid carcinoma is the most common thyroid malignancy. Most
4421 | papillary thyroid carcinomas contain BRAF mutations or RET/PTC
4422 | rearrangements, thus providing targets for biologic therapy. Our
4423 | previous studies had suggested papillary thyroid carcinomas (PTCs) with
4424 | a BRAF mutation and the RET/PTC1 rearrangement have different
4425 | sensitivities to MEK1/2 inhibitors, suggesting different signaling
4426 | transduction pathways were involved.Src signaling transduction pathway
4427 | in PTC cells was examined using Src inhibitors (PP2, SU6656, or
4428 | dasatinib) and si-Src RNA in vitro by Western blot analysis and
4429 | proliferation analysis. An orthotopic xenograft mouse model was used for
4430 | the in vivo studies using dasatinib.In PTC cells, Src inhibitors
4431 | suppressed p-Src and p-FAK and inhibited cell growth. In addition,
4432 | significant suppression and extension of the p-ERK1/2 dephosphorylation
4433 | were detected in RET/PTC1-rearranged cells in combination with an MEK
4434 | inhibitor (CI-1040). The Src family kinase/ABL inhibitor, dasatinib,
4435 | significantly decreased tumor volume in mice inoculated with PTC cells
4436 | carrying the RET/PTC1 rearrangement. In BRAF-mutated PTC cells, Src
4437 | inhibitors effectively suppressed p-Src expression and dasatinib
4438 | significantly decreased tumor volume with twice daily treatment.Src
4439 | inhibitors effectively inhibited the Src signaling transduction pathway
4440 | in PTC cells in vitro and dasatinib suppressed tumor growth in vivo.
4441 | These results suggested that Src signaling transduction pathway plays an
4442 | important role in regulating growth in PTC cells. Combination of Src and
4443 | MEK1/2 inhibitors extended the dephosphorylation of extracellular
4444 | signal-regulated kinase (ERK)1/2 in PTCs carrying the RET/PTC1
4445 | rearrangement suggesting that combination therapy with complementary
4446 | inhibitors of other signaling transduction pathways may be needed to
4447 | effectively suppress growth and induce apoptosis in these cells.
4448 | Author String:
4449 | Ying C Henderson, Rafael Toro-Serra, Yunyun Chen, Junsun Ryu, Mitchell J
4450 | Frederick, Ge Zhou, Gary E Gallick, Stephen Y Lai, Gary L Clayman
4451 | Citation: Henderson et al., 2014
4452 | Citation Id: 23729178
4453 | Id: 1972
4454 | Journal: Head Neck
4455 | Link: /sources/1972
4456 | Name: PubMed: Henderson et al., 2014
4457 | Open Access: True
4458 | Pmc Id: PMC4401074
4459 | Publication Date: 2014-3
4460 | Retracted: False
4461 | Source Type: PUBMED
4462 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23729178
4463 | Title: Src inhibitors in suppression of papillary thyroid carcinoma growth.
4464 |
4465 | ##### Therapies
4466 | Deprecated: False
4467 | Id: 20
4468 | Link: /therapies/20
4469 | Name: Dasatinib
4470 |
4471 | #### Evidence Items
4472 | Description:
4473 | In an in vitro study, WiDr, HT-29 and RKO cell lines expressing BRAF
4474 | V600E mutation was associated with sensitivity to regorafenib treatment,
4475 | as compared to Caco-2 and KM12SM cells expressing wild-type BRAF.
4476 | Resistance was determined by assessing cell proliferation and migration.
4477 | Evidence Direction: SUPPORTS
4478 | Evidence Level: D
4479 | Evidence Type: PREDICTIVE
4480 | Flagged: False
4481 | Id: 3776
4482 | Name: EID3776
4483 | Significance: SENSITIVITYRESPONSE
4484 | Variant Origin: SOMATIC
4485 |
4486 | ##### Disease
4487 | Disease Url: https://www.disease-ontology.org/?id=DOID:219
4488 | Display Name: Colon Cancer
4489 | Doid: 219
4490 | Id: 119
4491 | Link: /diseases/119
4492 | Name: Colon Cancer
4493 |
4494 | ##### My Disease Info
4495 | Do Def: A colorectal cancer that is located_in the colon.
4496 | Icd10: C18
4497 | Mesh: D003110
4498 | Mondo Id: MONDO:0021063
4499 | Ncit: C9242
4500 |
4501 | ##### Molecular Profile
4502 | Id: 12
4503 |
4504 | ##### Source
4505 | Abstract:
4506 | Interaction between tumor cells and stromal cells plays an important
4507 | role in the growth and metastasis of colon cancer. We previously found
4508 | that carcinoma-associated fibroblasts (CAFs) expressed platelet-derived
4509 | growth factor receptor-β (PDGFR-β) and that PDGFR targeted therapy using
4510 | imatinib or nilotinib inhibited stromal reaction. Bone marrow-derived
4511 | mesenchymal stem cells (MSCs) migrate to tumor stroma and differentiate
4512 | into CAFs. A novel oral multikinase inhibitor regorafenib inhibits
4513 | receptor tyrosine kinases expressed on stromal cells (vascular
4514 | endothelial growth factor receptor 1-3, TIE2, PDGFR-β, and fibroblast
4515 | growth factors) and tumor cells (c-KIT, RET, and BRAF). These molecules
4516 | are involved in tumor growth, angiogenesis, lymphangiogenesis, and
4517 | stromal activation. Therefore, we examined whether regorafenib impaired
4518 | the tumor-promoting effect of CAFs/MSCs. KM12SM human colon cancer cells
4519 | alone or KM12SM cells with MSCs were transplanted into the cecal wall of
4520 | nude mice. Co-implantation of KM12SM cells with MSCs into the cecal wall
4521 | of nude mice produced tumors with abundant stromal component and
4522 | promoted tumor growth and lymph node metastasis. Single treatment with
4523 | regorafenib inhibited tumor growth and metastasis by inhibiting both
4524 | tumor cells and stromal reaction. This tumor-inhibitory effect of
4525 | regorafenib was more obvious in tumors developed by co-implanting KM12SM
4526 | cells with MSCs. Our data suggested that targeting of the tumor
4527 | microenvironment with regorafenib affected tumor cell-MSC interaction,
4528 | which in turn inhibited the growth and metastasis of colon cancer.
4529 | Author String:
4530 | Hidehiko Takigawa, Yasuhiko Kitadai, Kei Shinagawa, Ryo Yuge, Yukihito
4531 | Higashi, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama
4532 | Citation: Takigawa et al., 2016
4533 | Citation Id: 26865419
4534 | Id: 1973
4535 | Journal: Cancer Sci
4536 | Link: /sources/1973
4537 | Name: PubMed: Takigawa et al., 2016
4538 | Open Access: True
4539 | Pmc Id: PMC5001714
4540 | Publication Date: 2016-5
4541 | Retracted: False
4542 | Source Type: PUBMED
4543 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26865419
4544 | Title:
4545 | Multikinase inhibitor regorafenib inhibits the growth and metastasis of
4546 | colon cancer with abundant stroma.
4547 |
4548 | ##### Therapies
4549 | Deprecated: False
4550 | Id: 27
4551 | Link: /therapies/27
4552 | Name: Regorafenib
4553 |
4554 | #### Evidence Items
4555 | Description:
4556 | In a retrospective study of 35 lung adenocarcinoma patients (with
4557 | chemotherapy previously administered in 86% of patients), patients
4558 | harboring a BRAF V600E mutation and treated with vemurafenib monotherapy
4559 | (n=29) were associated with an improved response rate; an overall
4560 | survival (with 1st-line therapy) of 25.63 months, a 54% overall response
4561 | rate and a 95% disease control rate were reported.
4562 | Evidence Direction: SUPPORTS
4563 | Evidence Level: B
4564 | Evidence Type: PREDICTIVE
4565 | Flagged: False
4566 | Id: 3782
4567 | Name: EID3782
4568 | Significance: SENSITIVITYRESPONSE
4569 | Variant Origin: SOMATIC
4570 |
4571 | ##### Disease
4572 | Disease Url: https://www.disease-ontology.org/?id=DOID:3910
4573 | Display Name: Lung Adenocarcinoma
4574 | Doid: 3910
4575 | Id: 30
4576 | Link: /diseases/30
4577 | Name: Lung Adenocarcinoma
4578 |
4579 | ##### My Disease Info
4580 | Do Def:
4581 | A lung non-small cell carcinoma that derives_from epithelial cells of
4582 | glandular origin.
4583 | Mesh: D000077192
4584 | Mondo Id: MONDO:0005061
4585 | Ncit: C27745, C3512
4586 | Disease Aliases:
4587 | - Bronchogenic Lung Adenocarcinoma
4588 | - Nonsmall Cell Adenocarcinoma
4589 |
4590 | ##### Molecular Profile
4591 | Id: 12
4592 |
4593 | ##### Source
4594 | Abstract:
4595 | Approximately 2% of lung adenocarcinomas have BRAF (v-Raf murine sarcoma
4596 | viral oncogene homolog B) mutations, including V600E and other types.
4597 | Vemurafenib, dabrafenib, and sorafenib as BRAF inhibitors are currently
4598 | tested in clinical trials, but access for patients is limited. The aim
4599 | of this study was to document the clinical course of patients treated
4600 | outside of clinical trials.We conducted a retrospective multicenter
4601 | cohort study in Europe of patients with advanced BRAF-mutant lung cancer
4602 | treated with known BRAF inhibitors. Data were anonymized and centrally
4603 | assessed for age, gender, smoking, histology, stage, local molecular
4604 | diagnostic results, systemic therapies, and survival. Best response was
4605 | assessed locally by RECIST1.1.We documented 35 patients treated in 17
4606 | centers with vemurafenib, dabrafenib, or sorafenib. Median age was 63
4607 | years (range 42-85); gender was balanced; 14 (40%) were never smokers;
4608 | all (100%) had adenocarcinoma; 29 (83%) had V600E; 6 (17%) had other
4609 | mutations; one of them had a concomitant KRAS mutation. Thirty (86%)
4610 | patients had chemotherapy in the first line. Overall survival with
4611 | first-line therapy was 25.3 months for V600E and 11.8 months for
4612 | non-V600E. Thirty-one patients received one BRAF inhibitor, and four
4613 | received a second inhibitor. Overall response rate with BRAF therapy was
4614 | 53%, and disease control rate was 85%. Median progression-free survival
4615 | with BRAF therapy was 5.0 months, and overall survival was 10.8
4616 | months.These results confirm the activity of targeted therapy in
4617 | patients with BRAF-mutant lung adenocarcinoma. Further trials are
4618 | warranted to study combination therapies and drug resistance mechanisms.
4619 | Author String:
4620 | Oliver Gautschi, Julie Milia, Bastien Cabarrou, Marie-Virginia Bluthgen,
4621 | Benjamin Besse, Egbert F Smit, Juergen Wolf, Solange Peters, Martin
4622 | Früh, Dieter Koeberle, Youssouf Oulkhouir, Martin Schuler, Alessandra
4623 | Curioni-Fontecedro, Benjamin Huret, Mallorie Kerjouan, Sebastian
4624 | Michels, Georg Pall, Sacha Rothschild, Gerald Schmid-Bindert, Matthias
4625 | Scheffler, Rémi Veillon, Luciano Wannesson, Joachim Diebold, Gérard
4626 | Zalcman, Thomas Filleron, Julien Mazières
4627 | Citation: Gautschi et al., 2015
4628 | Citation Id: 26200454
4629 | Id: 1979
4630 | Journal: J Thorac Oncol
4631 | Link: /sources/1979
4632 | Name: PubMed: Gautschi et al., 2015
4633 | Open Access: False
4634 | Publication Date: 2015-10
4635 | Retracted: False
4636 | Source Type: PUBMED
4637 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26200454
4638 | Title:
4639 | Targeted Therapy for Patients with BRAF-Mutant Lung Cancer: Results from
4640 | the European EURAF Cohort.
4641 |
4642 | ##### Therapies
4643 | Deprecated: False
4644 | Id: 4
4645 | Link: /therapies/4
4646 | Name: Vemurafenib
4647 |
4648 | #### Evidence Items
4649 | Description:
4650 | In a study of metastatic colorectal cancer patients who received 5-FU-
4651 | based first-line chemotherapy, those with BRAF V600E mutations had
4652 | reduced progression-free survival (4.3mo vs. 12.5mo, HR:4.9,
4653 | 95%CI:2.7-9.0, P<0.0001, univariate analysis; HR:4.0, 95%CI:2.2-7.4,
4654 | P<0.0001, multivariate analysis) and reduced overall survival (10.9mo
4655 | vs. 40.5mo, HR:4.5, 95%CI:2.4-8.4, P<0.0001, univariate analysis;
4656 | HR:4.1, 95%CI:2.1-8.0, P<0.0001, multivariate analysis) compared to
4657 | those with wildtype BRAF.
4658 | Evidence Direction: SUPPORTS
4659 | Evidence Level: B
4660 | Evidence Rating: 3
4661 | Evidence Type: PROGNOSTIC
4662 | Flagged: False
4663 | Id: 2116
4664 | Name: EID2116
4665 | Significance: POOR_OUTCOME
4666 | Variant Origin: SOMATIC
4667 |
4668 | ##### Disease
4669 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
4670 | Display Name: Colorectal Cancer
4671 | Doid: 9256
4672 | Id: 11
4673 | Link: /diseases/11
4674 | Name: Colorectal Cancer
4675 |
4676 | ##### My Disease Info
4677 | Do Def:
4678 | An intestinal cancer that effects the long, tube-like organ that is
4679 | connected to the small intestine at one end and the anus at the other.
4680 | Icd10: C18.9
4681 | Mondo Id: MONDO:0005575
4682 | Ncit: C4978
4683 |
4684 | ##### Molecular Profile
4685 | Id: 12
4686 |
4687 | ##### Source
4688 | Abstract:
4689 | We address the prognostic and predictive value of KRAS, PIK3CA and BRAF
4690 | mutations for clinical outcomes in response to active agents in the
4691 | treatment of metastatic colorectal cancer (mCRC).We determined KRAS,
4692 | BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC
4693 | at two institutions. All patients received 5-FU-based first-line
4694 | chemotherapy and treatment outcome was analysed retrospectively.KRAS,
4695 | BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%)
4696 | cases, respectively. Multivariate analysis uncovered BRAF mutation as an
4697 | independent prognostic factor for decreased survival (hazard ratio (HR)
4698 | 4.0, 95% confidence interval (CI) 2.1-7.6). In addition, patients with
4699 | BRAF-mutant tumours had significantly lower progression-free survival
4700 | (PFS: HR 4.0, 95% CI 2.2-7.4) than those whose tumors that carried wild-
4701 | type BRAF. Among 92 patients treated using chemotherapy and cetuximab as
4702 | salvage therapy, KRAS mutation was associated with lack of response
4703 | (P=0.002) and shorter PFS (P=0.09). BRAF (P=0.0005) and PIK3CA (P=0.01)
4704 | mutations also predicted reduced PFS in response to cetuximab salvage
4705 | therapy.These results underscore the potential of mutational profiling
4706 | to identify CRCs with different natural histories or treatment
4707 | responses. The adverse significance of BRAF mutation should inform
4708 | patient selection and stratification in clinical trials.
4709 | Author String:
4710 | J Souglakos, J Philips, R Wang, S Marwah, M Silver, M Tzardi, J Silver,
4711 | S Ogino, S Hooshmand, E Kwak, E Freed, J A Meyerhardt, Z Saridaki, V
4712 | Georgoulias, D Finkelstein, C S Fuchs, M H Kulke, R A Shivdasani
4713 | Citation: Souglakos et al., 2009
4714 | Citation Id: 19603024
4715 | Id: 1479
4716 | Journal: Br J Cancer
4717 | Link: /sources/1479
4718 | Name: PubMed: Souglakos et al., 2009
4719 | Open Access: True
4720 | Pmc Id: PMC2720232
4721 | Publication Date: 2009-8-4
4722 | Retracted: False
4723 | Source Type: PUBMED
4724 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19603024
4725 | Title:
4726 | Prognostic and predictive value of common mutations for treatment
4727 | response and survival in patients with metastatic colorectal cancer.
4728 |
4729 | #### Evidence Items
4730 | Description:
4731 | In a lung adenocarcinoma patient with brain metastases harboring BRAF
4732 | V600E mutation, BRAF V600E was associated with sensitivity to
4733 | vemurafenib treatment. Upon treatment with vemurafenib monotherapy, the
4734 | patient�s metastases demonstrated significant response and pleural right
4735 | effusion improvement was observed; however, at 4 months the patient�s
4736 | disease progressed resulting in death.
4737 | Evidence Direction: SUPPORTS
4738 | Evidence Level: C
4739 | Evidence Type: PREDICTIVE
4740 | Flagged: False
4741 | Id: 3780
4742 | Name: EID3780
4743 | Significance: SENSITIVITYRESPONSE
4744 | Variant Origin: SOMATIC
4745 |
4746 | ##### Disease
4747 | Disease Url: https://www.disease-ontology.org/?id=DOID:3910
4748 | Display Name: Lung Adenocarcinoma
4749 | Doid: 3910
4750 | Id: 30
4751 | Link: /diseases/30
4752 | Name: Lung Adenocarcinoma
4753 |
4754 | ##### My Disease Info
4755 | Do Def:
4756 | A lung non-small cell carcinoma that derives_from epithelial cells of
4757 | glandular origin.
4758 | Mesh: D000077192
4759 | Mondo Id: MONDO:0005061
4760 | Ncit: C27745, C3512
4761 | Disease Aliases:
4762 | - Bronchogenic Lung Adenocarcinoma
4763 | - Nonsmall Cell Adenocarcinoma
4764 |
4765 | ##### Molecular Profile
4766 | Id: 12
4767 |
4768 | ##### Source
4769 | Abstract:
4770 | Somatic BRAF mutations have been reported in 1-4% of non-small cell lung
4771 | cancer (NSCLC), primarily in adenocarcinomas with the BRAF (V600E)
4772 | mutation in about 50% of the cases. The role of BRAF mutation in NSCLC
4773 | and the treatment for tumors with such mutations is still evolving. Our
4774 | patient had metastatic NSCLC with metastases to her brain. Due to the
4775 | BRAF (V600E) mutation in her tumor and her poor functional status, we
4776 | offered her off-label treatment with vemurafenib, a BRAF inhibitor
4777 | approved for use in metastatic melanoma. Our patient's visceral disease
4778 | improved supporting vemurafenib's efficacy in the treatment of
4779 | metastatic BRAF-mutated NSCLC. The regression of intracranial disease
4780 | indicated vemurafenib was able to cross the blood-brain barrier and was
4781 | efficacious in treating brain metastases in this patient with lung
4782 | cancer.
4783 | Author String: Sara D Robinson, Joyce A O'Shaughnessy, C Lance Cowey, Kartik Konduri
4784 | Citation: Robinson et al., 2014
4785 | Citation Id: 24888229
4786 | Id: 1977
4787 | Journal: Lung Cancer
4788 | Link: /sources/1977
4789 | Name: PubMed: Robinson et al., 2014
4790 | Open Access: False
4791 | Publication Date: 2014-8
4792 | Retracted: False
4793 | Source Type: PUBMED
4794 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24888229
4795 | Title:
4796 | BRAF V600E-mutated lung adenocarcinoma with metastases to the brain
4797 | responding to treatment with vemurafenib.
4798 |
4799 | ##### Therapies
4800 | Deprecated: False
4801 | Id: 4
4802 | Link: /therapies/4
4803 | Name: Vemurafenib
4804 |
4805 | #### Evidence Items
4806 | Description:
4807 | In an in vitro study, the BCPAP cell line expressing a BRAF V600E
4808 | mutation was associated with sensitivity to vemurafenib treatment.
4809 | Sensitivity was determined by assessing cell viability and apoptotic
4810 | cell death. However, the 8505C cell line expressing a BRAF V600E
4811 | mutation and high MET protein phosphorylation levels was reported to be
4812 | insensitive to vemurafenib treatment.
4813 | Evidence Direction: SUPPORTS
4814 | Evidence Level: D
4815 | Evidence Type: PREDICTIVE
4816 | Flagged: False
4817 | Id: 3785
4818 | Name: EID3785
4819 | Significance: SENSITIVITYRESPONSE
4820 | Variant Origin: SOMATIC
4821 |
4822 | ##### Disease
4823 | Disease Url: https://www.disease-ontology.org/?id=DOID:3963
4824 | Display Name: Thyroid Gland Carcinoma
4825 | Doid: 3963
4826 | Id: 155
4827 | Link: /diseases/155
4828 | Name: Thyroid Gland Carcinoma
4829 |
4830 | ##### My Disease Info
4831 | Do Def: A thyroid gland cancer that has_material_basis_in epithelial cells.
4832 | Mesh: D013964
4833 | Mondo Id: MONDO:0015075
4834 | Ncit: C4815
4835 | Disease Aliases: Head And Neck Cancer, Thyroid, Thyroid Carcinoma
4836 |
4837 | ##### Molecular Profile
4838 | Id: 12
4839 |
4840 | ##### Source
4841 | Abstract:
4842 | BRAF (V600E) mutation is the most commonly detected genetic alteration
4843 | in thyroid cancer. Unlike its high treatment response to selective BRAF
4844 | inhibitor (PLX4032) in metastatic melanoma, the treatment response in
4845 | thyroid cancer is reported to be low. The purpose of this study is to
4846 | investigate the resistance mechanism responsible for this low treatment
4847 | response to BRAF inhibitor in order to maximize the effect of targeted
4848 | therapy. We examined the expression of feedback regulation mechanisms
4849 | and alterations in the upper signal transduction pathway in thyroid
4850 | cancer cell lines harboring BRAF mutation. Also, we investigated the
4851 | effect of dual inhibition from combinatorial therapy. Two thyroid cancer
4852 | cell lines, 8505C (anaplastic thyroid cancer) and BCPAP (papillary
4853 | thyroid cancer) were selected and treated with PLX4032 and its drug
4854 | sensitivity were examined and compared. Further investigation on the
4855 | changes in signals responsible for the different treatment response to
4856 | PLX4032 was carried out and the same experiment was performed on
4857 | orthotopic xenograft mouse models. Unlike BCPAP cells, 8505C cells
4858 | presented drug resistance to PLX4032 treatment and this was mainly due
4859 | to increased expression of c-Met. Effective inhibitions of c-Met, p-AKT,
4860 | and p-ERK were achieved after dual treatment with BRAF inhibitor
4861 | (PLX4032) and c-Met inhibitor (PHA665752). Similar results were
4862 | confirmed by in vivo study with orthotopic xenograft mouse model. c-Met-
4863 | mediated reactivation of the PI3K/AKT pathway and MAPK pathway
4864 | contributes to the relative insensitivity of BRAF (V600E) mutant
4865 | anaplastic thyroid cancer cells to PLX4032. Dual inhibition of BRAF and
4866 | c-Met leads to sustained treatment response. © 2015 Wiley Periodicals,
4867 | Inc.
4868 | Author String:
4869 | Hyung Kwon Byeon, Hwi Jung Na, Yeon Ju Yang, Hyeong Ju Kwon, Jae Won
4870 | Chang, Myung Jin Ban, Won Shik Kim, Dong Yeob Shin, Eun Jig Lee, Yoon
4871 | Woo Koh, Joo-Heon Yoon, Eun Chang Choi
4872 | Citation: Byeon et al., 2016
4873 | Citation Id: 26456083
4874 | Id: 1982
4875 | Journal: Mol Carcinog
4876 | Link: /sources/1982
4877 | Name: PubMed: Byeon et al., 2016
4878 | Open Access: False
4879 | Publication Date: 2016-11
4880 | Retracted: False
4881 | Source Type: PUBMED
4882 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26456083
4883 | Title:
4884 | c-Met-mediated reactivation of PI3K/AKT signaling contributes to
4885 | insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition.
4886 |
4887 | ##### Therapies
4888 | Deprecated: False
4889 | Id: 4
4890 | Link: /therapies/4
4891 | Name: Vemurafenib
4892 |
4893 | #### Evidence Items
4894 | Description:
4895 | An anaplastic pleomorphic xanthoastrocytoma patient harboring BRAF V600E
4896 | mutation was associated with improved response to vemurafenib treatment.
4897 | The patient was treated with radiation and temozolomide before
4898 | experiencing disease progression; subsequent treatment with vemurafenib
4899 | monotherapy, for a 12 week period, resulted in a near complete response.
4900 | Evidence Direction: SUPPORTS
4901 | Evidence Level: C
4902 | Evidence Type: PREDICTIVE
4903 | Flagged: False
4904 | Id: 3786
4905 | Name: EID3786
4906 | Significance: SENSITIVITYRESPONSE
4907 | Variant Origin: SOMATIC
4908 |
4909 | ##### Disease
4910 | Disease Url: https://www.disease-ontology.org/?id=DOID:4852
4911 | Display Name: Pleomorphic Xanthoastrocytoma
4912 | Doid: 4852
4913 | Id: 1124
4914 | Link: /diseases/1124
4915 | Name: Pleomorphic Xanthoastrocytoma
4916 |
4917 | ##### My Disease Info
4918 | Do Def:
4919 | A low grade glioma that is characterized by pleomorphic and lipidized
4920 | cells expressing GFAP often surrounded by a reticulin network and
4921 | eosinophilic granular bodies.
4922 | Icdo: 9424/3
4923 | Mondo Id: MONDO:0016690
4924 | Ncit: C4323
4925 | Disease Aliases: Pleomorphic Xantho-astrocytoma
4926 |
4927 | ##### Molecular Profile
4928 | Id: 12
4929 |
4930 | ##### Source
4931 | Author String:
4932 | Eudocia Q Lee, Sandra Ruland, Nicole R LeBoeuf, Patrick Y Wen, Sandro
4933 | Santagata
4934 | Citation: Lee et al., 2016
4935 | Citation Id: 25092772
4936 | Id: 1983
4937 | Journal: J Clin Oncol
4938 | Link: /sources/1983
4939 | Name: PubMed: Lee et al., 2016
4940 | Open Access: False
4941 | Publication Date: 2016-4-1
4942 | Retracted: False
4943 | Source Type: PUBMED
4944 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25092772
4945 | Title:
4946 | Successful Treatment of a Progressive BRAF V600E-Mutated Anaplastic
4947 | Pleomorphic Xanthoastrocytoma With Vemurafenib Monotherapy.
4948 |
4949 | ##### Therapies
4950 | Deprecated: False
4951 | Id: 4
4952 | Link: /therapies/4
4953 | Name: Vemurafenib
4954 |
4955 | #### Evidence Items
4956 | Description:
4957 | In a malignant peripheral nerve sheath tumor patient harboring a BRAF
4958 | V600E mutation, response to vemurafenib monotherapy was reported. Upon
4959 | identification of the BRAF V600E mutation, the patient was treated with
4960 | sorafenib monotherapy, but quickly progressed; subsequently, the patient
4961 | was treated with vemurafenib. 33 days after treatment was initiated,
4962 | tumor response was reported, as evident by the disappearance of chest
4963 | and abdominal skin lesions.
4964 | Evidence Direction: SUPPORTS
4965 | Evidence Level: C
4966 | Evidence Type: PREDICTIVE
4967 | Flagged: False
4968 | Id: 3788
4969 | Name: EID3788
4970 | Significance: SENSITIVITYRESPONSE
4971 | Variant Origin: SOMATIC
4972 |
4973 | ##### Disease
4974 | Disease Url: https://www.disease-ontology.org/?id=DOID:5940
4975 | Display Name: Malignant Peripheral Nerve Sheath Tumor
4976 | Doid: 5940
4977 | Id: 326
4978 | Link: /diseases/326
4979 | Name: Malignant Peripheral Nerve Sheath Tumor
4980 |
4981 | ##### My Disease Info
4982 | Icdo: 9540/3
4983 | Mesh: D018319
4984 | Mondo Id: MONDO:0017827
4985 | Ncit: C3798
4986 | Disease Aliases: Malignant Neoplasm Of The Peripheral Nerve Sheath
4987 |
4988 | ##### Molecular Profile
4989 | Id: 12
4990 |
4991 | ##### Source
4992 | Abstract:
4993 | No effective systemic treatment exists for malignant peripheral nerve
4994 | sheath tumors (MPNSTs). These tumors have been reported to show
4995 | increased activity in the mitogen-activated protein kinase pathway from
4996 | the loss of neurofibromatosis-1 regulation and occasionally from BRAF
4997 | V600E mutation. A patient with sporadic metastatic MPNST and the BRAF
4998 | V600E mutation was treated with standard doses of sorafenib and later
4999 | vemurafenib and followed for response. The patient showed a rapid but
5000 | modest and transient response to sorafenib and a very dramatic response
5001 | to vemurafenib. This case represents the first report of successful
5002 | systemic treatment of MPNST with an inhibitor of the BRAF V600E
5003 | mutation. It will be important to define the general utility of this
5004 | approach and related therapies in this disease.
5005 | Author String: Henry G Kaplan
5006 | Citation: Kaplan, 2013
5007 | Citation Id: 24335681
5008 | Id: 1958
5009 | Journal: J Natl Compr Canc Netw
5010 | Link: /sources/1958
5011 | Name: PubMed: Kaplan, 2013
5012 | Open Access: False
5013 | Publication Date: 2013-12-1
5014 | Retracted: False
5015 | Source Type: PUBMED
5016 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24335681
5017 | Title:
5018 | Vemurafenib treatment of BRAF V600E-mutated malignant peripheral nerve
5019 | sheath tumor.
5020 |
5021 | ##### Therapies
5022 | Deprecated: False
5023 | Id: 4
5024 | Link: /therapies/4
5025 | Name: Vemurafenib
5026 |
5027 | #### Evidence Items
5028 | Description:
5029 | A primary central nervous system (CNS)-histiocytic sarcoma patient
5030 | harboring BRAF V600E mutation was associated with improved response to
5031 | vemurafenib treatment. The patient was treated with vemurafenib
5032 | monotherapy and obtained a clinical, biological and radiologic response;
5033 | subsequently, the patient developed progressive disease and died 6
5034 | months after initial treatment with vemurafenib.
5035 | Evidence Direction: SUPPORTS
5036 | Evidence Level: C
5037 | Evidence Type: PREDICTIVE
5038 | Flagged: False
5039 | Id: 3789
5040 | Name: EID3789
5041 | Significance: SENSITIVITYRESPONSE
5042 | Variant Origin: SOMATIC
5043 |
5044 | ##### Disease
5045 | Disease Url: https://www.disease-ontology.org/?id=DOID:4231
5046 | Display Name: Histiocytoma
5047 | Doid: 4231
5048 | Id: 964
5049 | Link: /diseases/964
5050 | Name: Histiocytoma
5051 |
5052 | ##### My Disease Info
5053 | Icdo: 8831/0
5054 | Mesh: D051642
5055 | Mondo Id: MONDO:0005509
5056 | Ncit: C35765
5057 |
5058 | ##### Molecular Profile
5059 | Id: 12
5060 |
5061 | ##### Source
5062 | Author String:
5063 | Ahmed Idbaih, Karima Mokhtari, Jean-François Emile, Damien Galanaud,
5064 | Hayat Belaid, Simon de Bernard, Neila Benameur, Vlad-Ciprian Barlog,
5065 | Dimitri Psimaras, Jean Donadieu, Catherine Carpentier, Nadine Martin-
5066 | Duverneuil, Julien Haroche, Loic Feuvret, Noel Zahr, Jean-Yves Delattre,
5067 | Khê Hoang-Xuan
5068 | Citation: Idbaih et al., 2014
5069 | Citation Id: 25209580
5070 | Id: 1985
5071 | Journal: Neurology
5072 | Link: /sources/1985
5073 | Name: PubMed: Idbaih et al., 2014
5074 | Open Access: False
5075 | Publication Date: 2014-10-14
5076 | Retracted: False
5077 | Source Type: PUBMED
5078 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25209580
5079 | Title:
5080 | Dramatic response of a BRAF V600E-mutated primary CNS histiocytic
5081 | sarcoma to vemurafenib.
5082 |
5083 | ##### Therapies
5084 | Deprecated: False
5085 | Id: 4
5086 | Link: /therapies/4
5087 | Name: Vemurafenib
5088 |
5089 | #### Evidence Items
5090 | Description:
5091 | In a conjunctival malignant melanoma patient harboring a BRAF V600E
5092 | mutation, BRAF V600E was associated with response to vemurafenib
5093 | treatment. Prior to identification of the BRAF V600E mutation, the
5094 | patient was treated with cryotherapy, standard chemotherapy and whole
5095 | brain radiotherapy; the patient achieved a 4 month progression free
5096 | survival with vemurafenib treatment prior to disease progression.
5097 | Evidence Direction: SUPPORTS
5098 | Evidence Level: C
5099 | Evidence Type: PREDICTIVE
5100 | Flagged: False
5101 | Id: 3790
5102 | Name: EID3790
5103 | Significance: SENSITIVITYRESPONSE
5104 | Variant Origin: SOMATIC
5105 |
5106 | ##### Disease
5107 | Disease Url: https://www.disease-ontology.org/?id=DOID:1751
5108 | Display Name: Malignant Conjunctival Melanoma
5109 | Doid: 1751
5110 | Id: 2605
5111 | Link: /diseases/2605
5112 | Name: Malignant Conjunctival Melanoma
5113 |
5114 | ##### My Disease Info
5115 | Mondo Id: MONDO:0002096
5116 | Ncit: C4550
5117 | Disease Aliases:
5118 | - Conjunctival Melanoma
5119 | - Malignant Melanoma Of Conjunctiva
5120 |
5121 | ##### Molecular Profile
5122 | Id: 12
5123 |
5124 | ##### Source
5125 | Abstract:
5126 | Conjunctival malignant melanoma (CMM) is a rare malignancy and in the
5127 | advanced setting there is no effective treatment. In contrast, half of
5128 | cutaneous melanomas have BRAF mutations and treatment with BRAF
5129 | inhibitors is established for patients with disseminated disease. The
5130 | most common form of ocular melanoma, uveal melanoma, lacks these
5131 | mutations, however, their presence has been reported for CMM.We used the
5132 | BRAF inhibitor vemurafenib to treat a 53 year-old female suffering from
5133 | a BRAF(V600E) mutated metastatic CMM. The patient benefited from the
5134 | treatment, a response was evident within a week and she experienced a
5135 | progression free survival of four months.To our knowledge, this is the
5136 | first described case of response to vemurafenib treatment in a patient
5137 | with ocular melanoma.
5138 | Author String: A Maleka, G Åström, P Byström, G J Ullenhag
5139 | Citation: Maleka et al., 2016
5140 | Citation Id: 27520988
5141 | Id: 1986
5142 | Journal: BMC Cancer
5143 | Link: /sources/1986
5144 | Name: PubMed: Maleka et al., 2016
5145 | Open Access: True
5146 | Pmc Id: PMC4983009
5147 | Publication Date: 2016-8-12
5148 | Retracted: False
5149 | Source Type: PUBMED
5150 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/27520988
5151 | Title:
5152 | A case report of a patient with metastatic ocular melanoma who
5153 | experienced a response to treatment with the BRAF inhibitor vemurafenib.
5154 |
5155 | ##### Therapies
5156 | Deprecated: False
5157 | Id: 4
5158 | Link: /therapies/4
5159 | Name: Vemurafenib
5160 |
5161 | #### Evidence Items
5162 | Description:
5163 | Chemotherapy-refractory, metastatic cholangiocarcinoma with CNS
5164 | involvement and a BRAF V600E mutation had a partial response at 8 weeks
5165 | to dabrafenib and trametinib combination with complete radiologic
5166 | regression at 12 weeks. At 6 months the patient was still on treatment.
5167 | Evidence Direction: SUPPORTS
5168 | Evidence Level: C
5169 | Evidence Rating: 3
5170 | Evidence Type: PREDICTIVE
5171 | Flagged: False
5172 | Id: 5902
5173 | Name: EID5902
5174 | Significance: SENSITIVITYRESPONSE
5175 | Variant Origin: SOMATIC
5176 |
5177 | ##### Disease
5178 | Disease Url: https://www.disease-ontology.org/?id=DOID:4947
5179 | Display Name: Cholangiocarcinoma
5180 | Doid: 4947
5181 | Id: 29
5182 | Link: /diseases/29
5183 | Name: Cholangiocarcinoma
5184 |
5185 | ##### My Disease Info
5186 | Do Def:
5187 | A bile duct adenocarcinoma that has_material_basis_in bile duct
5188 | epithelial cells.
5189 | Icd10: C22.1
5190 | Icdo: 8160/3
5191 | Mesh: D018281
5192 | Mondo Id: MONDO:0019087
5193 | Ncit: C4436, C8265
5194 | Disease Aliases:
5195 | - Adult Primary Cholangiocarcinoma
5196 | - Adult Primary Cholangiocellular Carcinoma
5197 | - Cholangiosarcoma
5198 |
5199 | ##### Molecular Profile
5200 | Id: 12
5201 |
5202 | ##### Source
5203 | Abstract:
5204 | Since the prognosis of advanced cholangiocarcinoma (CCA) remains poor
5205 | with traditional chemotherapy, attention has shifted to molecularly
5206 | targeted agents. Results of available clinical studies reveal little or
5207 | no benefit of using targeted agents in advanced CCA. Limitations of
5208 | these trials could be the lack of comprehensive molecular and genetic
5209 | characterization of CCA samples in order to identify potential drug
5210 | targets. Here we report a case of a 59-year-old female with
5211 | chemotherapy-refractor, metastatic extrahepatic cholangiocarcinoma
5212 | (EHCCA). After failure of first-line chemotherapy with cisplatin plus
5213 | gemcitabine, next generation sequencing (NGS) based tumor molecular
5214 | profiling was performed on aspiration cytological sample, that revealed
5215 | BRAF V600E mutation. Multidisciplinary team decided on the initiation of
5216 | combined treatment with BRAF and MEK inhibitors. Dabrafenib was started
5217 | orally 150 mg twice a day, adding trametinib 2 mg once a day. Right from
5218 | the initiation of targeted therapy, significant clinical improvement had
5219 | been observed. Even though the first restaging computed tomography (CT)
5220 | scan at 8 weeks revealed spectacular decrease in all metastatic sites, a
5221 | new hepatic mass of 67 mm × 40 mm was identified and interpreted as new
5222 | metastatic lesion. As the clinical and radiological response was
5223 | contradictory, CT-guided biopsy was taken from the hepatic lesion while
5224 | the therapy was continued on. Histopathologic evaluation excluded the
5225 | hepatic lesion from being a metastasis, instead described it as a
5226 | fibrotic, inflammatory lesion. At 12 week, PET CT confirmed further
5227 | tumor regression with complete regression of the multiple cerebral
5228 | metastases. The therapy has been extremely well tolerated by the
5229 | patient. According to our knowledge, this is the first reported case on
5230 | a successful treatment of EHCCA with the combination of dabrafenib and
5231 | trametinib. Our case highlights the importance of molecular profiling in
5232 | CCA, in order to find potential actionable driver mutations for
5233 | personalised treatment.
5234 | Author String:
5235 | Judit Kocsis, Anita Árokszállási, Csilla András, Ingrid Balogh, Edit
5236 | Béres, Júlia Déri, István Peták, Levente Jánváry, Zsolt Horváth
5237 | Citation: Kocsis et al., 2017
5238 | Citation Id: 28480077
5239 | Id: 2381
5240 | Journal: J Gastrointest Oncol
5241 | Link: /sources/2381
5242 | Name: PubMed: Kocsis et al., 2017
5243 | Open Access: True
5244 | Pmc Id: PMC5401859
5245 | Publication Date: 2017-4
5246 | Retracted: False
5247 | Source Type: PUBMED
5248 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/28480077
5249 | Title:
5250 | Combined dabrafenib and trametinib treatment in a case of chemotherapy-
5251 | refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic
5252 | clinical and radiological response with a confusing synchronic new liver
5253 | lesion.
5254 |
5255 | ##### Therapies
5256 | Deprecated: False
5257 | Id: 22
5258 | Link: /therapies/22
5259 | Name: Dabrafenib
5260 |
5261 | ##### Therapies
5262 | Deprecated: False
5263 | Id: 19
5264 | Link: /therapies/19
5265 | Name: Trametinib
5266 |
5267 | #### Evidence Items
5268 | Description:
5269 | Two cases of patients with BRAF V600E positive, refractory intrahepatic
5270 | cholangiocarcinoma showed excellent clinical and radiographic response
5271 | to combination dabrafenib and trametinib treatment. One patient achieved
5272 | complete remission at 6 months with progression at 9 months and the
5273 | other partial remission at 2 months and no progression as of 5 months.
5274 | Evidence Direction: SUPPORTS
5275 | Evidence Level: C
5276 | Evidence Rating: 3
5277 | Evidence Type: PREDICTIVE
5278 | Flagged: False
5279 | Id: 5903
5280 | Name: EID5903
5281 | Significance: SENSITIVITYRESPONSE
5282 | Variant Origin: SOMATIC
5283 |
5284 | ##### Disease
5285 | Disease Url: https://www.disease-ontology.org/?id=DOID:4928
5286 | Display Name: Intrahepatic Cholangiocarcinoma
5287 | Doid: 4928
5288 | Id: 1165
5289 | Link: /diseases/1165
5290 | Name: Intrahepatic Cholangiocarcinoma
5291 |
5292 | ##### My Disease Info
5293 | Do Def:
5294 | A cholangiocarcinoma that arises from the intrahepatic bile duct
5295 | epithelium in any site of the intrahepatic biliary tree.
5296 | Icd10: C22.1
5297 | Mesh: D018281
5298 | Mondo Id: MONDO:0003210
5299 | Ncit: C35417
5300 | Disease Aliases:
5301 | - Intrahepatic Bile Duct Carcinoma
5302 | - Peripheral Cholangiocarcinoma
5303 |
5304 | ##### Molecular Profile
5305 | Id: 12
5306 |
5307 | ##### Source
5308 | Abstract:
5309 | Intrahepatic cholangiocarcinoma (ICC) typically presents at an advanced
5310 | stage and is associated with a poor oncological outcome. The median
5311 | survival for metastatic ICC is less than 1 year with standard
5312 | chemotherapy. ICC is associated with distinct oncogenic drivers
5313 | including IDH (isocitrate dehydrogenase), HER-2 (human epidermal growth
5314 | factor 2), and BRAF (v-Raf murine sarcoma viral oncogene homolog B),
5315 | which may benefit from matching targeted therapies. Hereby we report 2
5316 | cases of BRAF V600E refractory ICC treated with dual BRAF and MEK
5317 | inhibitors (dabrafenib and trametinib) with excellent clinical and
5318 | radiological response to therapy and with protracted duration of disease
5319 | control. Our first patient achieved CR (complete remission) at 6 months
5320 | of treatment with ultimate disease progression at 9 months. The second
5321 | patient achieved a PR (partial response) at 2 months from starting
5322 | treatment and remains progression free at 5 months. Our results confirm
5323 | the activity of dual BRAF and MEK targeting in BRAF mutated ICC, adding
5324 | further support to 3 additional case-reports in the literature. Dual
5325 | targeting appears superior to other case reports with BRAF inhibition
5326 | alone and appear favorable to historic data with cytotoxic chemotherapy.
5327 | Given the poor outlook and refractoriness of BRAF mutant ICC, future
5328 | studies should focus on early integration of BRAF/MEK inhibition.
5329 | Author String: Viraj Lavingia, Marwan Fakih
5330 | Citation: Lavingia et al., 2016
5331 | Citation Id: 28078132
5332 | Id: 2380
5333 | Journal: J Gastrointest Oncol
5334 | Link: /sources/2380
5335 | Name: PubMed: Lavingia et al., 2016
5336 | Open Access: True
5337 | Pmc Id: PMC5177579
5338 | Publication Date: 2016-12
5339 | Retracted: False
5340 | Source Type: PUBMED
5341 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/28078132
5342 | Title:
5343 | Impressive response to dual BRAF and MEK inhibition in patients with
5344 | BRAF mutant intrahepatic cholangiocarcinoma-2 case reports and a brief
5345 | review.
5346 |
5347 | ##### Therapies
5348 | Deprecated: False
5349 | Id: 22
5350 | Link: /therapies/22
5351 | Name: Dabrafenib
5352 |
5353 | ##### Therapies
5354 | Deprecated: False
5355 | Id: 19
5356 | Link: /therapies/19
5357 | Name: Trametinib
5358 |
5359 | #### Evidence Items
5360 | Description:
5361 | Dabrafenib and trametinib combination showed durable response for a
5362 | patient with standard chemotherapy and radiation refractory, poorly
5363 | differentiated, intrahepatic cholangiocarcinoma harboring BRAF V600E. At
5364 | time of publication, 8.5 months, the patient was still on treatment.
5365 | Evidence Direction: SUPPORTS
5366 | Evidence Level: C
5367 | Evidence Rating: 3
5368 | Evidence Type: PREDICTIVE
5369 | Flagged: False
5370 | Id: 5904
5371 | Name: EID5904
5372 | Significance: SENSITIVITYRESPONSE
5373 | Variant Origin: SOMATIC
5374 |
5375 | ##### Disease
5376 | Disease Url: https://www.disease-ontology.org/?id=DOID:4928
5377 | Display Name: Intrahepatic Cholangiocarcinoma
5378 | Doid: 4928
5379 | Id: 1165
5380 | Link: /diseases/1165
5381 | Name: Intrahepatic Cholangiocarcinoma
5382 |
5383 | ##### My Disease Info
5384 | Do Def:
5385 | A cholangiocarcinoma that arises from the intrahepatic bile duct
5386 | epithelium in any site of the intrahepatic biliary tree.
5387 | Icd10: C22.1
5388 | Mesh: D018281
5389 | Mondo Id: MONDO:0003210
5390 | Ncit: C35417
5391 | Disease Aliases:
5392 | - Intrahepatic Bile Duct Carcinoma
5393 | - Peripheral Cholangiocarcinoma
5394 |
5395 | ##### Molecular Profile
5396 | Id: 12
5397 |
5398 | ##### Source
5399 | Abstract:
5400 | This is the case of a 47-year-old woman diagnosed with chemotherapy and
5401 | radiation-refractory BRAF V600E mutant, poorly differentiated
5402 | intrahepatic cholangiocarcinoma (ICC), with multiple metastatic lesions
5403 | within the liver, lungs, pleura, and bone, stage IV. Discussion of her
5404 | malignancy's next-generation sequencing genomic information at a
5405 | multidisciplinary molecular tumour board took place. The patient was
5406 | considered a suitable candidate for dual BRAF and MEK inhibition, with
5407 | the intent to prolong her survival and optimize the quality of life. We
5408 | report her excellent tolerance and exceptional response to dual therapy
5409 | with dabrafenib and trametinib, including symptomatic and sustained
5410 | near-complete radiological improvement. We also briefly review the
5411 | current knowledge of the genomics of cholangiocarcinoma with a focus on
5412 | BRAF mutations, and make a point of the importance of the establishment
5413 | of a molecular tumour board for personalized genomic medicine
5414 | approaches. To our knowledge, this is the first reported case of the use
5415 | of personalized genomic information for the successful management of a
5416 | patient with ICC, and it is also the first description of dual BRAF and
5417 | MEK targeted therapy in this malignancy, leading to what is considered
5418 | an exceptional response.
5419 | Author String:
5420 | Arturo Loaiza-Bonilla, Erica Clayton, Emma Furth, Mark O'Hara, Jennifer
5421 | Morrissette
5422 | Citation: Loaiza-Bonilla et al., 2014
5423 | Citation Id: 25435907
5424 | Id: 2379
5425 | Journal: Ecancermedicalscience
5426 | Link: /sources/2379
5427 | Name: PubMed: Loaiza-Bonilla et al., 2014
5428 | Open Access: True
5429 | Pmc Id: PMC4239128
5430 | Publication Date: 2014
5431 | Retracted: False
5432 | Source Type: PUBMED
5433 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25435907
5434 | Title:
5435 | Dramatic response to dabrafenib and trametinib combination in a BRAF
5436 | V600E-mutated cholangiocarcinoma: implementation of a molecular tumour
5437 | board and next-generation sequencing for personalized medicine.
5438 |
5439 | ##### Therapies
5440 | Deprecated: False
5441 | Id: 22
5442 | Link: /therapies/22
5443 | Name: Dabrafenib
5444 |
5445 | ##### Therapies
5446 | Deprecated: False
5447 | Id: 19
5448 | Link: /therapies/19
5449 | Name: Trametinib
5450 |
5451 | #### Evidence Items
5452 | Description:
5453 | The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or
5454 | SHH alterations to treatment with pertuzumab plus trastuzumab,
5455 | erlotinib, vemurafenib, or vismodegib, respectively. Among 2 patients
5456 | with BRAF V600E mutant colorectal cancer, 1 had a partial response.
5457 | Evidence Direction: SUPPORTS
5458 | Evidence Level: C
5459 | Evidence Rating: 2
5460 | Evidence Type: PREDICTIVE
5461 | Flagged: False
5462 | Id: 5960
5463 | Name: EID5960
5464 | Significance: SENSITIVITYRESPONSE
5465 | Variant Origin: SOMATIC
5466 |
5467 | ##### Disease
5468 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
5469 | Display Name: Colorectal Cancer
5470 | Doid: 9256
5471 | Id: 11
5472 | Link: /diseases/11
5473 | Name: Colorectal Cancer
5474 |
5475 | ##### My Disease Info
5476 | Do Def:
5477 | An intestinal cancer that effects the long, tube-like organ that is
5478 | connected to the small intestine at one end and the anus at the other.
5479 | Icd10: C18.9
5480 | Mondo Id: MONDO:0005575
5481 | Ncit: C4978
5482 |
5483 | ##### Molecular Profile
5484 | Id: 12
5485 |
5486 | ##### Source
5487 | Abstract:
5488 | Purpose Detection of specific molecular alterations in tumors guides the
5489 | selection of effective targeted treatment of patients with several types
5490 | of cancer. These molecular alterations may occur in other tumor types
5491 | for which the efficacy of targeted therapy remains unclear. The
5492 | MyPathway study evaluates the efficacy and safety of selected targeted
5493 | therapies in tumor types that harbor relevant genetic alterations but
5494 | are outside of current labeling for these treatments. Methods MyPathway
5495 | ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter,
5496 | nonrandomized, phase IIa multiple basket study. Patients with advanced
5497 | refractory solid tumors harboring molecular alterations in human
5498 | epidermal growth factor receptor-2, epidermal growth factor receptor,
5499 | v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway
5500 | are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or
5501 | vismodegib, respectively. The primary end point is investigator-assessed
5502 | objective response rate within each tumor-pathway cohort. Results
5503 | Between April 1, 2014 and November 1, 2016, 251 patients with 35
5504 | different tumor types received study treatment. The efficacy population
5505 | contains 230 treated patients who were evaluated for response or
5506 | discontinued treatment before evaluation. Fifty-two patients (23%) with
5507 | 14 different tumor types had objective responses (complete, n = 4;
5508 | partial, n = 48). Tumor-pathway cohorts with notable objective response
5509 | rates included human epidermal growth factor
5510 | receptor-2-amplified/overexpressing colorectal (38% [14 of 37]; 95% CI,
5511 | 23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1
5512 | V600-mutated non-small-cell lung cancer (43% [six of 14]; 95% CI, 18% to
5513 | 71%). Conclusion The four currently approved targeted therapy regimens
5514 | in the MyPathway study produced meaningful responses when administered
5515 | without chemotherapy in several refractory solid tumor types not
5516 | currently labeled for these agents.
5517 | Author String:
5518 | John D Hainsworth, Funda Meric-Bernstam, Charles Swanton, Herbert
5519 | Hurwitz, David R Spigel, Christopher Sweeney, Howard Burris, Ron Bose,
5520 | Bongin Yoo, Alisha Stein, Mary Beattie, Razelle Kurzrock
5521 | Citation: Hainsworth et al., 2018
5522 | Citation Id: 29320312
5523 | Id: 2414
5524 | Journal: J Clin Oncol
5525 | Link: /sources/2414
5526 | Name: PubMed: Hainsworth et al., 2018
5527 | Open Access: False
5528 | Publication Date: 2018-2-20
5529 | Retracted: False
5530 | Source Type: PUBMED
5531 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/29320312
5532 | Title:
5533 | Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular
5534 | Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple
5535 | Basket Study.
5536 |
5537 | ##### Therapies
5538 | Deprecated: False
5539 | Id: 4
5540 | Link: /therapies/4
5541 | Name: Vemurafenib
5542 |
5543 | #### Evidence Items
5544 | Description:
5545 | In this trial, 142 patients with metastatic, BRAF V600E mutant
5546 | colorectal cancer were randomized to receive either BRAF inhibitor
5547 | dabrafenib (D) + EGFR inhibitor panitumumab (P); or a triple therapy of
5548 | D + P and MEK inhibition with trametinib (T) or T + P. Confirmed
5549 | response rates for D+P (n=20), D+T+P (n=91), and T+P (n=31) were 10%,
5550 | 21%, and 0%, respectively.
5551 | Evidence Direction: SUPPORTS
5552 | Evidence Level: B
5553 | Evidence Rating: 4
5554 | Evidence Type: PREDICTIVE
5555 | Flagged: False
5556 | Id: 6123
5557 | Name: EID6123
5558 | Significance: SENSITIVITYRESPONSE
5559 | Variant Origin: SOMATIC
5560 |
5561 | ##### Disease
5562 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
5563 | Display Name: Colorectal Cancer
5564 | Doid: 9256
5565 | Id: 11
5566 | Link: /diseases/11
5567 | Name: Colorectal Cancer
5568 |
5569 | ##### My Disease Info
5570 | Do Def:
5571 | An intestinal cancer that effects the long, tube-like organ that is
5572 | connected to the small intestine at one end and the anus at the other.
5573 | Icd10: C18.9
5574 | Mondo Id: MONDO:0005575
5575 | Ncit: C4978
5576 |
5577 | ##### Molecular Profile
5578 | Id: 12
5579 |
5580 | ##### Source
5581 | Abstract:
5582 | Although BRAF inhibitor monotherapy yields response rates >50% in
5583 | BRAFV600-mutant melanoma, only approximately 5% of patients with
5584 | BRAFV600E colorectal cancer respond. Preclinical studies suggest that
5585 | the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive
5586 | feedback reactivation of MAPK signaling, often mediated by EGFR. This
5587 | clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) +
5588 | panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater
5589 | MAPK suppression and improved efficacy in 142 patients with BRAFV600E
5590 | colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were
5591 | 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired
5592 | pretreatment and on-treatment biopsies found that efficacy of D+T+P
5593 | correlated with increased MAPK suppression. Serial cell-free DNA
5594 | analysis revealed additional correlates of response and emergence of
5595 | KRAS and NRAS mutations on disease progression. Thus, targeting adaptive
5596 | feedback pathways in BRAFV600E colorectal cancer can improve efficacy,
5597 | but MAPK reactivation remains an important primary and acquired
5598 | resistance mechanism.Significance: This trial demonstrates that combined
5599 | BRAF + EGFR + MEK inhibition is tolerable, with promising activity in
5600 | patients with BRAFV600E colorectal cancer. Our findings highlight the
5601 | MAPK pathway as a critical target in BRAFV600E colorectal cancer and the
5602 | need to optimize strategies inhibiting this pathway to overcome both
5603 | primary and acquired resistance. Cancer Discov; 8(4); 428-43. ©2018
5604 | AACR.See related commentary by Janku, p. 389See related article by
5605 | Hazar-Rethinam et al., p. 417This article is highlighted in the In This
5606 | Issue feature, p. 371.
5607 | Author String:
5608 | Ryan B Corcoran, Thierry André, Chloe E Atreya, Jan H M Schellens,
5609 | Takayuki Yoshino, Johanna C Bendell, Antoine Hollebecque, Autumn J
5610 | McRee, Salvatore Siena, Gary Middleton, Kei Muro, Michael S Gordon,
5611 | Josep Tabernero, Rona Yaeger, Peter J O'Dwyer, Yves Humblet, Filip De
5612 | Vos, A Scott Jung, Jan C Brase, Savina Jaeger, Severine Bettinger,
5613 | Bijoyesh Mookerjee, Fatima Rangwala, Eric Van Cutsem
5614 | Citation: Corcoran et al., 2018
5615 | Citation Id: 29431699
5616 | Id: 2468
5617 | Journal: Cancer Discov
5618 | Link: /sources/2468
5619 | Name: PubMed: Corcoran et al., 2018
5620 | Open Access: True
5621 | Pmc Id: PMC5882509
5622 | Publication Date: 2018-4
5623 | Retracted: False
5624 | Source Type: PUBMED
5625 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/29431699
5626 | Title:
5627 | Combined BRAF, EGFR, and MEK Inhibition in Patients with
5628 | BRAFV600E-Mutant Colorectal Cancer.
5629 |
5630 | ##### Therapies
5631 | Deprecated: False
5632 | Id: 22
5633 | Link: /therapies/22
5634 | Name: Dabrafenib
5635 |
5636 | ##### Therapies
5637 | Deprecated: False
5638 | Id: 28
5639 | Link: /therapies/28
5640 | Name: Panitumumab
5641 |
5642 | ##### Therapies
5643 | Deprecated: False
5644 | Id: 19
5645 | Link: /therapies/19
5646 | Name: Trametinib
5647 |
5648 | #### Evidence Items
5649 | Description:
5650 | Of metastatic colorectal cancer patients treated with bevacizumab-based
5651 | first-line therapy, those with BRAF V600E mutations had reduced
5652 | progression-free survival compared to those with wildtype BRAF (4.2mo
5653 | vs. 12.5mo, HR:5.1, 95%CI:2.4-11.1, P<0.0001).
5654 | Evidence Direction: SUPPORTS
5655 | Evidence Level: B
5656 | Evidence Type: PREDICTIVE
5657 | Flagged: False
5658 | Id: 2120
5659 | Name: EID2120
5660 | Significance: RESISTANCE
5661 | Variant Origin: SOMATIC
5662 |
5663 | ##### Disease
5664 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
5665 | Display Name: Colorectal Cancer
5666 | Doid: 9256
5667 | Id: 11
5668 | Link: /diseases/11
5669 | Name: Colorectal Cancer
5670 |
5671 | ##### My Disease Info
5672 | Do Def:
5673 | An intestinal cancer that effects the long, tube-like organ that is
5674 | connected to the small intestine at one end and the anus at the other.
5675 | Icd10: C18.9
5676 | Mondo Id: MONDO:0005575
5677 | Ncit: C4978
5678 |
5679 | ##### Molecular Profile
5680 | Id: 12
5681 |
5682 | ##### Source
5683 | Abstract:
5684 | We address the prognostic and predictive value of KRAS, PIK3CA and BRAF
5685 | mutations for clinical outcomes in response to active agents in the
5686 | treatment of metastatic colorectal cancer (mCRC).We determined KRAS,
5687 | BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC
5688 | at two institutions. All patients received 5-FU-based first-line
5689 | chemotherapy and treatment outcome was analysed retrospectively.KRAS,
5690 | BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%)
5691 | cases, respectively. Multivariate analysis uncovered BRAF mutation as an
5692 | independent prognostic factor for decreased survival (hazard ratio (HR)
5693 | 4.0, 95% confidence interval (CI) 2.1-7.6). In addition, patients with
5694 | BRAF-mutant tumours had significantly lower progression-free survival
5695 | (PFS: HR 4.0, 95% CI 2.2-7.4) than those whose tumors that carried wild-
5696 | type BRAF. Among 92 patients treated using chemotherapy and cetuximab as
5697 | salvage therapy, KRAS mutation was associated with lack of response
5698 | (P=0.002) and shorter PFS (P=0.09). BRAF (P=0.0005) and PIK3CA (P=0.01)
5699 | mutations also predicted reduced PFS in response to cetuximab salvage
5700 | therapy.These results underscore the potential of mutational profiling
5701 | to identify CRCs with different natural histories or treatment
5702 | responses. The adverse significance of BRAF mutation should inform
5703 | patient selection and stratification in clinical trials.
5704 | Author String:
5705 | J Souglakos, J Philips, R Wang, S Marwah, M Silver, M Tzardi, J Silver,
5706 | S Ogino, S Hooshmand, E Kwak, E Freed, J A Meyerhardt, Z Saridaki, V
5707 | Georgoulias, D Finkelstein, C S Fuchs, M H Kulke, R A Shivdasani
5708 | Citation: Souglakos et al., 2009
5709 | Citation Id: 19603024
5710 | Id: 1479
5711 | Journal: Br J Cancer
5712 | Link: /sources/1479
5713 | Name: PubMed: Souglakos et al., 2009
5714 | Open Access: True
5715 | Pmc Id: PMC2720232
5716 | Publication Date: 2009-8-4
5717 | Retracted: False
5718 | Source Type: PUBMED
5719 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19603024
5720 | Title:
5721 | Prognostic and predictive value of common mutations for treatment
5722 | response and survival in patients with metastatic colorectal cancer.
5723 |
5724 | ##### Therapies
5725 | Deprecated: False
5726 | Id: 33
5727 | Link: /therapies/33
5728 | Name: Bevacizumab
5729 |
5730 | #### Evidence Items
5731 | Description:
5732 | In patients with papillary thyroid cancer harboring both BRAF V600E and
5733 | the TERT promotor mutation C228T (N=35), recurrence-free survival is
5734 | worse than in patients harboring one of these mutations (N=159 BRAF,
5735 | N=26 TERT promoter mutated) or no mutations in either gene
5736 | (N=287)(P<0.001).
5737 | Evidence Direction: SUPPORTS
5738 | Evidence Level: B
5739 | Evidence Rating: 5
5740 | Evidence Type: PROGNOSTIC
5741 | Flagged: False
5742 | Id: 656
5743 | Name: EID656
5744 | Significance: POOR_OUTCOME
5745 | Variant Origin: SOMATIC
5746 |
5747 | ##### Disease
5748 | Disease Url: https://www.disease-ontology.org/?id=DOID:3969
5749 | Display Name: Papillary Thyroid Carcinoma
5750 | Doid: 3969
5751 | Id: 156
5752 | Link: /diseases/156
5753 | Name: Papillary Thyroid Carcinoma
5754 |
5755 | ##### My Disease Info
5756 | Do Def:
5757 | A differentiated thyroid gland carcinoma that is characterized by the
5758 | small mushroom shape of the tumor which has a stem attached to the
5759 | epithelial layer and arises from the follicular cells of the thyroid
5760 | gland.
5761 | Icdo: 8260/3
5762 | Mesh: D000077273
5763 | Mondo Id: MONDO:0005075
5764 | Ncit: C4035
5765 | Disease Aliases:
5766 | - Papillary Carcinoma Of The Thyroid Gland
5767 | - Papillary Carcinoma Of Thyroid
5768 | - Thyroid Gland Papillary Carcinoma
5769 |
5770 | ##### Molecular Profile
5771 | Id: 12
5772 |
5773 | ##### Source
5774 | Abstract:
5775 | To investigate the prognostic value of the BRAF V600E mutation and the
5776 | recently identified TERT promoter mutation chr5:1,295,228C>T (C228T),
5777 | individually and in their coexistence, in papillary thyroid cancer
5778 | (PTC).We performed a retrospective study of the relationship of BRAF and
5779 | TERT C228T mutations with clinicopathologic outcomes of PTC in 507
5780 | patients (365 women and 142 men) age 45.9 ± 14.0 years (mean ± SD) with
5781 | a median follow-up of 24 months (interquartile range, 8 to 78
5782 | months).Coexisting BRAF V600E and TERT C228T mutations were more
5783 | commonly associated with high-risk clinicopathologic characteristics of
5784 | PTC than they were individually. Tumor recurrence rates were 25.8% (50
5785 | of 194;77.60 recurrences per 1,000 person-years; 95% CI, 58.81 to
5786 | 102.38) versus 9.6% (30 of 313; 22.88 recurrences per 1,000 person-
5787 | years; 95% CI, 16.00 to 32.72) in BRAF mutation-positive versus
5788 | -negative patients (hazard ratio [HR], 3.22; 95% CI, 2.05 to 5.07) and
5789 | 47.5% (29 of 61; 108.55 recurrences per 1,000 person-years; 95% CI,
5790 | 75.43 to 156.20) versus 11.4% (51 of 446; 30.21 recurrences per 1,000
5791 | person-years; 95% CI, 22.96 to 39.74) in TERT mutation-positive versus
5792 | -negative patients (HR, 3.46; 95% CI, 2.19 to 5.45). Recurrence rates
5793 | were 68.6% (24 of 35; 211.76 recurrences per 1,000 person-years; 95% CI,
5794 | 141.94 to 315.94) versus 8.7% (25 of 287; 21.60 recurrences per 1,000
5795 | person-years; 95% CI, 14.59 to 31.97) in patients harboring both
5796 | mutations versus patients harboring neither mutation (HR, 8.51; 95% CI,
5797 | 4.84 to 14.97), which remained significant after clinicopathologic
5798 | cofactor adjustments. Disease-free patient survival curves displayed a
5799 | moderate decline with BRAF V600E or TERT C228T alone but a sharp decline
5800 | with two coexisting mutations.Coexisting BRAF V600E and TERT C228T
5801 | mutations form a novel genetic background that defines PTC with the
5802 | worst clinicopathologic outcomes, providing unique prognostic and
5803 | therapeutic implications.
5804 | Author String:
5805 | Mingzhao Xing, Rengyun Liu, Xiaoli Liu, Avaniyapuram Kannan Murugan,
5806 | Guangwu Zhu, Martha A Zeiger, Sara Pai, Justin Bishop
5807 | Citation: Xing et al., 2014
5808 | Citation Id: 25024077
5809 | Id: 413
5810 | Journal: J Clin Oncol
5811 | Link: /sources/413
5812 | Name: PubMed: Xing et al., 2014
5813 | Open Access: True
5814 | Pmc Id: PMC4145183
5815 | Publication Date: 2014-9-1
5816 | Retracted: False
5817 | Source Type: PUBMED
5818 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25024077
5819 | Title:
5820 | BRAF V600E and TERT promoter mutations cooperatively identify the most
5821 | aggressive papillary thyroid cancer with highest recurrence.
5822 |
5823 | #### Evidence Items
5824 | Description:
5825 | Thyroid nodule with BRAF V600E mutation is highly correlated with
5826 | papillary thyroid cancer.
5827 | Evidence Direction: SUPPORTS
5828 | Evidence Level: B
5829 | Evidence Rating: 5
5830 | Evidence Type: DIAGNOSTIC
5831 | Flagged: False
5832 | Id: 80
5833 | Name: EID80
5834 | Significance: POSITIVE
5835 | Variant Origin: SOMATIC
5836 |
5837 | ##### Disease
5838 | Disease Url: https://www.disease-ontology.org/?id=DOID:3969
5839 | Display Name: Papillary Thyroid Carcinoma
5840 | Doid: 3969
5841 | Id: 156
5842 | Link: /diseases/156
5843 | Name: Papillary Thyroid Carcinoma
5844 |
5845 | ##### My Disease Info
5846 | Do Def:
5847 | A differentiated thyroid gland carcinoma that is characterized by the
5848 | small mushroom shape of the tumor which has a stem attached to the
5849 | epithelial layer and arises from the follicular cells of the thyroid
5850 | gland.
5851 | Icdo: 8260/3
5852 | Mesh: D000077273
5853 | Mondo Id: MONDO:0005075
5854 | Ncit: C4035
5855 | Disease Aliases:
5856 | - Papillary Carcinoma Of The Thyroid Gland
5857 | - Papillary Carcinoma Of Thyroid
5858 | - Thyroid Gland Papillary Carcinoma
5859 |
5860 | ##### Molecular Profile
5861 | Id: 12
5862 |
5863 | ##### Source
5864 | Abstract:
5865 | BRAF(V600E) is the most frequent genetic mutation in papillary thyroid
5866 | cancer (PTC) and has been reported as an independent predictor of poor
5867 | prognosis of these patients. Current guidelines do not recommend the use
5868 | of BRAF(V600E) mutational analysis on cytologic specimens from fine
5869 | needle aspiration due to several reasons. Recently, immunohistochemistry
5870 | using VE1, a mouse anti-human BRAF(V600E) antibody, has been reported as
5871 | a highly reliable technique in detecting BRAF-mutated thyroid and
5872 | nonthyroid cancers. The aim of this study was to test the reliability of
5873 | VE1 immunohistochemistry on microhistologic samples from core needle
5874 | biopsy (CNB) in identifying BRAF-mutated PTC. A series of 30 nodules
5875 | (size ranging from 7 to 22 mm) from 30 patients who underwent surgery
5876 | following CNB were included in the study. All these lesions had had
5877 | inconclusive cytology. In all cases, both VE1 and BRAF(V600E) genotypes
5878 | were evaluated. After surgery, final histology demonstrated 21 cancers
5879 | and 9 benign lesions. CNB correctly diagnosed 20/20 PTC and 5/5
5880 | adenomatous nodules. One follicular thyroid cancer and 4 benign lesions
5881 | were assessed at CNB as uncertain follicular neoplasm. VE1
5882 | immunohistochemistry revealed 8 mutated PTC and 22 negative cases. A
5883 | 100% agreement was found when positive and negative VE1 results were
5884 | compared with BRAF mutational status. These data are the first
5885 | demonstration that VE1 immunohistochemistry performed on thyroid CNB
5886 | samples perfectly matches with genetic analysis of BRAF status. Thus,
5887 | VE1 antibody can be used on thyroid microhistologic specimens to detect
5888 | BRAF(V600E)-mutated PTC before surgery.
5889 | Author String:
5890 | A Crescenzi, L Guidobaldi, N Nasrollah, S Taccogna, D D Cicciarella
5891 | Modica, L Turrini, G Nigri, F Romanelli, S Valabrega, L Giovanella, A
5892 | Onetti Muda, P Trimboli
5893 | Citation: Crescenzi et al., 2014
5894 | Citation Id: 24570209
5895 | Id: 94
5896 | Journal: Horm Metab Res
5897 | Link: /sources/94
5898 | Name: PubMed: Crescenzi et al., 2014
5899 | Open Access: False
5900 | Publication Date: 2014-5
5901 | Retracted: False
5902 | Source Type: PUBMED
5903 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24570209
5904 | Title:
5905 | Immunohistochemistry for BRAF(V600E) antibody VE1 performed in core
5906 | needle biopsy samples identifies mutated papillary thyroid cancers.
5907 |
5908 | #### Evidence Items
5909 | Description:
5910 | In this Phase III trial (NCT01584648 COMBI-d), previously untreated
5911 | patients with unresectable stage IIIC or IV melanoma with BRAF V600E
5912 | (359 patients) or V600K (61 patients) received dabrafenib and trametinib
5913 | or dabrafenib alone with primary endpoint of progression free survival
5914 | and secondary endpoints including disease response. The hazard ratio for
5915 | progression or death in the V600E group was 0.81 for dabrafenib-
5916 | trametinib vs dabrafenib-alone. Of 179 V600E patients in the dabrafenib-
5917 | trametinib group, 68% of patients had a response, which was 15
5918 | percentage points higher than in the dabrafenib-alone group (95% CI, 4
5919 | to 24; P=0.006).
5920 | Evidence Direction: SUPPORTS
5921 | Evidence Level: B
5922 | Evidence Rating: 5
5923 | Evidence Type: PREDICTIVE
5924 | Flagged: False
5925 | Id: 6938
5926 | Name: EID6938
5927 | Significance: SENSITIVITYRESPONSE
5928 | Variant Origin: SOMATIC
5929 |
5930 | ##### Disease
5931 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
5932 | Display Name: Melanoma
5933 | Doid: 1909
5934 | Id: 7
5935 | Link: /diseases/7
5936 | Name: Melanoma
5937 |
5938 | ##### My Disease Info
5939 | Do Def:
5940 | A cell type cancer that has_material_basis_in abnormally proliferating
5941 | cells derives_from melanocytes which are found in skin, the bowel and
5942 | the eye.
5943 | Icdo: 8720/3
5944 | Mesh: D008545
5945 | Mondo Id: MONDO:0005105
5946 | Ncit: C3224
5947 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
5948 |
5949 | ##### Molecular Profile
5950 | Id: 12
5951 |
5952 | ##### Source
5953 | Abstract:
5954 | Combined BRAF and MEK inhibition, as compared with BRAF inhibition
5955 | alone, delays the emergence of resistance and reduces toxic effects in
5956 | patients who have melanoma with BRAF V600E or V600K mutations.In this
5957 | phase 3 trial, we randomly assigned 423 previously untreated patients
5958 | who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E
5959 | or V600K mutation to receive a combination of dabrafenib (150 mg orally
5960 | twice daily) and trametinib (2 mg orally once daily) or dabrafenib and
5961 | placebo. The primary end point was progression-free survival. Secondary
5962 | end points included overall survival, response rate, response duration,
5963 | and safety. A preplanned interim overall survival analysis was
5964 | conducted.The median progression-free survival was 9.3 months in the
5965 | dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group
5966 | (hazard ratio for progression or death in the dabrafenib-trametinib
5967 | group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The
5968 | overall response rate was 67% in the dabrafenib-trametinib group and 51%
5969 | in the dabrafenib-only group (P=0.002). At 6 months, the interim overall
5970 | survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib
5971 | alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02).
5972 | However, a specified efficacy-stopping boundary (two-sided P=0.00028)
5973 | was not crossed. Rates of adverse events were similar in the two groups,
5974 | although more dose modifications occurred in the dabrafenib-trametinib
5975 | group. The rate of cutaneous squamous-cell carcinoma was lower in the
5976 | dabrafenib-trametinib group than in the dabrafenib-only group (2% vs.
5977 | 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was
5978 | more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib
5979 | group.A combination of dabrafenib and trametinib, as compared with
5980 | dabrafenib alone, improved the rate of progression-free survival in
5981 | previously untreated patients who had metastatic melanoma with BRAF
5982 | V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical
5983 | Trials.gov number, NCT01584648.).
5984 | Author String:
5985 | Georgina V Long, Daniil Stroyakovskiy, Helen Gogas, Evgeny Levchenko,
5986 | Filippo de Braud, James Larkin, Claus Garbe, Thomas Jouary, Axel
5987 | Hauschild, Jean Jacques Grob, Vanna Chiarion Sileni, Celeste Lebbe,
5988 | Mario Mandalà, Michael Millward, Ana Arance, Igor Bondarenko, John B A G
5989 | Haanen, Johan Hansson, Jochen Utikal, Virginia Ferraresi, Nadezhda
5990 | Kovalenko, Peter Mohr, Volodymyr Probachai, Dirk Schadendorf, Paul
5991 | Nathan, Caroline Robert, Antoni Ribas, Douglas J DeMarini, Jhangir G
5992 | Irani, Michelle Casey, Daniele Ouellet, Anne-Marie Martin, Ngocdiep Le,
5993 | Kiran Patel, Keith Flaherty
5994 | Citation: Long et al., 2014
5995 | Citation Id: 25265492
5996 | Id: 2671
5997 | Journal: N Engl J Med
5998 | Link: /sources/2671
5999 | Name: PubMed: Long et al., 2014
6000 | Open Access: False
6001 | Publication Date: 2014-11-13
6002 | Retracted: False
6003 | Source Type: PUBMED
6004 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25265492
6005 | Title:
6006 | Combined BRAF and MEK inhibition versus BRAF inhibition alone in
6007 | melanoma.
6008 |
6009 | ##### Therapies
6010 | Deprecated: False
6011 | Id: 22
6012 | Link: /therapies/22
6013 | Name: Dabrafenib
6014 |
6015 | ##### Therapies
6016 | Deprecated: False
6017 | Id: 19
6018 | Link: /therapies/19
6019 | Name: Trametinib
6020 |
6021 | #### Evidence Items
6022 | Description:
6023 | In this trial, 19 patients with pediatric brain tumours (1 patient with
6024 | Astrocytoma, 1 with Fibrillary Astrocytoma, 10 with Pilocytic
6025 | Astrocytoma, 5 with Ganglioglioma and 2 with Pleomorphic
6026 | Xanthoastrocytoma) harbouring BRAF V600E were treated with vemurafenib.
6027 | The study reported a positive response to the treatment, with 1 complete
6028 | response, 5 partial responses, and 13 patients with stable disease.
6029 | Evidence Direction: SUPPORTS
6030 | Evidence Level: B
6031 | Evidence Rating: 3
6032 | Evidence Type: PREDICTIVE
6033 | Flagged: False
6034 | Id: 11770
6035 | Name: EID11770
6036 | Significance: SENSITIVITYRESPONSE
6037 | Variant Origin: SOMATIC
6038 |
6039 | ##### Disease
6040 | Disease Url: https://www.disease-ontology.org/?id=DOID:0080829
6041 | Display Name: Low Grade Glioma
6042 | Doid: 0080829
6043 | Id: 3047
6044 | Link: /diseases/3047
6045 | Name: Low Grade Glioma
6046 |
6047 | ##### My Disease Info
6048 | Do Def:
6049 | A cell type benign neoplasm that has_material_basis_in glial cells
6050 | (astrocytes, oligodendrocytes or ependymocytes).
6051 | Mondo Id: MONDO:0021637
6052 | Ncit: C132067
6053 | Disease Aliases: Benign Glioma
6054 |
6055 | ##### Molecular Profile
6056 | Id: 12
6057 |
6058 | ##### Source
6059 | Abstract:
6060 | Background: BRAFV600E mutation is present in a subset of pediatric brain
6061 | tumors. Vemurafenib is an oral, selective ATP-competitive inhibitor of
6062 | BRAFV600E kinase. The goal of this multi-center study conducted through
6063 | the Pacific Pediatric Neuro-Oncology Consortium (PNOC) was to determine
6064 | the recommended phase 2 dose (RP2D) and dose limiting toxicities (DLTs)
6065 | in children < 18 years with recurrent or progressive BRAFV600E mutant
6066 | brain tumors. Results: Nineteen eligible patients were enrolled. Eleven
6067 | patients had received three or more prior therapies. Data reported are
6068 | from the start of treatment for the first patient (April 30 2014)
6069 | through August 31 2019. The RP2D was defined as 550 mg/m2 twice daily
6070 | after DLT criteria adjustment for rash. Related grade ≥ 3 adverse events
6071 | included secondary keratoacanthoma (n = 1); rash (n =16); and fever (n =
6072 | 5). Subjects received a median of 23 cycles (range 3-63). Four patients
6073 | remain on treatment. Centrally reviewed best radiographic responses
6074 | included 1 complete response, 5 partial responses, and 13 stable
6075 | disease. The steady-state area under the curve (AUC0-∞median) was 604
6076 | mg*h/L (range 329-1052). Methods: Vemurafenib was given starting at 550
6077 | mg/m2, twice daily which corresponds to the adult RP2D. Adverse events
6078 | were graded using the NIH Common Terminology Criteria for Adverse Events
6079 | (CTCAE) version 4.0. Central imaging review was performed.
6080 | Pharmacokinetic sampling was performed. Conclusions: Vemurafenib has
6081 | promising anti-tumor activity in recurrent BRAF V600E-positive brain
6082 | tumors with manageable toxicity. A phase 2 study is ongoing
6083 | (NCT01748149).
6084 | Author String:
6085 | Theodore Nicolaides, Kellie J Nazemi, John Crawford, Lindsay Kilburn,
6086 | Jane Minturn, Amar Gajjar, Karen Gauvain, Sarah Leary, Girish Dhall,
6087 | Mariam Aboian, Giles Robinson, Janel Long-Boyle, Hechuan Wang, Annette M
6088 | Molinaro, Sabine Mueller, Michael Prados
6089 | Citation: Nicolaides et al., 2020
6090 | Citation Id: 32523649
6091 | Id: 4902
6092 | Journal: Oncotarget
6093 | Link: /sources/4902
6094 | Name: PubMed: Nicolaides et al., 2020
6095 | Open Access: True
6096 | Pmc Id: PMC7260122
6097 | Publication Date: 2020-5-26
6098 | Retracted: False
6099 | Source Type: PUBMED
6100 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/32523649
6101 | Title:
6102 | Phase I study of vemurafenib in children with recurrent or progressive
6103 | BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology
6104 | Consortium study (PNOC-002).
6105 |
6106 | ##### Therapies
6107 | Deprecated: False
6108 | Id: 4
6109 | Link: /therapies/4
6110 | Name: Vemurafenib
6111 |
6112 | #### Evidence Items
6113 | Description:
6114 | Patients with completely resected colorectal adenocarcinoma (Stage II-
6115 | III) were treated with fluorouracil and leucovorin +/- ironotecan. Of
6116 | the 1,307 FFPE samples tested, V600E was observed in 31 Stage II samples
6117 | (7.6%) and 72 Stage III samples (7.9%). V600E was prognostic for overall
6118 | survival, but not for relapse-free survival, in patients with stages II
6119 | and III combined, and in stage III alone. For all MSI low and stable
6120 | tumors, BRAF V600E positive samples had a hazard ratio (HR) of 2.19 (95%
6121 | CI, 1.43 to 3.37, P=0.00034). For all samples in the cohort (MSI-H and
6122 | MSI-L) BRAF V600E positive samples had a 1.66 HR (95% CI, 1.15 to 2.40,
6123 | P=0.0069). The authors note prognostic value for BRAF V600E, especially
6124 | in non-MSI high tumors.
6125 | Evidence Direction: SUPPORTS
6126 | Evidence Level: B
6127 | Evidence Rating: 4
6128 | Evidence Type: PROGNOSTIC
6129 | Flagged: False
6130 | Id: 7156
6131 | Name: EID7156
6132 | Significance: POOR_OUTCOME
6133 | Variant Origin: SOMATIC
6134 |
6135 | ##### Disease
6136 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
6137 | Display Name: Colorectal Cancer
6138 | Doid: 9256
6139 | Id: 11
6140 | Link: /diseases/11
6141 | Name: Colorectal Cancer
6142 |
6143 | ##### My Disease Info
6144 | Do Def:
6145 | An intestinal cancer that effects the long, tube-like organ that is
6146 | connected to the small intestine at one end and the anus at the other.
6147 | Icd10: C18.9
6148 | Mondo Id: MONDO:0005575
6149 | Ncit: C4978
6150 |
6151 | ##### Molecular Profile
6152 | Id: 12
6153 |
6154 | ##### Source
6155 | Abstract:
6156 | Mutations within the KRAS proto-oncogene have predictive value but are
6157 | of uncertain prognostic value in the treatment of advanced colorectal
6158 | cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278
6159 | patients with stage II to III colon cancer, to evaluate the prognostic
6160 | value of KRAS and BRAF tumor mutation status in this setting.Formalin-
6161 | fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively
6162 | collected and DNA was extracted from tissue sections from 1,404 cases.
6163 | Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed
6164 | by allele-specific real-time polymerase chain reaction. Survival
6165 | analyses were based on univariate and multivariate proportional hazard
6166 | regression models.KRAS and BRAF tumor mutation rates were 37.0% and
6167 | 7.9%, respectively, and were not significantly different according to
6168 | tumor stage. In a multivariate analysis containing stage, tumor site,
6169 | nodal status, sex, age, grade, and microsatellite instability (MSI)
6170 | status, KRAS mutation was associated with grade (P = .0016), while BRAF
6171 | mutation was significantly associated with female sex (P = .017), and
6172 | highly significantly associated with right-sided tumors, older age, high
6173 | grade, and MSI-high tumors (all P < 10(-4)). In univariate and
6174 | multivariate analysis, KRAS mutations did not have a major prognostic
6175 | value regarding relapse-free survival (RFS) or overall survival (OS).
6176 | BRAF mutation was not prognostic for RFS, but was for OS, particularly
6177 | in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard
6178 | ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003).In stage II-III colon cancer,
6179 | the KRAS mutation status does not have major prognostic value. BRAF is
6180 | prognostic for OS in MS-L/S tumors.
6181 | Author String:
6182 | Arnaud D Roth, Sabine Tejpar, Mauro Delorenzi, Pu Yan, Roberto Fiocca,
6183 | Dirk Klingbiel, Daniel Dietrich, Bart Biesmans, György Bodoky, Carlo
6184 | Barone, Enrique Aranda, Bernard Nordlinger, Laura Cisar, Roberto
6185 | Labianca, David Cunningham, Eric Van Cutsem, Fred Bosman
6186 | Citation: Roth et al., 2010
6187 | Citation Id: 20008640
6188 | Id: 2783
6189 | Journal: J Clin Oncol
6190 | Link: /sources/2783
6191 | Name: PubMed: Roth et al., 2010
6192 | Open Access: False
6193 | Publication Date: 2010-1-20
6194 | Retracted: False
6195 | Source Type: PUBMED
6196 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/20008640
6197 | Title:
6198 | Prognostic role of KRAS and BRAF in stage II and III resected colon
6199 | cancer: results of the translational study on the PETACC-3, EORTC 40993,
6200 | SAKK 60-00 trial.
6201 |
6202 | #### Evidence Items
6203 | Description:
6204 | In a phase 2 trial, patients with radioiodine refractory papillary
6205 | thyroid carcinoma harboring BRAF mutation were treated with dabrafenib
6206 | alone or combination with trametinib. 94% of patients had BRAF V600E.
6207 | The response rate was 50% (11/22) for dabrafenib and 54% (13/24) for
6208 | dabrafenb and trametinib combination.
6209 | Evidence Direction: SUPPORTS
6210 | Evidence Level: B
6211 | Evidence Rating: 3
6212 | Evidence Type: PREDICTIVE
6213 | Flagged: False
6214 | Id: 7762
6215 | Name: EID7762
6216 | Significance: SENSITIVITYRESPONSE
6217 | Variant Origin: SOMATIC
6218 |
6219 | ##### Disease
6220 | Disease Url: https://www.disease-ontology.org/?id=DOID:3969
6221 | Display Name: Papillary Thyroid Carcinoma
6222 | Doid: 3969
6223 | Id: 156
6224 | Link: /diseases/156
6225 | Name: Papillary Thyroid Carcinoma
6226 |
6227 | ##### My Disease Info
6228 | Do Def:
6229 | A differentiated thyroid gland carcinoma that is characterized by the
6230 | small mushroom shape of the tumor which has a stem attached to the
6231 | epithelial layer and arises from the follicular cells of the thyroid
6232 | gland.
6233 | Icdo: 8260/3
6234 | Mesh: D000077273
6235 | Mondo Id: MONDO:0005075
6236 | Ncit: C4035
6237 | Disease Aliases:
6238 | - Papillary Carcinoma Of The Thyroid Gland
6239 | - Papillary Carcinoma Of Thyroid
6240 | - Thyroid Gland Papillary Carcinoma
6241 |
6242 | ##### Molecular Profile
6243 | Id: 12
6244 |
6245 | ##### Source
6246 | Abstract:
6247 | Background: BRAF mutations are present in ~44% of papillary thyroid
6248 | carcinoma (PTC) and its role in development of PTC is well established.
6249 | We hypothesized that dabrafenib (BRAF inhibitor) would have efficacy in
6250 | BRAF mutated PTC and that combining it with trametinib (MEK inhibitor)
6251 | would result in greater clinical efficacy than dabrafenib alone, through
6252 | vertical inhibition of the RAF/MAP/ERK pathway and mitigation of
6253 | potential mechanisms of resistance. Methods: Patients (pts) with BRAF
6254 | mutated radioiodine refractory PTC who had evidence of disease
6255 | progression within 13 months prior were randomized to Arm A (dabrafenib
6256 | 150 mg PO BID) or Arm B (dabrafenib 150 mg PO BID + trametinib 2 mg PO
6257 | qd). Cross-over to Arm B was allowed at time of progression. Responses
6258 | were assessed by modified RECISTv1.1 every 2 months. Primary endpoint
6259 | was objective response rate (ORR) (complete-, partial- and minor-
6260 | response). With assumed true ORR of 15% vs 35%; and 90% power to
6261 | identify the correct regimen as most promising, 26 pts were to be
6262 | accrued in each Arm. Results: In this randomized phase 2 trial, 53 pts
6263 | (median age 63 years, 38 females) were enrolled; 25% of pts had 1-3
6264 | prior therapy with multi-kinase inhibitors. Median follow up was 13
6265 | months. Preliminary efficacy results are outlined in Table. The
6266 | treatment-related adverse events were similar to previously reported
6267 | phase III clinical trial of these drugs in melanoma. Conclusions: Single
6268 | agent dabrafenib, as well as combination of dabrafenib/trametinib are
6269 | well tolerated therapies that result in similar high objective response
6270 | rates with durable responses in pts with progressive BRAF-mutated PTC.
6271 | BRAF-pathway targeted therapies provide novel treatment options.
6272 | Clinical trial information: NCT01723202Arm A (n=26)DabrafenibArm B
6273 | (n=27)Dabrafenib + Trametinibp-valueAssessable pts (n)2224Partial
6274 | response109Minor response (MR)*14Objective Response11/22 (50%)13/24
6275 | (54%)0.78Stable ds910Progressive ds21Median Progression Free Survival
6276 | (months) (95% CI)11.4 (3.8 – NR)15.1 (11.7 –NR)0.27Median Duration of
6277 | response (months)(95% CI)15.6 (4.2 – NR)13.3 (9.7 – NR)0.87*MR was
6278 | defined as 20-29% decrease in the sum of diameters of target lesions;
6279 | NR=not reached
6280 | Author String: Manisha H. Shah
6281 | Citation: Manisha H. Shah, 2017, ASCO Annual Meeting, Abstract 6022
6282 | Citation Id: 145877
6283 | Id: 3096
6284 | Journal: J Clin Oncol 35, 2017 (suppl; abstr 6022)
6285 | Link: /sources/3096
6286 | Name: ASCO: Manisha H. Shah, 2017, ASCO Annual Meeting, Abstract 6022
6287 | Open Access: False
6288 | Publication Date: 2017-1-12
6289 | Retracted: False
6290 | Source Type: ASCO
6291 | Source Url: https://meetinglibrary.asco.org/record/145877/abstract
6292 | Title:
6293 | Results of randomized phase II trial of dabrafenib versus dabrafenib
6294 | plus trametinib in BRAF-mutated papillary thyroid carcinoma.
6295 |
6296 | ##### Therapies
6297 | Deprecated: False
6298 | Id: 22
6299 | Link: /therapies/22
6300 | Name: Dabrafenib
6301 |
6302 | ##### Therapies
6303 | Deprecated: False
6304 | Id: 19
6305 | Link: /therapies/19
6306 | Name: Trametinib
6307 |
6308 | #### Evidence Items
6309 | Description:
6310 | This NCI-MATCH trial was conducted in 35 patients of which 29 were
6311 | included in the primary efficacy analysis with tumors with BRAF V600E
6312 | mutations, and treated with a combination of dabrafenib and trametinib.
6313 | The ORR was 37.9% (90% CI, 22.9-54.9). The median PFS and median OS were
6314 | 11.4 months (90% CI, 8.4-16.3) and 28.6 months respectively. Meaningful
6315 | results were achieved with this treatment with an overall DCR of 75.9%.
6316 | Evidence Direction: SUPPORTS
6317 | Evidence Level: B
6318 | Evidence Rating: 3
6319 | Evidence Type: PREDICTIVE
6320 | Flagged: False
6321 | Id: 11672
6322 | Name: EID11672
6323 | Significance: SENSITIVITYRESPONSE
6324 | Variant Origin: SOMATIC
6325 |
6326 | ##### Disease
6327 | Disease Url: https://www.disease-ontology.org/?id=DOID:162
6328 | Display Name: Cancer
6329 | Doid: 162
6330 | Id: 216
6331 | Link: /diseases/216
6332 | Name: Cancer
6333 |
6334 | ##### My Disease Info
6335 | Do Def: A cancer that is classified based on the organ it starts in.
6336 | Mesh: D009371
6337 | Mondo Id: MONDO:0004992
6338 | Disease Aliases: Malignant Neoplasm, Malignant Tumor, Primary Cancer
6339 |
6340 | ##### Molecular Profile
6341 | Id: 12
6342 |
6343 | ##### Source
6344 | Abstract:
6345 | BRAFV600 mutations are commonly found in melanoma and thyroid cancers
6346 | and to a lesser degree in other tumor types. Subprotocol H (EAY131-H) of
6347 | the NCI-MATCH platform trial sought to investigate the selective BRAF
6348 | inhibitor dabrafenib and the MEK1/2 inhibitor trametinib in patients
6349 | with solid tumors, lymphomas, or multiple myeloma whose tumors harbored
6350 | a BRAFV600 mutation.EAY131-H is an open-label, single-arm study.
6351 | Patients with melanoma, thyroid, or colorectal cancer were excluded;
6352 | patients with non-small-cell lung cancer were later excluded in an
6353 | amendment. Patients received dabrafenib 150 mg twice per day and
6354 | trametinib 2 mg per day continuously until disease progression or
6355 | intolerable toxicity. The primary end point was centrally assessed
6356 | objective response rate (ORR); secondary end points included
6357 | progression-free survival (PFS), 6-month PFS, and overall
6358 | survival.Thirty-five patients were enrolled, and 29 were included in the
6359 | primary efficacy analysis as prespecified in the protocol. Median age
6360 | was 59 years, and 45% of the patients had received ≥ 3 lines of therapy.
6361 | The confirmed ORR was 38% (90% CI, 22.9% to 54.9%) with P < .0001
6362 | against a null rate of 5%, and PFS was 11.4 months (90% CI, 8.4 to 16.3
6363 | months); responses were seen in 7 distinct tumor types. Seven patients
6364 | had a duration of response of > 12 months, including 4 patients with a
6365 | duration of response of > 24 months. An additional 8 patients had a PFS
6366 | > 6 months. The median overall survival was 28.6 months. Reported
6367 | adverse events were comparable to those noted in previously reported
6368 | profiles of dabrafenib and trametinib.This study met its primary end
6369 | point, with an ORR of 38% (P < .0001) in this mixed histology,
6370 | pretreated cohort. This promising activity warrants additional
6371 | investigations in BRAFV600-mutated tumors outside of currently approved
6372 | indications.
6373 | Author String:
6374 | April K S Salama, Shuli Li, Erin R Macrae, Jong-In Park, Edith P
6375 | Mitchell, James A Zwiebel, Helen X Chen, Robert J Gray, Lisa M McShane,
6376 | Larry V Rubinstein, David Patton, P Mickey Williams, Stanley R Hamilton,
6377 | Deborah K Armstrong, Barbara A Conley, Carlos L Arteaga, Lyndsay N
6378 | Harris, Peter J O'Dwyer, Alice P Chen, Keith T Flaherty
6379 | Citation: Salama et al., 2020
6380 | Citation Id: 32758030
6381 | Id: 4834
6382 | Journal: J Clin Oncol
6383 | Link: /sources/4834
6384 | Name: PubMed: Salama et al., 2020
6385 | Open Access: True
6386 | Pmc Id: PMC7676884
6387 | Publication Date: 2020-11-20
6388 | Retracted: False
6389 | Source Type: PUBMED
6390 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/32758030
6391 | Title:
6392 | Dabrafenib and Trametinib in Patients With Tumors With BRAFV600E
6393 | Mutations: Results of the NCI-MATCH Trial Subprotocol H.
6394 |
6395 | ##### Therapies
6396 | Deprecated: False
6397 | Id: 22
6398 | Link: /therapies/22
6399 | Name: Dabrafenib
6400 |
6401 | ##### Therapies
6402 | Deprecated: False
6403 | Id: 19
6404 | Link: /therapies/19
6405 | Name: Trametinib
6406 |
6407 | #### Evidence Items
6408 | Description:
6409 | This preclinical study examined vemurafenib efficacy on various
6410 | colorectal cancer cell lines and in mouse xenograft experiments. Of the
6411 | cell lines tested, six harbored BRAF V600E (and WT KRAS) and three
6412 | harbored BRAF WT (but mutant KRAS). Of the six BRAF V600E expressing
6413 | cell lines, four were sensitive to vemurafenib (IC50 ranging between
6414 | 0.025 and 0.35 uM; HT29, Colo205, Colo741, LS411N). Cell lines
6415 | expressing the BRAF V600E mutation responded better to vemurafenib
6416 | treatment than cells wildtype for BRAF as measured by reduced cellular
6417 | proliferation and inhibition of MET and ERK phosphorylation (none of the
6418 | three BRAF wt cell lines had IC50s less than 10uM). Authors note that
6419 | one of the vemurafenib-resistant cell lines harboring BRAF V600E (RKO)
6420 | harbored a concurrent activating PIK3CA H1047R mutation. Nude, athymic
6421 | mice with HT29 xenografts treated with vemurafenib experienced
6422 | substantial tumor inhibition and increased lifespan at every dose
6423 | tested, though authors found 75 mg/kg twice daily to be optimal (95%
6424 | tumor growth inhibition, 90% increased lifespan compared to vehicle
6425 | treated controls).
6426 | Evidence Direction: SUPPORTS
6427 | Evidence Level: D
6428 | Evidence Rating: 2
6429 | Evidence Type: PREDICTIVE
6430 | Flagged: False
6431 | Id: 99
6432 | Name: EID99
6433 | Significance: SENSITIVITYRESPONSE
6434 | Variant Origin: SOMATIC
6435 |
6436 | ##### Disease
6437 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
6438 | Display Name: Colorectal Cancer
6439 | Doid: 9256
6440 | Id: 11
6441 | Link: /diseases/11
6442 | Name: Colorectal Cancer
6443 |
6444 | ##### My Disease Info
6445 | Do Def:
6446 | An intestinal cancer that effects the long, tube-like organ that is
6447 | connected to the small intestine at one end and the anus at the other.
6448 | Icd10: C18.9
6449 | Mondo Id: MONDO:0005575
6450 | Ncit: C4978
6451 |
6452 | ##### Molecular Profile
6453 | Id: 12
6454 |
6455 | ##### Source
6456 | Abstract:
6457 | The protein kinase BRAF is a key component of the RAS-RAF signaling
6458 | pathway which plays an important role in regulating cell proliferation,
6459 | differentiation, and survival. Mutations in BRAF at codon 600 promote
6460 | catalytic activity and are associated with 8% of all human (solid)
6461 | tumors, including 8% to 10% of colorectal cancers (CRC). Here, we report
6462 | the preclinical characterization of vemurafenib (RG7204; PLX4032;
6463 | RO5185426), a first-in-class, specific small molecule inhibitor of
6464 | BRAF(V600E) in BRAF-mutated CRC cell lines and tumor xenograft models.
6465 | As a single agent, vemurafenib shows dose-dependent inhibition of ERK
6466 | and MEK phosphorylation, thereby arresting cell proliferation in
6467 | BRAF(V600)-expressing cell lines and inhibiting tumor growth in
6468 | BRAF(V600E) bearing xenograft models. Because vemurafenib has shown
6469 | limited single-agent clinical activity in BRAF(V600E)-mutant metastatic
6470 | CRC, we therefore explored a range of combination therapies, with both
6471 | standard agents and targeted inhibitors in preclinical xenograft models.
6472 | In a BRAF-mutant CRC xenograft model with de novo resistance to
6473 | vemurafenib (RKO), tumor growth inhibition by vemurafenib was enhanced
6474 | by combining with an AKT inhibitor (MK-2206). The addition of
6475 | vemurafenib to capecitabine and/or bevacizumab, cetuximab and/or
6476 | irinotecan, or erlotinib resulted in increased antitumor activity and
6477 | improved survival in xenograft models. Together, our findings suggest
6478 | that the administration of vemurafenib in combination with standard-of-
6479 | care or novel targeted therapies may lead to enhanced and sustained
6480 | clinical antitumor efficacy in CRCs harboring the BRAF(V600E) mutation.
6481 | Author String:
6482 | Hong Yang, Brian Higgins, Kenneth Kolinsky, Kathryn Packman, William D
6483 | Bradley, Richard J Lee, Kathleen Schostack, Mary Ellen Simcox, Scott
6484 | Kopetz, David Heimbrook, Brian Lestini, Gideon Bollag, Fei Su
6485 | Citation: Yang et al., 2012
6486 | Citation Id: 22180495
6487 | Id: 108
6488 | Journal: Cancer Res
6489 | Link: /sources/108
6490 | Name: PubMed: Yang et al., 2012
6491 | Open Access: False
6492 | Publication Date: 2012-2-1
6493 | Retracted: False
6494 | Source Type: PUBMED
6495 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22180495
6496 | Title:
6497 | Antitumor activity of BRAF inhibitor vemurafenib in preclinical models
6498 | of BRAF-mutant colorectal cancer.
6499 |
6500 | ##### Therapies
6501 | Deprecated: False
6502 | Id: 4
6503 | Link: /therapies/4
6504 | Name: Vemurafenib
6505 |
6506 | #### Evidence Items
6507 | Description:
6508 | This in vivo study examined the efficacy of various treatments on
6509 | athymic nude mice xenografted with colorectal cancer HT29 cells, which
6510 | harbor BRAF V600E. The authors sought to understand whether the addition
6511 | of vemurafenib (a BRAF V600E inhibitor) to agents approved for the
6512 | treatment of metastatic colorectal cancer increased therapeutic
6513 | efficacy, and which combinations worked best. Erlotinib and vemurafenib
6514 | combination therapy resulted in >100% tumor growth inhibition (TGI) and
6515 | 142% increased lifespan (ILS) compared to vehicle treated controls. Of
6516 | ten treated mice, 9 experienced partial response. Doublet therapy
6517 | produced a greater increase in TGI and ILS than either agent in
6518 | isolation.
6519 | Evidence Direction: SUPPORTS
6520 | Evidence Level: D
6521 | Evidence Rating: 3
6522 | Evidence Type: PREDICTIVE
6523 | Flagged: False
6524 | Id: 8507
6525 | Name: EID8507
6526 | Significance: SENSITIVITYRESPONSE
6527 | Variant Origin: SOMATIC
6528 |
6529 | ##### Disease
6530 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
6531 | Display Name: Colorectal Cancer
6532 | Doid: 9256
6533 | Id: 11
6534 | Link: /diseases/11
6535 | Name: Colorectal Cancer
6536 |
6537 | ##### My Disease Info
6538 | Do Def:
6539 | An intestinal cancer that effects the long, tube-like organ that is
6540 | connected to the small intestine at one end and the anus at the other.
6541 | Icd10: C18.9
6542 | Mondo Id: MONDO:0005575
6543 | Ncit: C4978
6544 |
6545 | ##### Molecular Profile
6546 | Id: 12
6547 |
6548 | ##### Source
6549 | Abstract:
6550 | The protein kinase BRAF is a key component of the RAS-RAF signaling
6551 | pathway which plays an important role in regulating cell proliferation,
6552 | differentiation, and survival. Mutations in BRAF at codon 600 promote
6553 | catalytic activity and are associated with 8% of all human (solid)
6554 | tumors, including 8% to 10% of colorectal cancers (CRC). Here, we report
6555 | the preclinical characterization of vemurafenib (RG7204; PLX4032;
6556 | RO5185426), a first-in-class, specific small molecule inhibitor of
6557 | BRAF(V600E) in BRAF-mutated CRC cell lines and tumor xenograft models.
6558 | As a single agent, vemurafenib shows dose-dependent inhibition of ERK
6559 | and MEK phosphorylation, thereby arresting cell proliferation in
6560 | BRAF(V600)-expressing cell lines and inhibiting tumor growth in
6561 | BRAF(V600E) bearing xenograft models. Because vemurafenib has shown
6562 | limited single-agent clinical activity in BRAF(V600E)-mutant metastatic
6563 | CRC, we therefore explored a range of combination therapies, with both
6564 | standard agents and targeted inhibitors in preclinical xenograft models.
6565 | In a BRAF-mutant CRC xenograft model with de novo resistance to
6566 | vemurafenib (RKO), tumor growth inhibition by vemurafenib was enhanced
6567 | by combining with an AKT inhibitor (MK-2206). The addition of
6568 | vemurafenib to capecitabine and/or bevacizumab, cetuximab and/or
6569 | irinotecan, or erlotinib resulted in increased antitumor activity and
6570 | improved survival in xenograft models. Together, our findings suggest
6571 | that the administration of vemurafenib in combination with standard-of-
6572 | care or novel targeted therapies may lead to enhanced and sustained
6573 | clinical antitumor efficacy in CRCs harboring the BRAF(V600E) mutation.
6574 | Author String:
6575 | Hong Yang, Brian Higgins, Kenneth Kolinsky, Kathryn Packman, William D
6576 | Bradley, Richard J Lee, Kathleen Schostack, Mary Ellen Simcox, Scott
6577 | Kopetz, David Heimbrook, Brian Lestini, Gideon Bollag, Fei Su
6578 | Citation: Yang et al., 2012
6579 | Citation Id: 22180495
6580 | Id: 108
6581 | Journal: Cancer Res
6582 | Link: /sources/108
6583 | Name: PubMed: Yang et al., 2012
6584 | Open Access: False
6585 | Publication Date: 2012-2-1
6586 | Retracted: False
6587 | Source Type: PUBMED
6588 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22180495
6589 | Title:
6590 | Antitumor activity of BRAF inhibitor vemurafenib in preclinical models
6591 | of BRAF-mutant colorectal cancer.
6592 |
6593 | ##### Therapies
6594 | Deprecated: False
6595 | Id: 4
6596 | Link: /therapies/4
6597 | Name: Vemurafenib
6598 |
6599 | ##### Therapies
6600 | Deprecated: False
6601 | Id: 15
6602 | Link: /therapies/15
6603 | Name: Erlotinib
6604 |
6605 | #### Evidence Items
6606 | Description:
6607 | This study examined outcomes of 240 rectum cancer patients treated with
6608 | total mesorectal excision therapy. Tumor samples were obtained at the
6609 | time of surgery and genotyped for BRAF exon 15 mutations. BRAF V600E was
6610 | identified in 5 cases. The authors reported that no differences were
6611 | found in overall survival between patients with and without BRAF
6612 | mutations (P > 0.1).
6613 | Evidence Direction: DOES_NOT_SUPPORT
6614 | Evidence Level: C
6615 | Evidence Rating: 2
6616 | Evidence Type: PROGNOSTIC
6617 | Flagged: False
6618 | Id: 2362
6619 | Name: EID2362
6620 | Significance: POOR_OUTCOME
6621 | Variant Origin: SOMATIC
6622 |
6623 | ##### Disease
6624 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
6625 | Display Name: Colorectal Cancer
6626 | Doid: 9256
6627 | Id: 11
6628 | Link: /diseases/11
6629 | Name: Colorectal Cancer
6630 |
6631 | ##### My Disease Info
6632 | Do Def:
6633 | An intestinal cancer that effects the long, tube-like organ that is
6634 | connected to the small intestine at one end and the anus at the other.
6635 | Icd10: C18.9
6636 | Mondo Id: MONDO:0005575
6637 | Ncit: C4978
6638 |
6639 | ##### Molecular Profile
6640 | Id: 12
6641 |
6642 | ##### Source
6643 | Abstract:
6644 | Identifying rectal cancer patients at risk for local recurrence would
6645 | allow for refinement in the selection of patients who would benefit from
6646 | preoperative radiotherapy. PIK3CA, KRAS, and BRAF mutations are commonly
6647 | found in colon cancers, but their prevalence has not been clearly
6648 | assessed in rectal cancer. In this study, we aim to determine the
6649 | mutation frequencies of PIK3CA, KRAS, and BRAF and to investigate
6650 | whether a mutation may be used as a prognostic parameter in rectal
6651 | cancer patients.We evaluated DNA mutations in PIK3CA, KRAS, and BRAF in
6652 | 240 stage I to III rectal tumors obtained from nonirradiated patients
6653 | from the Dutch Total Mesorectal Excision trial.PIK3CA, KRAS, and BRAF
6654 | mutations were identified in 19 (7.9%), 81 (33.9%), and 5 (2.1%) rectal
6655 | cancers. Patients with PIK3CA mutations developed more local recurrences
6656 | (5-year risks, 27.8% versus 9.4%; P = 0.006) and tended to develop these
6657 | recurrences more rapidly after surgery (median local recurrence-free
6658 | interval since surgery: 7.9 versus 19.6 months; P = 0.07) than patients
6659 | without PIK3CA mutations. In multivariate analysis, PIK3CA mutations
6660 | remained as an independent predictor for the development of local
6661 | recurrences (hazard ratio, 3.4; 95% confidence interval, 1.2-9.2; P =
6662 | 0.017), next to tumor-node-metastasis stage.PIK3CA mutations can be used
6663 | as a biomarker in identifying rectal cancer patients with an increased
6664 | risk for local recurrences. Currently, our findings suggest that
6665 | prospective evaluation of PIK3CA mutation status could reduce
6666 | overtreatment by preoperative radiotherapy for the low-risk patients who
6667 | might otherwise only experience the side effects.
6668 | Author String:
6669 | Youji He, Laura J Van't Veer, Izabela Mikolajewska-Hanclich, Marie-
6670 | Louise F van Velthuysen, Eliane C M Zeestraten, Iris D Nagtegaal,
6671 | Cornelis J H van de Velde, Corrie A M Marijnen
6672 | Citation: He et al., 2009
6673 | Citation Id: 19903786
6674 | Id: 1475
6675 | Journal: Clin Cancer Res
6676 | Link: /sources/1475
6677 | Name: PubMed: He et al., 2009
6678 | Open Access: False
6679 | Publication Date: 2009-11-15
6680 | Retracted: False
6681 | Source Type: PUBMED
6682 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19903786
6683 | Title: PIK3CA mutations predict local recurrences in rectal cancer patients.
6684 |
6685 | #### Evidence Items
6686 | Description:
6687 | In a study of metastatic colorectal cancer patients treated with
6688 | capecitabine, oxaliplatin, bevacizumab, and cetuximab those with BRAF
6689 | V600E mutations had reduced progression-free survival (6.6mo vs. 10.4mo,
6690 | P=0.01) and reduced overall survival (15.2mo vs. 21.5mo, P=0.001)
6691 | compared to those with wildtype BRAF.
6692 | Evidence Direction: SUPPORTS
6693 | Evidence Level: B
6694 | Evidence Rating: 3
6695 | Evidence Type: PREDICTIVE
6696 | Flagged: False
6697 | Id: 8646
6698 | Name: EID8646
6699 | Significance: RESISTANCE
6700 | Variant Origin: SOMATIC
6701 |
6702 | ##### Disease
6703 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
6704 | Display Name: Colorectal Cancer
6705 | Doid: 9256
6706 | Id: 11
6707 | Link: /diseases/11
6708 | Name: Colorectal Cancer
6709 |
6710 | ##### My Disease Info
6711 | Do Def:
6712 | An intestinal cancer that effects the long, tube-like organ that is
6713 | connected to the small intestine at one end and the anus at the other.
6714 | Icd10: C18.9
6715 | Mondo Id: MONDO:0005575
6716 | Ncit: C4978
6717 |
6718 | ##### Molecular Profile
6719 | Id: 12
6720 |
6721 | ##### Source
6722 | Author String: Jolien Tol, Iris D Nagtegaal, Cornelis J A Punt
6723 | Citation: Tol et al., 2009
6724 | Citation Id: 19571295
6725 | Id: 1481
6726 | Journal: N Engl J Med
6727 | Link: /sources/1481
6728 | Name: PubMed: Tol et al., 2009
6729 | Open Access: False
6730 | Publication Date: 2009-7-2
6731 | Retracted: False
6732 | Source Type: PUBMED
6733 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19571295
6734 | Title: BRAF mutation in metastatic colorectal cancer.
6735 |
6736 | ##### Therapies
6737 | Deprecated: False
6738 | Id: 16
6739 | Link: /therapies/16
6740 | Name: Cetuximab
6741 |
6742 | ##### Therapies
6743 | Deprecated: False
6744 | Id: 33
6745 | Link: /therapies/33
6746 | Name: Bevacizumab
6747 |
6748 | ##### Therapies
6749 | Deprecated: False
6750 | Id: 32
6751 | Link: /therapies/32
6752 | Name: Capecitabine
6753 |
6754 | ##### Therapies
6755 | Deprecated: False
6756 | Id: 237
6757 | Link: /therapies/237
6758 | Name: Oxaliplatin
6759 |
6760 | #### Evidence Items
6761 | Description:
6762 | Multicenter, phase 1, dose-escalation trial of PLX4032 (Vemurafenib).
6763 | Treatment of metastatic melanoma with PLX4032 in patients with tumors
6764 | that carry the V600E BRAF mutation resulted in complete or partial tumor
6765 | regression in the majority of patients (N=37/48). Patients without the
6766 | V600E mutation had evidence of tumor regression.
6767 | Evidence Direction: SUPPORTS
6768 | Evidence Level: B
6769 | Evidence Rating: 4
6770 | Evidence Type: PREDICTIVE
6771 | Flagged: False
6772 | Id: 1749
6773 | Name: EID1749
6774 | Significance: SENSITIVITYRESPONSE
6775 | Variant Origin: SOMATIC
6776 |
6777 | ##### Disease
6778 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
6779 | Display Name: Melanoma
6780 | Doid: 1909
6781 | Id: 7
6782 | Link: /diseases/7
6783 | Name: Melanoma
6784 |
6785 | ##### My Disease Info
6786 | Do Def:
6787 | A cell type cancer that has_material_basis_in abnormally proliferating
6788 | cells derives_from melanocytes which are found in skin, the bowel and
6789 | the eye.
6790 | Icdo: 8720/3
6791 | Mesh: D008545
6792 | Mondo Id: MONDO:0005105
6793 | Ncit: C3224
6794 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
6795 |
6796 | ##### Molecular Profile
6797 | Id: 12
6798 |
6799 | ##### Source
6800 | Abstract:
6801 | The identification of somatic mutations in the gene encoding the serine-
6802 | threonine protein kinase B-RAF (BRAF) in the majority of melanomas
6803 | offers an opportunity to test oncogene-targeted therapy for this
6804 | disease.We conducted a multicenter, phase 1, dose-escalation trial of
6805 | PLX4032 (also known as RG7204), an orally available inhibitor of mutated
6806 | BRAF, followed by an extension phase involving the maximum dose that
6807 | could be administered without adverse effects (the recommended phase 2
6808 | dose). Patients received PLX4032 twice daily until they had disease
6809 | progression. Pharmacokinetic analysis and tumor-response assessments
6810 | were conducted in all patients. In selected patients, tumor biopsy was
6811 | performed before and during treatment to validate BRAF inhibition.A
6812 | total of 55 patients (49 of whom had melanoma) were enrolled in the
6813 | dose-escalation phase, and 32 additional patients with metastatic
6814 | melanoma who had BRAF with the V600E mutation were enrolled in the
6815 | extension phase. The recommended phase 2 dose was 960 mg twice daily,
6816 | with increases in the dose limited by grade 2 or 3 rash, fatigue, and
6817 | arthralgia. In the dose-escalation cohort, among the 16 patients with
6818 | melanoma whose tumors carried the V600E BRAF mutation and who were
6819 | receiving 240 mg or more of PLX4032 twice daily, 10 had a partial
6820 | response and 1 had a complete response. Among the 32 patients in the
6821 | extension cohort, 24 had a partial response and 2 had a complete
6822 | response. The estimated median progression-free survival among all
6823 | patients was more than 7 months.Treatment of metastatic melanoma with
6824 | PLX4032 in patients with tumors that carry the V600E BRAF mutation
6825 | resulted in complete or partial tumor regression in the majority of
6826 | patients. (Funded by Plexxikon and Roche Pharmaceuticals.)
6827 | Author String:
6828 | Keith T Flaherty, Igor Puzanov, Kevin B Kim, Antoni Ribas, Grant A
6829 | McArthur, Jeffrey A Sosman, Peter J O'Dwyer, Richard J Lee, Joseph F
6830 | Grippo, Keith Nolop, Paul B Chapman
6831 | Citation: Flaherty et al., 2010
6832 | Citation Id: 20818844
6833 | Id: 352
6834 | Journal: N Engl J Med
6835 | Link: /sources/352
6836 | Name: PubMed: Flaherty et al., 2010
6837 | Open Access: True
6838 | Pmc Id: PMC3724529
6839 | Publication Date: 2010-8-26
6840 | Retracted: False
6841 | Source Type: PUBMED
6842 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/20818844
6843 | Title: Inhibition of mutated, activated BRAF in metastatic melanoma.
6844 |
6845 | ##### Therapies
6846 | Deprecated: False
6847 | Id: 4
6848 | Link: /therapies/4
6849 | Name: Vemurafenib
6850 |
6851 | #### Evidence Items
6852 | Description:
6853 | In a retrospective study of 300 stage IV melanoma patients, patients
6854 | with BRAF V600E mutation (n=175) were associated with a 4.8% (8/167)
6855 | complete response, a 58.1% (97/167) partial response and stable disease
6856 | in 22.2% (37/167) of cases, while 15% (25/167) of patients harboring
6857 | BRAF V600E experienced progressive disease.
6858 | Evidence Direction: SUPPORTS
6859 | Evidence Level: B
6860 | Evidence Rating: 3
6861 | Evidence Type: PREDICTIVE
6862 | Flagged: False
6863 | Id: 3757
6864 | Name: EID3757
6865 | Significance: SENSITIVITYRESPONSE
6866 | Variant Origin: SOMATIC
6867 |
6868 | ##### Disease
6869 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
6870 | Display Name: Melanoma
6871 | Doid: 1909
6872 | Id: 7
6873 | Link: /diseases/7
6874 | Name: Melanoma
6875 |
6876 | ##### My Disease Info
6877 | Do Def:
6878 | A cell type cancer that has_material_basis_in abnormally proliferating
6879 | cells derives_from melanocytes which are found in skin, the bowel and
6880 | the eye.
6881 | Icdo: 8720/3
6882 | Mesh: D008545
6883 | Mondo Id: MONDO:0005105
6884 | Ncit: C3224
6885 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
6886 |
6887 | ##### Molecular Profile
6888 | Id: 12
6889 |
6890 | ##### Source
6891 | Abstract:
6892 | Kinase inhibitors targeting the BRAF V600 mutation have become standard
6893 | in the treatment of metastatic melanoma. Albeit in wide clinical use,
6894 | the patterns associated with therapy outcome are not fully elucidated.
6895 | The present study was aimed to identify predictive factors of therapy
6896 | response and survival under the BRAF inhibitor vemurafenib.This
6897 | multicenter retrospective study analyzed patient, tumor, and
6898 | pretreatment characteristics collected in BRAF V600-mutated stage IV
6899 | melanoma patients before single-agent therapy with the BRAF inhibitor
6900 | vemurafenib.A total of 300 patients from 14 centers were included into
6901 | this study with a median follow-up time of 13.0 months. Median
6902 | progression-free survival (PFS) was 5.1 months; median overall survival
6903 | (OS) was 7.6 months. Best response under vemurafenib was associated with
6904 | serum lactate dehydrogenase (LDH; ≤ versus >upper normal limit; P =
6905 | 0.0000001), Eastern Cooperative Oncology Group (ECOG) overall
6906 | performance status (OPS) (0 versus ≥ 1; P = 0.00089), and BRAF mutation
6907 | subtype (V600E versus V600K; P = 0.016). Multivariate analysis
6908 | identified ECOG OPS ≥ 1 [hazard ratio (HR) = 1.88; P = 0.00005],
6909 | immunotherapy pretreatment (HR = 0.53; P = 0.0067), elevated serum LDH
6910 | (HR = 1.45; P = 0.012), age >55 years (HR = 0.72; P = 0.019), and
6911 | chemotherapy pretreatment (HR = 1.39; P = 0.036) as independent
6912 | predictors of PFS. For OS, elevated serum LDH (HR = 1.99; P = 0.00012),
6913 | ECOG OPS ≥ 1 (HR = 1.90; P = 0.00063), age >55 years (HR = 0.65; P =
6914 | 0.011), kinase inhibitor pretreatment (HR = 1.86; P = 0.014),
6915 | immunotherapy pretreatment (HR = 0.57; P = 0.025), chemotherapy
6916 | pretreatment (HR = 2.17; P = 0.039), and male gender (HR = 0.70; 95%
6917 | confidence interval 0.50-0.98; P = 0.039) were found as predictors.Our
6918 | data demonstrate that the type of pretreatment strongly influences the
6919 | outcome of vemurafenib therapy, with a precedent immunotherapy showing a
6920 | positive, and a prior chemotherapy and kinase inhibitors showing a
6921 | negative impact on survival, respectively. Moreover, we show that the
6922 | patient's OPS, serum LDH, age, and gender independently impact
6923 | vemurafenib therapy outcome. These findings should be taken into account
6924 | for the future design of therapy sequencing in BRAF V600 mutation-
6925 | positive melanoma patients.
6926 | Author String:
6927 | S Ugurel, C Loquai, K Kähler, J Hassel, C Berking, L Zimmer, I Haubitz,
6928 | I Satzger, T Müller-Brenne, N C Mikhaimer, J C Becker, K J Kilian, D
6929 | Schadendorf, L Heinzerling, M Kaatz, J Utikal, D Göppner, C Pföhler, A
6930 | Pflugfelder, R Mössner, R Gutzmer
6931 | Citation: Ugurel et al., 2015
6932 | Citation Id: 25524477
6933 | Id: 1957
6934 | Journal: Ann Oncol
6935 | Link: /sources/1957
6936 | Name: PubMed: Ugurel et al., 2015
6937 | Open Access: False
6938 | Publication Date: 2015-3
6939 | Retracted: False
6940 | Source Type: PUBMED
6941 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25524477
6942 | Title:
6943 | A multicenter DeCOG study on predictors of vemurafenib therapy outcome
6944 | in melanoma: pretreatment impacts survival.
6945 |
6946 | ##### Therapies
6947 | Deprecated: False
6948 | Id: 4
6949 | Link: /therapies/4
6950 | Name: Vemurafenib
6951 |
6952 | #### Evidence Items
6953 | Description:
6954 | A stage 4B, low-grade papillary serous ovarian adenocarcinoma patient,
6955 | harboring a BRAF V600E mutation was associated with response to
6956 | vemurafenib monotherapy. The patient was treated with standard
6957 | chemotherapy, hormone therapy and bevacizumab prior to the
6958 | identification of the BRAF V600E mutation; next, the patient was treated
6959 | with paclitaxel and an anti-HER3 antibody and finally with vemurafenib,
6960 | obtaining a partial response of greater than 1 year.
6961 | Evidence Direction: SUPPORTS
6962 | Evidence Level: C
6963 | Evidence Rating: 3
6964 | Evidence Type: PREDICTIVE
6965 | Flagged: False
6966 | Id: 3787
6967 | Name: EID3787
6968 | Significance: SENSITIVITYRESPONSE
6969 | Variant Origin: SOMATIC
6970 |
6971 | ##### Disease
6972 | Disease Url: https://www.disease-ontology.org/?id=DOID:0050933
6973 | Display Name: Ovarian Serous Carcinoma
6974 | Doid: 0050933
6975 | Id: 87
6976 | Link: /diseases/87
6977 | Name: Ovarian Serous Carcinoma
6978 |
6979 | ##### My Disease Info
6980 | Do Def:
6981 | An ovarian carcinoma that has_material_basis_in the lining of the ovary
6982 | and produces a serum-like fluid.
6983 | Mondo Id: MONDO:0005211
6984 |
6985 | ##### Molecular Profile
6986 | Id: 12
6987 |
6988 | ##### Source
6989 | Abstract:
6990 | Low-grade serous ovarian adenocarcinomas (LGSOC) make up approximately
6991 | 10 % of serous ovarian carcinomas. While rarely aggressive, this slow-
6992 | growing tumor is well known to respond poorly to chemotherapy. Specific
6993 | treatments for this ovarian subtype are lacking, with the same global
6994 | approaches used for high grade cases being applied for LGSOC patients.
6995 | LGSOCs have been reported to have a specific genetic profile, with
6996 | notable implication of the MAPK pathway. This has opened up
6997 | opportunities for novel therapeutic strategies, with in particular the
6998 | use of targeted therapies. We report here the case of a heavily
6999 | pretreated unresectable BRAF p.V600E-mutated LGSOC, which we treated
7000 | vemurafenib, a BRAF inhibitor specific for V600E mutations. We saw
7001 | impressive efficacy, with a long-term partial response along with CA125
7002 | reductions and symptom relief. Although this mutation is present in
7003 | LGSOC at very a low incidence, we recommend routine testing for BRAF and
7004 | other targetable mutations in this patient population, along with
7005 | further evaluation in the increasingly popular basket trial approach.
7006 | Author String:
7007 | Pierre Combe, Laure Chauvenet, Marie-Aude Lefrère-Belda, Hélène Blons,
7008 | Caroline Rousseau, Stéphane Oudard, Eric Pujade-Lauraine
7009 | Citation: Combe et al., 2015
7010 | Citation Id: 26490654
7011 | Id: 1984
7012 | Journal: Invest New Drugs
7013 | Link: /sources/1984
7014 | Name: PubMed: Combe et al., 2015
7015 | Open Access: False
7016 | Publication Date: 2015-12
7017 | Retracted: False
7018 | Source Type: PUBMED
7019 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26490654
7020 | Title:
7021 | Sustained response to vemurafenib in a low grade serous ovarian cancer
7022 | with a BRAF V600E mutation.
7023 |
7024 | ##### Therapies
7025 | Deprecated: False
7026 | Id: 4
7027 | Link: /therapies/4
7028 | Name: Vemurafenib
7029 |
7030 | #### Evidence Items
7031 | Description:
7032 | A 51 year old male anaplastic thyroid cancer patient harboring BRAF
7033 | V600E experienced rapid improvement in response to vemurafenib. The
7034 | patient was initially treated with paclitaxel and carboplatin but
7035 | experienced disease progression; subsequently, the patient was treated
7036 | concurrently with vemurafenib and radiation therapy and achieved near
7037 | complete regression of metastatic disease.
7038 | Evidence Direction: SUPPORTS
7039 | Evidence Level: C
7040 | Evidence Rating: 3
7041 | Evidence Type: PREDICTIVE
7042 | Flagged: False
7043 | Id: 3743
7044 | Name: EID3743
7045 | Significance: SENSITIVITYRESPONSE
7046 | Variant Origin: SOMATIC
7047 |
7048 | ##### Disease
7049 | Disease Url: https://www.disease-ontology.org/?id=DOID:0080522
7050 | Display Name: Anaplastic Thyroid Carcinoma
7051 | Doid: 0080522
7052 | Id: 3040
7053 | Link: /diseases/3040
7054 | Name: Anaplastic Thyroid Carcinoma
7055 |
7056 | ##### My Disease Info
7057 | Do Def: A thyroid gland carcinoma that is composed of undifferentiated cells.
7058 | Mondo Id: MONDO:0006468
7059 | Ncit: C3878
7060 | Disease Aliases: Thyroid Gland Anaplastic Carcinoma
7061 |
7062 | ##### Molecular Profile
7063 | Id: 12
7064 |
7065 | ##### Source
7066 | Author String: Michael H Rosove, Parvin F Peddi, John A Glaspy
7067 | Citation: Rosove et al., 2013
7068 | Citation Id: 23406047
7069 | Id: 1948
7070 | Journal: N Engl J Med
7071 | Link: /sources/1948
7072 | Name: PubMed: Rosove et al., 2013
7073 | Open Access: False
7074 | Publication Date: 2013-2-14
7075 | Retracted: False
7076 | Source Type: PUBMED
7077 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23406047
7078 | Title: BRAF V600E inhibition in anaplastic thyroid cancer.
7079 |
7080 | ##### Therapies
7081 | Deprecated: False
7082 | Id: 4
7083 | Link: /therapies/4
7084 | Name: Vemurafenib
7085 |
7086 | ##### Therapies
7087 | Deprecated: False
7088 | Id: 360
7089 | Link: /therapies/360
7090 | Name: Radiation Therapy
7091 |
7092 | #### Evidence Items
7093 | Description:
7094 | Using Sanger sequencing, BRAFV600E mutations were identified in 21 of
7095 | 285 patients with PLGGs (7.4%). This mutation was enriched in
7096 | hemispheric tumors (p<0.007) and was associated with shorter
7097 | progression-free survival (p=0.011) and overall survival (p=0.032) [mt
7098 | (n=18) vs wt (n=166)].
7099 | Evidence Direction: SUPPORTS
7100 | Evidence Level: B
7101 | Evidence Rating: 4
7102 | Evidence Type: PROGNOSTIC
7103 | Flagged: False
7104 | Id: 7191
7105 | Name: EID7191
7106 | Significance: POOR_OUTCOME
7107 | Variant Origin: SOMATIC
7108 |
7109 | ##### Disease
7110 | Disease Url: https://www.disease-ontology.org/?id=DOID:0080830
7111 | Display Name: Childhood Low-grade Glioma
7112 | Doid: 0080830
7113 | Id: 3048
7114 | Link: /diseases/3048
7115 | Name: Childhood Low-grade Glioma
7116 |
7117 | ##### My Disease Info
7118 | Do Def:
7119 | A low-grade glioma that occurs in children and encompasses tumors of
7120 | astrocytic, oligodendroglial, and mixed glial-neuronal histology.
7121 | Mondo Id: MONDO:0859591
7122 | Disease Aliases: Pediatric Low-grade Glioma
7123 |
7124 | ##### Molecular Profile
7125 | Id: 12
7126 |
7127 | ##### Source
7128 | Abstract:
7129 | Pediatric low-grade gliomas (PLGGs) consist of a number of entities with
7130 | overlapping histological features. PLGGs have much better prognosis than
7131 | the adult counterparts, but a significant proportion of PLGGs suffers
7132 | from tumor progression and recurrence. It has been shown that pediatric
7133 | and adult low-grade gliomas are molecularly distinct. Yet the clinical
7134 | significance of some of newer biomarkers discovered by genomic studies
7135 | has not been fully investigated. In this study, we evaluated in a large
7136 | cohort of 289 PLGGs a list of biomarkers and examined their clinical
7137 | relevance. TERT promoter (TERTp), H3F3A and BRAF V600E mutations were
7138 | detected by direct sequencing. ATRX nuclear loss was examined by
7139 | immunohistochemistry. CDKN2A deletion, KIAA1549-BRAF fusion, and MYB
7140 | amplification were determined by fluorescence in situ hybridization
7141 | (FISH). TERTp, H3F3A, and BRAF V600E mutations were identified in 2.5,
7142 | 6.4, and 7.4% of PLGGs, respectively. ATRX loss was found in 4.9% of
7143 | PLGGs. CDKN2A deletion, KIAA1549-BRAF fusion and MYB amplification were
7144 | detected in 8.8, 32.0 and 10.6% of PLGGs, respectively. Survival
7145 | analysis revealed that TERTp mutation, H3F3A mutation, and ATRX loss
7146 | were significantly associated with poor PFS (p < 0.0001, p < 0.0001, and
7147 | p = 0.0002) and OS (p < 0.0001, p < 0.0001, and p < 0.0001). BRAF V600E
7148 | was associated with shorter PFS (p = 0.011) and OS (p = 0.032) in a
7149 | subset of PLGGs. KIAA1549-BRAF fusion was a good prognostic marker for
7150 | longer PFS (p = 0.0017) and OS (p = 0.0029). MYB amplification was also
7151 | a favorable marker for a longer PFS (p = 0.040). Importantly, we showed
7152 | that these molecular biomarkers can be used to stratify PLGGs into low-
7153 | (KIAA1549-BRAF fusion or MYB amplification), intermediate-I (BRAF V600E
7154 | and/or CDKN2A deletion), intermediate-II (no biomarker), and high-risk
7155 | (TERTp or H3F3A mutation or ATRX loss) groups with distinct PFS (p <
7156 | 0.0001) and OS (p < 0.0001). This scheme should aid in clinical
7157 | decision-making.
7158 | Author String:
7159 | Rui Ryan Yang, Abudumijiti Aibaidula, Wei-Wei Wang, Aden Ka-Yin Chan,
7160 | Zhi-Feng Shi, Zhen-Yu Zhang, Danny Tat Ming Chan, Wai Sang Poon, Xian-
7161 | Zhi Liu, Wen-Cai Li, Rui-Qi Zhang, Yan-Xi Li, Nellie Yuk-Fei Chung, Hong
7162 | Chen, Jingsong Wu, Liangfu Zhou, Kay Ka-Wai Li, Ho-Keung Ng
7163 | Citation: Yang et al., 2018
7164 | Citation Id: 29948154
7165 | Id: 2816
7166 | Journal: Acta Neuropathol
7167 | Link: /sources/2816
7168 | Name: PubMed: Yang et al., 2018
7169 | Open Access: False
7170 | Publication Date: 2018-10
7171 | Retracted: False
7172 | Source Type: PUBMED
7173 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/29948154
7174 | Title: Pediatric low-grade gliomas can be molecularly stratified for risk.
7175 |
7176 | ##### Phenotypes
7177 | Description:
7178 | Onset of disease manifestations before adulthood, defined here as before
7179 | the age of 16 years, but excluding neonatal or congenital onset.
7180 | Hpo Id: HP:0410280
7181 | Id: 15320
7182 | Link: /phenotypes/15320
7183 | Name: Pediatric onset
7184 | Url: https://hpo.jax.org/app/browse/term/HP:0410280
7185 |
7186 | ##### Phenotypes
7187 | Description:
7188 | Onset of disease at an age of greater than or equal to 16 to under 19
7189 | years.
7190 | Hpo Id: HP:0025708
7191 | Id: 16642
7192 | Link: /phenotypes/16642
7193 | Name: Early young adult onset
7194 | Url: https://hpo.jax.org/app/browse/term/HP:0025708
7195 |
7196 | #### Evidence Items
7197 | Description:
7198 | Interim analysis of a basket trial evaluating the combination of
7199 | dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in previously
7200 | treated V600E-mutated patients showed 11/16 patients with anaplastic
7201 | thyroid carcinoma responded to treatment (overall response rate 69%; 95%
7202 | CI, 41% to 89%). Seven patients had ongoing responses. Median duration
7203 | of response, progression-free survival, and overall survival were not
7204 | reached after 120 weeks.
7205 | Evidence Direction: SUPPORTS
7206 | Evidence Level: B
7207 | Evidence Rating: 4
7208 | Evidence Type: PREDICTIVE
7209 | Flagged: False
7210 | Id: 6975
7211 | Name: EID6975
7212 | Significance: SENSITIVITYRESPONSE
7213 | Variant Origin: SOMATIC
7214 |
7215 | ##### Disease
7216 | Disease Url: https://www.disease-ontology.org/?id=DOID:0080522
7217 | Display Name: Anaplastic Thyroid Carcinoma
7218 | Doid: 0080522
7219 | Id: 3040
7220 | Link: /diseases/3040
7221 | Name: Anaplastic Thyroid Carcinoma
7222 |
7223 | ##### My Disease Info
7224 | Do Def: A thyroid gland carcinoma that is composed of undifferentiated cells.
7225 | Mondo Id: MONDO:0006468
7226 | Ncit: C3878
7227 | Disease Aliases: Thyroid Gland Anaplastic Carcinoma
7228 |
7229 | ##### Molecular Profile
7230 | Id: 12
7231 |
7232 | ##### Source
7233 | Abstract:
7234 | Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor)
7235 | and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated
7236 | anaplastic thyroid cancer, a rare, aggressive, and highly lethal
7237 | malignancy with poor patient outcomes and no systemic therapies with
7238 | clinical benefit. Methods In this phase II, open-label trial, patients
7239 | with predefined BRAF V600E-mutated malignancies received dabrafenib 150
7240 | mg twice daily and trametinib 2 mg once daily until unacceptable
7241 | toxicity, disease progression, or death. The primary end point was
7242 | investigator-assessed overall response rate. Secondary end points
7243 | included duration of response, progression-free survival, overall
7244 | survival, and safety. Results Sixteen patients with BRAF V600E-mutated
7245 | anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks;
7246 | range, 4 to 120 weeks). All patients had received prior radiation
7247 | treatment and/or surgery, and six had received prior systemic therapy.
7248 | The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to
7249 | 89%), with seven ongoing responses. Median duration of response,
7250 | progression-free survival, and overall survival were not reached as a
7251 | result of a lack of events, with 12-month estimates of 90%, 79%, and
7252 | 80%, respectively. The safety population was composed of 100 patients
7253 | who were enrolled with seven rare tumor histologies. Common adverse
7254 | events were fatigue (38%), pyrexia (37%), and nausea (35%). No new
7255 | safety signals were detected. Conclusion Dabrafenib plus trametinib is
7256 | the first regimen demonstrated to have robust clinical activity in BRAF
7257 | V600E-mutated anaplastic thyroid cancer and was well tolerated. These
7258 | findings represent a meaningful therapeutic advance for this orphan
7259 | disease.
7260 | Author String:
7261 | Vivek Subbiah, Robert J Kreitman, Zev A Wainberg, Jae Yong Cho, Jan H M
7262 | Schellens, Jean Charles Soria, Patrick Y Wen, Christoph Zielinski, Maria
7263 | E Cabanillas, Gladys Urbanowitz, Bijoyesh Mookerjee, Dazhe Wang, Fatima
7264 | Rangwala, Bhumsuk Keam
7265 | Citation: Subbiah et al., 2018
7266 | Citation Id: 29072975
7267 | Id: 2686
7268 | Journal: J Clin Oncol
7269 | Link: /sources/2686
7270 | Name: PubMed: Subbiah et al., 2018
7271 | Open Access: True
7272 | Pmc Id: PMC5791845
7273 | Publication Date: 2018-1-1
7274 | Retracted: False
7275 | Source Type: PUBMED
7276 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/29072975
7277 | Title:
7278 | Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or
7279 | Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer.
7280 |
7281 | ##### Therapies
7282 | Deprecated: False
7283 | Id: 22
7284 | Link: /therapies/22
7285 | Name: Dabrafenib
7286 |
7287 | ##### Therapies
7288 | Deprecated: False
7289 | Id: 19
7290 | Link: /therapies/19
7291 | Name: Trametinib
7292 |
7293 | #### Evidence Items
7294 | Description:
7295 | Thirty-two patients with BRAF V600E positive metastatic colorectal
7296 | cancer (mCRC) and 7 patients with other cancers were treated with a
7297 | combination of BRAF-inhibitor vemurafenib (960 mg twice daily) and EGFR-
7298 | inhibitor erlotinib (150 mg daily) in a phase Ib/II trial. No dose-
7299 | limiting toxicities were observed. Overall response rates were 32%
7300 | [10/31, 16% (5/31) confirmed] in patients with mCRC and 43% (3/7) in
7301 | patients with other cancers, with clinical benefit rates of 65% and
7302 | 100%, respectively. Early ctDNA dynamics were predictive of treatment
7303 | efficacy. Serial ctDNA monitoring revealed distinct patterns of acquired
7304 | treatment resistance. Convergent genomic evolution was observed with
7305 | frequent emergence of MAPK pathway alterations, including polyclonal
7306 | KRAS, NRAS, and MAP2K1 mutations, and MET amplification.
7307 | Evidence Direction: SUPPORTS
7308 | Evidence Level: B
7309 | Evidence Rating: 3
7310 | Evidence Type: PREDICTIVE
7311 | Flagged: False
7312 | Id: 11427
7313 | Name: EID11427
7314 | Significance: SENSITIVITYRESPONSE
7315 | Variant Origin: SOMATIC
7316 |
7317 | ##### Disease
7318 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
7319 | Display Name: Colorectal Cancer
7320 | Doid: 9256
7321 | Id: 11
7322 | Link: /diseases/11
7323 | Name: Colorectal Cancer
7324 |
7325 | ##### My Disease Info
7326 | Do Def:
7327 | An intestinal cancer that effects the long, tube-like organ that is
7328 | connected to the small intestine at one end and the anus at the other.
7329 | Icd10: C18.9
7330 | Mondo Id: MONDO:0005575
7331 | Ncit: C4978
7332 |
7333 | ##### Molecular Profile
7334 | Id: 12
7335 |
7336 | ##### Source
7337 | Abstract:
7338 | BRAF V600E mutant metastatic colorectal cancer represents a significant
7339 | clinical problem, with combination approaches being developed clinically
7340 | with oral BRAF inhibitors combined with EGFR-targeting antibodies. While
7341 | compelling preclinical data have highlighted the effectiveness of
7342 | combination therapy with vemurafenib and small-molecule EGFR inhibitors,
7343 | gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy
7344 | has not been investigated in clinical studies.We conducted a phase Ib/II
7345 | dose-escalation/expansion trial investigating the safety/efficacy of the
7346 | BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib.Thirty-two
7347 | patients with BRAF V600E positive metastatic colorectal cancer (mCRC)
7348 | and 7 patients with other cancers were enrolled. No dose-limiting
7349 | toxicities were observed in escalation, with vemurafenib 960 mg twice
7350 | daily with erlotinib 150 mg daily selected as the recommended phase II
7351 | dose. Among 31 evaluable patients with mCRC and 7 with other cancers,
7352 | overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43%
7353 | (3/7), respectively, with clinical benefit rates of 65% and 100%. Early
7354 | ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA
7355 | monitoring revealed distinct patterns of convergent genomic evolution
7356 | associated with acquired treatment resistance, with frequent emergence
7357 | of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1
7358 | mutations, and MET amplification.The Erlotinib and Vemurafenib In
7359 | Combination Trial study demonstrated a safe and novel combination of two
7360 | oral inhibitors targeting BRAF and EGFR. The dynamic assessment of
7361 | serial ctDNA was a useful measure of underlying genomic changes in
7362 | response to this combination and in understanding potential mechanisms
7363 | of resistance.
7364 | Author String:
7365 | Lavinia Tan, Ben Tran, Jeanne Tie, Ben Markman, Sumi Ananda, Niall C
7366 | Tebbutt, Michael Michael, Emma Link, Stephen Q Wong, Sushma
7367 | Chandrashekar, Jerick Guinto, David Ritchie, Rachel Koldej, Benjamin J
7368 | Solomon, Grant A McArthur, Rodney J Hicks, Peter Gibbs, Sarah-Jane
7369 | Dawson, Jayesh Desai
7370 | Citation: Tan et al., 2023
7371 | Citation Id: 36638198
7372 | Id: 4534
7373 | Journal: Clin Cancer Res
7374 | Link: /sources/4534
7375 | Name: PubMed: Tan et al., 2023
7376 | Open Access: True
7377 | Pmc Id: PMC10011885
7378 | Publication Date: 2023-3-14
7379 | Retracted: False
7380 | Source Type: PUBMED
7381 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/36638198
7382 | Title:
7383 | A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in BRAF V600E
7384 | Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT
7385 | (Erlotinib and Vemurafenib In Combination Trial) Study.
7386 |
7387 | ##### Therapies
7388 | Deprecated: False
7389 | Id: 4
7390 | Link: /therapies/4
7391 | Name: Vemurafenib
7392 |
7393 | ##### Therapies
7394 | Deprecated: False
7395 | Id: 15
7396 | Link: /therapies/15
7397 | Name: Erlotinib
7398 |
7399 | #### Evidence Items
7400 | Description:
7401 | In this trial, 665 patients having metastatic colorectal cancer were
7402 | randomly assigned in 1:1:1 ratio to receive encorafenib plus cetuximab
7403 | plus binimetinib, encorafenib plus cetuximab, investigators' choice of
7404 | irinotecan plus cetuximab or FOLFIRI, this evidence item further shares
7405 | analysis of safety and efficacy data and concludes that encorafenib plus
7406 | cetuximab with or without binimetinib improved OS, PFS and ORR in
7407 | patients with BRAF-V600E mutated metastatic colorectal cancer. It also
7408 | concluded that encorafenib plus cetuximab doublet therapy could be used
7409 | as a standard care for previously treated patients with BRAF-V600E-mCRC
7410 | as OS efficacy was similar with or without binimetinib.
7411 | Evidence Direction: SUPPORTS
7412 | Evidence Level: B
7413 | Evidence Rating: 5
7414 | Evidence Type: PREDICTIVE
7415 | Flagged: False
7416 | Id: 11436
7417 | Name: EID11436
7418 | Significance: SENSITIVITYRESPONSE
7419 | Variant Origin: SOMATIC
7420 |
7421 | ##### Disease
7422 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
7423 | Display Name: Colorectal Cancer
7424 | Doid: 9256
7425 | Id: 11
7426 | Link: /diseases/11
7427 | Name: Colorectal Cancer
7428 |
7429 | ##### My Disease Info
7430 | Do Def:
7431 | An intestinal cancer that effects the long, tube-like organ that is
7432 | connected to the small intestine at one end and the anus at the other.
7433 | Icd10: C18.9
7434 | Mondo Id: MONDO:0005575
7435 | Ncit: C4978
7436 |
7437 | ##### Molecular Profile
7438 | Id: 12
7439 |
7440 | ##### Source
7441 | Abstract:
7442 | BEACON CRC evaluated encorafenib plus cetuximab with or without
7443 | binimetinib versus investigators' choice of irinotecan or FOLFIRI plus
7444 | cetuximab in patients with BRAFV600E-mutant metastatic colorectal cancer
7445 | (mCRC), after progression on 1-2 prior regimens. In the previously
7446 | reported primary analysis, encorafenib, binimetinib plus cetuximab
7447 | (ENCO/BINI/CETUX; triplet) and encorafenib plus cetuximab (ENCO/CETUX;
7448 | doublet) regimens improved overall survival (OS) and objective response
7449 | rate (ORR; by blinded central review) versus standard of care. The
7450 | purpose of this analysis was to report updated efficacy and safety
7451 | data.In this open-label, phase III trial, 665 patients with BRAF
7452 | V600E-mutant mCRC were randomly assigned 1:1:1 to receive triplet,
7453 | doublet, or control. Primary end points were OS and independently
7454 | reviewed ORR comparing triplet to control. OS for doublet versus control
7455 | was a key secondary end point. Updated analyses include 6 months of
7456 | additional follow-up and ORR for all randomized patients.Patients
7457 | received triplet (n = 224), doublet (n = 220), or control (n = 221).
7458 | Median OS was 9.3 months (95% CI, 8.2 to 10.8) for triplet and 5.9
7459 | months (95% CI, 5.1 to 7.1) for control (hazard ratio [HR], 0.60 [95%
7460 | CI, 0.47 to 0.75]). Median OS for doublet was 9.3 months (95% CI, 8.0 to
7461 | 11.3) (HR v control, 0.61 [95% CI, 0.48 to 0.77]). Confirmed ORR was
7462 | 26.8% (95% CI, 21.1% to 33.1%) for triplet, 19.5% (95% CI, 14.5% to
7463 | 25.4%) for doublet, and 1.8% (95% CI, 0.5% to 4.6%) for control. Adverse
7464 | events were consistent with the prior primary analysis, with grade ≥ 3
7465 | adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet, and
7466 | control, respectively.In the BEACON CRC study, encorafenib plus
7467 | cetuximab improved OS, ORR, and progression-free survival in previously
7468 | treated patients in the metastatic setting compared with standard
7469 | chemotherapy. Based on the primary and updated analyses, encorafenib
7470 | plus cetuximab is a new standard care regimen for previously treated
7471 | patients with BRAF V600E mCRC.
7472 | Author String:
7473 | Josep Tabernero, Axel Grothey, Eric Van Cutsem, Rona Yaeger, Harpreet
7474 | Wasan, Takayuki Yoshino, Jayesh Desai, Fortunato Ciardiello, Fotios
7475 | Loupakis, Yong Sang Hong, Neeltje Steeghs, Tormod Kyrre Guren, Hendrik-
7476 | Tobias Arkenau, Pilar Garcia-Alfonso, Elena Elez, Ashwin Gollerkeri,
7477 | Kati Maharry, Janna Christy-Bittel, Scott Kopetz
7478 | Citation: Tabernero et al., 2021
7479 | Citation Id: 33503393
7480 | Id: 3807
7481 | Journal: J Clin Oncol
7482 | Link: /sources/3807
7483 | Name: PubMed: Tabernero et al., 2021
7484 | Open Access: True
7485 | Pmc Id: PMC8078423
7486 | Publication Date: 2021-2-1
7487 | Retracted: False
7488 | Source Type: PUBMED
7489 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/33503393
7490 | Title:
7491 | Encorafenib Plus Cetuximab as a New Standard of Care for Previously
7492 | Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival
7493 | Results and Subgroup Analyses from the BEACON Study.
7494 |
7495 | ##### Therapies
7496 | Deprecated: False
7497 | Id: 20589
7498 | Link: /therapies/20589
7499 | Name: Cetuximab/Encorafenib Regimen
7500 |
7501 | #### Evidence Items
7502 | Description:
7503 | In an open-label, phase 3 randomized trial, 250 patients with either
7504 | previously untreated, stage IV or unresectable stage III BRAF V600E
7505 | mutation-positive melanoma were randomly assigned (3:1) to receive
7506 | dabrafenib 150 mg twice daily, orally or dacarbazine 1000 mg/m(2)
7507 | intravenously every 3 weeks. The median progression-free survival was
7508 | 5.1 months for dabrafenib and 2.7 months for dacarbazine, with a hazard
7509 | ratio of 0.30 (95% CI: 0.18 – 0.51; p < 0.0001). Treatment-related
7510 | adverse events of grade 2 or greater occurred in 100/187 patients who
7511 | received dabrafenib and in 26/59 patients who received dacarbazine.
7512 | Evidence Direction: SUPPORTS
7513 | Evidence Level: A
7514 | Evidence Rating: 4
7515 | Evidence Type: PREDICTIVE
7516 | Flagged: False
7517 | Id: 11244
7518 | Name: EID11244
7519 | Significance: SENSITIVITYRESPONSE
7520 | Variant Origin: SOMATIC
7521 |
7522 | ##### Disease
7523 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
7524 | Display Name: Melanoma
7525 | Doid: 1909
7526 | Id: 7
7527 | Link: /diseases/7
7528 | Name: Melanoma
7529 |
7530 | ##### My Disease Info
7531 | Do Def:
7532 | A cell type cancer that has_material_basis_in abnormally proliferating
7533 | cells derives_from melanocytes which are found in skin, the bowel and
7534 | the eye.
7535 | Icdo: 8720/3
7536 | Mesh: D008545
7537 | Mondo Id: MONDO:0005105
7538 | Ncit: C3224
7539 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
7540 |
7541 | ##### Molecular Profile
7542 | Id: 12
7543 |
7544 | ##### Source
7545 | Abstract:
7546 | Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a
7547 | manageable safety profile in studies of phase 1 and 2 in patients with
7548 | BRAF(V600)-mutated metastatic melanoma. We studied the efficacy of
7549 | dabrafenib in patients with BRAF(V600E)-mutated metastatic melanoma.We
7550 | enrolled patients in this open-label phase 3 trial between Dec 23, 2010,
7551 | and Sept 1, 2011. This report is based on a data cutoff date of Dec 19,
7552 | 2011. Patients aged 18 years or older with previously untreated, stage
7553 | IV or unresectable stage III BRAF(V600E) mutation-positive melanoma were
7554 | randomly assigned (3:1) to receive dabrafenib (150 mg twice daily,
7555 | orally) or dacarbazine (1000 mg/m(2) intravenously every 3 weeks).
7556 | Patients were stratified according to American Joint Committee on Cancer
7557 | stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was
7558 | investigator-assessed progression-free survival and was analysed by
7559 | intention to treat; safety was assessed per protocol. This study is
7560 | registered with ClinicalTrials.gov, number NCT01227889.Of the 733
7561 | patients screened, 250 were randomly assigned to receive either
7562 | dabrafenib (187 patients) or dacarbazine (63 patients). Median
7563 | progression-free survival was 5·1 months for dabrafenib and 2·7 months
7564 | for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18-0·51;
7565 | p<0·0001). At data cutoff, 107 (57%) patients in the dabrafenib group
7566 | and 14 (22%) in the dacarbazine group remained on randomised treatment.
7567 | Treatment-related adverse events (grade 2 or higher) occurred in 100
7568 | (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the
7569 | 59 patients who received dacarbazine. The most common adverse events
7570 | with dabrafenib were skin-related toxic effects, fever, fatigue,
7571 | arthralgia, and headache. The most common adverse events with
7572 | dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia.
7573 | Grade 3-4 adverse events were uncommon in both groups.Dabrafenib
7574 | significantly improved progression-free survival compared with
7575 | dacarbazine.GlaxoSmithKline.
7576 | Author String:
7577 | Axel Hauschild, Jean-Jacques Grob, Lev V Demidov, Thomas Jouary, Ralf
7578 | Gutzmer, Michael Millward, Piotr Rutkowski, Christian U Blank, Wilson H
7579 | Miller, Eckhart Kaempgen, Salvador Martín-Algarra, Boguslawa
7580 | Karaszewska, Cornelia Mauch, Vanna Chiarion-Sileni, Anne-Marie Martin,
7581 | Suzanne Swann, Patricia Haney, Beloo Mirakhur, Mary E Guckert, Vicki
7582 | Goodman, Paul B Chapman
7583 | Citation: Hauschild et al., 2012
7584 | Citation Id: 22735384
7585 | Id: 1500
7586 | Journal: Lancet
7587 | Link: /sources/1500
7588 | Name: PubMed: Hauschild et al., 2012
7589 | Open Access: False
7590 | Publication Date: 2012-7-28
7591 | Retracted: False
7592 | Source Type: PUBMED
7593 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22735384
7594 | Title:
7595 | Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-
7596 | label, phase 3 randomised controlled trial.
7597 |
7598 | ##### Therapies
7599 | Deprecated: False
7600 | Id: 22
7601 | Link: /therapies/22
7602 | Name: Dabrafenib
7603 |
7604 | #### Evidence Items
7605 | Description:
7606 | Five colorectal cancer (CRC) cell lines with BRAF V600E mutation were
7607 | resistant to treatment with the BRAF inhibitor vemurafenib. An RNAi
7608 | screen in the WiDr cell line (a V600E CRC line) identified EGFR as an
7609 | enhancer for survival when exposed to vemurafenib. Treatment with
7610 | vemurafenib and an EGFR inhibitor (cetuximab or gefitinib) in V600E CRC
7611 | cells (WiDr, VACO432 and KM20) showed inhibited growth as well as
7612 | induction of the cleaved PARP apoptotic marker.
7613 | Evidence Direction: SUPPORTS
7614 | Evidence Level: D
7615 | Evidence Rating: 3
7616 | Evidence Type: PREDICTIVE
7617 | Flagged: False
7618 | Id: 10328
7619 | Name: EID10328
7620 | Significance: SENSITIVITYRESPONSE
7621 | Variant Origin: SOMATIC
7622 |
7623 | ##### Disease
7624 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
7625 | Display Name: Colorectal Cancer
7626 | Doid: 9256
7627 | Id: 11
7628 | Link: /diseases/11
7629 | Name: Colorectal Cancer
7630 |
7631 | ##### My Disease Info
7632 | Do Def:
7633 | An intestinal cancer that effects the long, tube-like organ that is
7634 | connected to the small intestine at one end and the anus at the other.
7635 | Icd10: C18.9
7636 | Mondo Id: MONDO:0005575
7637 | Ncit: C4978
7638 |
7639 | ##### Molecular Profile
7640 | Id: 12
7641 |
7642 | ##### Source
7643 | Abstract:
7644 | Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug
7645 | PLX4032 (vemurafenib) is highly effective in the treatment of melanoma.
7646 | However, colon cancer patients harbouring the same BRAF(V600E) oncogenic
7647 | lesion have poor prognosis and show only a very limited response to this
7648 | drug. To investigate the cause of the limited therapeutic effect of
7649 | PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-
7650 | interference-based genetic screen in human cells to search for kinases
7651 | whose knockdown synergizes with BRAF(V600E) inhibition. We report that
7652 | blockade of the epidermal growth factor receptor (EGFR) shows strong
7653 | synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E)
7654 | mutant colon cancers that inhibition of EGFR by the antibody drug
7655 | cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly
7656 | synergistic with BRAF(V600E) inhibition, both in vitro and in vivo.
7657 | Mechanistically, we find that BRAF(V600E) inhibition causes a rapid
7658 | feedback activation of EGFR, which supports continued proliferation in
7659 | the presence of BRAF(V600E) inhibition. Melanoma cells express low
7660 | levels of EGFR and are therefore not subject to this feedback
7661 | activation. Consistent with this, we find that ectopic expression of
7662 | EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Our
7663 | data suggest that BRAF(V600E) mutant colon cancers (approximately 8-10%
7664 | of all colon cancers), for which there are currently no targeted
7665 | treatment options available, might benefit from combination therapy
7666 | consisting of BRAF and EGFR inhibitors.
7667 | Author String:
7668 | Anirudh Prahallad, Chong Sun, Sidong Huang, Federica Di Nicolantonio,
7669 | Ramon Salazar, Davide Zecchin, Roderick L Beijersbergen, Alberto
7670 | Bardelli, René Bernards
7671 | Citation: Prahallad et al., 2012
7672 | Citation Id: 22281684
7673 | Id: 344
7674 | Journal: Nature
7675 | Link: /sources/344
7676 | Name: PubMed: Prahallad et al., 2012
7677 | Open Access: False
7678 | Publication Date: 2012-1-26
7679 | Retracted: False
7680 | Source Type: PUBMED
7681 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22281684
7682 | Title:
7683 | Unresponsiveness of colon cancer to BRAF(V600E) inhibition through
7684 | feedback activation of EGFR.
7685 |
7686 | ##### Therapies
7687 | Deprecated: False
7688 | Id: 4
7689 | Link: /therapies/4
7690 | Name: Vemurafenib
7691 |
7692 | ##### Therapies
7693 | Deprecated: False
7694 | Id: 14
7695 | Link: /therapies/14
7696 | Name: Gefitinib
7697 |
7698 | #### Evidence Items
7699 | Description:
7700 | Five colorectal cancer (CRC) cell lines (VACO432, HT29, SNU-C5, KM20,
7701 | WiDr) with BRAF V600E mutation were resistant to treatment with the BRAF
7702 | inhibitor vemurafenib. An RNAi screen in the WiDr cell line (a V600E CRC
7703 | line) identified EGFR as an enhancer for survival when exposed to
7704 | vemurafenib. Treatment with vemurafenib and an EGFR inhibitor (cetuximab
7705 | or gefitinib) in V600E CRC cells (WiDr, VACO432 and KM20) showed
7706 | inhibited growth as well as induction of the cleaved PARP apoptotic
7707 | marker. Xenografts of WiDr and VACO432 cell lines showed similar tumour
7708 | growth when treated with vemurafenib or control treatment, suggesting
7709 | resistance to vemurafenib in vivo.
7710 | Evidence Direction: SUPPORTS
7711 | Evidence Level: D
7712 | Evidence Rating: 3
7713 | Evidence Type: PREDICTIVE
7714 | Flagged: False
7715 | Id: 10329
7716 | Name: EID10329
7717 | Significance: RESISTANCE
7718 | Variant Origin: SOMATIC
7719 |
7720 | ##### Disease
7721 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
7722 | Display Name: Colorectal Cancer
7723 | Doid: 9256
7724 | Id: 11
7725 | Link: /diseases/11
7726 | Name: Colorectal Cancer
7727 |
7728 | ##### My Disease Info
7729 | Do Def:
7730 | An intestinal cancer that effects the long, tube-like organ that is
7731 | connected to the small intestine at one end and the anus at the other.
7732 | Icd10: C18.9
7733 | Mondo Id: MONDO:0005575
7734 | Ncit: C4978
7735 |
7736 | ##### Molecular Profile
7737 | Id: 12
7738 |
7739 | ##### Source
7740 | Abstract:
7741 | Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug
7742 | PLX4032 (vemurafenib) is highly effective in the treatment of melanoma.
7743 | However, colon cancer patients harbouring the same BRAF(V600E) oncogenic
7744 | lesion have poor prognosis and show only a very limited response to this
7745 | drug. To investigate the cause of the limited therapeutic effect of
7746 | PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-
7747 | interference-based genetic screen in human cells to search for kinases
7748 | whose knockdown synergizes with BRAF(V600E) inhibition. We report that
7749 | blockade of the epidermal growth factor receptor (EGFR) shows strong
7750 | synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E)
7751 | mutant colon cancers that inhibition of EGFR by the antibody drug
7752 | cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly
7753 | synergistic with BRAF(V600E) inhibition, both in vitro and in vivo.
7754 | Mechanistically, we find that BRAF(V600E) inhibition causes a rapid
7755 | feedback activation of EGFR, which supports continued proliferation in
7756 | the presence of BRAF(V600E) inhibition. Melanoma cells express low
7757 | levels of EGFR and are therefore not subject to this feedback
7758 | activation. Consistent with this, we find that ectopic expression of
7759 | EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Our
7760 | data suggest that BRAF(V600E) mutant colon cancers (approximately 8-10%
7761 | of all colon cancers), for which there are currently no targeted
7762 | treatment options available, might benefit from combination therapy
7763 | consisting of BRAF and EGFR inhibitors.
7764 | Author String:
7765 | Anirudh Prahallad, Chong Sun, Sidong Huang, Federica Di Nicolantonio,
7766 | Ramon Salazar, Davide Zecchin, Roderick L Beijersbergen, Alberto
7767 | Bardelli, René Bernards
7768 | Citation: Prahallad et al., 2012
7769 | Citation Id: 22281684
7770 | Id: 344
7771 | Journal: Nature
7772 | Link: /sources/344
7773 | Name: PubMed: Prahallad et al., 2012
7774 | Open Access: False
7775 | Publication Date: 2012-1-26
7776 | Retracted: False
7777 | Source Type: PUBMED
7778 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22281684
7779 | Title:
7780 | Unresponsiveness of colon cancer to BRAF(V600E) inhibition through
7781 | feedback activation of EGFR.
7782 |
7783 | ##### Therapies
7784 | Deprecated: False
7785 | Id: 4
7786 | Link: /therapies/4
7787 | Name: Vemurafenib
7788 |
7789 | #### Evidence Items
7790 | Description:
7791 | In this case series, 11 patients with ECD or ECD/LCH (Seven had ECD and
7792 | four had overlapped ECD/LCH) were treated with single-agent dabrafenib
7793 | as initial histiocytosis therapy, following the failure of chemotherapy
7794 | or radiation, or following discontinuation of vemurafenib therapy
7795 | because of toxicity or intolerance were assessed. Dabrafenib monotherapy
7796 | was initially dosed from 50mg BID to 150mg twice daily. FDG-PET/CT scans
7797 | were performed prior to starting dabrafenib and in follow-up to measure
7798 | disease response in nearly all cases. For the five patients treated with
7799 | dabrafenib as initial therapy or following failure of conventional
7800 | therapy, three had a partial metabolic response and two had a complete
7801 | metabolic response by FDG-PET; all had a complete clinical response. In
7802 | three of these six patients, dabrafenib maintained their clinical and
7803 | metabolic response to vemurafenib; the sixth patient had been treated
7804 | with interferon-a with poor clinical response, and dabrafenib achieved a
7805 | sustained clinical and metabolic response. Two patients who stopped
7806 | vemurafenib for arthralgia or fatigue stopped dabrafenib for similar
7807 | intolerance after four and nine months, respectively.
7808 | Evidence Direction: SUPPORTS
7809 | Evidence Level: B
7810 | Evidence Rating: 4
7811 | Evidence Type: PREDICTIVE
7812 | Flagged: False
7813 | Id: 11303
7814 | Name: EID11303
7815 | Significance: SENSITIVITYRESPONSE
7816 | Variant Origin: SOMATIC
7817 |
7818 | ##### Disease
7819 | Disease Url: https://www.disease-ontology.org/?id=DOID:2571
7820 | Display Name: Langerhans-cell Histiocytosis
7821 | Doid: 2571
7822 | Id: 2136
7823 | Link: /diseases/2136
7824 | Name: Langerhans-cell Histiocytosis
7825 |
7826 | ##### My Disease Info
7827 | Do Def:
7828 | A histiocytosis that is characterized by clonal proliferation of
7829 | Langerhans cells.
7830 | Icd10: ["C96.0", "C96.6"]
7831 | Icdo: 9751/1
7832 | Mesh: ["C538636", "D006646"]
7833 | Mondo Id: MONDO:0018310
7834 | Ncit: C3107, C3160
7835 | Disease Aliases:
7836 | - Histiocytosis X
7837 | - Langerhan's Cell Histiocytosis
7838 | - Langerhans Cell Granulomatosis
7839 | - Letterer-Siwe Disease
7840 | - Letterer-Siwe Disease Involving Intra-abdominal Lymph Nodes
7841 | - Letterer-Siwe Disease Involving Intrapelvic Lymph Nodes
7842 | - Letterer-Siwe Disease Involving Intrathoracic Lymph Nodes
7843 | - Letterer-Siwe Disease Involving Lymph Nodes Of Axilla And Upper Limb
7844 | - Letterer-Siwe Disease Involving Lymph Nodes Of Head, Face And Neck
7845 | - Letterer-Siwe Disease Involving Lymph Nodes Of Head, Face, And Neck
7846 | - Letterer-Siwe Disease Involving Lymph Nodes Of Inguinal Region And Lower Limb
7847 | - Letterer-Siwe Disease Involving Lymph Nodes Of Multiple Sites
7848 | - Letterer-Siwe Disease Involving Spleen
7849 | - Letterer-Siwe Disease Of Intra-abdominal Lymph Nodes
7850 | - Letterer-Siwe Disease Of Intrapelvic Lymph Nodes
7851 | - Letterer-Siwe Disease Of Intrathoracic Lymph Nodes
7852 | - Letterer-Siwe Disease Of Lymph Nodes Of Axilla And Upper Limb
7853 | - Letterer-Siwe Disease Of Lymph Nodes Of Axilla And/or Upper Limb
7854 | - Letterer-Siwe Disease Of Lymph Nodes Of Head, Face And Neck
7855 | - Letterer-Siwe Disease Of Lymph Nodes Of Head, Face And/or Neck
7856 | - Letterer-Siwe Disease Of Lymph Nodes Of Inguinal Region Amd/or Lower Limb
7857 | - Letterer-Siwe Disease Of Lymph Nodes Of Inguinal Region And Lower Limb
7858 | - Letterer-Siwe Disease Of Lymph Nodes Of Inguinal Region And/or Lower Limb
7859 | - Letterer-Siwe Disease Of Lymph Nodes Of Multiple Sites
7860 | - Letterer-Siwe Disease Of Spleen
7861 |
7862 | ##### Molecular Profile
7863 | Id: 12
7864 |
7865 | ##### Source
7866 | Author String:
7867 | Ankush Bhatia, Gary Ulaner, Raajit Rampal, David M Hyman, Omar Abdel-
7868 | Wahab, Benjamin H Durham, Ahmet Dogan, Neval Ozkaya, Mario E Lacouture,
7869 | Julio Hajdenberg, Chezi Ganzel, Eli L Diamond
7870 | Citation: Bhatia et al., 2018
7871 | Citation Id: 29472347
7872 | Id: 4648
7873 | Journal: Haematologica
7874 | Link: /sources/4648
7875 | Name: PubMed: Bhatia et al., 2018
7876 | Open Access: True
7877 | Pmc Id: PMC5865413
7878 | Publication Date: 2018-4
7879 | Retracted: False
7880 | Source Type: PUBMED
7881 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/29472347
7882 | Title: Single-agent dabrafenib for BRAFV600E-mutated histiocytosis.
7883 |
7884 | ##### Therapies
7885 | Deprecated: False
7886 | Id: 22
7887 | Link: /therapies/22
7888 | Name: Dabrafenib
7889 |
7890 | #### Evidence Items
7891 | Description:
7892 | In this case series, the authors assessed the efficacy and safety of
7893 | swapping cetuximab for panitumumab as some patients are unable to
7894 | tolerate treatment with the mouse/human chimeric monoclonal IgG1
7895 | antibody cetuximab. Panitumumab is a fully humanized IgG2 anti-EGFR
7896 | antibody that has a different binding site and also has a distinct
7897 | toxicity profile, causing fewer infusion reactions than cetuximab. Case
7898 | one was a 70-year-old female presenting with progressive metastatic
7899 | colorectal cancer after undergoing prior treatment with FOLFOX in 2016
7900 | and 2020 (2020 in combination with bevacizumab). Molecular profiling of
7901 | the patient’s tumour revealed a BRAF V600E mutation (KRAS-, NRAS wild-
7902 | type, MSS). Cetuximab and encorafenib were applied for three cycles
7903 | without any grade III/IV toxicities. However, the fourth infusion of
7904 | cetuximab had to be aborted due to a strong infusion reaction, which had
7905 | to be treated with dimenhydrinate and prednisone. The cetuximab was
7906 | swapped for panitumumab, and except for Grade I-II skin toxicity, no
7907 | panitumumab-related side effects occurred. After 15 months, the patient
7908 | is still stable under combination therapy with encorafenib plus
7909 | panitumumab. Case two is a 67-year-old male presenting for adjuvant
7910 | therapy after resection of rectal cancer. The patient progressed during
7911 | adjuvant treatment with capecitabine. Molecular characterization of the
7912 | malignancy revealed a BRAF V600E mutation (KRAS-, NRAS wild-type, MSS).
7913 | Treatment with FOLFOXIRI plus cetuximab was initiated, to which the
7914 | patient initially responded well. Due to progressive disease after about
7915 | 10 months, second-line treatment with capecitabine plus bevacizumab was
7916 | initiated. Under this therapy, the patient developed multiple brain
7917 | metastases which were treated by surgical and radiotherapeutic
7918 | interventions. After switching to encorafenib and cetuximab, the first
7919 | infusion of cetuximab led to a severe allergic reaction with pronounced
7920 | respiratory symptoms. After the switch to panitumumab, no further
7921 | infusion reaction occurred, and besides grade I skin toxicity, no other
7922 | relevant side effects were apparent. The patient achieved a good partial
7923 | remission at three and six months. However, after ten months of
7924 | panitumumab and encorafenib, the patient progressed.
7925 | Evidence Direction: SUPPORTS
7926 | Evidence Level: C
7927 | Evidence Rating: 2
7928 | Evidence Type: PREDICTIVE
7929 | Flagged: False
7930 | Id: 11309
7931 | Name: EID11309
7932 | Significance: SENSITIVITYRESPONSE
7933 | Variant Origin: SOMATIC
7934 |
7935 | ##### Disease
7936 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
7937 | Display Name: Colorectal Cancer
7938 | Doid: 9256
7939 | Id: 11
7940 | Link: /diseases/11
7941 | Name: Colorectal Cancer
7942 |
7943 | ##### My Disease Info
7944 | Do Def:
7945 | An intestinal cancer that effects the long, tube-like organ that is
7946 | connected to the small intestine at one end and the anus at the other.
7947 | Icd10: C18.9
7948 | Mondo Id: MONDO:0005575
7949 | Ncit: C4978
7950 |
7951 | ##### Molecular Profile
7952 | Id: 12
7953 |
7954 | ##### Source
7955 | Author String:
7956 | Christian Rausch, Charlotte Schwicht, Daphne Doedens, Roswitha
7957 | Forstpointner, Christoph Benedikt Westphalen, Volker Heinemann
7958 | Citation: Rausch et al., 2022
7959 | Citation Id: 35970034
7960 | Id: 4650
7961 | Journal: Eur J Cancer
7962 | Link: /sources/4650
7963 | Name: PubMed: Rausch et al., 2022
7964 | Open Access: False
7965 | Publication Date: 2022-10
7966 | Retracted: False
7967 | Source Type: PUBMED
7968 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/35970034
7969 | Title:
7970 | Panitumumab can safely and effectively be substituted for cetuximab in
7971 | the treatment of BRAF V600Emut metastatic colorectal cancer (mCRC) - A
7972 | case series.
7973 |
7974 | ##### Therapies
7975 | Deprecated: False
7976 | Id: 28
7977 | Link: /therapies/28
7978 | Name: Panitumumab
7979 |
7980 | ##### Therapies
7981 | Deprecated: False
7982 | Id: 483
7983 | Link: /therapies/483
7984 | Name: Encorafenib
7985 |
7986 | #### Evidence Items
7987 | Description:
7988 | In this case study, a 32-year-old man, previously fit and well,
7989 | presented with a two-month history of vertigo, right visual disturbance,
7990 | dysphagia, and ataxia. Brain MRI revealed a large mixed solid and cystic
7991 | mass within the upper pons, with heterogeneous enhancement extending
7992 | along the left third cranial nerve root exit. The patient subsequently
7993 | underwent posterior fossa craniotomy and excisional biopsy of the
7994 | brainstem tumour. Histology showed a WHO grade 1 ganglioglioma with a
7995 | pilocytic glial component. After four years from the initial diagnosis,
7996 | MRI surveillance revealed progression in the cystic component of the
7997 | lesion, with worsening neurological symptoms including right sixth nerve
7998 | palsy, tongue fasciculations and right-sided hemi-anesthesia. Testing of
7999 | his initial biopsy specimen demonstrated a BRAF V600E mutation (Sequenom
8000 | OncoFOCUS Panel v3.0). The patient was started on vemurafenib 960 mg
8001 | twice daily and cobimetinib 60 mg daily. Treatment was complicated by a
8002 | grade 2 maculopapular rash and grade 2 ALT elevation and was withheld
8003 | until improvement of toxicities back to grade 1. The patient restarted
8004 | vemurafenib at 720 mg twice daily and cobimetinib at 60 mg daily. At 13
8005 | weeks post-commencement, restaging MRI demonstrated a partial response,
8006 | with a substantial reduction in the solid component of the lesion and a
8007 | lesser reduction in the cystic component. Objective clinical improvement
8008 | with the resolution of tongue fasciculations and subjective improvement
8009 | in sensory abnormalities and diplopia have been observed. At the time of
8010 | publication, the patient was in an ongoing partial response.
8011 | Evidence Direction: SUPPORTS
8012 | Evidence Level: C
8013 | Evidence Rating: 1
8014 | Evidence Type: PREDICTIVE
8015 | Flagged: False
8016 | Id: 11310
8017 | Name: EID11310
8018 | Significance: SENSITIVITYRESPONSE
8019 | Variant Origin: SOMATIC
8020 |
8021 | ##### Disease
8022 | Disease Url: https://www.disease-ontology.org/?id=DOID:5078
8023 | Display Name: Ganglioglioma
8024 | Doid: 5078
8025 | Id: 2604
8026 | Link: /diseases/2604
8027 | Name: Ganglioglioma
8028 |
8029 | ##### My Disease Info
8030 | Do Def: A cell type benign neoplasm that has_material_basis_in glial-type cells.
8031 | Icdo: 9505/1
8032 | Mesh: D018303
8033 | Mondo Id: MONDO:0016733
8034 | Ncit: C27362, C27363, C3788
8035 | Disease Aliases:
8036 | - Adult Ganglioglioma
8037 | - CNS Ganglioglioma
8038 | - Childhood Ganglioglioma
8039 |
8040 | ##### Molecular Profile
8041 | Id: 12
8042 |
8043 | ##### Source
8044 | Abstract:
8045 | Post-surgical management of low grade gangliogliomas is controversial
8046 | with paucity of data for the use of chemotherapy. BRAF mutations are
8047 | present in a number of glioma subtypes and offer an opportunity for
8048 | treatment with targeted therapy.A 32-year-old man with an unresectable,
8049 | BRAF V600E mutant, WHO grade 1 ganglioglioma is commenced on combination
8050 | BRAF and MEK inhibition (vemurafenib and cobimetinib). Partial
8051 | radiological and clinical response was noted after 13 weeks of
8052 | treatment. Treatment complication with grade 2 skin and liver toxicity
8053 | was resolved with dose interruption and reduction.Combination BRAF and
8054 | MEK inhibition present a safe and feasible treatment strategy in
8055 | unresectable BRAF V600E mutant low grade ganglioglioma.
8056 | Author String: Wing Hing Yau, Malaka Ameratunga
8057 | Citation: Yau et al., 2020
8058 | Citation Id: 31985841
8059 | Id: 4651
8060 | Journal: J Clin Pharm Ther
8061 | Link: /sources/4651
8062 | Name: PubMed: Yau et al., 2020
8063 | Open Access: False
8064 | Publication Date: 2020-10
8065 | Retracted: False
8066 | Source Type: PUBMED
8067 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/31985841
8068 | Title:
8069 | Combination of BRAF and MEK inhibition in BRAF V600E mutant low-grade
8070 | ganglioglioma.
8071 |
8072 | ##### Therapies
8073 | Deprecated: False
8074 | Id: 4
8075 | Link: /therapies/4
8076 | Name: Vemurafenib
8077 |
8078 | ##### Therapies
8079 | Deprecated: False
8080 | Id: 342
8081 | Link: /therapies/342
8082 | Name: Cobimetinib
8083 |
8084 | #### Evidence Items
8085 | Description:
8086 | In this case series, two patients with BRAF V600E mutant pleomorphic
8087 | xanthoastrocytoma were treated using the BRAF inhibitor dabrafenib and
8088 | trametinib in combination with the MEK inhibitor trametinib. Patient one
8089 | is a 48-year-old female with progressive anaplastic pleomorphic
8090 | xanthoastrocytoma (PXA). She initially presented with a seizure and
8091 | underwent a craniotomy and resection followed by adjuvant radiotherapy.
8092 | She remained in remission for 3 years. Subsequent relapses over 2 years
8093 | were treated with three further debulking surgeries, cyst drainage and
8094 | chemotherapy. Chemotherapy regimens included six cycles of procarbazine,
8095 | CCNU (lomustine), vincristine; six cycles of temozolomide and three
8096 | cycles of carboplatin. MRI after three cycles of carboplatin showed
8097 | tumour progression. Analysis of archival tumour tissue from an earlier
8098 | surgery identified a BRAF V600E mutation using DNA sequencing.
8099 | Histopathology showed glial tumour cells with significant nuclear
8100 | pleomorphism and abundant eosinophilic glassy cytoplasm, multiple giant
8101 | cells, brisk mitotic activity and necrosis. Immunohistochemistry for
8102 | BRAF V600E was strongly positive, while IDH1R132H was negative, and ATRX
8103 | was retained. The Ki67 proliferation index was 15%. She started
8104 | treatment with the BRAF inhibitor dabrafenib dosed at 150 mg twice daily
8105 | in combination with the MEK inhibitor trametinib dosed at 2 mg once
8106 | daily. MRI of the brain at this time showed a decrease in the bulk of
8107 | partially enhancing cystic/necrotic mass with a reduction of mass
8108 | effect. Subsequent interval MRI, 4 months following commencement of
8109 | dabrafenib and trametinib shows continued reduction in the size of both
8110 | solid and cystic disease. At the last review, 8 months following the
8111 | start of treatment, she was well, with a noted improvement in fatigue
8112 | and resolution of headaches. She continues on dabrafenib and trametinib.
8113 | Patient two was a previously treated patient that underwent successful
8114 | for relapsed BRAF V600E mutated anaplastic pleomorphic xanthoastrocytoma
8115 | with dabrafenib, following intolerance to vemurafenib. The patient
8116 | continued dabrafenib for 18 months, at which point she chose to stop
8117 | therapy and commence radiological surveillance. She had no visible
8118 | disease on MRI at this time. She subsequently had radiological
8119 | progression and now is undergoing subsequent treatment with a
8120 | combination therapy of dabrafenib and trametinib. Two months after
8121 | stopping dabrafenib, the first surveillance MRI demonstrated a new 8 mm
8122 | homogeneously enhancing nodular lesion on the posteromedial aspect of
8123 | the surgical cavity. The patient was re-started on dabrafenib at 150 mg
8124 | twice daily with the addition of trametinib at 2 mg once daily. Serial
8125 | MRIs demonstrated improvement with near complete response of the
8126 | enhancing nodule on the most recent MRI.
8127 | Evidence Direction: SUPPORTS
8128 | Evidence Level: C
8129 | Evidence Rating: 2
8130 | Evidence Type: PREDICTIVE
8131 | Flagged: False
8132 | Id: 11311
8133 | Name: EID11311
8134 | Significance: SENSITIVITYRESPONSE
8135 | Variant Origin: SOMATIC
8136 |
8137 | ##### Disease
8138 | Disease Url: https://www.disease-ontology.org/?id=DOID:4852
8139 | Display Name: Pleomorphic Xanthoastrocytoma
8140 | Doid: 4852
8141 | Id: 1124
8142 | Link: /diseases/1124
8143 | Name: Pleomorphic Xanthoastrocytoma
8144 |
8145 | ##### My Disease Info
8146 | Do Def:
8147 | A low grade glioma that is characterized by pleomorphic and lipidized
8148 | cells expressing GFAP often surrounded by a reticulin network and
8149 | eosinophilic granular bodies.
8150 | Icdo: 9424/3
8151 | Mondo Id: MONDO:0016690
8152 | Ncit: C4323
8153 | Disease Aliases: Pleomorphic Xantho-astrocytoma
8154 |
8155 | ##### Molecular Profile
8156 | Id: 12
8157 |
8158 | ##### Source
8159 | Abstract:
8160 | BRAFV600E mutations have been identified in a number of glioma subtypes,
8161 | most frequently in pleomorphic xanthoastrocytoma, ganglioglioma,
8162 | pilocytic astrocytoma, and epithelioid glioblastoma. Although the
8163 | development of BRAF inhibitors has dramatically improved the clinical
8164 | outcome for patients with BRAFV600E mutant tumors, resistance develops
8165 | in a majority of patients due to reactivation of the MAPK pathway.
8166 | Addition of MEK inhibition to BRAF inhibition improves survival. Here we
8167 | report successful treatment of two patients with BRAFV600E mutant
8168 | pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in
8169 | combination with the MEK inhibitor trametinib.
8170 | Author String: Nicholas F Brown, Thomas Carter, Neil Kitchen, Paul Mulholland
8171 | Citation: Brown et al., 2017
8172 | Citation Id: 28984141
8173 | Id: 4652
8174 | Journal: CNS Oncol
8175 | Link: /sources/4652
8176 | Name: PubMed: Brown et al., 2017
8177 | Open Access: True
8178 | Pmc Id: PMC6004887
8179 | Publication Date: 2017-10
8180 | Retracted: False
8181 | Source Type: PUBMED
8182 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/28984141
8183 | Title: Dabrafenib and trametinib in BRAFV600E mutated glioma.
8184 |
8185 | ##### Therapies
8186 | Deprecated: False
8187 | Id: 22
8188 | Link: /therapies/22
8189 | Name: Dabrafenib
8190 |
8191 | ##### Therapies
8192 | Deprecated: False
8193 | Id: 19
8194 | Link: /therapies/19
8195 | Name: Trametinib
8196 |
8197 | #### Evidence Items
8198 | Description:
8199 | This study is part of an ongoing open-label, single-arm, phase 2 Rare
8200 | Oncology Agnostic Research (ROAR) basket trial enlisting 45 patients (31
8201 | with glioblastoma) into the high-grade glioma cohort (other patients had
8202 | anaplastic pleomorphic xanthoastrocytoma, anaplastic astrocytoma (n = 5
8203 | each), anaplastic ganglioglioma, anaplastic oligodendroglioma,
8204 | astroblastoma, and undifferentiated glioma (n = 1 each). Further, 13
8205 | patients were enrolled into the low-grade glioma cohort (ganglioglioma,
8206 | n = 4; diffuse astrocytoma, n = 2; pleomorphic xanthoastrocytoma, n = 2;
8207 | choroid plexus papilloma [gangliocytoma or ganglioglioma, localised
8208 | astrocytoma, pilocytic astrocytoma, and well differentiated astrocytoma,
8209 | n = 1 each]). Patients received oral dabrafenib at 150 mg orally, twice
8210 | daily and oral trametinib at 2 mg orally once daily. In the high-grade
8211 | glioma cohort, median follow-up was 12.7 months (IQR 5.4 – 32.3) and 15
8212 | (95% CI: 20 – 49) of 45 patients had an objective response, including
8213 | three complete responses and 12 partial responses. In the low-grade
8214 | glioma cohort, median follow-up was 32.2 months (IQR 25.1 – 47.8). Nine
8215 | (95% CI: 39 – 91) of 13 patients had an objective response, including
8216 | one complete response, six partial responses, and two minor responses.
8217 | Evidence Direction: SUPPORTS
8218 | Evidence Level: A
8219 | Evidence Rating: 1
8220 | Evidence Type: PREDICTIVE
8221 | Flagged: False
8222 | Id: 11312
8223 | Name: EID11312
8224 | Significance: SENSITIVITYRESPONSE
8225 | Variant Origin: SOMATIC
8226 |
8227 | ##### Disease
8228 | Disease Url: https://www.disease-ontology.org/?id=DOID:4852
8229 | Display Name: Pleomorphic Xanthoastrocytoma
8230 | Doid: 4852
8231 | Id: 1124
8232 | Link: /diseases/1124
8233 | Name: Pleomorphic Xanthoastrocytoma
8234 |
8235 | ##### My Disease Info
8236 | Do Def:
8237 | A low grade glioma that is characterized by pleomorphic and lipidized
8238 | cells expressing GFAP often surrounded by a reticulin network and
8239 | eosinophilic granular bodies.
8240 | Icdo: 9424/3
8241 | Mondo Id: MONDO:0016690
8242 | Ncit: C4323
8243 | Disease Aliases: Pleomorphic Xantho-astrocytoma
8244 |
8245 | ##### Molecular Profile
8246 | Id: 12
8247 |
8248 | ##### Source
8249 | Abstract:
8250 | Effective treatments are needed to improve outcomes for high-grade
8251 | glioma and low-grade glioma. The activity and safety of dabrafenib plus
8252 | trametinib were evaluated in adult patients with recurrent or
8253 | progressive BRAFV600E mutation-positive high-grade glioma and low-grade
8254 | glioma.This study is part of an ongoing open-label, single-arm, phase 2
8255 | Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and
8256 | academic cancer centres in 13 countries (Austria, Belgium, Canada,
8257 | France, Germany, Italy, Japan, the Netherlands, Norway, South Korea,
8258 | Spain, Sweden, and the USA). The study enrolled patients aged 18 years
8259 | or older with an Eastern Cooperative Oncology Group performance status
8260 | of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade
8261 | glioma and low-grade glioma received dabrafenib 150 mg twice daily plus
8262 | trametinib 2 mg once daily orally until unacceptable toxicity, disease
8263 | progression, or death. In the high-grade glioma cohort, patients were
8264 | required to have measurable disease at baseline using the Response
8265 | Assessment in Neuro-Oncology high-grade glioma response criteria and
8266 | have been treated previously with radiotherapy and first-line
8267 | chemotherapy or concurrent chemoradiotherapy. Patients with low-grade
8268 | glioma were required to have measurable non-enhancing disease (except
8269 | pilocytic astrocytoma) at baseline using the Response Assessment in
8270 | Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the
8271 | evaluable intention-to-treat population, was investigator-assessed
8272 | objective response rate (complete response plus partial response for
8273 | high-grade glioma and complete response plus partial response plus minor
8274 | response for low-grade glioma). This trial is ongoing, but is closed for
8275 | enrolment, NCT02034110.Between April 17, 2014, and July 25, 2018, 45
8276 | patients (31 with glioblastoma) were enrolled into the high-grade glioma
8277 | cohort and 13 patients were enrolled into the low-grade glioma cohort.
8278 | The results presented here are based on interim analysis 16 (data cutoff
8279 | Sept 14, 2020). In the high-grade glioma cohort, median follow-up was
8280 | 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had
8281 | an objective response by investigator assessment, including three
8282 | complete responses and 12 partial responses. In the low-grade glioma
8283 | cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95%
8284 | CI 39-91) of 13 patients had an objective response by investigator
8285 | assessment, including one complete response, six partial responses, and
8286 | two minor responses. Grade 3 or worse adverse events were reported in 31
8287 | (53%) patients, the most common being fatigue (five [9%]), decreased
8288 | neutrophil count (five [9%]), headache (three [5%]), and neutropenia
8289 | (three [5%]).Dabrafenib plus trametinib showed clinically meaningful
8290 | activity in patients with BRAFV600E mutation-positive recurrent or
8291 | refractory high-grade glioma and low-grade glioma, with a safety profile
8292 | consistent with that in other indications. BRAFV600E testing could
8293 | potentially be adopted in clinical practice for patients with
8294 | glioma.Novartis.
8295 | Author String:
8296 | Patrick Y Wen, Alexander Stein, Martin van den Bent, Jacques De Greve,
8297 | Antje Wick, Filip Y F L de Vos, Nikolas von Bubnoff, Myra E van Linde,
8298 | Albert Lai, Gerald W Prager, Mario Campone, Angelica Fasolo, Jose A
8299 | Lopez-Martin, Tae Min Kim, Warren P Mason, Ralf-Dieter Hofheinz, Jean-
8300 | Yves Blay, Daniel C Cho, Anas Gazzah, Damien Pouessel, Jeffrey Yachnin,
8301 | Aislyn Boran, Paul Burgess, Palanichamy Ilankumaran, Eduard Gasal, Vivek
8302 | Subbiah
8303 | Citation: Wen et al., 2022
8304 | Citation Id: 34838156
8305 | Id: 4204
8306 | Journal: Lancet Oncol
8307 | Link: /sources/4204
8308 | Name: PubMed: Wen et al., 2022
8309 | Open Access: False
8310 | Publication Date: 2022-1
8311 | Retracted: False
8312 | Source Type: PUBMED
8313 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/34838156
8314 | Title:
8315 | Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade
8316 | and high-grade glioma (ROAR): a multicentre, open-label, single-arm,
8317 | phase 2, basket trial.
8318 |
8319 | ##### Therapies
8320 | Deprecated: False
8321 | Id: 22
8322 | Link: /therapies/22
8323 | Name: Dabrafenib
8324 |
8325 | ##### Therapies
8326 | Deprecated: False
8327 | Id: 19
8328 | Link: /therapies/19
8329 | Name: Trametinib
8330 |
8331 | #### Evidence Items
8332 | Description:
8333 | This study is part of an ongoing open-label, single-arm, phase 2 Rare
8334 | Oncology Agnostic Research (ROAR) basket trial enlisting 45 patients (31
8335 | with glioblastoma) into the high-grade glioma cohort (other patients had
8336 | anaplastic pleomorphic xanthoastrocytoma, anaplastic astrocytoma (n = 5
8337 | each), anaplastic ganglioglioma, anaplastic oligodendroglioma,
8338 | astroblastoma, and undifferentiated glioma (n = 1 each). Further, 13
8339 | patients were enrolled into the low-grade glioma cohort (ganglioglioma,
8340 | n = 4; diffuse astrocytoma, n = 2; pleomorphic xanthoastrocytoma, n = 2;
8341 | choroid plexus papilloma [gangliocytoma or ganglioglioma, localized
8342 | astrocytoma, pilocytic astrocytoma, and well-differentiated astrocytoma,
8343 | n = 1 each]). Patients received oral dabrafenib at 150 mg orally, twice
8344 | daily and oral trametinib at 2 mg orally once daily. In the high-grade
8345 | glioma cohort, median follow-up was 12.7 months (IQR 5.4 – 32.3) and 15
8346 | (95% CI: 20 – 49) of 45 patients had an objective response, including
8347 | three complete responses and 12 partial responses. In the low-grade
8348 | glioma cohort, the median follow-up was 32.2 months (IQR 25.1 – 47.8).
8349 | Nine (95% CI: 39 – 91) of 13 patients had an objective response,
8350 | including one complete response, six partial responses, and two minor
8351 | responses.
8352 | Evidence Direction: SUPPORTS
8353 | Evidence Level: A
8354 | Evidence Rating: 1
8355 | Evidence Type: PREDICTIVE
8356 | Flagged: False
8357 | Id: 11313
8358 | Name: EID11313
8359 | Significance: SENSITIVITYRESPONSE
8360 | Variant Origin: SOMATIC
8361 |
8362 | ##### Disease
8363 | Disease Url: https://www.disease-ontology.org/?id=DOID:4851
8364 | Display Name: Pilocytic Astrocytoma
8365 | Doid: 4851
8366 | Id: 166
8367 | Link: /diseases/166
8368 | Name: Pilocytic Astrocytoma
8369 |
8370 | ##### My Disease Info
8371 | Do Def:
8372 | A childhood low-grade glioma that is characterized by cells that look
8373 | like fibers when viewed under a microscope and is located_in the brain.
8374 | Icdo: 9421/1
8375 | Mesh: D001254
8376 | Mondo Id: MONDO:0016691
8377 | Ncit: C4047
8378 | Disease Aliases: Grade I Astrocytic Tumor, Piloid Astrocytoma
8379 |
8380 | ##### Molecular Profile
8381 | Id: 12
8382 |
8383 | ##### Source
8384 | Abstract:
8385 | Effective treatments are needed to improve outcomes for high-grade
8386 | glioma and low-grade glioma. The activity and safety of dabrafenib plus
8387 | trametinib were evaluated in adult patients with recurrent or
8388 | progressive BRAFV600E mutation-positive high-grade glioma and low-grade
8389 | glioma.This study is part of an ongoing open-label, single-arm, phase 2
8390 | Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and
8391 | academic cancer centres in 13 countries (Austria, Belgium, Canada,
8392 | France, Germany, Italy, Japan, the Netherlands, Norway, South Korea,
8393 | Spain, Sweden, and the USA). The study enrolled patients aged 18 years
8394 | or older with an Eastern Cooperative Oncology Group performance status
8395 | of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade
8396 | glioma and low-grade glioma received dabrafenib 150 mg twice daily plus
8397 | trametinib 2 mg once daily orally until unacceptable toxicity, disease
8398 | progression, or death. In the high-grade glioma cohort, patients were
8399 | required to have measurable disease at baseline using the Response
8400 | Assessment in Neuro-Oncology high-grade glioma response criteria and
8401 | have been treated previously with radiotherapy and first-line
8402 | chemotherapy or concurrent chemoradiotherapy. Patients with low-grade
8403 | glioma were required to have measurable non-enhancing disease (except
8404 | pilocytic astrocytoma) at baseline using the Response Assessment in
8405 | Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the
8406 | evaluable intention-to-treat population, was investigator-assessed
8407 | objective response rate (complete response plus partial response for
8408 | high-grade glioma and complete response plus partial response plus minor
8409 | response for low-grade glioma). This trial is ongoing, but is closed for
8410 | enrolment, NCT02034110.Between April 17, 2014, and July 25, 2018, 45
8411 | patients (31 with glioblastoma) were enrolled into the high-grade glioma
8412 | cohort and 13 patients were enrolled into the low-grade glioma cohort.
8413 | The results presented here are based on interim analysis 16 (data cutoff
8414 | Sept 14, 2020). In the high-grade glioma cohort, median follow-up was
8415 | 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had
8416 | an objective response by investigator assessment, including three
8417 | complete responses and 12 partial responses. In the low-grade glioma
8418 | cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95%
8419 | CI 39-91) of 13 patients had an objective response by investigator
8420 | assessment, including one complete response, six partial responses, and
8421 | two minor responses. Grade 3 or worse adverse events were reported in 31
8422 | (53%) patients, the most common being fatigue (five [9%]), decreased
8423 | neutrophil count (five [9%]), headache (three [5%]), and neutropenia
8424 | (three [5%]).Dabrafenib plus trametinib showed clinically meaningful
8425 | activity in patients with BRAFV600E mutation-positive recurrent or
8426 | refractory high-grade glioma and low-grade glioma, with a safety profile
8427 | consistent with that in other indications. BRAFV600E testing could
8428 | potentially be adopted in clinical practice for patients with
8429 | glioma.Novartis.
8430 | Author String:
8431 | Patrick Y Wen, Alexander Stein, Martin van den Bent, Jacques De Greve,
8432 | Antje Wick, Filip Y F L de Vos, Nikolas von Bubnoff, Myra E van Linde,
8433 | Albert Lai, Gerald W Prager, Mario Campone, Angelica Fasolo, Jose A
8434 | Lopez-Martin, Tae Min Kim, Warren P Mason, Ralf-Dieter Hofheinz, Jean-
8435 | Yves Blay, Daniel C Cho, Anas Gazzah, Damien Pouessel, Jeffrey Yachnin,
8436 | Aislyn Boran, Paul Burgess, Palanichamy Ilankumaran, Eduard Gasal, Vivek
8437 | Subbiah
8438 | Citation: Wen et al., 2022
8439 | Citation Id: 34838156
8440 | Id: 4204
8441 | Journal: Lancet Oncol
8442 | Link: /sources/4204
8443 | Name: PubMed: Wen et al., 2022
8444 | Open Access: False
8445 | Publication Date: 2022-1
8446 | Retracted: False
8447 | Source Type: PUBMED
8448 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/34838156
8449 | Title:
8450 | Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade
8451 | and high-grade glioma (ROAR): a multicentre, open-label, single-arm,
8452 | phase 2, basket trial.
8453 |
8454 | ##### Therapies
8455 | Deprecated: False
8456 | Id: 22
8457 | Link: /therapies/22
8458 | Name: Dabrafenib
8459 |
8460 | ##### Therapies
8461 | Deprecated: False
8462 | Id: 19
8463 | Link: /therapies/19
8464 | Name: Trametinib
8465 |
8466 | #### Evidence Items
8467 | Description:
8468 | In a genetic screen of 87 lung cancer cell lines, one MEK-dependent cell
8469 | line HCC364 contained a BRAF-V600E mutation. In growth assays, the MEK
8470 | inhibitor PD-0325901 reduced proliferation in growth assays of the
8471 | HCC364 cell line (IC50=3.2 nmol/L). Additionally, cells exposed to
8472 | PD-0325901 exhibited an increase in apoptosis, as measured by induction
8473 | of PARP cleavage.
8474 | Evidence Direction: SUPPORTS
8475 | Evidence Level: D
8476 | Evidence Type: PREDICTIVE
8477 | Flagged: False
8478 | Id: 2143
8479 | Name: EID2143
8480 | Significance: SENSITIVITYRESPONSE
8481 | Variant Origin: SOMATIC
8482 |
8483 | ##### Disease
8484 | Disease Url: https://www.disease-ontology.org/?id=DOID:3908
8485 | Display Name: Lung Non-small Cell Carcinoma
8486 | Doid: 3908
8487 | Id: 8
8488 | Link: /diseases/8
8489 | Name: Lung Non-small Cell Carcinoma
8490 |
8491 | ##### My Disease Info
8492 | Do Def:
8493 | A lung carcinoma that is characterized as any type of epithelial lung
8494 | cancer other than small cell lung carcinoma.
8495 | Mesh: D002289
8496 | Mondo Id: MONDO:0005233
8497 | Ncit: C2926
8498 | Disease Aliases:
8499 | - Non-small Cell Lung Cancer
8500 | - Non-small Cell Lung Carcinoma
8501 |
8502 | ##### Molecular Profile
8503 | Id: 12
8504 |
8505 | ##### Source
8506 | Abstract:
8507 | Hyperactivated extracellular signal-regulated kinase (ERK) signaling is
8508 | common in human cancer and is often the result of activating mutations
8509 | in BRAF, RAS, and upstream receptor tyrosine kinases. To characterize
8510 | the mitogen-activated protein kinase/ERK kinase (MEK)/ERK dependence of
8511 | lung cancers harboring BRAF kinase domain mutations, we screened a large
8512 | panel of human lung cancer cell lines (n = 87) and tumors (n = 916) for
8513 | BRAF mutations. We found that non-small cell lung cancers (NSCLC) cells
8514 | with both V600E and non-V600E BRAF mutations were selectively sensitive
8515 | to MEK inhibition compared with those harboring mutations in epidermal
8516 | growth factor receptor (EGFR), KRAS, or ALK and ROS kinase fusions.
8517 | Supporting its classification as a "driver" mutation in the cells in
8518 | which it is expressed, MEK inhibition in (V600E)BRAF NSCLC cells led to
8519 | substantial induction of apoptosis, comparable with that seen with EGFR
8520 | kinase inhibition in EGFR mutant NSCLC models. Despite high basal ERK
8521 | phosphorylation, EGFR mutant cells were uniformly resistant to MEK
8522 | inhibition. Conversely, BRAF mutant cell lines were resistant to EGFR
8523 | inhibition. These data, together with the nonoverlapping pattern of EGFR
8524 | and BRAF mutations in human lung cancer, suggest that these lesions
8525 | define distinct clinical entities whose treatment should be guided by
8526 | prospective real-time genotyping. To facilitate such an effort, we
8527 | developed a mass spectrometry-based genotyping method for the detection
8528 | of hotspot mutations in BRAF, KRAS, and EGFR. Using this assay, we
8529 | confirmed that BRAF mutations can be identified in a minority of NSCLC
8530 | tumors and that patients whose tumors harbor BRAF mutations have a
8531 | distinct clinical profile compared with those whose tumors harbor kinase
8532 | domain mutations in EGFR.
8533 | Author String:
8534 | Christine A Pratilas, Aphrothiti J Hanrahan, Ensar Halilovic, Yogindra
8535 | Persaud, Junichi Soh, Dhananjay Chitale, Hisayuki Shigematsu, Hiromasa
8536 | Yamamoto, Ayana Sawai, Manickam Janakiraman, Barry S Taylor, William
8537 | Pao, Shinichi Toyooka, Marc Ladanyi, Adi Gazdar, Neal Rosen, David B
8538 | Solit
8539 | Citation: Pratilas et al., 2008
8540 | Citation Id: 19010912
8541 | Id: 341
8542 | Journal: Cancer Res
8543 | Link: /sources/341
8544 | Name: PubMed: Pratilas et al., 2008
8545 | Open Access: True
8546 | Pmc Id: PMC2649746
8547 | Publication Date: 2008-11-15
8548 | Retracted: False
8549 | Source Type: PUBMED
8550 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19010912
8551 | Title: Genetic predictors of MEK dependence in non-small cell lung cancer.
8552 |
8553 | ##### Therapies
8554 | Deprecated: False
8555 | Id: 29
8556 | Link: /therapies/29
8557 | Name: Mirdametinib
8558 |
8559 | #### Evidence Items
8560 | Description:
8561 | In these two phase II studies (Italy and U.S. locations), BRAF
8562 | V600E-mutant hairy-cell leukemia was treated with vemurafenib at a dose
8563 | of 960 mg twice daily to investigate its efficacy. The overall response
8564 | rates were 96% (25 of 26 patients who could be evaluated) after a median
8565 | of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12
8566 | weeks in the U.S. study. The rates of complete response were 35% and 42%
8567 | in the two trials, respectively. In the Italian trial, the median
8568 | relapse-free survival was 9 months; the relapse-free survival was
8569 | significantly longer among patients who had a complete response than
8570 | among those who had a partial response (19 months vs. 6 months; HR,
8571 | 0.26; 95% CI: 0.10 - 0.68; p = 0.006). The median treatment-free
8572 | survival was 21.5 months in all 26 patients who could be evaluated, and
8573 | it did not differ significantly between the group of patients who had a
8574 | complete response and the group of those who had a partial response (25
8575 | months and 18 months, respectively; p = 0.21). In the U.S. trial, at 1
8576 | year, the rate of progression-free survival was 73% (95% CI: 55 - 97)
8577 | and the rate of overall survival was 91% (95% CI: 79 - 99). Disease
8578 | progression occurred in 7 of 24 patients, including 3 patients who had
8579 | had a complete response and 4 who had had a partial response. At 1 year
8580 | after response, the cumulative incidence of relapse was 27% (95% CI: 7 -
8581 | 51). Lastly, the frequent persistence of phosphorylated ERK–positive
8582 | leukemic cells in bone marrow at the end of treatment suggests bypass
8583 | reactivation of MEK and ERK as a resistance mechanism.
8584 | Evidence Direction: SUPPORTS
8585 | Evidence Level: B
8586 | Evidence Rating: 3
8587 | Evidence Type: PREDICTIVE
8588 | Flagged: False
8589 | Id: 11315
8590 | Name: EID11315
8591 | Significance: SENSITIVITYRESPONSE
8592 | Variant Origin: SOMATIC
8593 |
8594 | ##### Disease
8595 | Disease Url: https://www.disease-ontology.org/?id=DOID:285
8596 | Display Name: Hairy Cell Leukemia
8597 | Doid: 285
8598 | Id: 665
8599 | Link: /diseases/665
8600 | Name: Hairy Cell Leukemia
8601 |
8602 | ##### My Disease Info
8603 | Do Def:
8604 | A chronic lymphocytic leukemia that is characterized by over production
8605 | of B cells (lymphocytes) by the bone marrow where the B cells appear
8606 | hairy under a microscope.
8607 | Icd10: C91.4
8608 | Icdo: 9940/3
8609 | Mesh: D007943
8610 | Mondo Id: MONDO:0018935
8611 | Ncit: C7402
8612 |
8613 | ##### Molecular Profile
8614 | Id: 12
8615 |
8616 | ##### Source
8617 | Abstract:
8618 | BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We
8619 | assessed the safety and activity of the oral BRAF inhibitor vemurafenib
8620 | in patients with hairy-cell leukemia that had relapsed after treatment
8621 | with a purine analogue or who had disease that was refractory to purine
8622 | analogues.We conducted two phase 2, single-group, multicenter studies of
8623 | vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in
8624 | the United States. The therapy was administered for a median of 16 weeks
8625 | in the Italian study and 18 weeks in the U.S. study. Primary end points
8626 | were the complete response rate (in the Italian trial) and the overall
8627 | response rate (in the U.S. trial). Enrollment was completed (28
8628 | patients) in the Italian trial in April 2013 and is still open (26 of 36
8629 | planned patients) in the U.S. trial.The overall response rates were 96%
8630 | (25 of 26 patients who could be evaluated) after a median of 8 weeks in
8631 | the Italian study and 100% (24 of 24) after a median of 12 weeks in the
8632 | U.S. study. The rates of complete response were 35% (9 of 26 patients)
8633 | and 42% (10 of 24) in the two trials, respectively. In the Italian
8634 | trial, after a median follow-up of 23 months, the median relapse-free
8635 | survival was 19 months among patients with a complete response and 6
8636 | months among those with a partial response; the median treatment-free
8637 | survival was 25 months and 18 months, respectively. In the U.S. trial,
8638 | at 1 year, the progression-free survival rate was 73% and the overall
8639 | survival rate was 91%. Drug-related adverse events were usually of grade
8640 | 1 or 2, and the events most frequently leading to dose reductions were
8641 | rash and arthralgia or arthritis. Secondary cutaneous tumors (treated
8642 | with simple excision) developed in 7 of 50 patients. The frequent
8643 | persistence of phosphorylated ERK-positive leukemic cells in bone marrow
8644 | at the end of treatment suggests bypass reactivation of MEK and ERK as a
8645 | resistance mechanism.A short oral course of vemurafenib was highly
8646 | effective in patients with relapsed or refractory hairy-cell leukemia.
8647 | (Funded by the Associazione Italiana per la Ricerca sul Cancro and
8648 | others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number
8649 | NCT01711632.).
8650 | Author String:
8651 | Enrico Tiacci, Jae H Park, Luca De Carolis, Stephen S Chung, Alessandro
8652 | Broccoli, Sasinya Scott, Francesco Zaja, Sean Devlin, Alessandro
8653 | Pulsoni, Young R Chung, Michele Cimminiello, Eunhee Kim, Davide Rossi,
8654 | Richard M Stone, Giovanna Motta, Alan Saven, Marzia Varettoni, Jessica K
8655 | Altman, Antonella Anastasia, Michael R Grever, Achille Ambrosetti, Kanti
8656 | R Rai, Vincenzo Fraticelli, Mario E Lacouture, Angelo M Carella, Ross L
8657 | Levine, Pietro Leoni, Alessandro Rambaldi, Franca Falzetti, Stefano
8658 | Ascani, Monia Capponi, Maria P Martelli, Christopher Y Park, Stefano A
8659 | Pileri, Neal Rosen, Robin Foà, Michael F Berger, Pier L Zinzani, Omar
8660 | Abdel-Wahab, Brunangelo Falini, Martin S Tallman
8661 | Citation: Tiacci et al., 2015
8662 | Citation Id: 26352686
8663 | Id: 1043
8664 | Journal: N Engl J Med
8665 | Link: /sources/1043
8666 | Name: PubMed: Tiacci et al., 2015
8667 | Open Access: True
8668 | Pmc Id: PMC4811324
8669 | Publication Date: 2015-10-29
8670 | Retracted: False
8671 | Source Type: PUBMED
8672 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26352686
8673 | Title: Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.
8674 |
8675 | ##### Therapies
8676 | Deprecated: False
8677 | Id: 4
8678 | Link: /therapies/4
8679 | Name: Vemurafenib
8680 |
8681 | #### Evidence Items
8682 | Description:
8683 | In a mouse xenograft model, tumors derived from pilocytic astrocytoma
8684 | cells that expressed BRAF V600E experienced a complete response to
8685 | treatment with selumetinib, whereas tumors derived from a wildtype BRAF
8686 | pilocytic astrocytoma cell line were resistant to selumetinib.
8687 | Evidence Direction: SUPPORTS
8688 | Evidence Level: D
8689 | Evidence Type: PREDICTIVE
8690 | Flagged: False
8691 | Id: 2144
8692 | Name: EID2144
8693 | Significance: SENSITIVITYRESPONSE
8694 | Variant Origin: SOMATIC
8695 |
8696 | ##### Disease
8697 | Disease Url: https://www.disease-ontology.org/?id=DOID:3070
8698 | Display Name: High Grade Glioma
8699 | Doid: 3070
8700 | Id: 695
8701 | Link: /diseases/695
8702 | Name: High Grade Glioma
8703 |
8704 | ##### My Disease Info
8705 | Do Def:
8706 | A cell type cancer that has_material_basis_in glial cells and is located
8707 | in brain or located in spine.
8708 | Icdo: 9380/3
8709 | Mesh: D005910
8710 | Mondo Id: MONDO:0100342
8711 | Ncit: C3059, C4822
8712 | Disease Aliases:
8713 | - Glial Cell Tumor
8714 | - Glioma, Malignant
8715 | - Malignant Glioma
8716 | - Malignant Neuroglial Tumor
8717 | - Neuroglial Tumor
8718 |
8719 | ##### Molecular Profile
8720 | Id: 12
8721 |
8722 | ##### Source
8723 | Abstract:
8724 | AZD6244 (ARRY-142886) is a potent small molecule inhibitor of MEK1/2
8725 | that is in phase 2 clinical development.AZD6244 was tested against the
8726 | Pediatric Preclinical Testing Program (PPTP) in vitro panel (1 nM-10
8727 | microM). In vivo AZD6244 was tested at a dose of 100 mg/kg administered
8728 | orally twice daily 5 days per week for 6 weeks. Subsequently, AZD6244
8729 | was evaluated against two juvenile pilocytic astrocytoma (JPA)
8730 | xenografts using once and twice daily dosing schedules. Phosphorylation
8731 | of ERK1/2 was used as a surrogate for in vivo inhibition of MEK1/2 was
8732 | determined by immunoblotting.At the highest concentration used in vitro
8733 | (10 microM) AZD6244 only inhibited growth by 50% in 5 of the 23 cell
8734 | lines. Against the in vivo tumor panels, AZD6244 induced significant
8735 | differences in EFS distribution in 10 of 37 (27%) solid tumor models and
8736 | 0 of 6 acute lymphoblastic leukemia (ALL) models. There were no
8737 | objective responses. Pharmacodynamic studies indicated at this dose and
8738 | schedule AZD6244 completely inhibited ERK1/2 phosphorylation. AZD6244
8739 | was evaluated against two JPA xenografts, BT-35 (wild-type BRAF) and
8740 | BT-40 (mutant [V600E] BRAF). BT-40 xenografts were highly sensitive to
8741 | AZD6244, whereas BT-35 xenografts progressed on AZD6244 treatment.At the
8742 | dose and schedule of administration used, AZD6244 as a single agent had
8743 | limited in vitro and in vivo activity against the PPTP tumor panels
8744 | despite inhibition of MEK1/2 activity. However, AZD6244 was highly
8745 | active against BT-40 JPA xenografts that harbor constitutively activated
8746 | BRAF, causing complete regressions.
8747 | Author String:
8748 | E Anders Kolb, Richard Gorlick, Peter J Houghton, Christopher L Morton,
8749 | Geoffrey Neale, Stephen T Keir, Hernan Carol, Richard Lock, Doris
8750 | Phelps, Min H Kang, C Patrick Reynolds, John M Maris, Catherine Billups,
8751 | Malcolm A Smith
8752 | Citation: Kolb et al., 2010
8753 | Citation Id: 20806365
8754 | Id: 1498
8755 | Journal: Pediatr Blood Cancer
8756 | Link: /sources/1498
8757 | Name: PubMed: Kolb et al., 2010
8758 | Open Access: True
8759 | Pmc Id: PMC3004092
8760 | Publication Date: 2010-10
8761 | Retracted: False
8762 | Source Type: PUBMED
8763 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/20806365
8764 | Title:
8765 | Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric
8766 | Preclinical Testing Program.
8767 |
8768 | ##### Therapies
8769 | Deprecated: False
8770 | Id: 63
8771 | Link: /therapies/63
8772 | Name: Selumetinib
8773 |
8774 | #### Evidence Items
8775 | Description:
8776 | Following treatment with sorafenib, thyroid cancer cell lines with BRAF
8777 | V600E mutations had severely reduced proliferation rates, but cells with
8778 | wildtype BRAF were insensitive (P<0.0001).
8779 | Evidence Direction: SUPPORTS
8780 | Evidence Level: D
8781 | Evidence Type: PREDICTIVE
8782 | Flagged: False
8783 | Id: 2142
8784 | Name: EID2142
8785 | Significance: SENSITIVITYRESPONSE
8786 | Variant Origin: SOMATIC
8787 |
8788 | ##### Disease
8789 | Disease Url: https://www.disease-ontology.org/?id=DOID:1781
8790 | Display Name: Thyroid Cancer
8791 | Doid: 1781
8792 | Id: 16
8793 | Link: /diseases/16
8794 | Name: Thyroid Cancer
8795 |
8796 | ##### My Disease Info
8797 | Do Def:
8798 | An endocrine gland cancer located in the thyroid gland located in the
8799 | neck below the thyroid cartilage.
8800 | Icd10: C73
8801 | Mesh: D013964
8802 | Mondo Id: MONDO:0002108
8803 | Ncit: C3414, C7510
8804 | Disease Aliases:
8805 | - Malignant Neoplasm Of Thyroid Gland
8806 | - Malignant Tumour Of Thyroid Gland
8807 | - Neoplasm Of Thyroid Gland
8808 | - Thyroid Gland Cancer
8809 | - Thyroid Gland Neoplasm
8810 | - Thyroid Neoplasm
8811 |
8812 | ##### Molecular Profile
8813 | Id: 12
8814 |
8815 | ##### Source
8816 | Abstract:
8817 | Oncogenic conversion of BRAF occurs in approximately 44% of papillary
8818 | thyroid carcinomas and 24% of anaplastic thyroid carcinomas. In
8819 | papillary thyroid carcinomas, this mutation is associated with an
8820 | unfavorable clinicopathologic outcome. Our aim was to exploit BRAF as a
8821 | potential therapeutic target for thyroid carcinoma.We used RNA
8822 | interference to evaluate the effect of BRAF knockdown in the human
8823 | anaplastic thyroid carcinoma cell lines FRO and ARO carrying the BRAF
8824 | V600E (V600EBRAF) mutation. We also exploited the effect of BAY 43-9006
8825 | [N-(3-trifluoromethyl-4-chlorophenyl)-N'-(4-(2-methylcarbamoyl
8826 | pyridin-4-yl)oxyphenyl)urea], a multikinase inhibitor able to inhibit
8827 | RAF family kinases in a panel of six (V600E)BRAF-positive thyroid
8828 | carcinoma cell lines and in nude mice bearing ARO cell xenografts.
8829 | Statistical tests were two sided.Knockdown of BRAF by small inhibitory
8830 | duplex RNA, but not control small inhibitory duplex RNA, inhibited the
8831 | mitogen-activated protein kinase signaling cascade and the growth of ARO
8832 | and FRO cells (P < 0.0001). These effects were mimicked by thyroid
8833 | carcinoma cell treatment with BAY 43-9006 (IC50 = 0.5-1 micromol/L; P <
8834 | 0.0001), whereas the compound had negligible effects in normal
8835 | thyrocytes. ARO cell tumor xenografts were significantly (P < 0.0001)
8836 | smaller in nude mice treated with BAY 43-9006 than in control mice. This
8837 | inhibition was associated with suppression of phospho-mitogen-activated
8838 | protein kinase levels.BRAF provides signals crucial for proliferation of
8839 | thyroid carcinoma cells spontaneously harboring the (V600E)BRAF mutation
8840 | and, therefore, BRAF suppression might have therapeutic potential in
8841 | (V600E)BRAF-positive thyroid cancer.
8842 | Author String:
8843 | Giuliana Salvatore, Valentina De Falco, Paolo Salerno, Tito Claudio
8844 | Nappi, Stefano Pepe, Giancarlo Troncone, Francesca Carlomagno, Rosa
8845 | Marina Melillo, Scott M Wilhelm, Massimo Santoro
8846 | Citation: Salvatore et al., 2006
8847 | Citation Id: 16533790
8848 | Id: 1497
8849 | Journal: Clin Cancer Res
8850 | Link: /sources/1497
8851 | Name: PubMed: Salvatore et al., 2006
8852 | Open Access: False
8853 | Publication Date: 2006-3-1
8854 | Retracted: False
8855 | Source Type: PUBMED
8856 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16533790
8857 | Title: BRAF is a therapeutic target in aggressive thyroid carcinoma.
8858 |
8859 | ##### Therapies
8860 | Deprecated: False
8861 | Id: 6
8862 | Link: /therapies/6
8863 | Name: Sorafenib
8864 |
8865 | #### Evidence Items
8866 | Description:
8867 | In a phase 2 clinical trial with 250 metastatic melanoma BRAF-V600E
8868 | patients, treatment groups were randomly assigned to either dabrafenib,
8869 | BRAF specific inhibitor, (n=187) or dacarbazine, a standard
8870 | chemotherapeutic agent (n=63). Patients treated with dabrafenib were
8871 | associated with improved progression-free survival (5.1mo vs. 2.7mo,
8872 | HR:0.30, 95% CI:0.18-0.51, P<0.0001) compared with patients undergoing
8873 | dacarbazine therapy.
8874 | Evidence Direction: SUPPORTS
8875 | Evidence Level: B
8876 | Evidence Type: PREDICTIVE
8877 | Flagged: False
8878 | Id: 2146
8879 | Name: EID2146
8880 | Significance: SENSITIVITYRESPONSE
8881 | Variant Origin: SOMATIC
8882 |
8883 | ##### Disease
8884 | Disease Url: https://www.disease-ontology.org/?id=DOID:8923
8885 | Display Name: Skin Melanoma
8886 | Doid: 8923
8887 | Id: 206
8888 | Link: /diseases/206
8889 | Name: Skin Melanoma
8890 |
8891 | ##### My Disease Info
8892 | Do Def: A skin cancer that has_material_basis_in melanocytes.
8893 | Icd10: C43.9
8894 | Mesh: C562393
8895 | Mondo Id: MONDO:0005012
8896 | Ncit: C3510
8897 | Disease Aliases:
8898 | - Cutaneous Melanoma
8899 | - Malignant Ear Melanoma
8900 | - Malignant Lip Melanoma
8901 | - Malignant Lower Limb Melanoma
8902 | - Malignant Melanoma Of Ear And/or External Auricular Canal
8903 | - Malignant Melanoma Of Skin Of Lower Limb
8904 | - Malignant Melanoma Of Skin Of Trunk Except Scrotum
8905 | - Malignant Melanoma Of Skin Of Upper Limb
8906 | - Malignant Neck Melanoma
8907 | - Malignant Scalp Melanoma
8908 | - Malignant Trunk Melanoma
8909 | - Malignant Upper Limb Melanoma
8910 |
8911 | ##### Molecular Profile
8912 | Id: 12
8913 |
8914 | ##### Source
8915 | Abstract:
8916 | Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a
8917 | manageable safety profile in studies of phase 1 and 2 in patients with
8918 | BRAF(V600)-mutated metastatic melanoma. We studied the efficacy of
8919 | dabrafenib in patients with BRAF(V600E)-mutated metastatic melanoma.We
8920 | enrolled patients in this open-label phase 3 trial between Dec 23, 2010,
8921 | and Sept 1, 2011. This report is based on a data cutoff date of Dec 19,
8922 | 2011. Patients aged 18 years or older with previously untreated, stage
8923 | IV or unresectable stage III BRAF(V600E) mutation-positive melanoma were
8924 | randomly assigned (3:1) to receive dabrafenib (150 mg twice daily,
8925 | orally) or dacarbazine (1000 mg/m(2) intravenously every 3 weeks).
8926 | Patients were stratified according to American Joint Committee on Cancer
8927 | stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was
8928 | investigator-assessed progression-free survival and was analysed by
8929 | intention to treat; safety was assessed per protocol. This study is
8930 | registered with ClinicalTrials.gov, number NCT01227889.Of the 733
8931 | patients screened, 250 were randomly assigned to receive either
8932 | dabrafenib (187 patients) or dacarbazine (63 patients). Median
8933 | progression-free survival was 5·1 months for dabrafenib and 2·7 months
8934 | for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18-0·51;
8935 | p<0·0001). At data cutoff, 107 (57%) patients in the dabrafenib group
8936 | and 14 (22%) in the dacarbazine group remained on randomised treatment.
8937 | Treatment-related adverse events (grade 2 or higher) occurred in 100
8938 | (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the
8939 | 59 patients who received dacarbazine. The most common adverse events
8940 | with dabrafenib were skin-related toxic effects, fever, fatigue,
8941 | arthralgia, and headache. The most common adverse events with
8942 | dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia.
8943 | Grade 3-4 adverse events were uncommon in both groups.Dabrafenib
8944 | significantly improved progression-free survival compared with
8945 | dacarbazine.GlaxoSmithKline.
8946 | Author String:
8947 | Axel Hauschild, Jean-Jacques Grob, Lev V Demidov, Thomas Jouary, Ralf
8948 | Gutzmer, Michael Millward, Piotr Rutkowski, Christian U Blank, Wilson H
8949 | Miller, Eckhart Kaempgen, Salvador Martín-Algarra, Boguslawa
8950 | Karaszewska, Cornelia Mauch, Vanna Chiarion-Sileni, Anne-Marie Martin,
8951 | Suzanne Swann, Patricia Haney, Beloo Mirakhur, Mary E Guckert, Vicki
8952 | Goodman, Paul B Chapman
8953 | Citation: Hauschild et al., 2012
8954 | Citation Id: 22735384
8955 | Id: 1500
8956 | Journal: Lancet
8957 | Link: /sources/1500
8958 | Name: PubMed: Hauschild et al., 2012
8959 | Open Access: False
8960 | Publication Date: 2012-7-28
8961 | Retracted: False
8962 | Source Type: PUBMED
8963 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22735384
8964 | Title:
8965 | Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-
8966 | label, phase 3 randomised controlled trial.
8967 |
8968 | ##### Therapies
8969 | Deprecated: False
8970 | Id: 22
8971 | Link: /therapies/22
8972 | Name: Dabrafenib
8973 |
8974 | #### Evidence Items
8975 | Description:
8976 | A pediatric pilocytic astrocytoma patient harboring BRAF V600E mutation,
8977 | BRAF V600E mutation was associated with response to vemurafenib
8978 | monotherapy. The patient was treated with standard chemotherapy regimens
8979 | prior to the identification of the BRAF V600E mutation; subsequently,
8980 | vemurafenib was administered (initially in combination with standard
8981 | chemotherapy) and an overall regression achieved, with lack of disease
8982 | progression noted at 15 months of vemurafenib therapy.
8983 | Evidence Direction: SUPPORTS
8984 | Evidence Level: C
8985 | Evidence Type: PREDICTIVE
8986 | Flagged: False
8987 | Id: 3772
8988 | Name: EID3772
8989 | Significance: SENSITIVITYRESPONSE
8990 | Variant Origin: SOMATIC
8991 |
8992 | ##### Disease
8993 | Disease Url: https://www.disease-ontology.org/?id=DOID:4851
8994 | Display Name: Pilocytic Astrocytoma
8995 | Doid: 4851
8996 | Id: 166
8997 | Link: /diseases/166
8998 | Name: Pilocytic Astrocytoma
8999 |
9000 | ##### My Disease Info
9001 | Do Def:
9002 | A childhood low-grade glioma that is characterized by cells that look
9003 | like fibers when viewed under a microscope and is located_in the brain.
9004 | Icdo: 9421/1
9005 | Mesh: D001254
9006 | Mondo Id: MONDO:0016691
9007 | Ncit: C4047
9008 | Disease Aliases: Grade I Astrocytic Tumor, Piloid Astrocytoma
9009 |
9010 | ##### Molecular Profile
9011 | Id: 12
9012 |
9013 | ##### Source
9014 | Abstract:
9015 | The BRAF V600E missense mutation is known to be present in a subset of
9016 | central nervous system tumors. We report a patient with a BRAF V600E
9017 | mutated pilomyxoid astrocytoma who failed multiple conventional
9018 | chemotherapy regimens. Treatment with vemurafenib, a molecularly
9019 | targeted therapy against the mutant BRAF V600E kinase, combined with
9020 | vinblastine resulted in tumor regression. Furthermore, this patient
9021 | experienced almost immediate progression of disease after holding
9022 | vemurafenib for only 2-3 weeks, suggesting that the tumor response is
9023 | vemurafenib dependent. This population of patients may benefit from
9024 | targeted therapy and testing of individual tumors for BRAF mutations is
9025 | justified.
9026 | Author String: Mary Skrypek, Nicholas Foreman, Daniel Guillaume, Christopher Moertel
9027 | Citation: Skrypek et al., 2014
9028 | Citation Id: 24821190
9029 | Id: 1969
9030 | Journal: Pediatr Blood Cancer
9031 | Link: /sources/1969
9032 | Name: PubMed: Skrypek et al., 2014
9033 | Open Access: False
9034 | Publication Date: 2014-11
9035 | Retracted: False
9036 | Source Type: PUBMED
9037 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24821190
9038 | Title: Pilomyxoid astrocytoma treated successfully with vemurafenib.
9039 |
9040 | ##### Therapies
9041 | Deprecated: False
9042 | Id: 4
9043 | Link: /therapies/4
9044 | Name: Vemurafenib
9045 |
9046 | #### Evidence Items
9047 | Description:
9048 | Combined PI3K inhibitor GDC0941 and BRAF inhibitor PLX4720
9049 | administration to NSG mice subcutanousely injected with colorectal cell
9050 | lines with a BRAF V600E mutation effectively inhibited tumor growth and
9051 | reduced cellular proliferation.
9052 | Evidence Direction: SUPPORTS
9053 | Evidence Level: D
9054 | Evidence Rating: 3
9055 | Evidence Type: PREDICTIVE
9056 | Flagged: False
9057 | Id: 96
9058 | Name: EID96
9059 | Significance: SENSITIVITYRESPONSE
9060 | Variant Origin: SOMATIC
9061 |
9062 | ##### Disease
9063 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
9064 | Display Name: Colorectal Cancer
9065 | Doid: 9256
9066 | Id: 11
9067 | Link: /diseases/11
9068 | Name: Colorectal Cancer
9069 |
9070 | ##### My Disease Info
9071 | Do Def:
9072 | An intestinal cancer that effects the long, tube-like organ that is
9073 | connected to the small intestine at one end and the anus at the other.
9074 | Icd10: C18.9
9075 | Mondo Id: MONDO:0005575
9076 | Ncit: C4978
9077 |
9078 | ##### Molecular Profile
9079 | Id: 12
9080 |
9081 | ##### Source
9082 | Abstract:
9083 | We show that BRAF(V600E) initiates an alternative pathway to colorectal
9084 | cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma
9085 | sequence. This pathway underlies significant subsets of CRCs with
9086 | distinctive pathomorphologic/genetic/epidemiologic/clinical
9087 | characteristics. Genetic and functional analyses in mice revealed a
9088 | series of stage-specific molecular alterations driving different phases
9089 | of tumor evolution and uncovered mechanisms underlying this stage
9090 | specificity. We further demonstrate dose-dependent effects of oncogenic
9091 | signaling, with physiologic Braf(V600E) expression being sufficient for
9092 | hyperplasia induction, but later stage intensified Mapk-signaling
9093 | driving both tumor progression and activation of intrinsic tumor
9094 | suppression. Such phenomena explain, for example, the inability of p53
9095 | to restrain tumor initiation as well as its importance in invasiveness
9096 | control, and the late stage specificity of its somatic mutation.
9097 | Finally, systematic drug screening revealed sensitivity of this CRC
9098 | subtype to targeted therapeutics, including Mek or combinatorial
9099 | PI3K/Braf inhibition.
9100 | Author String:
9101 | Roland Rad, Juan Cadiñanos, Lena Rad, Ignacio Varela, Alexander Strong,
9102 | Lydia Kriegl, Fernando Constantino-Casas, Stefan Eser, Maren Hieber,
9103 | Barbara Seidler, Stacey Price, Mario F Fraga, Vincenzo Calvanese, Gary
9104 | Hoffman, Hannes Ponstingl, Günter Schneider, Kosuke Yusa, Carolyn Grove,
9105 | Roland M Schmid, Wei Wang, George Vassiliou, Thomas Kirchner, Ultan
9106 | McDermott, Pentao Liu, Dieter Saur, Allan Bradley
9107 | Citation: Rad et al., 2013
9108 | Citation Id: 23845441
9109 | Id: 106
9110 | Journal: Cancer Cell
9111 | Link: /sources/106
9112 | Name: PubMed: Rad et al., 2013
9113 | Open Access: True
9114 | Pmc Id: PMC3706745
9115 | Publication Date: 2013-7-8
9116 | Retracted: False
9117 | Source Type: PUBMED
9118 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23845441
9119 | Title:
9120 | A genetic progression model of Braf(V600E)-induced intestinal
9121 | tumorigenesis reveals targets for therapeutic intervention.
9122 |
9123 | ##### Therapies
9124 | Deprecated: False
9125 | Id: 30
9126 | Link: /therapies/30
9127 | Name: PLX4720
9128 |
9129 | ##### Therapies
9130 | Deprecated: False
9131 | Id: 477
9132 | Link: /therapies/477
9133 | Name: Pictilisib Bismesylate
9134 |
9135 | #### Evidence Items
9136 | Description:
9137 | Preclinical study analyzing the differential response to MEK inhibitors
9138 | in KRAS and BRAF mutant cancer cell lines and mouse xenografts.
9139 | Inhibition of active, phosphorylated MEK by GDC-0973 (cobimetinib) is
9140 | required for strong inhibition of the MAPK pathway in BRAF-mutant
9141 | tumours. This study provides mechanistic rationale for improved efficacy
9142 | of cobimetinib in BRAF-mutant models compared to MEK inhibitors acting
9143 | through an alternative mechanism (GDC-0623 and G-573).
9144 | Evidence Direction: SUPPORTS
9145 | Evidence Level: D
9146 | Evidence Rating: 3
9147 | Evidence Type: PREDICTIVE
9148 | Flagged: False
9149 | Id: 1141
9150 | Name: EID1141
9151 | Significance: SENSITIVITYRESPONSE
9152 | Variant Origin: SOMATIC
9153 |
9154 | ##### Disease
9155 | Disease Url: https://www.disease-ontology.org/?id=DOID:162
9156 | Display Name: Cancer
9157 | Doid: 162
9158 | Id: 216
9159 | Link: /diseases/216
9160 | Name: Cancer
9161 |
9162 | ##### My Disease Info
9163 | Do Def: A cancer that is classified based on the organ it starts in.
9164 | Mesh: D009371
9165 | Mondo Id: MONDO:0004992
9166 | Disease Aliases: Malignant Neoplasm, Malignant Tumor, Primary Cancer
9167 |
9168 | ##### Molecular Profile
9169 | Id: 12
9170 |
9171 | ##### Source
9172 | Abstract:
9173 | KRAS and BRAF activating mutations drive tumorigenesis through
9174 | constitutive activation of the MAPK pathway. As these tumours represent
9175 | an area of high unmet medical need, multiple allosteric MEK inhibitors,
9176 | which inhibit MAPK signalling in both genotypes, are being tested in
9177 | clinical trials. Impressive single-agent activity in BRAF-mutant
9178 | melanoma has been observed; however, efficacy has been far less robust
9179 | in KRAS-mutant disease. Here we show that, owing to distinct mechanisms
9180 | regulating MEK activation in KRAS- versus BRAF-driven tumours, different
9181 | mechanisms of inhibition are required for optimal antitumour activity in
9182 | each genotype. Structural and functional analysis illustrates that MEK
9183 | inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and
9184 | G-573, the former currently in phase I clinical trials) form a strong
9185 | hydrogen-bond interaction with S212 in MEK that is critical for blocking
9186 | MEK feedback phosphorylation by wild-type RAF. Conversely, potent
9187 | inhibition of active, phosphorylated MEK is required for strong
9188 | inhibition of the MAPK pathway in BRAF-mutant tumours, resulting in
9189 | superior efficacy in this genotype with GDC-0973 (also known as
9190 | cobimetinib), a MEK inhibitor currently in phase III clinical trials.
9191 | Our study highlights that differences in the activation state of MEK in
9192 | KRAS-mutant tumours versus BRAF-mutant tumours can be exploited through
9193 | the design of inhibitors that uniquely target these distinct activation
9194 | states of MEK. These inhibitors are currently being evaluated in
9195 | clinical trials to determine whether improvements in therapeutic index
9196 | within KRAS versus BRAF preclinical models translate to improved
9197 | clinical responses in patients.
9198 | Author String:
9199 | Georgia Hatzivassiliou, Jacob R Haling, Huifen Chen, Kyung Song, Steve
9200 | Price, Robert Heald, Joanne F M Hewitt, Mark Zak, Ariana Peck, Christine
9201 | Orr, Mark Merchant, Klaus P Hoeflich, Jocelyn Chan, Shiuh-Ming Luoh,
9202 | Daniel J Anderson, Mary J C Ludlam, Christian Wiesmann, Mark Ultsch,
9203 | Lori S Friedman, Shiva Malek, Marcia Belvin
9204 | Citation: Hatzivassiliou et al., 2013
9205 | Citation Id: 23934108
9206 | Id: 790
9207 | Journal: Nature
9208 | Link: /sources/790
9209 | Name: PubMed: Hatzivassiliou et al., 2013
9210 | Open Access: False
9211 | Publication Date: 2013-9-12
9212 | Retracted: False
9213 | Source Type: PUBMED
9214 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23934108
9215 | Title:
9216 | Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus
9217 | BRAF-driven cancers.
9218 |
9219 | ##### Therapies
9220 | Deprecated: False
9221 | Id: 342
9222 | Link: /therapies/342
9223 | Name: Cobimetinib
9224 |
9225 | #### Evidence Items
9226 | Description:
9227 | This meta-analysis of 7 randomized control trials evaluating overall
9228 | survival (OS) (8 for progression free survival) could not definitely
9229 | state that survival benefit of anti-EGFR monoclonal antibodies is
9230 | limited to patients with wild type BRAF. In other words, the authors
9231 | believe that there is insufficient data to justify the exclusion of
9232 | anti-EGFR monoclonal antibody therapy for patients with mutant BRAF. In
9233 | these studies, mutant BRAF specifically meant the V600E mutation.
9234 | Evidence Direction: DOES_NOT_SUPPORT
9235 | Evidence Level: B
9236 | Evidence Rating: 4
9237 | Evidence Type: PREDICTIVE
9238 | Flagged: False
9239 | Id: 816
9240 | Name: EID816
9241 | Significance: RESISTANCE
9242 | Variant Origin: SOMATIC
9243 |
9244 | ##### Disease
9245 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
9246 | Display Name: Colorectal Cancer
9247 | Doid: 9256
9248 | Id: 11
9249 | Link: /diseases/11
9250 | Name: Colorectal Cancer
9251 |
9252 | ##### My Disease Info
9253 | Do Def:
9254 | An intestinal cancer that effects the long, tube-like organ that is
9255 | connected to the small intestine at one end and the anus at the other.
9256 | Icd10: C18.9
9257 | Mondo Id: MONDO:0005575
9258 | Ncit: C4978
9259 |
9260 | ##### Molecular Profile
9261 | Id: 12
9262 |
9263 | ##### Source
9264 | Abstract:
9265 | Metastatic colorectal cancer (mCRC) that harbours a BRAF V600E mutation
9266 | (BRAF MT) is associated with poorer outcomes. However, whether this
9267 | mutation is predictive of treatment benefit from anti-epidermal growth
9268 | factor receptor (EGFR) monoclonal antibodies (mAbs) is uncertain.We
9269 | conducted a systematic review and meta-analysis of randomised controlled
9270 | trials (RCTs) published up to July 2014 that evaluated the effect of
9271 | BRAF MT on the treatment benefit from anti-EGFR mAbs for mCRC.Seven RCTs
9272 | met the inclusion criteria for assessment of overall survival (OS),
9273 | whereas eight RCTs met the inclusion criteria for assessment of
9274 | progression-free survival (PFS). For RAS WT/BRAF MT tumours, the hazard
9275 | ratio for OS benefit with anti-EGFR mAbs was 0.97 (95% CI; 0.67-1.41),
9276 | whereas the hazard ratio was 0.81 (95% CI; 0.70-0.95) for RAS WT/BRAF WT
9277 | tumours. However, the test of interaction (P=0.43) was not statistically
9278 | significant, highlighting that the observed differences in the effect of
9279 | anti-EGFR mAbs on OS according to the BRAF mutation status may be due to
9280 | chance alone. Regarding PFS benefit with anti-EGFR mAbs, the hazard
9281 | ratio was 0.86 (95% CI; 0.61-1.21) for RAS WT/BRAF MT tumours as
9282 | compared with 0.62 (95% CI; 0.50-0.77) for RAS WT/BRAF WT tumours (test
9283 | of interaction, P=0.07).This meta-analysis demonstrates that there is
9284 | insufficient evidence to definitively state that RAS WT/BRAF MT
9285 | individuals attain a different treatment benefit from anti-EGFR mAbs for
9286 | mCRC compared with RAS WT/BRAF WT individuals. As such, there are
9287 | insufficient data to justify the exclusion of anti-EGFR mAb therapy for
9288 | patients with RAS WT/BRAF MT mCRC.
9289 | Author String:
9290 | A Rowland, M M Dias, M D Wiese, G Kichenadasse, R A McKinnon, C S
9291 | Karapetis, M J Sorich
9292 | Citation: Rowland et al., 2015
9293 | Citation Id: 25989278
9294 | Id: 548
9295 | Journal: Br J Cancer
9296 | Link: /sources/548
9297 | Name: PubMed: Rowland et al., 2015
9298 | Open Access: True
9299 | Pmc Id: PMC4580381
9300 | Publication Date: 2015-6-9
9301 | Retracted: False
9302 | Source Type: PUBMED
9303 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25989278
9304 | Title:
9305 | Meta-analysis of BRAF mutation as a predictive biomarker of benefit from
9306 | anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic
9307 | colorectal cancer.
9308 |
9309 | ##### Therapies
9310 | Deprecated: False
9311 | Id: 16
9312 | Link: /therapies/16
9313 | Name: Cetuximab
9314 |
9315 | ##### Therapies
9316 | Deprecated: False
9317 | Id: 28
9318 | Link: /therapies/28
9319 | Name: Panitumumab
9320 |
9321 | #### Evidence Items
9322 | Description:
9323 | In 47 patients with Hairy Cell Leukemia, sequencing discovered a V600E
9324 | mutation in all 47 of the sequenced patients.
9325 | Evidence Direction: SUPPORTS
9326 | Evidence Level: B
9327 | Evidence Rating: 4
9328 | Evidence Type: DIAGNOSTIC
9329 | Flagged: False
9330 | Id: 1127
9331 | Name: EID1127
9332 | Significance: POSITIVE
9333 | Variant Origin: SOMATIC
9334 |
9335 | ##### Disease
9336 | Disease Url: https://www.disease-ontology.org/?id=DOID:285
9337 | Display Name: Hairy Cell Leukemia
9338 | Doid: 285
9339 | Id: 665
9340 | Link: /diseases/665
9341 | Name: Hairy Cell Leukemia
9342 |
9343 | ##### My Disease Info
9344 | Do Def:
9345 | A chronic lymphocytic leukemia that is characterized by over production
9346 | of B cells (lymphocytes) by the bone marrow where the B cells appear
9347 | hairy under a microscope.
9348 | Icd10: C91.4
9349 | Icdo: 9940/3
9350 | Mesh: D007943
9351 | Mondo Id: MONDO:0018935
9352 | Ncit: C7402
9353 |
9354 | ##### Molecular Profile
9355 | Id: 12
9356 |
9357 | ##### Source
9358 | Abstract:
9359 | Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity
9360 | whose underlying genetic lesion is still obscure.We searched for HCL-
9361 | associated mutations by performing massively parallel sequencing of the
9362 | whole exome of leukemic and matched normal cells purified from the
9363 | peripheral blood of an index patient with HCL. Findings were validated
9364 | by Sanger sequencing in 47 additional patients with HCL.Whole-exome
9365 | sequencing identified five missense somatic clonal mutations that were
9366 | confirmed on Sanger sequencing, including a heterozygous mutation in
9367 | BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is
9368 | oncogenic in other tumors, further analyses were focused on this genetic
9369 | lesion. The same BRAF mutation was noted in all the other 47 patients
9370 | with HCL who were evaluated by means of Sanger sequencing. None of the
9371 | 195 patients with other peripheral B-cell lymphomas or leukemias who
9372 | were evaluated carried the BRAF V600E variant, including 38 patients
9373 | with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas
9374 | or leukemias. In immunohistologic and Western blot studies, HCL cells
9375 | expressed phosphorylated MEK and ERK (the downstream targets of the BRAF
9376 | kinase), indicating a constitutive activation of the RAF-MEK-ERK
9377 | mitogen-activated protein kinase pathway in HCL. In vitro incubation of
9378 | BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720,
9379 | a specific inhibitor of active BRAF, led to a marked decrease in
9380 | phosphorylated ERK and MEK. CONCLUSIONS; The BRAF V600E mutation was
9381 | present in all patients with HCL who were evaluated. This finding may
9382 | have implications for the pathogenesis, diagnosis, and targeted therapy
9383 | of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and
9384 | others.).
9385 | Author String:
9386 | Enrico Tiacci, Vladimir Trifonov, Gianluca Schiavoni, Antony Holmes,
9387 | Wolfgang Kern, Maria Paola Martelli, Alessandra Pucciarini, Barbara
9388 | Bigerna, Roberta Pacini, Victoria A Wells, Paolo Sportoletti, Valentina
9389 | Pettirossi, Roberta Mannucci, Oliver Elliott, Arcangelo Liso, Achille
9390 | Ambrosetti, Alessandro Pulsoni, Francesco Forconi, Livio Trentin,
9391 | Gianpietro Semenzato, Giorgio Inghirami, Monia Capponi, Francesco Di
9392 | Raimondo, Caterina Patti, Luca Arcaini, Pellegrino Musto, Stefano
9393 | Pileri, Claudia Haferlach, Susanne Schnittger, Giovanni Pizzolo, Robin
9394 | Foà, Laurent Farinelli, Torsten Haferlach, Laura Pasqualucci, Raul
9395 | Rabadan, Brunangelo Falini
9396 | Citation: Tiacci et al., 2011
9397 | Citation Id: 21663470
9398 | Id: 780
9399 | Journal: N Engl J Med
9400 | Link: /sources/780
9401 | Name: PubMed: Tiacci et al., 2011
9402 | Open Access: True
9403 | Pmc Id: PMC3689585
9404 | Publication Date: 2011-6-16
9405 | Retracted: False
9406 | Source Type: PUBMED
9407 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21663470
9408 | Title: BRAF mutations in hairy-cell leukemia.
9409 | Molecular Profile Aliases: RS113488022, VAL600GLU, V640E, VAL640GLU
9410 |
9411 | #### Variants
9412 | Id: 12
9413 | Link: /variants/12
9414 | Name: V600E
9415 |
9416 | ### Molecular Profiles
9417 | Id: 4170
9418 | Molecular Profile Score: 2.5
9419 | Name: BRAF V600E AND BRAF V600M
9420 |
9421 | #### Evidence Items
9422 | Description:
9423 | A single 66-year old male patient with advanced melanoma thought to have
9424 | concomitant BRAF V600E and V600M mutations responded rapidly to
9425 | dabrafenib. His shoulder lesion reduced by 60% after 1 week of therapy
9426 | and was gone after 1 month.
9427 | Evidence Direction: SUPPORTS
9428 | Evidence Level: C
9429 | Evidence Rating: 1
9430 | Evidence Type: PREDICTIVE
9431 | Flagged: False
9432 | Id: 73
9433 | Name: EID73
9434 | Significance: SENSITIVITYRESPONSE
9435 | Variant Origin: SOMATIC
9436 |
9437 | ##### Disease
9438 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
9439 | Display Name: Melanoma
9440 | Doid: 1909
9441 | Id: 7
9442 | Link: /diseases/7
9443 | Name: Melanoma
9444 |
9445 | ##### My Disease Info
9446 | Do Def:
9447 | A cell type cancer that has_material_basis_in abnormally proliferating
9448 | cells derives_from melanocytes which are found in skin, the bowel and
9449 | the eye.
9450 | Icdo: 8720/3
9451 | Mesh: D008545
9452 | Mondo Id: MONDO:0005105
9453 | Ncit: C3224
9454 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
9455 |
9456 | ##### Molecular Profile
9457 | Id: 4170
9458 |
9459 | ##### Source
9460 | Abstract:
9461 | The recent findings brought the necessity of testing the mutational
9462 | status of a series of genes which had been already identified as
9463 | responsible for melanomas development and progression, such as BRAF,
9464 | CKIT and PTEN: the consequent results are, in fact, essential to guide
9465 | the assessment of the novel treatment protocols based on tailored
9466 | targeted therapies. We present here the case of a 66 year-old male
9467 | patient, diagnosed with an advanced melanoma in June 2011, and treated
9468 | with Dabrafenib for double mutant metastatic disease. The patient was
9469 | referred to our attention for a large exophytic malignant melanoma on
9470 | the left shoulder. After complete surgical excision and elective lymph
9471 | node dissection for presence of metastatic sentinel lymph node, the
9472 | patient has started high-dose interferon alfa-2b injections as adjuvant
9473 | therapy for a complete negative staging. The treatment was interrupted
9474 | in August 2011 due to the appearance of metastatic lymph nodes. Tumor
9475 | burden was rapidly growing reaching in few months the size of a tennis
9476 | ball for the tumor mass located in the shoulder. Mutational study of the
9477 | tumor revealed a double BRAF mutation on V-600E and V600M. This finding
9478 | incited us to enroll the patient in compassionate Dabrafenib clinical
9479 | trial. The therapy was started on may 2012 at 150 mg bid dosage. Almost
9480 | surprisingly for the rapidity of the effect, one week later the lesion
9481 | on the shoulder has reduced its size by 60% and one month later it has
9482 | completely disappeared from sight. CT scan of June 2012 documented the
9483 | astonishing clinical response.
9484 | Author String: Giovanni Ponti, Aldo Tomasi, Giovanni Pellacani
9485 | Citation: Ponti et al., 2012
9486 | Citation Id: 23031422
9487 | Id: 88
9488 | Journal: J Hematol Oncol
9489 | Link: /sources/88
9490 | Name: PubMed: Ponti et al., 2012
9491 | Open Access: True
9492 | Pmc Id: PMC3473234
9493 | Publication Date: 2012-10-2
9494 | Retracted: False
9495 | Source Type: PUBMED
9496 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23031422
9497 | Title:
9498 | Overwhelming response to Dabrafenib in a patient with double BRAF
9499 | mutation (V600E; V600M) metastatic malignant melanoma.
9500 |
9501 | ##### Therapies
9502 | Deprecated: False
9503 | Id: 22
9504 | Link: /therapies/22
9505 | Name: Dabrafenib
9506 |
9507 | #### Variants
9508 | Id: 12
9509 | Link: /variants/12
9510 | Name: V600E
9511 |
9512 | #### Variants
9513 | Id: 1405
9514 | Link: /variants/1405
9515 | Name: V600M
9516 |
9517 | ### Molecular Profiles
9518 | Id: 4173
9519 | Molecular Profile Score: 1.0
9520 | Name: BRAF V600E AND BRAF Amplification
9521 |
9522 | #### Evidence Items
9523 | Description:
9524 | AURELIA trial indicated substantial improvement in progression-free
9525 | survival and overall survival in ovarian cancer patients with PD-L1
9526 | positive expression in response to bevacizumab plus single regime
9527 | chemotherapy (BC) treatment (p<0.05). In identifying the
9528 | clinicopathologic characteristics, over-expression of PD-L1 indicated
9529 | close association with low histological grade, advanced FIGO stage and
9530 | ascites volume >2,000 mL (p>0.05). These results are suggestive of over-
9531 | expression of PD-L1 being associative with more malignant epithelial
9532 | ovarian cancer phenotypes and expression of PD-L1 potentially
9533 | corresponding to BC treatment. Additionally combinational therapies of
9534 | bevacizumab with PD-L1 inhibitor atezolizumab in vivo elicited
9535 | synergistic effects greater than the control and each single treatment
9536 | (p<0.05).
9537 | Evidence Direction: SUPPORTS
9538 | Evidence Level: B
9539 | Evidence Rating: 1
9540 | Evidence Type: PREDICTIVE
9541 | Flagged: False
9542 | Id: 9885
9543 | Name: EID9885
9544 | Significance: SENSITIVITYRESPONSE
9545 | Variant Origin: NA
9546 |
9547 | ##### Disease
9548 | Disease Url: https://www.disease-ontology.org/?id=DOID:2152
9549 | Display Name: Epithelial Ovarian Cancer
9550 | Doid: 2152
9551 | Id: 225
9552 | Link: /diseases/225
9553 | Name: Epithelial Ovarian Cancer
9554 |
9555 | ##### My Disease Info
9556 | Do Def: An ovarian cancer that is derives_from ovarian surface epithelium.
9557 | Mondo Id: MONDO:0002229
9558 | Ncit: C4381
9559 |
9560 | ##### Molecular Profile
9561 | Id: 4173
9562 |
9563 | ##### Source
9564 | Abstract:
9565 | The AURELIA trial demonstrated that adding Bevacizumab to chemotherapy
9566 | significantly improved progression-free survival (PFS) for platinum
9567 | resistant recurrent ovarian cancer. Recently, immunotherapy also
9568 | presented potential anti-tumor effects in several malignant solid
9569 | tumors. This study aimed to investigate whether combining anti-PD-L1
9570 | Atezolizumab with BEV may have a synergistic effect and enhance the
9571 | efficacy of both treatments in cisplatin resistant epithelial ovarian
9572 | cancer (CREOC). We retrospectively analyzed 124 epithelial ovarian
9573 | cancer (EOC) patients from Gynecologic Oncology Department of Tianjin
9574 | Cancer Hospital between January 2013 and June 2018, who all were
9575 | diagnosed with cisplatin resistance due to progressing <6 months after
9576 | completing platinum-based therapy. Based on responding to at least 2
9577 | cycles of Bevacizumab-containing chemotherapy (BC), these Patients were
9578 | divided into BC response group and BC non-response group.
9579 | Immunohistochemistry was used to detect that PD-L1 expression and tumor
9580 | angiogenesis-related proteins (VEGF and Semaphorin4D) in tissues from
9581 | 124 patients with CREOC. The positive expressions of PD-L1, VEGF, and
9582 | Semaphorin4D (SEMA4D) were found in 58.73, 50.79, and 71.43% of the 63
9583 | cases CREOC tissues with BC response, respectively, which were
9584 | significantly higher than that in the 61 cases BC non-response group (P
9585 | < 0.05). PD-L1 expression correlated with SEMA4D and VEGF positively (r
9586 | = 0.344 and 0.363, P < 0.001). Over-expressions of PD-L1, VEGF and
9587 | SEMA4D are associated with more malignant clinicopathologic
9588 | characteristics of CREOC Patients. In survival analysis, patients'
9589 | response to BC was the independent factor for evaluation of PFS and
9590 | overall survival (OS). Cell functional assays showed that Atezolizumab
9591 | in combination with Bevacizumab inhibited the proliferation, migration,
9592 | and invasion of cisplatin resistant ovarian cancer cell line A2780cis in
9593 | vitro synergistically, which maybe associate with Bevacizumab
9594 | suppressing the epithelial-mesenchymal transition (EMT) and PD-L1
9595 | expression by targeting STAT3. Furthermore, Bevacizumab and Atezolizumab
9596 | induced synergistic anti-tumor effect in vivo. These findings suggest a
9597 | novel therapeutic strategy for cisplatin resistant recurrent EOC and its
9598 | mechanism warrants further study.
9599 | Author String: Lei Zhang, Ying Chen, Fangxuan Li, Lewen Bao, Wenxin Liu
9600 | Citation: Zhang et al., 2019
9601 | Citation Id: 31105696
9602 | Id: 4206
9603 | Journal: Front Immunol
9604 | Link: /sources/4206
9605 | Name: PubMed: Zhang et al., 2019
9606 | Open Access: True
9607 | Pmc Id: PMC6498972
9608 | Publication Date: 2019
9609 | Retracted: False
9610 | Source Type: PUBMED
9611 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/31105696
9612 | Title:
9613 | Atezolizumab and Bevacizumab Attenuate Cisplatin Resistant Ovarian
9614 | Cancer Cells Progression Synergistically via Suppressing Epithelial-
9615 | Mesenchymal Transition.
9616 |
9617 | ##### Therapies
9618 | Deprecated: False
9619 | Id: 261
9620 | Link: /therapies/261
9621 | Name: Atezolizumab
9622 |
9623 | ##### Therapies
9624 | Deprecated: False
9625 | Id: 33
9626 | Link: /therapies/33
9627 | Name: Bevacizumab
9628 |
9629 | #### Evidence Items
9630 | Description:
9631 | COLO201 and COLO206F cells harboring BRAF V600E mutations were cloned to
9632 | be MEK inhibitor (AZD6244 [selumetinib]) resistant. The mechanism of
9633 | this resistance was shown to be amplification of the BRAF V600E gene.
9634 | BRAF V600E amplification was observed in 1/11 colorectal cancer patient
9635 | samples evaluated, indicating this subclone (28% of cells) would be MEK
9636 | inhibitor resistant.
9637 | Evidence Direction: SUPPORTS
9638 | Evidence Level: E
9639 | Evidence Rating: 4
9640 | Evidence Type: PREDICTIVE
9641 | Flagged: False
9642 | Id: 92
9643 | Name: EID92
9644 | Significance: RESISTANCE
9645 | Variant Origin: SOMATIC
9646 |
9647 | ##### Disease
9648 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
9649 | Display Name: Colorectal Cancer
9650 | Doid: 9256
9651 | Id: 11
9652 | Link: /diseases/11
9653 | Name: Colorectal Cancer
9654 |
9655 | ##### My Disease Info
9656 | Do Def:
9657 | An intestinal cancer that effects the long, tube-like organ that is
9658 | connected to the small intestine at one end and the anus at the other.
9659 | Icd10: C18.9
9660 | Mondo Id: MONDO:0005575
9661 | Ncit: C4978
9662 |
9663 | ##### Molecular Profile
9664 | Id: 4173
9665 |
9666 | ##### Source
9667 | Abstract:
9668 | Oncogenic BRAF mutations are found in several tumor types, including
9669 | melanomas and colorectal cancers. Tumors with BRAF mutations have
9670 | increased mitogen-activated protein kinase pathway activity and
9671 | heightened sensitivity to BRAF and MEK (mitogen-activated or
9672 | extracellular signal-regulated protein kinase kinase) inhibitors. To
9673 | identify potential mechanisms of acquired drug resistance, we generated
9674 | clones resistant to the allosteric MEK inhibitor AZD6244 from two BRAF
9675 | V600E mutant colorectal cancer cell lines that are highly sensitive to
9676 | MEK or BRAF inhibition. These AZD6244-resistant (AR) clones, which
9677 | exhibited cross-resistance to BRAF inhibitors, acquired resistance
9678 | through amplification of the BRAF gene. A small percentage of treatment-
9679 | naïve parental cells showed preexisting BRAF amplification. We observed
9680 | similar amplification in a subset of cells in a BRAF-mutant colorectal
9681 | cancer. In cell lines, BRAF amplification increased the abundance of
9682 | phosphorylated MEK and impaired the ability of AZD6244 to inhibit ERK
9683 | (extracellular signal-regulated kinase) phosphorylation. The ability of
9684 | AZD6244 to inhibit ERK phosphorylation in AR cells was restored by
9685 | treatment with a BRAF inhibitor at low concentrations that reduced the
9686 | abundance of phosphorylated MEK to amounts observed in parental cells.
9687 | Combined MEK and BRAF inhibition fully overcame resistance to MEK or
9688 | BRAF inhibitors alone and was also more effective in parental cells
9689 | compared to treatment with either inhibitor alone. These findings
9690 | implicate BRAF amplification as a mechanism of resistance to both MEK
9691 | and BRAF inhibitors and suggest combined MEK and BRAF inhibition as a
9692 | clinical strategy to overcome, or possibly prevent, this mechanism of
9693 | resistance.
9694 | Author String:
9695 | Ryan B Corcoran, Dora Dias-Santagata, Kristin Bergethon, A John Iafrate,
9696 | Jeffrey Settleman, Jeffrey A Engelman
9697 | Citation: Corcoran et al., 2010
9698 | Citation Id: 21098728
9699 | Id: 102
9700 | Journal: Sci Signal
9701 | Link: /sources/102
9702 | Name: PubMed: Corcoran et al., 2010
9703 | Open Access: True
9704 | Pmc Id: PMC3372405
9705 | Publication Date: 2010-11-23
9706 | Retracted: False
9707 | Source Type: PUBMED
9708 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21098728
9709 | Title:
9710 | BRAF gene amplification can promote acquired resistance to MEK
9711 | inhibitors in cancer cells harboring the BRAF V600E mutation.
9712 |
9713 | ##### Therapies
9714 | Deprecated: False
9715 | Id: 63
9716 | Link: /therapies/63
9717 | Name: Selumetinib
9718 |
9719 | #### Variants
9720 | Id: 12
9721 | Link: /variants/12
9722 | Name: V600E
9723 |
9724 | #### Variants
9725 | Id: 1269
9726 | Link: /variants/1269
9727 | Name: Amplification
9728 |
9729 | ### Molecular Profiles
9730 | Id: 4174
9731 | Molecular Profile Score: 10.0
9732 | Name: BRAF Amplification AND ( BRAF V600E OR BRAF V600K )
9733 |
9734 | #### Evidence Items
9735 | Description:
9736 | In a retrospective study of 44 relapsed melanoma patients harboring BRAF
9737 | V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK
9738 | pathway reactivation mechanisms were implicated in acquired resistance
9739 | to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following
9740 | MAPK pathway variants were found in progressive tumors with patient
9741 | matched baseline tumors (some patients donated samples from multiple
9742 | geographically/temporally distinct progressive tumors): NRAS mutations
9743 | (G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive
9744 | tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive
9745 | tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57
9746 | (19%) of progressive tumors, mutant BRAF alternative splice variants
9747 | (novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of
9748 | progressive tumor RNA.
9749 | Evidence Direction: SUPPORTS
9750 | Evidence Level: B
9751 | Evidence Rating: 2
9752 | Evidence Type: PREDICTIVE
9753 | Flagged: False
9754 | Id: 6262
9755 | Name: EID6262
9756 | Significance: RESISTANCE
9757 | Variant Origin: SOMATIC
9758 |
9759 | ##### Disease
9760 | Disease Url: https://www.disease-ontology.org/?id=DOID:1909
9761 | Display Name: Melanoma
9762 | Doid: 1909
9763 | Id: 7
9764 | Link: /diseases/7
9765 | Name: Melanoma
9766 |
9767 | ##### My Disease Info
9768 | Do Def:
9769 | A cell type cancer that has_material_basis_in abnormally proliferating
9770 | cells derives_from melanocytes which are found in skin, the bowel and
9771 | the eye.
9772 | Icdo: 8720/3
9773 | Mesh: D008545
9774 | Mondo Id: MONDO:0005105
9775 | Ncit: C3224
9776 | Disease Aliases: Malignant Melanoma, Naevocarcinoma
9777 |
9778 | ##### Molecular Profile
9779 | Id: 4174
9780 |
9781 | ##### Source
9782 | Abstract:
9783 | BRAF inhibitors elicit rapid antitumor responses in the majority of
9784 | patients with BRAF(V600)-mutant melanoma, but acquired drug resistance
9785 | is almost universal. We sought to identify the core resistance pathways
9786 | and the extent of tumor heterogeneity during disease progression. We
9787 | show that mitogen-activated protein kinase reactivation mechanisms were
9788 | detected among 70% of disease-progressive tissues, with RAS mutations,
9789 | mutant BRAF amplification, and alternative splicing being most common.
9790 | We also detected PI3K-PTEN-AKT-upregulating genetic alterations among
9791 | 22% of progressive melanomas. Distinct molecular lesions in both core
9792 | drug escape pathways were commonly detected concurrently in the same
9793 | tumor or among multiple tumors from the same patient. Beyond harboring
9794 | extensively heterogeneous resistance mechanisms, melanoma regrowth
9795 | emerging from BRAF inhibitor selection displayed branched evolution
9796 | marked by altered mutational spectra/signatures and increased fitness.
9797 | Thus, melanoma genomic heterogeneity contributes significantly to BRAF
9798 | inhibitor treatment failure, implying upfront, cotargeting of two core
9799 | pathways as an essential strategy for durable responses.
9800 | Author String:
9801 | Hubing Shi, Willy Hugo, Xiangju Kong, Aayoung Hong, Richard C Koya,
9802 | Gatien Moriceau, Thinle Chodon, Rongqing Guo, Douglas B Johnson,
9803 | Kimberly B Dahlman, Mark C Kelley, Richard F Kefford, Bartosz
9804 | Chmielowski, John A Glaspy, Jeffrey A Sosman, Nicolas van Baren,
9805 | Georgina V Long, Antoni Ribas, Roger S Lo
9806 | Citation: Shi et al., 2014
9807 | Citation Id: 24265155
9808 | Id: 1941
9809 | Journal: Cancer Discov
9810 | Link: /sources/1941
9811 | Name: PubMed: Shi et al., 2014
9812 | Open Access: True
9813 | Pmc Id: PMC3936420
9814 | Publication Date: 2014-1
9815 | Retracted: False
9816 | Source Type: PUBMED
9817 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24265155
9818 | Title:
9819 | Acquired resistance and clonal evolution in melanoma during BRAF
9820 | inhibitor therapy.
9821 |
9822 | ##### Therapies
9823 | Deprecated: False
9824 | Id: 4
9825 | Link: /therapies/4
9826 | Name: Vemurafenib
9827 |
9828 | ##### Therapies
9829 | Deprecated: False
9830 | Id: 22
9831 | Link: /therapies/22
9832 | Name: Dabrafenib
9833 |
9834 | #### Variants
9835 | Id: 12
9836 | Link: /variants/12
9837 | Name: V600E
9838 |
9839 | #### Variants
9840 | Id: 1269
9841 | Link: /variants/1269
9842 | Name: Amplification
9843 |
9844 | #### Variants
9845 | Id: 563
9846 | Link: /variants/563
9847 | Name: V600K
9848 |
9849 | ### Molecular Profiles
9850 | Id: 4213
9851 | Molecular Profile Score: 0.0
9852 | Name: NOT KRAS Mutation AND ( BRAF V600E OR BRAF D594G )
9853 |
9854 | #### Evidence Items
9855 | Description:
9856 | The Medical Research Council (MRC) COIN trial consisted of patients with
9857 | histologically confirmed adenocarcinoma of the colon or rectum,
9858 | inoperable metastatic or locoregional measurable disease, and who had
9859 | not received chemotherapy for metastatic disease.
9860 |
9861 | In arm A patients were given oxaliplatin and fluoropyrimidine
9862 | chemotherapy.
9863 | In arm B patients were given the same chemotherapy with additional
9864 | cetuximab.
9865 |
9866 |
9867 | BRAF D594G was found in 12 patients (0.9%), and V600E was found in 90
9868 | (7% of patients).
9869 |
9870 | Overall Survival in arm A was 10.0 months, and arm B was 7.2 months with
9871 | HR 1.18 (95% CI 0.76-1.81, p=0.46), indicating no sensitizing effect for
9872 | the presence of the BRAF mutations for cetuximab in KRAS WT patients.
9873 | Evidence Direction: DOES_NOT_SUPPORT
9874 | Evidence Level: B
9875 | Evidence Rating: 3
9876 | Evidence Type: PREDICTIVE
9877 | Flagged: False
9878 | Id: 11060
9879 | Name: EID11060
9880 | Significance: SENSITIVITYRESPONSE
9881 | Variant Origin: SOMATIC
9882 |
9883 | ##### Disease
9884 | Disease Url: https://www.disease-ontology.org/?id=DOID:0050861
9885 | Display Name: Colorectal Adenocarcinoma
9886 | Doid: 0050861
9887 | Id: 57
9888 | Link: /diseases/57
9889 | Name: Colorectal Adenocarcinoma
9890 |
9891 | ##### My Disease Info
9892 | Do Def:
9893 | A colorectal carcinoma that derives_from epithelial cells of glandular
9894 | origin.
9895 | Mondo Id: MONDO:0005008
9896 | Ncit: C5105
9897 |
9898 | ##### Molecular Profile
9899 | Id: 4213
9900 |
9901 | ##### Source
9902 | Abstract:
9903 | In the Medical Research Council (MRC) COIN trial, the epidermal growth
9904 | factor receptor (EGFR)-targeted antibody cetuximab was added to standard
9905 | chemotherapy in first-line treatment of advanced colorectal cancer with
9906 | the aim of assessing effect on overall survival.In this randomised
9907 | controlled trial, patients who were fit for but had not received
9908 | previous chemotherapy for advanced colorectal cancer were randomly
9909 | assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the
9910 | same combination plus cetuximab (arm B), or intermittent chemotherapy
9911 | (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused
9912 | fluouroracil plus leucovorin) was decided before randomisation.
9913 | Randomisation was done centrally (via telephone) by the MRC Clinical
9914 | Trials Unit using minimisation. Treatment allocation was not masked. The
9915 | comparison of arms A and C is described in a companion paper. Here, we
9916 | present the comparison of arm A and B, for which the primary outcome was
9917 | overall survival in patients with KRAS wild-type tumours. Analysis was
9918 | by intention to treat. Further analyses with respect to NRAS, BRAF, and
9919 | EGFR status were done. The trial is registered, ISRCTN27286448.1630
9920 | patients were randomly assigned to treatment groups (815 to standard
9921 | therapy and 815 to addition of cetuximab). Tumour samples from 1316
9922 | (81%) patients were used for somatic molecular analyses; 565 (43%) had
9923 | KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367;
9924 | arm B, n=362), overall survival did not differ between treatment groups
9925 | (median survival 17·9 months [IQR 10·3-29·2] in the control group vs
9926 | 17·0 months [9·4-30·1] in the cetuximab group; HR 1·04, 95% CI
9927 | 0·87-1·23, p=0·67). Similarly, there was no effect on progression-free
9928 | survival (8·6 months [IQR 5·0-12·5] in the control group vs 8·6 months
9929 | [5·1-13·8] in the cetuximab group; HR 0·96, 0·82-1·12, p=0·60). Overall
9930 | response rate increased from 57% (n=209) with chemotherapy alone to 64%
9931 | (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin
9932 | and gastrointestinal toxic effects were increased with cetuximab (14 vs
9933 | 114 and 67 vs 97 patients in the control group vs the cetuximab group
9934 | with KRAS wild-type tumours, respectively). Overall survival differs by
9935 | somatic mutation status irrespective of treatment received: BRAF mutant,
9936 | 8·8 months (IQR 4·5-27·4); KRAS mutant, 14·4 months (8·5-24·0); all
9937 | wild-type, 20·1 months (11·5-31·7).This trial has not confirmed a
9938 | benefit of addition of cetuximab to oxaliplatin-based chemotherapy in
9939 | first-line treatment of patients with advanced colorectal cancer.
9940 | Cetuximab increases response rate, with no evidence of benefit in
9941 | progression-free or overall survival in KRAS wild-type patients or even
9942 | in patients selected by additional mutational analysis of their tumours.
9943 | The use of cetuximab in combination with oxaliplatin and capecitabine in
9944 | first-line chemotherapy in patients with widespread metastases cannot be
9945 | recommended.Cancer Research UK, Cancer Research Wales, UK Medical
9946 | Research Council, Merck KGgA.
9947 | Author String:
9948 | Timothy S Maughan, Richard A Adams, Christopher G Smith, Angela M Meade,
9949 | Matthew T Seymour, Richard H Wilson, Shelley Idziaszczyk, Rebecca
9950 | Harris, David Fisher, Sarah L Kenny, Edward Kay, Jenna K Mitchell, Ayman
9951 | Madi, Bharat Jasani, Michelle D James, John Bridgewater, M John Kennedy,
9952 | Bart Claes, Diether Lambrechts, Richard Kaplan, Jeremy P Cheadle
9953 | Citation: Maughan et al., 2011
9954 | Citation Id: 21641636
9955 | Id: 2784
9956 | Journal: Lancet
9957 | Link: /sources/2784
9958 | Name: PubMed: Maughan et al., 2011
9959 | Open Access: True
9960 | Pmc Id: PMC3159415
9961 | Publication Date: 2011-6-18
9962 | Retracted: False
9963 | Source Type: PUBMED
9964 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21641636
9965 | Title:
9966 | Addition of cetuximab to oxaliplatin-based first-line combination
9967 | chemotherapy for treatment of advanced colorectal cancer: results of the
9968 | randomised phase 3 MRC COIN trial.
9969 |
9970 | ##### Therapies
9971 | Deprecated: False
9972 | Id: 16
9973 | Link: /therapies/16
9974 | Name: Cetuximab
9975 |
9976 | ##### Therapies
9977 | Deprecated: False
9978 | Id: 199
9979 | Link: /therapies/199
9980 | Name: Chemotherapy
9981 |
9982 | #### Variants
9983 | Id: 611
9984 | Link: /variants/611
9985 | Name: D594G
9986 |
9987 | #### Variants
9988 | Id: 12
9989 | Link: /variants/12
9990 | Name: V600E
9991 |
9992 | #### Variants
9993 | Id: 336
9994 | Link: /variants/336
9995 | Name: Mutation
9996 |
9997 | ### Molecular Profiles
9998 | Id: 4241
9999 | Molecular Profile Score: 0.0
10000 | Name: BRAF V600E AND EZH2 Y646F
10001 |
10002 | #### Evidence Items
10003 | Description:
10004 | Experiment with immunodeficient mice transplanted with melanoma cell
10005 | lines indicates EZH2 inhibitor JQEZ5 might be effective in combination
10006 | with a B-RAF inhibitor in RAF-mutant melanoma.
10007 | Evidence Direction: SUPPORTS
10008 | Evidence Level: D
10009 | Evidence Rating: 4
10010 | Evidence Type: PREDICTIVE
10011 | Flagged: False
10012 | Id: 6952
10013 | Name: EID6952
10014 | Significance: SENSITIVITYRESPONSE
10015 | Variant Origin: SOMATIC
10016 |
10017 | ##### Disease
10018 | Disease Url: https://www.disease-ontology.org/?id=DOID:8923
10019 | Display Name: Skin Melanoma
10020 | Doid: 8923
10021 | Id: 206
10022 | Link: /diseases/206
10023 | Name: Skin Melanoma
10024 |
10025 | ##### My Disease Info
10026 | Do Def: A skin cancer that has_material_basis_in melanocytes.
10027 | Icd10: C43.9
10028 | Mesh: C562393
10029 | Mondo Id: MONDO:0005012
10030 | Ncit: C3510
10031 | Disease Aliases:
10032 | - Cutaneous Melanoma
10033 | - Malignant Ear Melanoma
10034 | - Malignant Lip Melanoma
10035 | - Malignant Lower Limb Melanoma
10036 | - Malignant Melanoma Of Ear And/or External Auricular Canal
10037 | - Malignant Melanoma Of Skin Of Lower Limb
10038 | - Malignant Melanoma Of Skin Of Trunk Except Scrotum
10039 | - Malignant Melanoma Of Skin Of Upper Limb
10040 | - Malignant Neck Melanoma
10041 | - Malignant Scalp Melanoma
10042 | - Malignant Trunk Melanoma
10043 | - Malignant Upper Limb Melanoma
10044 |
10045 | ##### Molecular Profile
10046 | Id: 4241
10047 |
10048 | ##### Source
10049 | Abstract:
10050 | B cell lymphoma and melanoma harbor recurrent mutations in the gene
10051 | encoding the EZH2 histone methyltransferase (EZH2), but the carcinogenic
10052 | role of these mutations is unclear. Here we describe a mouse model in
10053 | which the most common somatic Ezh2 gain-of-function mutation
10054 | (EZH2(Y646F) in human; Ezh2(Y641F) in mouse) is conditionally expressed.
10055 | Expression of Ezh2(Y641F) in mouse B cells or melanocytes caused high-
10056 | penetrance lymphoma or melanoma, respectively. Overexpression of the
10057 | anti-apoptotic protein Bcl2, but not the oncoprotein Myc, or loss of the
10058 | tumor suppressor protein p53 (encoded by Trp53 in mice) further
10059 | accelerated lymphoma progression. Expression of the mutant Braf but not
10060 | the mutant Nras oncoprotein further accelerated melanoma progression.
10061 | Although expression of Ezh2(Y641F) globally increased the abundance of
10062 | trimethylated Lys27 of histone H3 (H3K27me3), it also caused a
10063 | widespread redistribution of this repressive mark, including a loss of
10064 | H3K27me3 that was associated with increased transcription at many loci.
10065 | These results suggest that Ezh2(Y641F) induces lymphoma and melanoma
10066 | through a vast reorganization of chromatin structure, inducing both
10067 | repression and activation of polycomb-regulated loci.
10068 | Author String:
10069 | George P Souroullas, William R Jeck, Joel S Parker, Jeremy M Simon, Jie-
10070 | Yu Liu, Joshiawa Paulk, Jessie Xiong, Kelly S Clark, Yuri Fedoriw, Jun
10071 | Qi, Christin E Burd, James E Bradner, Norman E Sharpless
10072 | Citation: Souroullas et al., 2016
10073 | Citation Id: 27135738
10074 | Id: 2307
10075 | Journal: Nat Med
10076 | Link: /sources/2307
10077 | Name: PubMed: Souroullas et al., 2016
10078 | Open Access: True
10079 | Pmc Id: PMC4899144
10080 | Publication Date: 2016-6
10081 | Retracted: False
10082 | Source Type: PUBMED
10083 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/27135738
10084 | Title:
10085 | An oncogenic Ezh2 mutation induces tumors through global redistribution
10086 | of histone 3 lysine 27 trimethylation.
10087 |
10088 | ##### Therapies
10089 | Deprecated: False
10090 | Id: 541
10091 | Link: /therapies/541
10092 | Name: JQEZ5
10093 |
10094 | #### Variants
10095 | Id: 2989
10096 | Link: /variants/2989
10097 | Name: Y646F
10098 |
10099 | #### Variants
10100 | Id: 12
10101 | Link: /variants/12
10102 | Name: V600E
10103 |
10104 | ### Molecular Profiles
10105 | Id: 4251
10106 | Molecular Profile Score: 0.0
10107 | Name: BRAF V600E AND EGFR L858R AND EGFR T790M
10108 |
10109 | #### Evidence Items
10110 | Description:
10111 | A 42 year old man with non-smoking history presented with EGFR L858R
10112 | positive lung adenocarcinoma. He was given various treatments including
10113 | erlotinib and gefitinib and progressed four years later. biopsy revealed
10114 | EGFR T790M mutation, and osimertinib treatment was given. Partial
10115 | response was seen, and progression occurred after 13 months. BRAF V600E
10116 | mutation was found in progressed tumor cells, but was not reported
10117 | before osimertinib resistance.
10118 | Evidence Direction: SUPPORTS
10119 | Evidence Level: C
10120 | Evidence Rating: 3
10121 | Evidence Type: PREDICTIVE
10122 | Flagged: False
10123 | Id: 11098
10124 | Name: EID11098
10125 | Significance: RESISTANCE
10126 | Variant Origin: SOMATIC
10127 |
10128 | ##### Disease
10129 | Disease Url: https://www.disease-ontology.org/?id=DOID:3910
10130 | Display Name: Lung Adenocarcinoma
10131 | Doid: 3910
10132 | Id: 30
10133 | Link: /diseases/30
10134 | Name: Lung Adenocarcinoma
10135 |
10136 | ##### My Disease Info
10137 | Do Def:
10138 | A lung non-small cell carcinoma that derives_from epithelial cells of
10139 | glandular origin.
10140 | Mesh: D000077192
10141 | Mondo Id: MONDO:0005061
10142 | Ncit: C27745, C3512
10143 | Disease Aliases:
10144 | - Bronchogenic Lung Adenocarcinoma
10145 | - Nonsmall Cell Adenocarcinoma
10146 |
10147 | ##### Molecular Profile
10148 | Id: 4251
10149 |
10150 | ##### Source
10151 | Author String: Alessandra Bearz, Elisa De Carlo, Roberto Doliana, Monica Schiappacassi
10152 | Citation: Bearz et al., 2017
10153 | Citation Id: 29074209
10154 | Id: 4545
10155 | Journal: J Thorac Oncol
10156 | Link: /sources/4545
10157 | Name: PubMed: Bearz et al., 2017
10158 | Open Access: False
10159 | Publication Date: 2017-11
10160 | Retracted: False
10161 | Source Type: PUBMED
10162 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/29074209
10163 | Title:
10164 | Acquired BRAF V600E Mutation as Resistant Mechanism after Treatment with
10165 | Third-Generation EGFR Tyrosine Kinase Inhibitor.
10166 |
10167 | ##### Therapies
10168 | Deprecated: False
10169 | Id: 187
10170 | Link: /therapies/187
10171 | Name: Osimertinib
10172 |
10173 | #### Variants
10174 | Id: 34
10175 | Link: /variants/34
10176 | Name: T790M
10177 |
10178 | #### Variants
10179 | Id: 33
10180 | Link: /variants/33
10181 | Name: L858R
10182 |
10183 | #### Variants
10184 | Id: 12
10185 | Link: /variants/12
10186 | Name: V600E
10187 |
10188 | ### Molecular Profiles
10189 | Id: 4452
10190 | Molecular Profile Score: 0.0
10191 | Name:
10192 | BRAF V600E AND CDKN2A Deletion AND CDKN2B Deletion AND TET2 E796K AND
10193 | BAX L76R AND AXIN2 P455K
10194 |
10195 | #### Evidence Items
10196 | Description:
10197 | In this case study, a 28-year-old male with BRAF V600E-mutant anaplastic
10198 | ganglioglioma was started with vemurafenib at 960 mg twice daily in
10199 | March 2015 for tumour recurrence despite one surgical resection and
10200 | adjuvant radiation therapy. He had a partial response with a tumour
10201 | shrinkage up to 55% according to RANO (response assessment in neuro-
10202 | oncology) criteria that was observed after 4 cycles. However, the
10203 | response to vemurafenib only lasted for 14 cycles until May 2016 when
10204 | his brain MRI showed local recurrence. Whole-exome sequencing of matched
10205 | tumour and germline DNA and RNA sequencing was carried out and the BRAF
10206 | V600E mutation was confirmed, along with a focal homozygous deletion of
10207 | CDKN2A and CDKN2B at the 9p21 locus. No additional molecular alteration
10208 | in MAPK genes was found. Three other somatic variants were identified. A
10209 | TET2 (p.Glu796Lys) mutation was found in both tumours. Mutations of BAX
10210 | (p.Leu76Arg) and AXIN2 (p.Pro455Lys) were only detected in the recurrent
10211 | tumour. These 3 genetic variants were not previously reported in the
10212 | literature or in public databases, including ExAC, ClinVar, and COSMIC,
10213 | and were annotated as variants of unknown significance. The patient was
10214 | then started with combined vemurafenib at 960 mg twice daily and
10215 | cobimetinib at 60 mg daily, 21 days every 28 days in November 2016. A
10216 | complete response was observed after 3 months of combined treatment. At
10217 | the last follow-up, after 16 months of treatment, there is no evidence
10218 | of recurrence.
10219 | Evidence Direction: SUPPORTS
10220 | Evidence Level: C
10221 | Evidence Rating: 1
10222 | Evidence Type: PREDICTIVE
10223 | Flagged: False
10224 | Id: 11314
10225 | Name: EID11314
10226 | Significance: SENSITIVITYRESPONSE
10227 | Variant Origin: SOMATIC
10228 |
10229 | ##### Disease
10230 | Disease Url: https://www.disease-ontology.org/?id=DOID:5078
10231 | Display Name: Ganglioglioma
10232 | Doid: 5078
10233 | Id: 2604
10234 | Link: /diseases/2604
10235 | Name: Ganglioglioma
10236 |
10237 | ##### My Disease Info
10238 | Do Def: A cell type benign neoplasm that has_material_basis_in glial-type cells.
10239 | Icdo: 9505/1
10240 | Mesh: D018303
10241 | Mondo Id: MONDO:0016733
10242 | Ncit: C27362, C27363, C3788
10243 | Disease Aliases:
10244 | - Adult Ganglioglioma
10245 | - CNS Ganglioglioma
10246 | - Childhood Ganglioglioma
10247 |
10248 | ##### Molecular Profile
10249 | Id: 4452
10250 |
10251 | ##### Source
10252 | Author String:
10253 | Mehdi Touat, Julie Gratieux, Stephanie Condette Auliac, Karine Sejean,
10254 | Sorin Aldea, Julien Savatovsky, Géraldine Perkins, Hélène Blons, Keith L
10255 | Ligon, Ahmed Idbaih, Antoine Hollebecque, Anne-Paule Gimenez-Roqueplo,
10256 | Pierre Laurent-Puig, Marc Sanson, Chiara Villa, Anna Luisa Di Stefano
10257 | Citation: Touat et al., 2018
10258 | Citation Id: 30120137
10259 | Id: 4653
10260 | Journal: Neurology
10261 | Link: /sources/4653
10262 | Name: PubMed: Touat et al., 2018
10263 | Open Access: True
10264 | Pmc Id: PMC9694795
10265 | Publication Date: 2018-9-11
10266 | Retracted: False
10267 | Source Type: PUBMED
10268 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/30120137
10269 | Title:
10270 | Vemurafenib and cobimetinib overcome resistance to vemurafenib in BRAF-
10271 | mutant ganglioglioma.
10272 |
10273 | ##### Therapies
10274 | Deprecated: False
10275 | Id: 4
10276 | Link: /therapies/4
10277 | Name: Vemurafenib
10278 |
10279 | ##### Therapies
10280 | Deprecated: False
10281 | Id: 342
10282 | Link: /therapies/342
10283 | Name: Cobimetinib
10284 |
10285 | #### Variants
10286 | Id: 4314
10287 | Link: /variants/4314
10288 | Name: Deletion
10289 |
10290 | #### Variants
10291 | Id: 4476
10292 | Link: /variants/4476
10293 | Name: E796K
10294 |
10295 | #### Variants
10296 | Id: 4477
10297 | Link: /variants/4477
10298 | Name: L76R
10299 |
10300 | #### Variants
10301 | Id: 4478
10302 | Link: /variants/4478
10303 | Name: P455K
10304 |
10305 | #### Variants
10306 | Id: 12
10307 | Link: /variants/12
10308 | Name: V600E
10309 |
10310 | #### Variants
10311 | Id: 2654
10312 | Link: /variants/2654
10313 | Name: Deletion
10314 |
10315 | ### Molecular Profiles
10316 | Id: 4453
10317 | Molecular Profile Score: 0.0
10318 | Name: BRAF V600E OR KIAA1549::BRAF Fusion
10319 |
10320 | #### Evidence Items
10321 | Description:
10322 | In this phase II trial on patients with pediatric low-grade glioma were
10323 | assigned to six unique strata according to histology, tumour location,
10324 | NF1 status, and BRAF aberration status. This study reports the results
10325 | of strata 1 and 3. Stratum 1 comprised patients with WHO grade I
10326 | pilocytic astrocytoma harbouring either one of the two most common BRAF
10327 | aberrations (KIAA1549–BRAF fusion or the BRAF V600E mutation. Stratum 3
10328 | comprised patients with any neurofibromatosis type 1 (NF1)-associated
10329 | pediatric low-grade glioma (WHO grades I and II). Selumetinib was dosed
10330 | at 25 mg/m2 twice daily in 28-day courses for up to 26 courses. In
10331 | stratum 1, nine of 25 patients achieved a sustained partial response
10332 | (95% CI: 18 – 57). The median follow-up for the 11 patients who had not
10333 | had a progression event by Aug 9, 2018, was 36.40 months (IQR 21.72 –
10334 | 45.59). The 2-year progression-free survival was 70% (95% CI: 47 – 85).
10335 | In stratum 3, ten of 25 patients achieved a sustained partial response
10336 | (95% CI: 21 – 61). The median follow-up was 48.60 months (IQR 39.14 –
10337 | 51.31) for the 17 patients without a progression event by Aug 9, 2018.
10338 | The 2-year progression-free survival was 96% (95% CI: 74 - 99).
10339 | Evidence Direction: SUPPORTS
10340 | Evidence Level: B
10341 | Evidence Rating: 3
10342 | Evidence Type: PREDICTIVE
10343 | Flagged: False
10344 | Id: 11316
10345 | Name: EID11316
10346 | Significance: SENSITIVITYRESPONSE
10347 | Variant Origin: SOMATIC
10348 |
10349 | ##### Disease
10350 | Disease Url: https://www.disease-ontology.org/?id=DOID:4851
10351 | Display Name: Pilocytic Astrocytoma
10352 | Doid: 4851
10353 | Id: 166
10354 | Link: /diseases/166
10355 | Name: Pilocytic Astrocytoma
10356 |
10357 | ##### My Disease Info
10358 | Do Def:
10359 | A childhood low-grade glioma that is characterized by cells that look
10360 | like fibers when viewed under a microscope and is located_in the brain.
10361 | Icdo: 9421/1
10362 | Mesh: D001254
10363 | Mondo Id: MONDO:0016691
10364 | Ncit: C4047
10365 | Disease Aliases: Grade I Astrocytic Tumor, Piloid Astrocytoma
10366 |
10367 | ##### Molecular Profile
10368 | Id: 4453
10369 |
10370 | ##### Source
10371 | Abstract:
10372 | Paediatric low-grade glioma is the most common CNS tumour of childhood.
10373 | Although overall survival is good, disease often recurs. No single
10374 | universally accepted treatment exists for these patients; however,
10375 | standard cytotoxic chemotherapies are generally used. We aimed to assess
10376 | the activity of selumetinib, a MEK1/2 inhibitor, in these patients.The
10377 | Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study
10378 | in patients with paediatric low-grade glioma in 11 hospitals in the USA.
10379 | Patients aged 3-21 years with a Lansky or Karnofsky performance score
10380 | greater than 60 and the presence of recurrent, refractory, or
10381 | progressive paediatric low-grade glioma after at least one standard
10382 | therapy were eligible for inclusion. Patients were assigned to six
10383 | unique strata according to histology, tumour location, NF1 status, and
10384 | BRAF aberration status; herein, we report the results of strata 1 and 3.
10385 | Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma
10386 | harbouring either one of the two most common BRAF aberrations
10387 | (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3
10388 | comprised patients with any neurofibromatosis type 1 (NF1)-associated
10389 | paediatric low-grade glioma (WHO grades I and II). Selumetinib was
10390 | provided as capsules given orally at the recommended phase 2 dose of 25
10391 | mg/m2 twice daily in 28-day courses for up to 26 courses. The primary
10392 | endpoint was the proportion of patients with a stratum-specific
10393 | objective response (partial response or complete response), as assessed
10394 | by the local site and sustained for at least 8 weeks. All responses were
10395 | reviewed centrally. All eligible patients who initiated treatment were
10396 | evaluable for the activity and toxicity analyses. Although the trial is
10397 | ongoing in other strata, enrolment and planned follow-up is complete for
10398 | strata 1 and 3. This trial is registered with ClinicalTrials.gov, number
10399 | NCT01089101.Between July 25, 2013, and June 12, 2015, 25 eligible and
10400 | evaluable patients were accrued to stratum 1, and between Aug 28, 2013,
10401 | and June 25, 2015, 25 eligible and evaluable patients were accrued to
10402 | stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients
10403 | achieved a sustained partial response. The median follow-up for the 11
10404 | patients who had not had a progression event by Aug 9, 2018, was 36·40
10405 | months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients
10406 | achieved a sustained partial response; median follow-up was 48·60 months
10407 | (IQR 39·14-51·31) for the 17 patients without a progression event by Aug
10408 | 9, 2018. The most frequent grade 3 or worse adverse events were elevated
10409 | creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]).
10410 | No treatment-realted deaths were reported.Selumetinib is active in
10411 | recurrent, refractory, or progressive pilocytic astrocytoma harbouring
10412 | common BRAF aberrations and NF1-associated paediatric low-grade glioma.
10413 | These results show that selumetinib could be an alternative to standard
10414 | chemotherapy for these subgroups of patients, and have directly led to
10415 | the development of two Children's Oncology Group phase 3 studies
10416 | comparing standard chemotherapy to selumetinib in patients with newly
10417 | diagnosed paediatric low-grade glioma both with and without NF1.National
10418 | Cancer Institute Cancer Therapy Evaluation Program, the American
10419 | Lebanese Syrian Associated Charities, and AstraZeneca.
10420 | Author String:
10421 | Jason Fangusaro, Arzu Onar-Thomas, Tina Young Poussaint, Shengjie Wu,
10422 | Azra H Ligon, Neal Lindeman, Anuradha Banerjee, Roger J Packer, Lindsay
10423 | B Kilburn, Stewart Goldman, Ian F Pollack, Ibrahim Qaddoumi, Regina I
10424 | Jakacki, Paul G Fisher, Girish Dhall, Patricia Baxter, Susan G
10425 | Kreissman, Clinton F Stewart, David T W Jones, Stefan M Pfister, Gilbert
10426 | Vezina, Jessica S Stern, Ashok Panigrahy, Zoltan Patay, Benita Tamrazi,
10427 | Jeremy Y Jones, Sofia S Haque, David S Enterline, Soonmee Cha, Michael J
10428 | Fisher, Laurence Austin Doyle, Malcolm Smith, Ira J Dunkel, Maryam
10429 | Fouladi
10430 | Citation: Fangusaro et al., 2019
10431 | Citation Id: 31151904
10432 | Id: 2973
10433 | Journal: Lancet Oncol
10434 | Link: /sources/2973
10435 | Name: PubMed: Fangusaro et al., 2019
10436 | Open Access: True
10437 | Pmc Id: PMC6628202
10438 | Publication Date: 2019-7
10439 | Retracted: False
10440 | Source Type: PUBMED
10441 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/31151904
10442 | Title:
10443 | Selumetinib in paediatric patients with BRAF-aberrant or
10444 | neurofibromatosis type 1-associated recurrent, refractory, or
10445 | progressive low-grade glioma: a multicentre, phase 2 trial.
10446 |
10447 | ##### Therapies
10448 | Deprecated: False
10449 | Id: 63
10450 | Link: /therapies/63
10451 | Name: Selumetinib
10452 |
10453 | #### Evidence Items
10454 | Description:
10455 | In this ongoing phase 2 trial (FIREFLY-1), 76 patients, aged 6 months to
10456 | 25 years, with pediatric low-grade glioma harbouring BRAF alterations
10457 | (BRAF fusions or BRAF V600E mutations) were treated with tovorafenib
10458 | (DAY-101). The overall response rate according to the RAPNO-LGG criteria
10459 | was 51% (95% CI; 40-63) and the median PFS and DOR were 13.8 months (95%
10460 | CI; 8.3-16.9) and 13.8 months (95% CI; 11.3 - NR) respectively. All
10461 | patients experienced at least one adverse event which may be treatment-
10462 | emergent, and 63% of the patients experienced Grade ≥3 adverse events.
10463 | Evidence Direction: SUPPORTS
10464 | Evidence Level: A
10465 | Evidence Rating: 5
10466 | Evidence Type: PREDICTIVE
10467 | Flagged: False
10468 | Id: 12016
10469 | Name: EID12016
10470 | Significance: SENSITIVITYRESPONSE
10471 | Variant Origin: SOMATIC
10472 |
10473 | ##### Disease
10474 | Disease Url: https://www.disease-ontology.org/?id=DOID:0080830
10475 | Display Name: Childhood Low-grade Glioma
10476 | Doid: 0080830
10477 | Id: 3048
10478 | Link: /diseases/3048
10479 | Name: Childhood Low-grade Glioma
10480 |
10481 | ##### My Disease Info
10482 | Do Def:
10483 | A low-grade glioma that occurs in children and encompasses tumors of
10484 | astrocytic, oligodendroglial, and mixed glial-neuronal histology.
10485 | Mondo Id: MONDO:0859591
10486 | Disease Aliases: Pediatric Low-grade Glioma
10487 |
10488 | ##### Molecular Profile
10489 | Id: 4453
10490 |
10491 | ##### Source
10492 | Abstract:
10493 | BRAF genomic alterations are the most common oncogenic drivers in
10494 | pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2
10495 | FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral,
10496 | selective, central nervous system-penetrant, type II RAF inhibitor
10497 | tovorafenib (420 mg m-2 once weekly; 600 mg maximum) in patients with
10498 | BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension
10499 | cohort, which provided treatment access for patients with RAF-altered
10500 | pLGG after arm 1 closure. Based on independent review, according to
10501 | Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG)
10502 | criteria, the overall response rate (ORR) of 67% met the arm 1
10503 | prespecified primary endpoint; median duration of response (DOR) was
10504 | 16.6 months; and median time to response (TTR) was 3.0 months (secondary
10505 | endpoints). Other select arm 1 secondary endpoints included ORR, DOR and
10506 | TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-
10507 | Grade Glioma (RAPNO) criteria and safety (assessed in all treated
10508 | patients and the primary endpoint for arm 2, n = 137). The ORR according
10509 | to RAPNO criteria (including minor responses) was 51%; median DOR was
10510 | 13.8 months; and median TTR was 5.3 months. The most common treatment-
10511 | related adverse events (TRAEs) were hair color changes (76%), elevated
10512 | creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred
10513 | in 42% of patients. Nine (7%) patients had TRAEs leading to
10514 | discontinuation of tovorafenib. These data indicate that tovorafenib
10515 | could be an effective therapy for BRAF-altered, relapsed/refractory
10516 | pLGG. ClinicalTrials.gov registration: NCT04775485 .
10517 | Author String:
10518 | Lindsay B Kilburn, Dong-Anh Khuong-Quang, Jordan R Hansford, Daniel
10519 | Landi, Jasper van der Lugt, Sarah E S Leary, Pablo Hernáiz Driever,
10520 | Simon Bailey, Sébastien Perreault, Geoffrey McCowage, Angela J Waanders,
10521 | David S Ziegler, Olaf Witt, Patricia A Baxter, Hyoung Jin Kang, Timothy
10522 | E Hassall, Jung Woo Han, Darren Hargrave, Andrea T Franson, Michal Yalon
10523 | Oren, Helen Toledano, Valérie Larouche, Cassie Kline, Mohamed S
10524 | Abdelbaki, Nada Jabado, Nicholas G Gottardo, Nicolas U Gerber, Nicholas
10525 | S Whipple, Devorah Segal, Susan N Chi, Liat Oren, Enrica E K Tan, Sabine
10526 | Mueller, Izzy Cornelio, Lisa McLeod, Xin Zhao, Ashley Walter, Daniel Da
10527 | Costa, Peter Manley, Samuel C Blackman, Roger J Packer, Karsten Nysom
10528 | Citation: Kilburn et al., 2024
10529 | Citation Id: 37978284
10530 | Id: 4991
10531 | Journal: Nat Med
10532 | Link: /sources/4991
10533 | Name: PubMed: Kilburn et al., 2024
10534 | Open Access: True
10535 | Pmc Id: PMC10803270
10536 | Publication Date: 2024-1
10537 | Retracted: False
10538 | Source Type: PUBMED
10539 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/37978284
10540 | Title:
10541 | The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric
10542 | low-grade glioma: the phase 2 FIREFLY-1 trial.
10543 |
10544 | ##### Therapies
10545 | Deprecated: False
10546 | Id: 1071
10547 | Link: /therapies/1071
10548 | Name: Tovorafenib
10549 |
10550 | #### Variants
10551 | Id: 618
10552 | Link: /variants/618
10553 | Name: Fusion
10554 |
10555 | #### Variants
10556 | Id: 12
10557 | Link: /variants/12
10558 | Name: V600E
10559 |
10560 | ### Molecular Profiles
10561 | Id: 4707
10562 | Molecular Profile Score: 15.0
10563 | Name: BRAF V600E OR BRAF K601E
10564 |
10565 | #### Evidence Items
10566 | Description:
10567 | This clinical study was conducted with 30 patients with colorectal
10568 | cancer harboring BRAF V600E (n = 29) or BRAF K601E (n=1) mutations,
10569 | treated with a combination of cobimetinib and vemurafenib. Of the 30
10570 | patients, only 27 were evaluable. An OR rate of 30% (95% CI; 14-50), and
10571 | DC rate of 52% (95% CI; 35-65) was noted. Eight patients had a partial
10572 | response with a median duration of 8.1 weeks (5.1-32.3 weeks) and six
10573 | patients had SD16+ with a median duration of 29.1 weeks (28.1-44.0
10574 | weeks). The reported PFS was 15.7 weeks (95% CI; 12.1-18.1) and OS was
10575 | 38.9 weeks (95% CI; 26.1-49.4). In 43% of the cohort, grade 3 AEs or
10576 | SAEs were observed, likely associated with the treatment.
10577 | Evidence Direction: SUPPORTS
10578 | Evidence Level: B
10579 | Evidence Rating: 3
10580 | Evidence Type: PREDICTIVE
10581 | Flagged: False
10582 | Id: 11670
10583 | Name: EID11670
10584 | Significance: SENSITIVITYRESPONSE
10585 | Variant Origin: SOMATIC
10586 |
10587 | ##### Disease
10588 | Disease Url: https://www.disease-ontology.org/?id=DOID:9256
10589 | Display Name: Colorectal Cancer
10590 | Doid: 9256
10591 | Id: 11
10592 | Link: /diseases/11
10593 | Name: Colorectal Cancer
10594 |
10595 | ##### My Disease Info
10596 | Do Def:
10597 | An intestinal cancer that effects the long, tube-like organ that is
10598 | connected to the small intestine at one end and the anus at the other.
10599 | Icd10: C18.9
10600 | Mondo Id: MONDO:0005575
10601 | Ncit: C4978
10602 |
10603 | ##### Molecular Profile
10604 | Id: 4707
10605 |
10606 | ##### Source
10607 | Abstract:
10608 | TAPUR is a phase II basket trial evaluating the antitumor activity of
10609 | commercially available targeted agents in patients with advanced cancer
10610 | and genomic alterations known to be drug targets. The results of a
10611 | cohort of patients with colorectal cancer (CRC) with BRAF mutations
10612 | treated with cobimetinib (C) plus vemurafenib (V) are reported.Eligible
10613 | patients had advanced CRC, no standard treatment options, measurable
10614 | disease (RECIST), Eastern Cooperative Oncology Group performance status
10615 | 0-2, adequate organ function, tumors with BRAF V600E/D/K/R mutations,
10616 | and no MAP2K1/2, MEK1/2, or NRAS mutations. C was taken 60 mg orally
10617 | once daily for 21 days followed by seven days off, and V was taken 960
10618 | mg orally twice daily. Simon's two-stage design was used with a primary
10619 | study end point of objective response or stable disease of at least 16
10620 | weeks duration. Secondary end points were progression-free survival,
10621 | overall survival, and safety.Thirty patients were enrolled from August
10622 | 2016 to August 2018; all had CRC with a BRAF V600E mutation except one
10623 | patient with a BRAF K601E mutation. Three patients were not evaluable
10624 | for efficacy. Eight patients with partial responses and six patients
10625 | with stable disease of at least 16 weeks duration were observed for
10626 | disease control and objective response rates of 52% (95% CI, 35 to 65)
10627 | and 30% (95% CI, 14 to 50), respectively. The null hypothesis of 15%
10628 | disease control rate was rejected (P < .0001). Thirteen patients had at
10629 | least one grade 3 adverse event or serious adverse event at least
10630 | possibly related to C + V: anemia, decreased lymphocytes, dyspnea,
10631 | diarrhea, elevated liver enzymes, fatigue, hypercalcemia,
10632 | hypophosphatemia, rash, photosensitivity, and upper gastrointestinal
10633 | hemorrhage.The combination of C + V has antitumor activity in heavily
10634 | pretreated patients with CRC with BRAF mutations.
10635 | Author String:
10636 | Kelsey A Klute, Michael Rothe, Elizabeth Garrett-Mayer, Pam K Mangat,
10637 | Reza Nazemzadeh, Kathleen J Yost, Herbert L Duvivier, Eugene R Ahn,
10638 | Timothy L Cannon, Olatunji B Alese, John C Krauss, Ramya Thota, Carmen J
10639 | Calfa, Crystal S Denlinger, Raegan O'Lone, Susan Halabi, Gina N
10640 | Grantham, Richard L Schilsky
10641 | Citation: Klute et al., 2022
10642 | Citation Id: 36409971
10643 | Id: 4832
10644 | Journal: JCO Precis Oncol
10645 | Link: /sources/4832
10646 | Name: PubMed: Klute et al., 2022
10647 | Open Access: False
10648 | Publication Date: 2022-11
10649 | Retracted: False
10650 | Source Type: PUBMED
10651 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/36409971
10652 | Title:
10653 | Cobimetinib Plus Vemurafenib in Patients With Colorectal Cancer With
10654 | BRAF Mutations: Results From the Targeted Agent and Profiling
10655 | Utilization Registry (TAPUR) Study.
10656 |
10657 | ##### Therapies
10658 | Deprecated: False
10659 | Id: 342
10660 | Link: /therapies/342
10661 | Name: Cobimetinib
10662 |
10663 | ##### Therapies
10664 | Deprecated: False
10665 | Id: 4
10666 | Link: /therapies/4
10667 | Name: Vemurafenib
10668 |
10669 | #### Variants
10670 | Id: 12
10671 | Link: /variants/12
10672 | Name: V600E
10673 |
10674 | #### Variants
10675 | Id: 584
10676 | Link: /variants/584
10677 | Name: K601E
10678 |
10679 | ### Molecular Profiles
10680 | Id: 4715
10681 | Molecular Profile Score: 0.0
10682 | Name:
10683 | BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1
10684 | Mutation
10685 |
10686 | #### Evidence Items
10687 | Description:
10688 | In this phase II study of the arm E of the NCI-COG pediatric MATCH
10689 | trial, 20 patients (median age: 14) were treated with Selumetinib. High-
10690 | grade glioma (n=7) and rhabdomyosarcoma (n=7) were the most common types
10691 | of cancers in this cohort. There was no objective response (PR or CR),
10692 | the best overall response being SD, in three patients. The 6-month PFS
10693 | rate was 15% (95% CI; 4-34). 25% of the patients had grade 3 or higher
10694 | AEs, possibly attributed to selumetinib treatment.
10695 | Evidence Direction: DOES_NOT_SUPPORT
10696 | Evidence Level: B
10697 | Evidence Rating: 3
10698 | Evidence Type: PREDICTIVE
10699 | Flagged: False
10700 | Id: 11681
10701 | Name: EID11681
10702 | Significance: SENSITIVITYRESPONSE
10703 | Variant Origin: SOMATIC
10704 |
10705 | ##### Disease
10706 | Disease Url: https://www.disease-ontology.org/?id=DOID:162
10707 | Display Name: Cancer
10708 | Doid: 162
10709 | Id: 216
10710 | Link: /diseases/216
10711 | Name: Cancer
10712 |
10713 | ##### My Disease Info
10714 | Do Def: A cancer that is classified based on the organ it starts in.
10715 | Mesh: D009371
10716 | Mondo Id: MONDO:0004992
10717 | Disease Aliases: Malignant Neoplasm, Malignant Tumor, Primary Cancer
10718 |
10719 | ##### Molecular Profile
10720 | Id: 4715
10721 |
10722 | ##### Source
10723 | Abstract:
10724 | The NCI-COG Pediatric MATCH trial assigns patients age 1-21 years with
10725 | relapsed or refractory solid tumors, lymphomas, and histiocytic
10726 | disorders to phase II studies of molecularly targeted therapies on the
10727 | basis of detection of predefined genetic alterations. Patients with
10728 | tumors harboring mutations or fusions driving activation of the mitogen-
10729 | activated protein kinase (MAPK) pathway were treated with the MEK
10730 | inhibitor selumetinib.Patients received selumetinib twice daily for
10731 | 28-day cycles until disease progression or intolerable toxicity. The
10732 | primary end point was objective response rate; secondary end points
10733 | included progression-free survival and tolerability of
10734 | selumetinib.Twenty patients (median age: 14 years) were treated. All
10735 | were evaluable for response and toxicities. The most frequent diagnoses
10736 | were high-grade glioma (HGG; n = 7) and rhabdomyosarcoma (n = 7).
10737 | Twenty-one actionable mutations were detected: hotspot mutations in KRAS
10738 | (n = 8), NRAS (n = 3), and HRAS (n = 1), inactivating mutations in NF1
10739 | (n = 7), and BRAF V600E (n = 2). No objective responses were observed.
10740 | Three patients had a best response of stable disease including two
10741 | patients with HGG (NF1 mutation, six cycles; KRAS mutation, 12 cycles).
10742 | Six-month progression-free survival was 15% (95% CI, 4 to 34). Five
10743 | patients (25%) experienced a grade 3 or higher adverse event that was
10744 | possibly or probably attributable to study drug.A national histology-
10745 | agnostic molecular screening strategy was effective at identifying
10746 | children and young adults eligible for treatment with selumetinib in the
10747 | first Pediatric MATCH treatment arm to be completed. MEK inhibitors have
10748 | demonstrated promising responses in some pediatric tumors (eg, low-grade
10749 | glioma and plexiform neurofibroma). However, selumetinib in this cohort
10750 | with treatment-refractory tumors harboring MAPK alterations demonstrated
10751 | limited efficacy, indicating that pathway mutation status alone is
10752 | insufficient to predict response to selumetinib monotherapy for
10753 | pediatric cancers.
10754 | Author String:
10755 | Olive S Eckstein, Carl E Allen, P Mickey Williams, Sinchita Roy-
10756 | Chowdhuri, David R Patton, Brent Coffey, Joel M Reid, Jin Piao, Lauren
10757 | Saguilig, Todd A Alonzo, Stacey L Berg, Nilsa C Ramirez, Alok Jaju,
10758 | Joyce Mhlanga, Elizabeth Fox, Douglas S Hawkins, Margaret M Mooney,
10759 | Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, D
10760 | Williams Parsons
10761 | Citation: Eckstein et al., 2022
10762 | Citation Id: 35363510
10763 | Id: 4841
10764 | Journal: J Clin Oncol
10765 | Link: /sources/4841
10766 | Name: PubMed: Eckstein et al., 2022
10767 | Open Access: True
10768 | Pmc Id: PMC9273373
10769 | Publication Date: 2022-7-10
10770 | Retracted: False
10771 | Source Type: PUBMED
10772 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/35363510
10773 | Title:
10774 | Phase II Study of Selumetinib in Children and Young Adults With Tumors
10775 | Harboring Activating Mitogen-Activated Protein Kinase Pathway Genetic
10776 | Alterations: Arm E of the NCI-COG Pediatric MATCH Trial.
10777 |
10778 | ##### Therapies
10779 | Deprecated: False
10780 | Id: 63
10781 | Link: /therapies/63
10782 | Name: Selumetinib
10783 |
10784 | #### Variants
10785 | Id: 275
10786 | Link: /variants/275
10787 | Name: Mutation
10788 |
10789 | #### Variants
10790 | Id: 12
10791 | Link: /variants/12
10792 | Name: V600E
10793 |
10794 | #### Variants
10795 | Id: 587
10796 | Link: /variants/587
10797 | Name: Mutation
10798 |
10799 | #### Variants
10800 | Id: 336
10801 | Link: /variants/336
10802 | Name: Mutation
10803 |
10804 | #### Variants
10805 | Id: 208
10806 | Link: /variants/208
10807 | Name: Mutation
10808 |
10809 | ### Molecular Profiles
10810 | Id: 4748
10811 | Molecular Profile Score: 0.0
10812 | Name:
10813 | BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1
10814 | Inactivating Mutation
10815 |
10816 | #### Evidence Items
10817 | Description:
10818 | In this Phase II study, 20 patients harboring activating RAS gene
10819 | mutations (KRAS = 8, NRAS = 3. HRAS = 1), BRAF V600E mutations, and NF1
10820 | inactivating mutations (n=7) were treated with Selumetinib. No objected
10821 | response was reported in these patients, and the six-month PFS was 15%
10822 | (95% CI; 4-34). 25% (n=5) of the patients experienced a grade 3 or
10823 | higher adverse effects, likely associated with selumetinib. Overall,
10824 | selumetinib had limited efficacy in this cohort.
10825 | Evidence Direction: DOES_NOT_SUPPORT
10826 | Evidence Level: B
10827 | Evidence Rating: 3
10828 | Evidence Type: PREDICTIVE
10829 | Flagged: False
10830 | Id: 11696
10831 | Name: EID11696
10832 | Significance: SENSITIVITYRESPONSE
10833 | Variant Origin: SOMATIC
10834 |
10835 | ##### Disease
10836 | Disease Url: https://www.disease-ontology.org/?id=DOID:162
10837 | Display Name: Cancer
10838 | Doid: 162
10839 | Id: 216
10840 | Link: /diseases/216
10841 | Name: Cancer
10842 |
10843 | ##### My Disease Info
10844 | Do Def: A cancer that is classified based on the organ it starts in.
10845 | Mesh: D009371
10846 | Mondo Id: MONDO:0004992
10847 | Disease Aliases: Malignant Neoplasm, Malignant Tumor, Primary Cancer
10848 |
10849 | ##### Molecular Profile
10850 | Id: 4748
10851 |
10852 | ##### Source
10853 | Abstract:
10854 | The NCI-COG Pediatric MATCH trial assigns patients age 1-21 years with
10855 | relapsed or refractory solid tumors, lymphomas, and histiocytic
10856 | disorders to phase II studies of molecularly targeted therapies on the
10857 | basis of detection of predefined genetic alterations. Patients with
10858 | tumors harboring mutations or fusions driving activation of the mitogen-
10859 | activated protein kinase (MAPK) pathway were treated with the MEK
10860 | inhibitor selumetinib.Patients received selumetinib twice daily for
10861 | 28-day cycles until disease progression or intolerable toxicity. The
10862 | primary end point was objective response rate; secondary end points
10863 | included progression-free survival and tolerability of
10864 | selumetinib.Twenty patients (median age: 14 years) were treated. All
10865 | were evaluable for response and toxicities. The most frequent diagnoses
10866 | were high-grade glioma (HGG; n = 7) and rhabdomyosarcoma (n = 7).
10867 | Twenty-one actionable mutations were detected: hotspot mutations in KRAS
10868 | (n = 8), NRAS (n = 3), and HRAS (n = 1), inactivating mutations in NF1
10869 | (n = 7), and BRAF V600E (n = 2). No objective responses were observed.
10870 | Three patients had a best response of stable disease including two
10871 | patients with HGG (NF1 mutation, six cycles; KRAS mutation, 12 cycles).
10872 | Six-month progression-free survival was 15% (95% CI, 4 to 34). Five
10873 | patients (25%) experienced a grade 3 or higher adverse event that was
10874 | possibly or probably attributable to study drug.A national histology-
10875 | agnostic molecular screening strategy was effective at identifying
10876 | children and young adults eligible for treatment with selumetinib in the
10877 | first Pediatric MATCH treatment arm to be completed. MEK inhibitors have
10878 | demonstrated promising responses in some pediatric tumors (eg, low-grade
10879 | glioma and plexiform neurofibroma). However, selumetinib in this cohort
10880 | with treatment-refractory tumors harboring MAPK alterations demonstrated
10881 | limited efficacy, indicating that pathway mutation status alone is
10882 | insufficient to predict response to selumetinib monotherapy for
10883 | pediatric cancers.
10884 | Author String:
10885 | Olive S Eckstein, Carl E Allen, P Mickey Williams, Sinchita Roy-
10886 | Chowdhuri, David R Patton, Brent Coffey, Joel M Reid, Jin Piao, Lauren
10887 | Saguilig, Todd A Alonzo, Stacey L Berg, Nilsa C Ramirez, Alok Jaju,
10888 | Joyce Mhlanga, Elizabeth Fox, Douglas S Hawkins, Margaret M Mooney,
10889 | Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, D
10890 | Williams Parsons
10891 | Citation: Eckstein et al., 2022
10892 | Citation Id: 35363510
10893 | Id: 4841
10894 | Journal: J Clin Oncol
10895 | Link: /sources/4841
10896 | Name: PubMed: Eckstein et al., 2022
10897 | Open Access: True
10898 | Pmc Id: PMC9273373
10899 | Publication Date: 2022-7-10
10900 | Retracted: False
10901 | Source Type: PUBMED
10902 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/35363510
10903 | Title:
10904 | Phase II Study of Selumetinib in Children and Young Adults With Tumors
10905 | Harboring Activating Mitogen-Activated Protein Kinase Pathway Genetic
10906 | Alterations: Arm E of the NCI-COG Pediatric MATCH Trial.
10907 |
10908 | ##### Therapies
10909 | Deprecated: False
10910 | Id: 63
10911 | Link: /therapies/63
10912 | Name: Selumetinib
10913 |
10914 | #### Variants
10915 | Id: 275
10916 | Link: /variants/275
10917 | Name: Mutation
10918 |
10919 | #### Variants
10920 | Id: 4643
10921 | Link: /variants/4643
10922 | Name: Inactivating Mutation
10923 |
10924 | #### Variants
10925 | Id: 12
10926 | Link: /variants/12
10927 | Name: V600E
10928 |
10929 | #### Variants
10930 | Id: 336
10931 | Link: /variants/336
10932 | Name: Mutation
10933 |
10934 | #### Variants
10935 | Id: 208
10936 | Link: /variants/208
10937 | Name: Mutation
10938 |
10939 | ### Molecular Profiles
10940 | Id: 4765
10941 | Molecular Profile Score: 0.0
10942 | Name: BRAF V600E AND ERBB2 Amplification AND SMAD4 LOSS AND TP53 V218E
10943 |
10944 | #### Evidence Items
10945 | Description:
10946 | In this clinical trial, 18 patients with pancreatic cancer were
10947 | recruited. In this case, the patient (74 y/F) with pancreatic cancer
10948 | harboring, BRAF V600E, SMAD4 Loss, ERBB2 amplification, and, TP53 V218E,
10949 | was treated with Trametinib, Trastuzumab, Lapatinib, and, Bevacizumab.
10950 | The trial reported a progression-free survival (PFS) of 7.8 months and
10951 | an overall survival (OS) of 9.4 months for this individual. The study
10952 | concluded that the patient derived clinical benefit, defined as stable
10953 | disease (SD) lasting at least 6 months, partial remission (PR), or
10954 | complete remission (CR).
10955 | Evidence Direction: SUPPORTS
10956 | Evidence Level: C
10957 | Evidence Rating: 3
10958 | Evidence Type: PREDICTIVE
10959 | Flagged: False
10960 | Id: 11712
10961 | Name: EID11712
10962 | Significance: SENSITIVITYRESPONSE
10963 | Variant Origin: SOMATIC
10964 |
10965 | ##### Disease
10966 | Disease Url: https://www.disease-ontology.org/?id=DOID:1793
10967 | Display Name: Pancreatic Cancer
10968 | Doid: 1793
10969 | Id: 556
10970 | Link: /diseases/556
10971 | Name: Pancreatic Cancer
10972 |
10973 | ##### My Disease Info
10974 | Do Def: An endocrine gland cancer located_in the pancreas.
10975 | Icd10: ["C25.0", "C25.1", "C25.2"]
10976 | Mesh: D010190
10977 | Mondo Id: MONDO:0009831
10978 | Ncit: C3305
10979 | Disease Aliases:
10980 | - Ca Body Of Pancreas
10981 | - Ca Head Of Pancreas
10982 | - Ca Tail Of Pancreas
10983 | - Malignant Neoplasm Of Body Of Pancreas
10984 | - Malignant Neoplasm Of Head Of Pancreas
10985 | - Malignant Neoplasm Of Tail Of Pancreas
10986 | - Pancreas Neoplasm
10987 | - Pancreatic Neoplasm
10988 | - Pancreatic Tumor
10989 |
10990 | ##### Molecular Profile
10991 | Id: 4765
10992 |
10993 | ##### Source
10994 | Abstract:
10995 | Despite progress, 2-year pancreatic cancer survival remains dismal. We
10996 | evaluated a biomarker-driven, combination/N-of-one strategy in 18
10997 | patients (advanced/metastatic pancreatic cancer) (from Molecular Tumor
10998 | Board). Targeted agents administered/patient = 2.5 (median) (range,
10999 | 1-4); first-line therapy (N = 5); second line, (N = 13). Comparing
11000 | patients (high versus low degrees of matching) (matching score ≥50%
11001 | versus <50%; reflecting number of alterations matched to targeted agents
11002 | divided by number of pathogenic alterations), survival was significantly
11003 | longer (hazard ratio [HR] 0.24 (95% confidence interval [CI],
11004 | 0.078-0.76, P = 0.016); clinical benefit rates (CBR) (stable disease ≥6
11005 | months/partial/complete response) trended higher (45.5 vs 0.0%, P =
11006 | 0.10); progression-free survival, HR, 95% CI, 0.36 (0.12-1.10) (p =
11007 | 0.075). First versus ≥2nd-line therapy had higher CBRs (80.0 vs 7.7%, P
11008 | = 0.008). No grade 3-4 toxicities occurred. The longest responder
11009 | achieved partial remission (17.5 months) by co-targeting MEK and CDK4/6
11010 | alterations (chemotherapy-free). Therefore, genomically matched targeted
11011 | agent combinations were active in these advanced pancreatic cancers.
11012 | Larger prospective trials are warranted.
11013 | Author String:
11014 | Justin Shaya, Shumei Kato, Jacob J Adashek, Hitendra Patel, Paul T
11015 | Fanta, Gregory P Botta, Jason K Sicklick, Razelle Kurzrock
11016 | Citation: Shaya et al., 2023
11017 | Citation Id: 36670111
11018 | Id: 4855
11019 | Journal: NPJ Genom Med
11020 | Link: /sources/4855
11021 | Name: PubMed: Shaya et al., 2023
11022 | Open Access: True
11023 | Pmc Id: PMC9860045
11024 | Publication Date: 2023-1-20
11025 | Retracted: False
11026 | Source Type: PUBMED
11027 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/36670111
11028 | Title:
11029 | Personalized matched targeted therapy in advanced pancreatic cancer: a
11030 | pilot cohort analysis.
11031 |
11032 | ##### Therapies
11033 | Deprecated: False
11034 | Id: 19
11035 | Link: /therapies/19
11036 | Name: Trametinib
11037 |
11038 | ##### Therapies
11039 | Deprecated: False
11040 | Id: 84
11041 | Link: /therapies/84
11042 | Name: Trastuzumab
11043 |
11044 | ##### Therapies
11045 | Deprecated: False
11046 | Id: 45
11047 | Link: /therapies/45
11048 | Name: Lapatinib
11049 |
11050 | ##### Therapies
11051 | Deprecated: False
11052 | Id: 33
11053 | Link: /therapies/33
11054 | Name: Bevacizumab
11055 |
11056 | #### Variants
11057 | Id: 306
11058 | Link: /variants/306
11059 | Name: Amplification
11060 |
11061 | #### Variants
11062 | Id: 4657
11063 | Link: /variants/4657
11064 | Name: V218E
11065 |
11066 | #### Variants
11067 | Id: 12
11068 | Link: /variants/12
11069 | Name: V600E
11070 |
11071 | #### Variants
11072 | Id: 564
11073 | Link: /variants/564
11074 | Name: LOSS
11075 |
11076 | ### Molecular Profiles
11077 | Id: 5175
11078 | Molecular Profile Score: 0.0
11079 | Name: BRAF V600E AND MSI Low
11080 |
11081 | #### Evidence Items
11082 | Description:
11083 | 5577 colon carcinoma tumors were evaluated for BRAF, KRAS, and mismatch
11084 | repair status. From those successfully evaluated, 201 had microsatellite
11085 | instability (MSI or MSI-H) and BRAF V600E, 72 had MSI and KRAS exon 2
11086 | mutation, and 204 had MSI and no KRAS or BRAF mutation. In addition, 279
11087 | were microsatellite stable (MSS or MSI-L) and BRAF V600E, 1450 had MSI
11088 | and KRAS exon 2 mutation, and 2205 had MSI and no KRAS or BRAF mutation.
11089 |
11090 | MSS patients with BRAF V600E were associated with shorter time to
11091 | recurrence (HR = 1.54, 95% CI = 1.23 to 1.92, P < .001).
11092 | Overall survival in MSS with BRAF V600E was poorer than wild-type (HR =
11093 | 2.01, 95% CI = 1.56 to 2.57, P < .001).
11094 |
11095 | This prognostic effect was not seen in BRAF or KRAS mutant patients that
11096 | had MSI tumors.
11097 | Evidence Direction: SUPPORTS
11098 | Evidence Level: B
11099 | Evidence Rating: 3
11100 | Evidence Type: PROGNOSTIC
11101 | Flagged: False
11102 | Id: 12072
11103 | Name: EID12072
11104 | Significance: POOR_OUTCOME
11105 | Variant Origin: SOMATIC
11106 |
11107 | ##### Disease
11108 | Disease Url: https://www.disease-ontology.org/?id=DOID:1520
11109 | Display Name: Colon Carcinoma
11110 | Doid: 1520
11111 | Id: 210
11112 | Link: /diseases/210
11113 | Name: Colon Carcinoma
11114 |
11115 | ##### My Disease Info
11116 | Do Def:
11117 | A colon cancer that has_material_basis_in abnormally proliferating cells
11118 | derives_from epithelial cells.
11119 | Mondo Id: MONDO:0002032
11120 | Ncit: C4910
11121 | Disease Aliases: Carcinoma Of Colon, Colonic Carcinoma
11122 |
11123 | ##### Molecular Profile
11124 | Id: 5175
11125 |
11126 | ##### Source
11127 | Abstract:
11128 | The prognostic value of BRAF and KRAS mutations within microsatellite-
11129 | unstable (MSI) and microsatellite-stable (MSS) subgroups of resected
11130 | colon carcinoma patients remains controversial. We examined this
11131 | question in prospectively collected biospecimens from stage III colon
11132 | cancer with separate analysis of MSI and MSS tumors from patients
11133 | receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy
11134 | trials.Three groups were defined: BRAF Mutant, KRAS Mutant, and double
11135 | wild-type. The analytic strategy involved estimation of study-specific
11136 | effects, assessment of homogeneity of results, and then analysis of
11137 | pooled data as no differences in patient outcome were found between
11138 | treatment arms in both trials. Associations of mutations with patient
11139 | outcome were analyzed, and multivariable models were adjusted for
11140 | treatment and relevant factors.Four thousand four hundred eleven tumors
11141 | were evaluable for BRAF and KRAS mutations and mismatch repair status;
11142 | 3934 were MSS and 477 were MSI. In MSS patients, all BRAF V600E
11143 | mutations (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.23
11144 | to 1.92, P < .001), KRAS codon 12 alterations, and p.G13D mutations (HR
11145 | = 1.60, 95% CI = 1.40 to 1.83, P < .001) were associated with shorter
11146 | time to recurrence (TTR) and shorter survival after relapse (SAR; HR =
11147 | 3.02 , 95% CI = 2.32 to 3.93, P < .001, and HR = 1.20, 95% CI = 1.01 to
11148 | 1.44, P = .04, respectively). Overall survival (OS) in MSS patients was
11149 | poorer for BRAF-mutant patients (HR = 2.01, 95% CI = 1.56 to 2.57, P <
11150 | .001) and KRAS-mutant patients (HR = 1.62, 95% CI = 1.38 to 1.91, P <
11151 | .001) vs wild-type. No prognostic role of KRAS or BRAF mutations was
11152 | seen in MSI patients. Furthermore, no interaction was found between
11153 | treatment arm (with or without cetuximab) and KRAS and BRAF mutations
11154 | for TTR or OS in MSS patients.In a pooled analysis of resected stage III
11155 | colon cancer patients receiving adjuvant FOLFOX, BRAF or KRAS mutations
11156 | are independently associated with shorter TTR, SAR, and OS in patients
11157 | with MSS, but not MSI, tumors. Future clinical trials in the adjuvant
11158 | setting should consider these mutations as important stratification
11159 | factors.
11160 | Author String:
11161 | Julien Taieb, Karine Le Malicot, Qian Shi, Frédérique Penault-Llorca,
11162 | Olivier Bouché, Josep Tabernero, Enrico Mini, Richard M Goldberg, Gunnar
11163 | Folprecht, Jean Luc Van Laethem, Daniel J Sargent, Steven R Alberts,
11164 | Jean Francois Emile, Pierre Laurent Puig, Frank A Sinicrope
11165 | Citation: Taieb et al., 2017
11166 | Citation Id: 28040692
11167 | Id: 5048
11168 | Journal: J Natl Cancer Inst
11169 | Link: /sources/5048
11170 | Name: PubMed: Taieb et al., 2017
11171 | Open Access: True
11172 | Pmc Id: PMC6075212
11173 | Publication Date: 2017-5
11174 | Retracted: False
11175 | Source Type: PUBMED
11176 | Source Url: http://www.ncbi.nlm.nih.gov/pubmed/28040692
11177 | Title:
11178 | Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III
11179 | Colon Cancer.
11180 |
11181 | #### Variants
11182 | Id: 12
11183 | Link: /variants/12
11184 | Name: V600E
11185 |
11186 | #### Variants
11187 | Id: 4985
11188 | Link: /variants/4985
11189 | Name: Low
11190 | Variant Aliases: RS113488022, VAL600GLU, V640E, VAL640GLU
11191 |
11192 | ## Clinvar
11193 | License: http://bit.ly/2SQdcI0
11194 | Allele Id: 29000
11195 | Alt: T
11196 | Chrom: 7
11197 | Cytogenic: 7q34
11198 | Omim: 164757.0001
11199 | Ref: A
11200 | Rsid: rs113488022
11201 | Type: single nucleotide variant
11202 | Variant Id: 13961
11203 |
11204 | ### Gene
11205 | Id: 673
11206 | Symbol: BRAF
11207 |
11208 | ### Hg19
11209 | End: 140453136
11210 | Start: 140453136
11211 |
11212 | ### Hg38
11213 | End: 140753336
11214 | Start: 140753336
11215 |
11216 | ### Hgvs
11217 | Coding:
11218 | - LRG_299t1:c.1799T>A
11219 | - NM_001354609.2:c.1799T>A
11220 | - NM_001374244.1:c.1919T>A
11221 | - NM_001374258.1:c.1919T>A
11222 | - NM_001378467.1:c.1808T>A
11223 | - NM_001378468.1:c.1799T>A
11224 | - NM_001378469.1:c.1733T>A
11225 | - NM_001378470.1:c.1697T>A
11226 | - NM_001378471.1:c.1688T>A
11227 | - NM_001378472.1:c.1643T>A
11228 | - NM_001378473.1:c.1643T>A
11229 | - NM_001378474.1:c.1799T>A
11230 | - NM_001378475.1:c.1535T>A
11231 | - NM_004333.6:c.1799T>A
11232 | Genomic:
11233 | - LRG_299:g.176429T>A
11234 | - NC_000007.12:g.140099605A>T
11235 | - NC_000007.13:g.140453136A>T
11236 | - NC_000007.14:g.140753336A>T
11237 | - NG_007873.3:g.176429T>A
11238 | Protein:
11239 | - LRG_299p1:p.Val600Glu
11240 | - NP_001341538.1:p.Val600Glu
11241 | - NP_001361173.1:p.Val640Glu
11242 | - NP_001361187.1:p.Val640Glu
11243 | - NP_001365396.1:p.Val603Glu
11244 | - NP_001365397.1:p.Val600Glu
11245 | - NP_001365398.1:p.Val578Glu
11246 | - NP_001365399.1:p.Val566Glu
11247 | - NP_001365400.1:p.Val563Glu
11248 | - NP_001365401.1:p.Val548Glu
11249 | - NP_001365402.1:p.Val548Glu
11250 | - NP_001365403.1:p.Val600Glu
11251 | - NP_001365404.1:p.Val512Glu
11252 | - NP_004324.2:p.Val600Glu
11253 | - P15056:p.Val600Glu
11254 | - p.V600E
11255 |
11256 | ### Rcv
11257 | Accession: RCV000014992
11258 | Clinical Significance: Pathogenic
11259 | Last Evaluated: 2014-09-04
11260 | Number Submitters: 1
11261 | Origin: somatic
11262 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11263 | Review Status: no assertion criteria provided
11264 |
11265 | #### Conditions
11266 | Name: Carcinoma of colon (CRC)
11267 |
11268 | ##### Identifiers
11269 | Medgen: C0699790
11270 | Mondo: MONDO:0002032
11271 | Synonyms: Colonic carcinoma, Colon carcinoma
11272 |
11273 | ### Rcv
11274 | Accession: RCV000014993
11275 | Clinical Significance: Pathogenic
11276 | Last Evaluated: 2014-09-04
11277 | Number Submitters: 2
11278 | Origin: somatic
11279 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11280 | Review Status: no assertion criteria provided
11281 |
11282 | #### Conditions
11283 | Name: Papillary thyroid carcinoma
11284 |
11285 | ##### Identifiers
11286 | Human Phenotype Ontology: HP:0002895
11287 | Medgen: C0238463
11288 | Mesh: D000077273
11289 | Mondo: MONDO:0005075
11290 | Orphanet: 146
11291 | Synonyms:
11292 | - NONMEDULLARY THYROID CARCINOMA, PAPILLARY
11293 | - Thyroid carcinoma, papillary, somatic
11294 | - Thyroid gland papillary carcinoma
11295 |
11296 | ### Rcv
11297 | Accession: RCV000014994
11298 | Clinical Significance: Pathogenic
11299 | Last Evaluated: 2014-09-04
11300 | Number Submitters: 1
11301 | Origin: somatic
11302 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11303 | Review Status: no assertion criteria provided
11304 |
11305 | #### Conditions
11306 | Name: Astrocytoma, low-grade, somatic
11307 |
11308 | ##### Identifiers
11309 | Medgen: C2674727
11310 |
11311 | ### Rcv
11312 | Accession: RCV000022677
11313 | Clinical Significance: Pathogenic
11314 | Last Evaluated: 2014-09-04
11315 | Number Submitters: 1
11316 | Origin: somatic
11317 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11318 | Review Status: no assertion criteria provided
11319 |
11320 | #### Conditions
11321 | Name: Nongerminomatous germ cell tumor
11322 |
11323 | ##### Identifiers
11324 | Medgen: C1266158
11325 | Mondo: MONDO:0021656
11326 | Synonyms:
11327 | - NONSEMINOMATOUS GERM CELL TUMORS, SOMATIC
11328 | - Germ cell tumor, nonseminomatous
11329 | - Non-seminomatous germ-cell tumors
11330 |
11331 | ### Rcv
11332 | Accession: RCV000037936
11333 | Clinical Significance: Pathogenic
11334 | Last Evaluated: 2009-05-29
11335 | Number Submitters: 2
11336 | Origin: somatic
11337 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11338 | Review Status: no assertion criteria provided
11339 |
11340 | #### Conditions
11341 | Name: Non-small cell lung carcinoma (NSCLC)
11342 |
11343 | ##### Identifiers
11344 | Human Phenotype Ontology: HP:0030358
11345 | Medgen: C0007131
11346 | Mesh: D002289
11347 | Mondo: MONDO:0005233
11348 | Synonyms: Non-small cell lung cancer
11349 |
11350 | ### Rcv
11351 | Accession: RCV000067669
11352 | Clinical Significance: Pathogenic
11353 | Last Evaluated: 2016-03-10
11354 | Number Submitters: 2
11355 | Origin: somatic
11356 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11357 | Review Status: no assertion criteria provided
11358 |
11359 | #### Conditions
11360 | Name: Melanoma
11361 |
11362 | ##### Identifiers
11363 | Human Phenotype Ontology: HP:0007474
11364 | Medgen: C0025202
11365 | Mesh: D008545
11366 | Mondo: MONDO:0005105
11367 |
11368 | ### Rcv
11369 | Accession: RCV000080903
11370 | Clinical Significance: Pathogenic
11371 | Last Evaluated: 2014-07-11
11372 | Number Submitters: 4
11373 | Origin: germline
11374 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11375 | Review Status: criteria provided, multiple submitters, no conflicts
11376 |
11377 | #### Conditions
11378 | Name: not provided
11379 |
11380 | ##### Identifiers
11381 | Medgen: C3661900
11382 | Synonyms: none provided
11383 |
11384 | ### Rcv
11385 | Accession: RCV000208763
11386 | Clinical Significance: not provided
11387 | Number Submitters: 1
11388 | Origin: somatic
11389 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11390 | Review Status: no assertion provided
11391 |
11392 | #### Conditions
11393 | Name: Cardio-facio-cutaneous syndrome
11394 |
11395 | ##### Identifiers
11396 | Medgen: C1275081
11397 | Mondo: MONDO:0015280
11398 | Omim: PS115150
11399 | Orphanet: 1340
11400 | Synonyms: Cardiofaciocutaneous syndrome, CFC syndrome
11401 |
11402 | ### Rcv
11403 | Accession: RCV000417746
11404 | Clinical Significance: Likely pathogenic
11405 | Last Evaluated: 2016-05-31
11406 | Number Submitters: 1
11407 | Origin: somatic
11408 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11409 | Review Status: no assertion criteria provided
11410 |
11411 | #### Conditions
11412 | Name: Malignant melanoma of skin (CMM)
11413 |
11414 | ##### Identifiers
11415 | Human Phenotype Ontology: HP:0012056
11416 | Medgen: C0151779
11417 | Mesh: C562393
11418 | Mondo: MONDO:0005012
11419 | Synonyms: Malignant melanoma, somatic, Cutaneous melanoma
11420 |
11421 | ### Rcv
11422 | Accession: RCV000420614
11423 | Clinical Significance: Likely pathogenic
11424 | Last Evaluated: 2015-07-14
11425 | Number Submitters: 1
11426 | Origin: somatic
11427 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11428 | Review Status: no assertion criteria provided
11429 |
11430 | #### Conditions
11431 | Name: Colonic neoplasm
11432 |
11433 | ##### Identifiers
11434 | Human Phenotype Ontology: HP:0100273
11435 | Medgen: C0009375
11436 | Mesh: D003110
11437 | Mondo: MONDO:0005401
11438 | Synonyms: Colonic Neoplasms, Neoplasm of the colon
11439 |
11440 | ### Rcv
11441 | Accession: RCV000424470
11442 | Clinical Significance: Likely pathogenic
11443 | Last Evaluated: 2016-05-31
11444 | Number Submitters: 1
11445 | Origin: somatic
11446 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11447 | Review Status: no assertion criteria provided
11448 |
11449 | #### Conditions
11450 | Name: Squamous cell carcinoma of the head and neck (HNSCC)
11451 |
11452 | ##### Identifiers
11453 | Medgen: C1168401
11454 | Mesh: D000077195
11455 | Mondo: MONDO:0010150
11456 | Omim: 275355
11457 | Orphanet: 67037
11458 | Synonyms:
11459 | - Head and neck squamous cell carcinoma
11460 | - Carcinoma, squamous cell of head and neck
11461 | - Squamous cell carcinoma, head and neck, somatic
11462 |
11463 | ### Rcv
11464 | Accession: RCV000425166
11465 | Clinical Significance: Likely pathogenic
11466 | Last Evaluated: 2016-05-31
11467 | Number Submitters: 1
11468 | Origin: somatic
11469 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11470 | Review Status: no assertion criteria provided
11471 |
11472 | #### Conditions
11473 | Name: Brainstem glioma
11474 |
11475 | ##### Identifiers
11476 | Human Phenotype Ontology: HP:0010796
11477 | Medgen: C0677865
11478 | Mondo: MONDO:0002911
11479 |
11480 | ### Rcv
11481 | Accession: RCV000425847
11482 | Clinical Significance: Likely pathogenic
11483 | Last Evaluated: 2016-05-31
11484 | Number Submitters: 1
11485 | Origin: somatic
11486 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11487 | Review Status: no assertion criteria provided
11488 |
11489 | #### Conditions
11490 | Name: Glioblastoma
11491 |
11492 | ##### Identifiers
11493 | Medgen: C0017636
11494 | Mesh: D005909
11495 | Mondo: MONDO:0018177
11496 | Synonyms:
11497 | - Giant cell glioblastoma (histologic variant)
11498 | - Gliosarcoma (histologic variant)
11499 |
11500 | ### Rcv
11501 | Accession: RCV000429915
11502 | Clinical Significance: Likely pathogenic
11503 | Last Evaluated: 2016-05-31
11504 | Number Submitters: 1
11505 | Origin: somatic
11506 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11507 | Review Status: no assertion criteria provided
11508 |
11509 | #### Conditions
11510 | Name: Lung adenocarcinoma
11511 |
11512 | ##### Identifiers
11513 | Human Phenotype Ontology: HP:0030078
11514 | Medgen: C0152013
11515 | Mesh: D000077192
11516 | Mondo: MONDO:0005061
11517 | Synonyms: Adenocarcinoma of lung, Adenocarcinoma of lung, somatic
11518 |
11519 | ### Rcv
11520 | Accession: RCV000430562
11521 | Clinical Significance: Likely pathogenic
11522 | Last Evaluated: 2019-08-31
11523 | Number Submitters: 2
11524 | Origin: somatic
11525 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11526 | Review Status: no assertion criteria provided
11527 |
11528 | #### Conditions
11529 | Name: Multiple myeloma (MM)
11530 |
11531 | ##### Identifiers
11532 | Human Phenotype Ontology: HP:0006775
11533 | Medgen: C0026764
11534 | Mesh: D009101
11535 | Mondo: MONDO:0009693
11536 | Omim: 254500
11537 | Orphanet: 85443
11538 | Synonyms:
11539 | - Plasma cell myeloma
11540 | - Kahler disease
11541 | - Myelomatosis
11542 | - Plasma cell dyscrasia
11543 | - Multiple myeloma, somatic
11544 |
11545 | ### Rcv
11546 | Accession: RCV000432628
11547 | Clinical Significance: Pathogenic
11548 | Last Evaluated: 2014-10-02
11549 | Number Submitters: 1
11550 | Origin: somatic
11551 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11552 | Review Status: no assertion criteria provided
11553 |
11554 | #### Conditions
11555 | Name: Ovarian neoplasm
11556 |
11557 | ##### Identifiers
11558 | Human Phenotype Ontology: HP:0100615
11559 | Medgen: C0919267
11560 | Mesh: D010051
11561 | Mondo: MONDO:0021068
11562 | Synonyms: Neoplasm of ovary, Ovarian tumor, Ovarian Neoplasms
11563 |
11564 | ### Rcv
11565 | Accession: RCV000433305
11566 | Clinical Significance: Pathogenic
11567 | Last Evaluated: 2014-10-02
11568 | Number Submitters: 1
11569 | Origin: somatic
11570 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11571 | Review Status: no assertion criteria provided
11572 |
11573 | #### Conditions
11574 | Name: Lung carcinoma
11575 |
11576 | ##### Identifiers
11577 | Medgen: C0684249
11578 | Mondo: MONDO:0005138
11579 |
11580 | ### Rcv
11581 | Accession: RCV000435441
11582 | Clinical Significance: Likely pathogenic
11583 | Last Evaluated: 2016-05-31
11584 | Number Submitters: 1
11585 | Origin: somatic
11586 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11587 | Review Status: no assertion criteria provided
11588 |
11589 | #### Conditions
11590 | Name: Neoplasm of brain
11591 |
11592 | ##### Identifiers
11593 | Human Phenotype Ontology: HP:0030692
11594 | Medgen: C0006118
11595 | Mesh: D001932
11596 | Mondo: MONDO:0021211
11597 | Synonyms: Brain tumour, Brain neoplasm, Brain Neoplasms
11598 |
11599 | ### Rcv
11600 | Accession: RCV000440540
11601 | Clinical Significance: Pathogenic
11602 | Last Evaluated: 2014-10-02
11603 | Number Submitters: 1
11604 | Origin: somatic
11605 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11606 | Review Status: no assertion criteria provided
11607 |
11608 | #### Conditions
11609 | Name: Gastrointestinal stromal tumor
11610 |
11611 | ##### Identifiers
11612 | Human Phenotype Ontology: HP:0100723
11613 | Medgen: C0238198
11614 | Mesh: D046152
11615 | Mondo: MONDO:0011719
11616 | Omim: 606764
11617 | Orphanet: 44890
11618 | Synonyms:
11619 | - Gastrointestinal Stromal Sarcoma
11620 | - Gastrointestinal stromal tumor, somatic
11621 | - Gastrointestinal stroma tumor
11622 |
11623 | ### Rcv
11624 | Accession: RCV000440802
11625 | Clinical Significance: Likely pathogenic
11626 | Last Evaluated: 2016-05-31
11627 | Number Submitters: 1
11628 | Origin: somatic
11629 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11630 | Review Status: no assertion criteria provided
11631 |
11632 | #### Conditions
11633 | Name: Papillary renal cell carcinoma, sporadic
11634 |
11635 | ##### Identifiers
11636 | Medgen: C1336078
11637 | Mesh: C538614
11638 |
11639 | ### Rcv
11640 | Accession: RCV000443448
11641 | Clinical Significance: Likely pathogenic
11642 | Last Evaluated: 2016-05-13
11643 | Number Submitters: 1
11644 | Origin: somatic
11645 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11646 | Review Status: no assertion criteria provided
11647 |
11648 | #### Conditions
11649 | Name: Neoplasm
11650 |
11651 | ##### Identifiers
11652 | Human Phenotype Ontology: HP:0006741
11653 | Medgen: C0027651
11654 | Mesh: D009369
11655 | Mondo: MONDO:0005070
11656 | Synonyms: Neoplasms, Neoplasm (disease)
11657 |
11658 | ### Rcv
11659 | Accession: RCV000443745
11660 | Clinical Significance: Pathogenic
11661 | Last Evaluated: 2016-05-31
11662 | Number Submitters: 1
11663 | Origin: somatic
11664 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11665 | Review Status: no assertion criteria provided
11666 |
11667 | #### Conditions
11668 | Name: Neoplasm of the large intestine
11669 |
11670 | ##### Identifiers
11671 | Human Phenotype Ontology: HP:0100834
11672 | Medgen: C0009404
11673 | Mesh: D015179
11674 | Mondo: MONDO:0005335
11675 | Synonyms: Colorectal Neoplasms, Colorectal neoplasm
11676 |
11677 | ### Rcv
11678 | Accession: RCV000662278
11679 | Clinical Significance: Pathogenic
11680 | Last Evaluated: 2015-05-07
11681 | Number Submitters: 2
11682 | Origin: somatic
11683 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11684 | Review Status: no assertion criteria provided
11685 |
11686 | #### Conditions
11687 | Name:
11688 | Cystic epithelial invagination containing papillae lined by columnar
11689 | epithelium
11690 |
11691 | ### Rcv
11692 | Accession: RCV000860020
11693 | Clinical Significance: Pathogenic
11694 | Number Submitters: 1
11695 | Origin: somatic
11696 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11697 | Review Status: no assertion criteria provided
11698 |
11699 | #### Conditions
11700 | Name: Cerebral arteriovenous malformation (BAVM)
11701 |
11702 | ##### Identifiers
11703 | Human Phenotype Ontology: HP:0002408
11704 | Medgen: C0917804
11705 | Mondo: MONDO:0007154
11706 | Omim: 108010
11707 | Orphanet: 46724
11708 | Synonyms:
11709 | - CEREBRAL ARTERIOVENOUS MALFORMATIONS
11710 | - Arteriovenous malformations of the brain
11711 |
11712 | ### Rcv
11713 | Accession: RCV001248834
11714 | Clinical Significance: Pathogenic
11715 | Last Evaluated: 2019-02-15
11716 | Number Submitters: 1
11717 | Origin: somatic
11718 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11719 | Review Status: no assertion criteria provided
11720 |
11721 | #### Conditions
11722 | Name: Nephroblastoma
11723 |
11724 | ##### Identifiers
11725 | Human Phenotype Ontology: HP:0000115
11726 | Medgen: C0027708
11727 | Mesh: D009396
11728 | Mondo: MONDO:0006058
11729 | Synonyms: Wilms tumor, Wilms' tumor
11730 |
11731 | ### Rcv
11732 | Accession: RCV001254874
11733 | Clinical Significance: Likely pathogenic
11734 | Number Submitters: 1
11735 | Origin: unknown
11736 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11737 | Review Status: no assertion criteria provided
11738 |
11739 | #### Conditions
11740 | Name: Malignant neoplastic disease
11741 |
11742 | ##### Identifiers
11743 | Medgen: C0006826
11744 | Mondo: MONDO:0004992
11745 | Synonyms: Cancer
11746 |
11747 | ### Rcv
11748 | Accession: RCV002051586
11749 | Clinical Significance: Pathogenic
11750 | Last Evaluated: 2022-02-09
11751 | Number Submitters: 1
11752 | Origin: somatic
11753 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11754 | Review Status: no assertion criteria provided
11755 |
11756 | #### Conditions
11757 | Name: Lymphangioma
11758 |
11759 | ##### Identifiers
11760 | Human Phenotype Ontology: HP:0100764
11761 | Medgen: C0024221
11762 | Mondo: MONDO:0002013
11763 |
11764 | ### Rcv
11765 | Accession: RCV003458334
11766 | Clinical Significance: Pathogenic
11767 | Last Evaluated: 2023-10-22
11768 | Number Submitters: 1
11769 | Origin: somatic
11770 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11771 | Review Status: criteria provided, single submitter
11772 |
11773 | #### Conditions
11774 | Name: Vascular malformation
11775 |
11776 | ##### Identifiers
11777 | Medgen: C0158570
11778 | Mondo: MONDO:0024291
11779 | Synonyms: Vascular malformations
11780 |
11781 | ### Rcv
11782 | Accession: RCV004018627
11783 | Clinical Significance: Likely pathogenic
11784 | Last Evaluated: 2022-05-23
11785 | Number Submitters: 1
11786 | Origin: germline
11787 | Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
11788 | Review Status: criteria provided, single submitter
11789 |
11790 | #### Conditions
11791 | Name: Cardiovascular phenotype
11792 |
11793 | ##### Identifiers
11794 | Medgen: CN230736
11795 |
11796 | ## Cosmic
11797 | License: http://bit.ly/2VMkY7R
11798 | Alt: A
11799 | Chrom: 7
11800 | Cosmic Id: COSM476
11801 | Mut Freq: 2.83
11802 | Mut Nt: T>A
11803 | Ref: T
11804 | Tumor Site: biliary_tract
11805 |
11806 | ### Hg19
11807 | End: 140453136
11808 | Start: 140453136
11809 |
11810 | ## Dbnsfp
11811 | License: http://bit.ly/2VLnQBz
11812 | Alt: T
11813 | Ancestral Allele: A
11814 | Chrom: 7
11815 | Ref: A
11816 | Reliability Index: 10
11817 | Rsid: rs113488022
11818 | Vep Canonical: YES
11819 |
11820 | ### Aa
11821 | Alt: E
11822 | Ref: V
11823 | Codon Degeneracy: 0
11824 | Codonpos: 2
11825 | Pos: 600, 640
11826 | Refcodon: GTG
11827 |
11828 | ### Alphamissense
11829 | Rankscore: 0.97238
11830 | Pred: P
11831 | Score: 0.9853, 0.9978, 0.9927, 0.9941
11832 |
11833 | ### Bayesdel
11834 |
11835 | #### Add Af
11836 | Pred: D
11837 | Rankscore: 0.89859
11838 | Score: 0.399079
11839 |
11840 | #### No Af
11841 | Pred: D
11842 | Rankscore: 0.89732
11843 | Score: 0.335473
11844 |
11845 | ### Bstatistic
11846 | Converted Rankscore: 0.46346
11847 | Score: 789.0
11848 |
11849 | ### Clinpred
11850 | Pred: D
11851 | Rankscore: 0.84315
11852 | Score: 0.993496775627136
11853 |
11854 | ### Clinvar
11855 | Clinvar Id: 13961
11856 | Hgvs: NC_000007.14:g.140753336A>T
11857 | Review: criteria_provided,_multiple_submitters,_no_conflicts
11858 | Clnsig: Pathogenic, drug_response, other
11859 | Medgen:
11860 | - C0025202
11861 | - C0027651
11862 | - C0027708
11863 | - C3661900
11864 | - C0158570
11865 | - C0024221
11866 | - C0017636
11867 | - C1275081
11868 | - C0346629
11869 | - C0006118
11870 | - C1266158
11871 | - C0238198
11872 | - C0238463
11873 | - C0151779
11874 | - C0684249
11875 | - C0919267
11876 | - C0917804
11877 | - C0026764
11878 | - C0007131
11879 | - C2674727
11880 | - C0677865
11881 | - C0006826
11882 | - C0152013
11883 | - C0009375
11884 | - C1336078
11885 | - C0009404
11886 | - C0699790
11887 | - C1168401
11888 | Omim: PS115150, 114500, 606764, 167000, 108010, 254500, 275355
11889 | Orphanet: 654, 2415, 360, 1340, 44890, 146, 46724, 29073, 85443, 67037
11890 | Trait:
11891 | - Melanoma
11892 | - Neoplasm
11893 | - Nephroblastoma
11894 | - not_provided
11895 | - Vascular_malformation
11896 | - Lymphangioma
11897 | - Glioblastoma
11898 | - Cardio-facio-cutaneous_syndrome
11899 | - Colorectal_cancer
11900 | - Neoplasm_of_brain
11901 | - Nongerminomatous_germ_cell_tumor
11902 | - Gastrointestinal_stromal_tumor
11903 | - Papillary_thyroid_carcinoma
11904 | - Malignant_melanoma_of_skin
11905 | - Lung_carcinoma
11906 | - Neoplasm_of_ovary
11907 | - Cerebral_arteriovenous_malformation
11908 | - Multiple_myeloma
11909 | - Non-small_cell_lung_carcinoma
11910 | - Astrocytoma,_low-grade,_somatic
11911 | - Brainstem_glioma
11912 | - Malignant_neoplastic_disease
11913 | - Lung_adenocarcinoma
11914 | - Cystic_epithelial_invagination_containing_papillae_lined_by_columnar_epithelium
11915 | - Colonic_neoplasm
11916 | - Papillary_renal_cell_carcinoma,_sporadic
11917 | - Neoplasm_of_the_large_intestine
11918 | - Carcinoma_of_colon
11919 | - Squamous_cell_carcinoma_of_the_head_and_neck
11920 | - Vemurafenib-Cobimetinib_Response
11921 | - Trametinib-Dabrafenib_Response
11922 | Var Source:
11923 | - ClinGen:CA123643
11924 | - Genetic_Testing_Registry_(GTR):GTR000522729
11925 | - Genetic_Testing_Registry_(GTR):GTR000575664
11926 | - Genetic_Testing_Registry_(GTR):GTR000575672
11927 | - Genetic_Testing_Registry_(GTR):GTR000575677
11928 | - OMIM:164757.0001
11929 | - UniProtKB:P15056#VAR_018629
11930 |
11931 | ### Dann
11932 | Rankscore: 0.42049
11933 | Score: 0.9848685552251786
11934 |
11935 | ### Deogen2
11936 | Pred: D
11937 | Rankscore: 0.95953
11938 | Score: 0.830668
11939 |
11940 | ### Eigen
11941 | Phred Coding: 4.637965
11942 | Raw Coding: 0.445381171133835
11943 | Raw Coding Rankscore: 0.63941
11944 |
11945 | ### Eigen-pc
11946 | Phred Coding: 5.634784
11947 | Raw Coding: 0.548689949287972
11948 | Raw Coding Rankscore: 0.71304
11949 |
11950 | ### Ensembl
11951 | Geneid: ENSG00000157764
11952 | Proteinid:
11953 | - ENSP00000419060
11954 | - ENSP00000496776
11955 | - ENSP00000493543
11956 | - ENSP00000288602
11957 | Transcriptid:
11958 | - ENST00000496384
11959 | - ENST00000644969
11960 | - ENST00000646891
11961 | - ENST00000288602
11962 |
11963 | ### Esm1b
11964 | Pred: D
11965 | Rankscore: 0.97691
11966 | Score: -15.954
11967 |
11968 | ### Eve
11969 | Class10 Pred: U
11970 | Class20 Pred: U
11971 | Class25 Pred: U
11972 | Class30 Pred: U
11973 | Class40 Pred: U
11974 | Class50 Pred: U
11975 | Class60 Pred: U
11976 | Class70 Pred: U
11977 | Class75 Pred: P
11978 | Class80 Pred: P
11979 | Class90 Pred: P
11980 | Rankscore: 0.71581
11981 | Score: 0.6445960741367582
11982 |
11983 | ### Exac
11984 | Ac: 2
11985 | Adj Ac: 2
11986 | Adj Af: 1.65e-05
11987 | Af: 1.647e-05
11988 |
11989 | #### Afr
11990 | Ac: 0
11991 | Af: 0.0
11992 |
11993 | #### Amr
11994 | Ac: 1
11995 | Af: 8.715e-05
11996 |
11997 | #### Eas
11998 | Ac: 0
11999 | Af: 0.0
12000 |
12001 | #### Fin
12002 | Ac: 0
12003 | Af: 0.0
12004 |
12005 | #### Nfe
12006 | Ac: 0
12007 | Af: 0.0
12008 |
12009 | #### Sas
12010 | Ac: 1
12011 | Af: 6.06e-05
12012 |
12013 | ### Exac Nonpsych
12014 | Ac: 2
12015 | Adj Ac: 2
12016 | Adj Af: 2.208e-05
12017 | Af: 2.204e-05
12018 |
12019 | #### Afr
12020 | Ac: 0
12021 | Af: 0.0
12022 |
12023 | #### Amr
12024 | Ac: 1
12025 | Af: 8.724e-05
12026 |
12027 | #### Eas
12028 | Ac: 0
12029 | Af: 0.0
12030 |
12031 | #### Fin
12032 | Ac: 0
12033 | Af: 0.0
12034 |
12035 | #### Nfe
12036 | Ac: 0
12037 | Af: 0.0
12038 |
12039 | #### Sas
12040 | Ac: 1
12041 | Af: 6.064e-05
12042 |
12043 | ### Exac Nontcga
12044 | Ac: 2
12045 | Adj Ac: 2
12046 | Adj Af: 1.886e-05
12047 | Af: 1.883e-05
12048 |
12049 | #### Afr
12050 | Ac: 0
12051 | Af: 0.0
12052 |
12053 | #### Amr
12054 | Ac: 1
12055 | Af: 8.998e-05
12056 |
12057 | #### Eas
12058 | Ac: 0
12059 | Af: 0.0
12060 |
12061 | #### Fin
12062 | Ac: 0
12063 | Af: 0.0
12064 |
12065 | #### Nfe
12066 | Ac: 0
12067 | Af: 0.0
12068 |
12069 | #### Sas
12070 | Ac: 1
12071 | Af: 6.098e-05
12072 |
12073 | ### Fathmm-mkl
12074 | Coding Group: AEFI
12075 | Coding Pred: D
12076 | Coding Rankscore: 0.83898
12077 | Coding Score: 0.98542
12078 |
12079 | ### Fathmm-xf
12080 | Coding Pred: D
12081 | Coding Rankscore: 0.87678
12082 | Coding Score: 0.914006
12083 |
12084 | ### Fitcons
12085 |
12086 | #### Gm12878
12087 | Confidence Value: 0
12088 | Rankscore: 0.7944
12089 | Score: 0.708844
12090 |
12091 | #### H1-hesc
12092 | Confidence Value: 0
12093 | Rankscore: 0.34648
12094 | Score: 0.602189
12095 |
12096 | #### Huvec
12097 | Confidence Value: 0
12098 | Rankscore: 0.65921
12099 | Score: 0.6691
12100 |
12101 | #### Integrated
12102 | Confidence Value: 0
12103 | Rankscore: 0.46895
12104 | Score: 0.6512
12105 |
12106 | ### Genocanyon
12107 | Rankscore: 0.74766
12108 | Score: 0.999999994558225
12109 |
12110 | ### Gerp++
12111 | Nr: 5.65
12112 | Rs: 5.65
12113 | Rs Rankscore: 0.86881
12114 |
12115 | ### Gmvp
12116 | Rankscore: 0.95276
12117 | Score: 0.9529287864278634
12118 |
12119 | ### Hg18
12120 | End: 140099605
12121 | Start: 140099605
12122 |
12123 | ### Hg19
12124 | End: 140453136
12125 | Start: 140453136
12126 |
12127 | ### Hg38
12128 | End: 140753336
12129 | Start: 140753336
12130 |
12131 | ### Interpro
12132 | Domain:
12133 | - Serine-threonine/tyrosine-protein kinase, catalytic domain|Protein kinase domain|Protein kinase domain
12134 |
12135 | ### List-s2
12136 | Rankscore: 0.29288
12137 | Pred: T
12138 | Score: 0.684632, 0.684232
12139 |
12140 | ### Lrt
12141 | Converted Rankscore: 0.8433
12142 | Omega: 0.0
12143 | Pred: D
12144 | Score: 0.0
12145 |
12146 | ### M-cap
12147 | Pred: D
12148 | Rankscore: 0.84885
12149 | Score: 0.171639
12150 |
12151 | ### Metalr
12152 | Pred: T
12153 | Rankscore: 0.6027
12154 | Score: 0.2357
12155 |
12156 | ### Metarnn
12157 | Rankscore: 0.87655
12158 | Pred: D
12159 | Score: 0.88336486
12160 |
12161 | ### Metasvm
12162 | Pred: T
12163 | Rankscore: 0.5694
12164 | Score: -0.7685
12165 |
12166 | ### Mpc
12167 | Rankscore: 0.98012
12168 | Score: 2.57041727597
12169 |
12170 | ### Mutationassessor
12171 | Pred: N
12172 | Rankscore: 0.16133
12173 | Score: 0.65
12174 |
12175 | ### Mutationtaster
12176 | Aae: V600E
12177 | Converted Rankscore: 0.81001
12178 | Model: simple_aae
12179 | Pred: D
12180 | Score: 1.0
12181 |
12182 | ### Mutformer
12183 | Rankscore: 0.99257
12184 | Score: 0.99925762
12185 |
12186 | ### Mutpred
12187 | Rankscore: 0.84872
12188 | Aa Change: V600E
12189 | Accession: P15056
12190 |
12191 | #### Pred
12192 | Mechanism: Gain of disorder
12193 | P Val: 0.0057
12194 | Score: 0.713
12195 |
12196 | ### Mvp
12197 | Rankscore: 0.9862
12198 | Score: 0.986356512902
12199 |
12200 | ### Phactboost
12201 | Rankscore: 0.98361
12202 | Score: 0.999853239760113
12203 |
12204 | ### Phastcons
12205 |
12206 | #### 100way Vertebrate
12207 | Rankscore: 0.71638
12208 | Score: 1.0
12209 |
12210 | #### 17way Primate
12211 | Rankscore: 0.91618
12212 | Score: 0.999
12213 |
12214 | #### 470way Mammalian
12215 | Rankscore: 0.68203
12216 | Score: 1.0
12217 |
12218 | ### Phylop
12219 |
12220 | #### 100way Vertebrate
12221 | Rankscore: 0.94474
12222 | Score: 9.236
12223 |
12224 | #### 17way Primate
12225 | Rankscore: 0.87069
12226 | Score: 0.75
12227 |
12228 | #### 470way Mammalian
12229 | Rankscore: 0.89583
12230 | Score: 11.216
12231 |
12232 | ### Polyphen2
12233 |
12234 | #### Hdiv
12235 | Pred: D
12236 | Rankscore: 0.57185
12237 | Score: 0.971
12238 |
12239 | #### Hvar
12240 | Pred: D
12241 | Rankscore: 0.67921
12242 | Score: 0.943
12243 |
12244 | ### Primateai
12245 | Pred: D
12246 | Rankscore: 0.9559
12247 | Score: 0.892686009407
12248 |
12249 | ### Revel
12250 | Rankscore: 0.98378
12251 | Score: 0.931
12252 |
12253 | ### Siphy 29way
12254 | Logodds Rankscore: 0.79463
12255 | Logodds Score: 15.9326
12256 |
12257 | #### Pi
12258 | A: 1.0
12259 | C: 0.0
12260 | G: 0.0
12261 | T: 0.0
12262 |
12263 | ### Varity
12264 |
12265 | #### Er
12266 | Rankscore: 0.98206
12267 | Score: 0.94685084
12268 |
12269 | #### Er Loo
12270 | Rankscore: 0.98903
12271 | Score: 0.9587261
12272 |
12273 | #### R
12274 | Rankscore: 0.97515
12275 | Score: 0.9623422
12276 |
12277 | #### R Loo
12278 | Rankscore: 0.97053
12279 | Score: 0.9577461
12280 | Appris: alternative2, principal2
12281 | Gencode Basic: Y
12282 | Genename: BRAF
12283 | Hgvsc: c.620T>A, c.1919T>A, c.1799T>A
12284 | Hgvsp: p.Val640Glu, p.Val207Glu, p.Val600Glu, p.V600E
12285 | Tsl: 5, 1
12286 |
12287 | ### Uniprot
12288 | Acc: H7C560
12289 | Entry: H7C560_HUMAN
12290 |
12291 | ### Uniprot
12292 | Acc: A0A2R8Y8E0
12293 | Entry: A0A2R8Y8E0_HUMAN
12294 |
12295 | ### Uniprot
12296 | Acc: P15056
12297 | Entry: BRAF_HUMAN
12298 |
12299 | ### Uniprot
12300 | Acc: A0A2U3TZI2
12301 | Entry: A0A2U3TZI2_HUMAN
12302 |
12303 | ## Dbsnp
12304 | License: http://bit.ly/2AqoLOc
12305 | Alt: T
12306 | Chrom: 7
12307 | Dbsnp Build: 156
12308 | Ref: A
12309 | Rsid: rs113488022
12310 | Vartype: snv
12311 |
12312 | ### Gene
12313 | Geneid: 673
12314 | Is Pseudo: False
12315 | Name: B-Raf proto-oncogene, serine/threonine kinase
12316 | Strand: -
12317 | Symbol: BRAF
12318 |
12319 | #### Rnas
12320 | Hgvs: NM_001354609.2:c.1799=
12321 | Refseq: NM_001354609.2
12322 |
12323 | ##### Codon Aligned Transcript Change
12324 | Deleted Sequence: GTG
12325 | Inserted Sequence: GTG
12326 | Position: 2023
12327 | Seq Id: NM_001354609.2
12328 |
12329 | ##### Protein
12330 |
12331 | ##### Variant
12332 |
12333 | ##### Spdi
12334 | Deleted Sequence: V
12335 | Inserted Sequence: V
12336 | Position: 599
12337 | Seq Id: NP_001341538.1
12338 |
12339 | ##### Protein Product
12340 | Refseq: NP_001341538.1
12341 |
12342 | ##### So
12343 | Accession: SO:0001580
12344 | Name: coding_sequence_variant
12345 |
12346 | #### Rnas
12347 | Hgvs: NM_001374244.1:c.1919=
12348 | Refseq: NM_001374244.1
12349 |
12350 | ##### Codon Aligned Transcript Change
12351 | Deleted Sequence: GTG
12352 | Inserted Sequence: GTG
12353 | Position: 2143
12354 | Seq Id: NM_001374244.1
12355 |
12356 | ##### Protein
12357 |
12358 | ##### Variant
12359 |
12360 | ##### Spdi
12361 | Deleted Sequence: V
12362 | Inserted Sequence: V
12363 | Position: 639
12364 | Seq Id: NP_001361173.1
12365 |
12366 | ##### Protein Product
12367 | Refseq: NP_001361173.1
12368 |
12369 | ##### So
12370 | Accession: SO:0001580
12371 | Name: coding_sequence_variant
12372 |
12373 | #### Rnas
12374 | Hgvs: NM_001374258.1:c.1919=
12375 | Refseq: NM_001374258.1
12376 |
12377 | ##### Codon Aligned Transcript Change
12378 | Deleted Sequence: GTG
12379 | Inserted Sequence: GTG
12380 | Position: 2143
12381 | Seq Id: NM_001374258.1
12382 |
12383 | ##### Protein
12384 |
12385 | ##### Variant
12386 |
12387 | ##### Spdi
12388 | Deleted Sequence: V
12389 | Inserted Sequence: V
12390 | Position: 639
12391 | Seq Id: NP_001361187.1
12392 |
12393 | ##### Protein Product
12394 | Refseq: NP_001361187.1
12395 |
12396 | ##### So
12397 | Accession: SO:0001580
12398 | Name: coding_sequence_variant
12399 |
12400 | #### Rnas
12401 | Hgvs: NM_001378467.1:c.1808=
12402 | Refseq: NM_001378467.1
12403 |
12404 | ##### Codon Aligned Transcript Change
12405 | Deleted Sequence: GTG
12406 | Inserted Sequence: GTG
12407 | Position: 2032
12408 | Seq Id: NM_001378467.1
12409 |
12410 | ##### Protein
12411 |
12412 | ##### Variant
12413 |
12414 | ##### Spdi
12415 | Deleted Sequence: V
12416 | Inserted Sequence: V
12417 | Position: 602
12418 | Seq Id: NP_001365396.1
12419 |
12420 | ##### Protein Product
12421 | Refseq: NP_001365396.1
12422 |
12423 | ##### So
12424 | Accession: SO:0001580
12425 | Name: coding_sequence_variant
12426 |
12427 | #### Rnas
12428 | Hgvs: NM_001378468.1:c.1799=
12429 | Refseq: NM_001378468.1
12430 |
12431 | ##### Codon Aligned Transcript Change
12432 | Deleted Sequence: GTG
12433 | Inserted Sequence: GTG
12434 | Position: 2023
12435 | Seq Id: NM_001378468.1
12436 |
12437 | ##### Protein
12438 |
12439 | ##### Variant
12440 |
12441 | ##### Spdi
12442 | Deleted Sequence: V
12443 | Inserted Sequence: V
12444 | Position: 599
12445 | Seq Id: NP_001365397.1
12446 |
12447 | ##### Protein Product
12448 | Refseq: NP_001365397.1
12449 |
12450 | ##### So
12451 | Accession: SO:0001580
12452 | Name: coding_sequence_variant
12453 |
12454 | #### Rnas
12455 | Hgvs: NM_001378469.1:c.1733=
12456 | Refseq: NM_001378469.1
12457 |
12458 | ##### Codon Aligned Transcript Change
12459 | Deleted Sequence: GTG
12460 | Inserted Sequence: GTG
12461 | Position: 1957
12462 | Seq Id: NM_001378469.1
12463 |
12464 | ##### Protein
12465 |
12466 | ##### Variant
12467 |
12468 | ##### Spdi
12469 | Deleted Sequence: V
12470 | Inserted Sequence: V
12471 | Position: 577
12472 | Seq Id: NP_001365398.1
12473 |
12474 | ##### Protein Product
12475 | Refseq: NP_001365398.1
12476 |
12477 | ##### So
12478 | Accession: SO:0001580
12479 | Name: coding_sequence_variant
12480 |
12481 | #### Rnas
12482 | Hgvs: NM_001378470.1:c.1697=
12483 | Refseq: NM_001378470.1
12484 |
12485 | ##### Codon Aligned Transcript Change
12486 | Deleted Sequence: GTG
12487 | Inserted Sequence: GTG
12488 | Position: 1921
12489 | Seq Id: NM_001378470.1
12490 |
12491 | ##### Protein
12492 |
12493 | ##### Variant
12494 |
12495 | ##### Spdi
12496 | Deleted Sequence: V
12497 | Inserted Sequence: V
12498 | Position: 565
12499 | Seq Id: NP_001365399.1
12500 |
12501 | ##### Protein Product
12502 | Refseq: NP_001365399.1
12503 |
12504 | ##### So
12505 | Accession: SO:0001580
12506 | Name: coding_sequence_variant
12507 |
12508 | #### Rnas
12509 | Hgvs: NM_001378471.1:c.1688=
12510 | Refseq: NM_001378471.1
12511 |
12512 | ##### Codon Aligned Transcript Change
12513 | Deleted Sequence: GTG
12514 | Inserted Sequence: GTG
12515 | Position: 1912
12516 | Seq Id: NM_001378471.1
12517 |
12518 | ##### Protein
12519 |
12520 | ##### Variant
12521 |
12522 | ##### Spdi
12523 | Deleted Sequence: V
12524 | Inserted Sequence: V
12525 | Position: 562
12526 | Seq Id: NP_001365400.1
12527 |
12528 | ##### Protein Product
12529 | Refseq: NP_001365400.1
12530 |
12531 | ##### So
12532 | Accession: SO:0001580
12533 | Name: coding_sequence_variant
12534 |
12535 | #### Rnas
12536 | Hgvs: NM_001378472.1:c.1643=
12537 | Refseq: NM_001378472.1
12538 |
12539 | ##### Codon Aligned Transcript Change
12540 | Deleted Sequence: GTG
12541 | Inserted Sequence: GTG
12542 | Position: 1742
12543 | Seq Id: NM_001378472.1
12544 |
12545 | ##### Protein
12546 |
12547 | ##### Variant
12548 |
12549 | ##### Spdi
12550 | Deleted Sequence: V
12551 | Inserted Sequence: V
12552 | Position: 547
12553 | Seq Id: NP_001365401.1
12554 |
12555 | ##### Protein Product
12556 | Refseq: NP_001365401.1
12557 |
12558 | ##### So
12559 | Accession: SO:0001580
12560 | Name: coding_sequence_variant
12561 |
12562 | #### Rnas
12563 | Hgvs: NM_001378473.1:c.1643=
12564 | Refseq: NM_001378473.1
12565 |
12566 | ##### Codon Aligned Transcript Change
12567 | Deleted Sequence: GTG
12568 | Inserted Sequence: GTG
12569 | Position: 1742
12570 | Seq Id: NM_001378473.1
12571 |
12572 | ##### Protein
12573 |
12574 | ##### Variant
12575 |
12576 | ##### Spdi
12577 | Deleted Sequence: V
12578 | Inserted Sequence: V
12579 | Position: 547
12580 | Seq Id: NP_001365402.1
12581 |
12582 | ##### Protein Product
12583 | Refseq: NP_001365402.1
12584 |
12585 | ##### So
12586 | Accession: SO:0001580
12587 | Name: coding_sequence_variant
12588 |
12589 | #### Rnas
12590 | Hgvs: NM_001378474.1:c.1799=
12591 | Refseq: NM_001378474.1
12592 |
12593 | ##### Codon Aligned Transcript Change
12594 | Deleted Sequence: GTG
12595 | Inserted Sequence: GTG
12596 | Position: 2023
12597 | Seq Id: NM_001378474.1
12598 |
12599 | ##### Protein
12600 |
12601 | ##### Variant
12602 |
12603 | ##### Spdi
12604 | Deleted Sequence: V
12605 | Inserted Sequence: V
12606 | Position: 599
12607 | Seq Id: NP_001365403.1
12608 |
12609 | ##### Protein Product
12610 | Refseq: NP_001365403.1
12611 |
12612 | ##### So
12613 | Accession: SO:0001580
12614 | Name: coding_sequence_variant
12615 |
12616 | #### Rnas
12617 | Hgvs: NM_001378475.1:c.1535=
12618 | Refseq: NM_001378475.1
12619 |
12620 | ##### Codon Aligned Transcript Change
12621 | Deleted Sequence: GTG
12622 | Inserted Sequence: GTG
12623 | Position: 1759
12624 | Seq Id: NM_001378475.1
12625 |
12626 | ##### Protein
12627 |
12628 | ##### Variant
12629 |
12630 | ##### Spdi
12631 | Deleted Sequence: V
12632 | Inserted Sequence: V
12633 | Position: 511
12634 | Seq Id: NP_001365404.1
12635 |
12636 | ##### Protein Product
12637 | Refseq: NP_001365404.1
12638 |
12639 | ##### So
12640 | Accession: SO:0001580
12641 | Name: coding_sequence_variant
12642 |
12643 | #### Rnas
12644 | Hgvs: NM_004333.6:c.1799=
12645 | Refseq: NM_004333.6
12646 |
12647 | ##### Codon Aligned Transcript Change
12648 | Deleted Sequence: GTG
12649 | Inserted Sequence: GTG
12650 | Position: 2023
12651 | Seq Id: NM_004333.6
12652 |
12653 | ##### Protein
12654 |
12655 | ##### Variant
12656 |
12657 | ##### Spdi
12658 | Deleted Sequence: V
12659 | Inserted Sequence: V
12660 | Position: 599
12661 | Seq Id: NP_004324.2
12662 |
12663 | ##### Protein Product
12664 | Refseq: NP_004324.2
12665 |
12666 | ##### So
12667 | Accession: SO:0001580
12668 | Name: coding_sequence_variant
12669 |
12670 | #### Rnas
12671 | Hgvs: XM_017012559.2:c.1919=
12672 | Refseq: XM_017012559.2
12673 |
12674 | ##### Codon Aligned Transcript Change
12675 | Deleted Sequence: GTG
12676 | Inserted Sequence: GTG
12677 | Position: 2143
12678 | Seq Id: XM_017012559.2
12679 |
12680 | ##### Protein
12681 |
12682 | ##### Variant
12683 |
12684 | ##### Spdi
12685 | Deleted Sequence: V
12686 | Inserted Sequence: V
12687 | Position: 639
12688 | Seq Id: XP_016868048.1
12689 |
12690 | ##### Protein Product
12691 | Refseq: XP_016868048.1
12692 |
12693 | ##### So
12694 | Accession: SO:0001580
12695 | Name: coding_sequence_variant
12696 |
12697 | #### Rnas
12698 | Hgvs: XM_047420766.1:c.1763=
12699 | Refseq: XM_047420766.1
12700 |
12701 | ##### Codon Aligned Transcript Change
12702 | Deleted Sequence: GTG
12703 | Inserted Sequence: GTG
12704 | Position: 1862
12705 | Seq Id: XM_047420766.1
12706 |
12707 | ##### Protein
12708 |
12709 | ##### Variant
12710 |
12711 | ##### Spdi
12712 | Deleted Sequence: V
12713 | Inserted Sequence: V
12714 | Position: 587
12715 | Seq Id: XP_047276722.1
12716 |
12717 | ##### Protein Product
12718 | Refseq: XP_047276722.1
12719 |
12720 | ##### So
12721 | Accession: SO:0001580
12722 | Name: coding_sequence_variant
12723 |
12724 | #### Rnas
12725 | Hgvs: XM_047420767.1:c.1919=
12726 | Refseq: XM_047420767.1
12727 |
12728 | ##### Codon Aligned Transcript Change
12729 | Deleted Sequence: GTG
12730 | Inserted Sequence: GTG
12731 | Position: 2143
12732 | Seq Id: XM_047420767.1
12733 |
12734 | ##### Protein
12735 |
12736 | ##### Variant
12737 |
12738 | ##### Spdi
12739 | Deleted Sequence: V
12740 | Inserted Sequence: V
12741 | Position: 639
12742 | Seq Id: XP_047276723.1
12743 |
12744 | ##### Protein Product
12745 | Refseq: XP_047276723.1
12746 |
12747 | ##### So
12748 | Accession: SO:0001580
12749 | Name: coding_sequence_variant
12750 |
12751 | #### Rnas
12752 | Hgvs: XM_047420768.1:c.1815-3918=
12753 | Refseq: XM_047420768.1
12754 |
12755 | ##### Protein Product
12756 | Refseq: XP_047276724.1
12757 |
12758 | ##### So
12759 | Accession: SO:0001627
12760 | Name: intron_variant
12761 |
12762 | #### Rnas
12763 | Hgvs: XM_047420769.1:c.1695-3918=
12764 | Refseq: XM_047420769.1
12765 |
12766 | ##### Protein Product
12767 | Refseq: XP_047276725.1
12768 |
12769 | ##### So
12770 | Accession: SO:0001627
12771 | Name: intron_variant
12772 |
12773 | #### Rnas
12774 | Hgvs: XM_047420770.1:c.1085=
12775 | Refseq: XM_047420770.1
12776 |
12777 | ##### Codon Aligned Transcript Change
12778 | Deleted Sequence: GTG
12779 | Inserted Sequence: GTG
12780 | Position: 1481
12781 | Seq Id: XM_047420770.1
12782 |
12783 | ##### Protein
12784 |
12785 | ##### Variant
12786 |
12787 | ##### Spdi
12788 | Deleted Sequence: V
12789 | Inserted Sequence: V
12790 | Position: 361
12791 | Seq Id: XP_047276726.1
12792 |
12793 | ##### Protein Product
12794 | Refseq: XP_047276726.1
12795 |
12796 | ##### So
12797 | Accession: SO:0001580
12798 | Name: coding_sequence_variant
12799 |
12800 | ### Hg19
12801 | End: 140453136
12802 | Start: 140453136
12803 |
12804 | ### Alleles
12805 | Allele: A
12806 |
12807 | #### Freq
12808 | Exac: 1.0
12809 | Gnomad Exomes: 1.0
12810 |
12811 | ### Alleles
12812 | Allele: T
12813 |
12814 | #### Freq
12815 | Exac: 0.0
12816 | Gnomad Exomes: 0.0
12817 | Citations:
12818 | - 12068308
12819 | - 12460918
12820 | - 12460919
12821 | - 12960123
12822 | - 14679157
12823 | - 15035987
12824 | - 19001320
12825 | - 19010912
12826 | - 19018267
12827 | - 19238210
12828 | - 19404918
12829 | - 19537845
12830 | - 19561230
12831 | - 20350999
12832 | - 20413299
12833 | - 20619739
12834 | - 20630094
12835 | - 20735442
12836 | - 20818844
12837 | - 21129611
12838 | - 21156289
12839 | - 21163703
12840 | - 21426297
12841 | - 21483012
12842 | - 21639808
12843 | - 21683865
12844 | - 21975775
12845 | - 22038996
12846 | - 22048237
12847 | - 22180495
12848 | - 22281684
12849 | - 22351686
12850 | - 22356324
12851 | - 22389471
12852 | - 22448344
12853 | - 22536370
12854 | - 22586120
12855 | - 22608338
12856 | - 22649091
12857 | - 22663011
12858 | - 22735384
12859 | - 22743296
12860 | - 22773810
12861 | - 22805292
12862 | - 22972589
12863 | - 22997239
12864 | - 23020132
12865 | - 23031422
12866 | - 23251002
12867 | - 23325582
12868 | - 23470635
12869 | - 23524406
12870 | - 23549875
12871 | - 23614898
12872 | - 23757202
12873 | - 23812671
12874 | - 23833300
12875 | - 23845441
12876 | - 23918947
12877 | - 24107445
12878 | - 24163374
12879 | - 24388723
12880 | - 24576830
12881 | - 24583796
12882 | - 24586605
12883 | - 24594804
12884 | - 25024077
12885 | - 25157968
12886 | - 25370471
12887 | - 25989278
12888 | - 26619011
12889 | - 26678033
12890 |
12891 | ## Docm
12892 | Aa Change: p.V600E
12893 | All Domains:
12894 | pfam_Ser-Thr/Tyr_kinase_cat_dom,pfam_Prot_kinase_dom,pfam_Raf-like_ras-
12895 | bd,pfam_Prot_Kinase_C-like_PE/DAG-bd,superfamily_Kinase-
12896 | like_dom,smart_Raf-like_ras-bd,smart_Prot_Kinase_C-like_PE/DAG-
12897 | bd,smart_Ser/Thr_dual-sp_kinase_dom,smart_Tyr_kinase_cat_dom,pfscan_Raf-
12898 | like_ras-bd,pfscan_Prot_Kinase_C-like_PE/DAG-
12899 | bd,pfscan_Prot_kinase_dom,prints_Ser-
12900 | Thr/Tyr_kinase_cat_dom,prints_DAG/PE-bd
12901 | Alt: T
12902 | C Position: c.1799
12903 | Chrom: 7
12904 | Default Gene Name: BRAF
12905 | Deletion Substructures: -
12906 | Disease: Thyroid Cancer
12907 | Doid: DOID:1781
12908 | Domain:
12909 | pfam_Ser-Thr/Tyr_kinase_cat_dom,pfam_Prot_kinase_dom,superfamily_Kinase-
12910 | like_dom,smart_Ser/Thr_dual-
12911 | sp_kinase_dom,smart_Tyr_kinase_cat_dom,pfscan_Prot_kinase_dom
12912 | Ensembl Gene Id: ENSG00000157764
12913 | Genename: BRAF
12914 | Genename Source: HGNC
12915 | Primary: 1
12916 | Pubmed Id:
12917 | 20818844, 19255327, 19773371, 12068308, 18541894, 19255327, 20368568,
12918 | 19773371
12919 | Ref: A
12920 | Source: MyCancerGenome
12921 | Strand: -1
12922 | Transcript Error: no_errors
12923 | Transcript Name: ENST00000288602
12924 | Transcript Source: ensembl
12925 | Transcript Species: human
12926 | Transcript Status: known
12927 | Transcript Version: 74_37
12928 | Trv Type: missense
12929 | Type: SNP
12930 | Ucsc Cons: 1
12931 | Url: http://www.mycancergenome.org/content/disease/thyroid-cancer/braf/54
12932 |
12933 | ### Hg19
12934 | End: 140453136
12935 | Start: 140453136
12936 |
12937 | ## Emv
12938 | License: http://bit.ly/2RieoY1
12939 | Egl Classification: Pathogenic
12940 | Egl Classification Date: 10/08/2013
12941 | Egl Protein: p.Val600Glu | p.V600E
12942 | Egl Variant: NM_004333.4:c.1799T>A
12943 | Exon: Ex15
12944 | Gene: BRAF
12945 | Variant Id: 15358
12946 | Hgvs:
12947 | - LRG_299t1:c.1799T>A
12948 | - NM_004333.4:c.1799T>A
12949 | - XM_005250045.1:c.1799T>A
12950 | - XM_005250046.1:c.1799T>A
12951 | - XM_005250047.1:c.1799T>A
12952 |
12953 | ## Exac
12954 | License: http://bit.ly/2H9c4hg
12955 | Af: 1.647e-05
12956 | Alleles: T
12957 | Alt: T
12958 | Baseqranksum: 1.1
12959 | Chrom: 7
12960 | Clippingranksum: -0.323
12961 | Culprit: FS
12962 | Fs: 0.0
12963 | Inbreedingcoeff: 0.0343
12964 | Ncc: 11
12965 | Pos: 140453136
12966 | Qd: 12.29
12967 | Readposranksum: 0.358
12968 | Ref: A
12969 | Type: snp
12970 | Vqslod: 4.08
12971 |
12972 | ### Ac
12973 | Ac: 2
12974 | Ac Adj: 2
12975 | Ac Afr: 0
12976 | Ac Amr: 1
12977 | Ac Eas: 0
12978 | Ac Female: 0
12979 | Ac Fin: 0
12980 | Ac Het: 2
12981 | Ac Hom: 0
12982 | Ac Male: 2
12983 | Ac Nfe: 0
12984 | Ac Oth: 0
12985 | Ac Sas: 1
12986 |
12987 | ### An
12988 | An: 121410
12989 | An Adj: 121220
12990 | An Afr: 10396
12991 | An Amr: 11474
12992 | An Eas: 8644
12993 | An Female: 54032
12994 | An Fin: 6610
12995 | An Male: 67188
12996 | An Nfe: 66688
12997 | An Oth: 906
12998 | An Sas: 16502
12999 |
13000 | ### Het
13001 | Het Afr: 0
13002 | Het Amr: 1
13003 | Het Eas: 0
13004 | Het Fin: 0
13005 | Het Nfe: 0
13006 | Het Oth: 0
13007 | Het Sas: 1
13008 |
13009 | ### Hom
13010 | Hom Afr: 0
13011 | Hom Amr: 0
13012 | Hom Eas: 0
13013 | Hom Fin: 0
13014 | Hom Nfe: 0
13015 | Hom Oth: 0
13016 | Hom Sas: 0
13017 |
13018 | ### Mq
13019 | Mq: 59.5
13020 | Mq0: 0
13021 | Mqranksum: -0.129
13022 |
13023 | ## Exac Nontcga
13024 | License: http://bit.ly/2H9c4hg
13025 | Af: 1.883e-05
13026 | Alleles: T
13027 | Alt: T
13028 | Baseqranksum: 1.1
13029 | Chrom: 7
13030 | Clippingranksum: -0.323
13031 | Culprit: FS
13032 | Fs: 0.0
13033 | Inbreedingcoeff: 0.0343
13034 | Ncc: 11
13035 | Pos: 140453136
13036 | Qd: 12.29
13037 | Readposranksum: 0.358
13038 | Ref: A
13039 | Type: snp
13040 | Vqslod: 4.08
13041 |
13042 | ### Ac
13043 | Ac: 2
13044 | Ac Adj: 2
13045 | Ac Afr: 0
13046 | Ac Amr: 1
13047 | Ac Eas: 0
13048 | Ac Female: 0
13049 | Ac Fin: 0
13050 | Ac Het: 2
13051 | Ac Hom: 0
13052 | Ac Male: 2
13053 | Ac Nfe: 0
13054 | Ac Oth: 0
13055 | Ac Sas: 1
13056 |
13057 | ### An
13058 | An: 106208
13059 | An Adj: 106034
13060 | An Afr: 9058
13061 | An Amr: 11114
13062 | An Eas: 7860
13063 | An Female: 45794
13064 | An Fin: 6610
13065 | An Male: 60240
13066 | An Nfe: 54302
13067 | An Oth: 692
13068 | An Sas: 16398
13069 |
13070 | ### Het
13071 | Het Afr: 0
13072 | Het Amr: 1
13073 | Het Eas: 0
13074 | Het Fin: 0
13075 | Het Nfe: 0
13076 | Het Oth: 0
13077 | Het Sas: 1
13078 |
13079 | ### Hom
13080 | Hom Afr: 0
13081 | Hom Amr: 0
13082 | Hom Eas: 0
13083 | Hom Fin: 0
13084 | Hom Nfe: 0
13085 | Hom Oth: 0
13086 | Hom Sas: 0
13087 |
13088 | ### Mq
13089 | Mq: 59.5
13090 | Mq0: 0
13091 | Mqranksum: -0.129
13092 |
13093 | ## Gnomad Exome
13094 | License: http://bit.ly/2I1cl1I
13095 | Alleles: T
13096 | Alt: T
13097 | Baseqranksum: 1.11
13098 | Chrom: 7
13099 | Clippingranksum: 0.007
13100 | Dp: 10269946
13101 | Fs: 0.0
13102 | Inbreedingcoeff: 0.06
13103 | Pab Max: 0.916129
13104 | Pos: 140453136
13105 | Qd: 14.92
13106 | Readposranksum: 0.421
13107 | Ref: A
13108 | Rf: 0.906237
13109 | Rsid: rs113488022
13110 | Sor: 0.739
13111 | Type: snp
13112 | Vqslod: 5.48
13113 | Vqsr Culprit: FS
13114 |
13115 | ### Ac
13116 | Ac: 1
13117 | Ac Afr: 0
13118 | Ac Afr Female: 0
13119 | Ac Afr Male: 0
13120 | Ac Amr: 0
13121 | Ac Amr Female: 0
13122 | Ac Amr Male: 0
13123 | Ac Asj: 0
13124 | Ac Asj Female: 0
13125 | Ac Asj Male: 0
13126 | Ac Eas: 0
13127 | Ac Eas Female: 0
13128 | Ac Eas Jpn: 0
13129 | Ac Eas Kor: 0
13130 | Ac Eas Male: 0
13131 | Ac Eas Oea: 0
13132 | Ac Female: 0
13133 | Ac Fin: 0
13134 | Ac Fin Female: 0
13135 | Ac Fin Male: 0
13136 | Ac Male: 1
13137 | Ac Nfe: 0
13138 | Ac Nfe Bgr: 0
13139 | Ac Nfe Est: 0
13140 | Ac Nfe Female: 0
13141 | Ac Nfe Male: 0
13142 | Ac Nfe Nwe: 0
13143 | Ac Nfe Onf: 0
13144 | Ac Nfe Seu: 0
13145 | Ac Nfe Swe: 0
13146 | Ac Oth: 0
13147 | Ac Oth Female: 0
13148 | Ac Oth Male: 0
13149 | Ac Sas: 1
13150 | Ac Sas Female: 0
13151 | Ac Sas Male: 1
13152 |
13153 | ### Af
13154 | Af: 3.97994e-06
13155 | Af Afr: 0.0
13156 | Af Afr Female: 0.0
13157 | Af Afr Male: 0.0
13158 | Af Amr: 0.0
13159 | Af Amr Female: 0.0
13160 | Af Amr Male: 0.0
13161 | Af Asj: 0.0
13162 | Af Asj Female: 0.0
13163 | Af Asj Male: 0.0
13164 | Af Eas: 0.0
13165 | Af Eas Female: 0.0
13166 | Af Eas Jpn: 0.0
13167 | Af Eas Kor: 0.0
13168 | Af Eas Male: 0.0
13169 | Af Eas Oea: 0.0
13170 | Af Female: 0.0
13171 | Af Fin: 0.0
13172 | Af Fin Female: 0.0
13173 | Af Fin Male: 0.0
13174 | Af Male: 7.3642e-06
13175 | Af Nfe: 0.0
13176 | Af Nfe Bgr: 0.0
13177 | Af Nfe Est: 0.0
13178 | Af Nfe Female: 0.0
13179 | Af Nfe Male: 0.0
13180 | Af Nfe Nwe: 0.0
13181 | Af Nfe Onf: 0.0
13182 | Af Nfe Seu: 0.0
13183 | Af Nfe Swe: 0.0
13184 | Af Oth: 0.0
13185 | Af Oth Female: 0.0
13186 | Af Oth Male: 0.0
13187 | Af Sas: 3.26669e-05
13188 | Af Sas Female: 0.0
13189 | Af Sas Male: 4.33501e-05
13190 |
13191 | ### An
13192 | An: 251260
13193 | An Afr: 16252
13194 | An Afr Female: 10070
13195 | An Afr Male: 6182
13196 | An Amr: 34528
13197 | An Amr Female: 20246
13198 | An Amr Male: 14282
13199 | An Asj: 10076
13200 | An Asj Female: 4900
13201 | An Asj Male: 5176
13202 | An Eas: 18392
13203 | An Eas Female: 9326
13204 | An Eas Jpn: 152
13205 | An Eas Kor: 3816
13206 | An Eas Male: 9066
13207 | An Eas Oea: 14424
13208 | An Female: 115468
13209 | An Fin: 21638
13210 | An Fin Female: 10364
13211 | An Fin Male: 11274
13212 | An Male: 135792
13213 | An Nfe: 113638
13214 | An Nfe Bgr: 2668
13215 | An Nfe Est: 240
13216 | An Nfe Female: 50102
13217 | An Nfe Male: 63536
13218 | An Nfe Nwe: 42154
13219 | An Nfe Onf: 30954
13220 | An Nfe Seu: 11496
13221 | An Nfe Swe: 26126
13222 | An Oth: 6124
13223 | An Oth Female: 2916
13224 | An Oth Male: 3208
13225 | An Sas: 30612
13226 | An Sas Female: 7544
13227 | An Sas Male: 23068
13228 |
13229 | ### Hom
13230 | Hom: 0
13231 | Hom Afr: 0
13232 | Hom Afr Female: 0
13233 | Hom Afr Male: 0
13234 | Hom Amr: 0
13235 | Hom Amr Female: 0
13236 | Hom Amr Male: 0
13237 | Hom Asj: 0
13238 | Hom Asj Female: 0
13239 | Hom Asj Male: 0
13240 | Hom Eas: 0
13241 | Hom Eas Female: 0
13242 | Hom Eas Jpn: 0
13243 | Hom Eas Kor: 0
13244 | Hom Eas Male: 0
13245 | Hom Eas Oea: 0
13246 | Hom Female: 0
13247 | Hom Fin: 0
13248 | Hom Fin Female: 0
13249 | Hom Fin Male: 0
13250 | Hom Male: 0
13251 | Hom Nfe: 0
13252 | Hom Nfe Bgr: 0
13253 | Hom Nfe Est: 0
13254 | Hom Nfe Female: 0
13255 | Hom Nfe Male: 0
13256 | Hom Nfe Nwe: 0
13257 | Hom Nfe Onf: 0
13258 | Hom Nfe Seu: 0
13259 | Hom Nfe Swe: 0
13260 | Hom Oth: 0
13261 | Hom Oth Female: 0
13262 | Hom Oth Male: 0
13263 | Hom Sas: 0
13264 | Hom Sas Female: 0
13265 | Hom Sas Male: 0
13266 |
13267 | ### Mq
13268 | Mq: 59.48
13269 | Mqranksum: 0.263
13270 |
13271 | ## Hg19
13272 | End: 140453136
13273 | Start: 140453136
13274 |
13275 | ## Mutdb
13276 | License: http://bit.ly/2SQ6fXA
13277 | Alt: A
13278 | Chrom: 7
13279 | Cosmic Id: 476, 1131
13280 | Mutpred Score: 0.705
13281 | Ref: T
13282 | Rsid: rs113488022
13283 | Strand: m
13284 | Uniprot Id: VAR_018629
13285 |
13286 | ### Hg19
13287 | End: 140453136
13288 | Start: 140453136
13289 |
13290 | ## Snpeff
13291 | License: http://bit.ly/2suyRKt
13292 |
13293 | ### Ann
13294 | Effect: missense_variant
13295 | Feature Id: NM_004333.4
13296 | Feature Type: transcript
13297 | Gene Id: BRAF
13298 | Genename: BRAF
13299 | Hgvs C: c.1799T>A
13300 | Hgvs P: p.Val600Glu
13301 | Putative Impact: MODERATE
13302 | Rank: 15
13303 | Total: 18
13304 | Transcript Biotype: protein_coding
13305 |
13306 | #### Cdna
13307 | Length: 2946
13308 | Position: 1860
13309 |
13310 | #### Cds
13311 | Length: 2301
13312 | Position: 1799
13313 |
13314 | #### Protein
13315 | Length: 766
13316 | Position: 600
13317 |
13318 | ## Vcf
13319 | Alt: T
13320 | Position: 140453136
13321 | Ref: A
13322 |
13323 | ## Cgi
13324 | License: http://bit.ly/2FqS871
13325 | Association: Responsive
13326 | Cdna: c.1799T>A
13327 | Drug: PLX4720 (BRAF inhibitor)
13328 | Evidence Level: Pre-clinical
13329 | Gene: BRAF
13330 | Primary Tumor Type: Malignant astrocytoma
13331 | Protein Change: BRAF:V600E
13332 | Region: inside_[cds_in_exon_15]
13333 | Source: PMC3638050
13334 | Transcript: ENST00000288602
13335 |
13336 | ## Cgi
13337 | License: http://bit.ly/2FqS871
13338 | Association: Responsive
13339 | Cdna: c.1799T>A
13340 | Drug: BRAF inhibitor + MEK inhibitors
13341 | Evidence Level: Early trials
13342 | Gene: BRAF
13343 | Primary Tumor Type: Thyroid
13344 | Protein Change: BRAF:V600E
13345 | Region: inside_[cds_in_exon_15]
13346 | Source: ASCO 2013 (abstr 9029)
13347 | Transcript: ENST00000288602
13348 |
13349 | ## Cgi
13350 | License: http://bit.ly/2FqS871
13351 | Association: Responsive
13352 | Cdna: c.1799T>A
13353 | Drug: Pan-RAF inhibitors
13354 | Evidence Level: Early trials
13355 | Gene: BRAF
13356 | Primary Tumor Type: Cutaneous melanoma
13357 | Protein Change: BRAF:V600E
13358 | Region: inside_[cds_in_exon_15]
13359 | Source:
13360 | ESMO 2015 (abstract 300);AACR 2016 (abstr CT005);AACR 2017 (abstr CT002)
13361 | Transcript: ENST00000288602
13362 |
13363 | ## Cgi
13364 | License: http://bit.ly/2FqS871
13365 | Association: Responsive
13366 | Cdna: c.1799T>A
13367 | Drug: BRAF inhibitors
13368 | Evidence Level: Case report
13369 | Gene: BRAF
13370 | Primary Tumor Type: Ovary
13371 | Protein Change: BRAF:V600E
13372 | Region: inside_[cds_in_exon_15]
13373 | Source: PMID:22608338
13374 | Transcript: ENST00000288602
13375 |
13376 | ## Cgi
13377 | License: http://bit.ly/2FqS871
13378 | Association: Resistant
13379 | Cdna: c.1799T>A
13380 | Drug: EGFR TK inhibitors
13381 | Evidence Level: Case report
13382 | Gene: BRAF
13383 | Primary Tumor Type: Lung adenocarcinoma
13384 | Protein Change: BRAF:V600E
13385 | Region: inside_[cds_in_exon_15]
13386 | Source: PMID:22773810
13387 | Transcript: ENST00000288602
13388 |
13389 | ## Cgi
13390 | License: http://bit.ly/2FqS871
13391 | Association: Responsive
13392 | Cdna: c.1799T>A
13393 | Drug: Trametinib (MEK inhibitor)
13394 | Evidence Level: FDA guidelines
13395 | Gene: BRAF
13396 | Primary Tumor Type: Cutaneous melanoma
13397 | Protein Change: BRAF:V600E
13398 | Region: inside_[cds_in_exon_15]
13399 | Source: FDA
13400 | Transcript: ENST00000288602
13401 |
13402 | ## Cgi
13403 | License: http://bit.ly/2FqS871
13404 | Association: Responsive
13405 | Cdna: c.1799T>A
13406 | Drug: BRAF inhibitors
13407 | Evidence Level: Pre-clinical
13408 | Gene: BRAF
13409 | Primary Tumor Type: Glioma
13410 | Protein Change: BRAF:V600E
13411 | Region: inside_[cds_in_exon_15]
13412 | Source: PMID:22038996;PMID:22586120
13413 | Transcript: ENST00000288602
13414 |
13415 | ## Cgi
13416 | License: http://bit.ly/2FqS871
13417 | Association: Responsive
13418 | Cdna: c.1799T>A
13419 | Drug: Vemurafenib + Cobimetinib (BRAF inhibitor + MEK inhibitor)
13420 | Evidence Level: FDA guidelines
13421 | Gene: BRAF
13422 | Primary Tumor Type: Cutaneous melanoma
13423 | Protein Change: BRAF:V600E
13424 | Region: inside_[cds_in_exon_15]
13425 | Source: FDA
13426 | Transcript: ENST00000288602
13427 |
13428 | ## Cgi
13429 | License: http://bit.ly/2FqS871
13430 | Association: Responsive
13431 | Cdna: c.1799T>A
13432 | Drug: BRAF inhibitor + PI3K pathway inhibitors
13433 | Evidence Level: Pre-clinical
13434 | Gene: BRAF
13435 | Primary Tumor Type: Cutaneous melanoma
13436 | Protein Change: BRAF:V600E
13437 | Region: inside_[cds_in_exon_15]
13438 | Source: PMID:22389471;PMID:21156289
13439 | Transcript: ENST00000288602
13440 |
13441 | ## Cgi
13442 | License: http://bit.ly/2FqS871
13443 | Association: Resistant
13444 | Cdna: c.1799T>A
13445 | Drug: Cetuximab (EGFR mAb inhibitor)
13446 | Evidence Level: Late trials
13447 | Gene: BRAF
13448 | Primary Tumor Type: Colorectal adenocarcinoma
13449 | Protein Change: BRAF:V600E
13450 | Region: inside_[cds_in_exon_15]
13451 | Source: PMID:20619739;PMID:21163703;PMID:23325582
13452 | Transcript: ENST00000288602
13453 |
13454 | ## Cgi
13455 | License: http://bit.ly/2FqS871
13456 | Association: Responsive
13457 | Cdna: c.1799T>A
13458 | Drug: ERK inhibitors
13459 | Evidence Level: Pre-clinical
13460 | Gene: BRAF
13461 | Primary Tumor Type: Cutaneous melanoma
13462 | Protein Change: BRAF:V600E
13463 | Region: inside_[cds_in_exon_15]
13464 | Source: PMID:23614898;PMID:22997239
13465 | Transcript: ENST00000288602
13466 |
13467 | ## Cgi
13468 | License: http://bit.ly/2FqS871
13469 | Association: Responsive
13470 | Cdna: c.1799T>A
13471 | Drug: MEK inhibitors
13472 | Evidence Level: Early trials
13473 | Gene: BRAF
13474 | Primary Tumor Type: Thyroid
13475 | Protein Change: BRAF:V600E
13476 | Region: inside_[cds_in_exon_15]
13477 | Source: PMID:22241789
13478 | Transcript: ENST00000288602
13479 |
13480 | ## Cgi
13481 | License: http://bit.ly/2FqS871
13482 | Association: Responsive
13483 | Cdna: c.1799T>A
13484 | Drug: Vemurafenib (BRAF inhibitor)
13485 | Evidence Level: Early trials
13486 | Gene: BRAF
13487 | Primary Tumor Type: Thyroid carcinoma
13488 | Protein Change: BRAF:V600E
13489 | Region: inside_[cds_in_exon_15]
13490 | Source: PMID:22608338;PMID:20818844;PMID:23489023
13491 | Transcript: ENST00000288602
13492 |
13493 | ## Cgi
13494 | License: http://bit.ly/2FqS871
13495 | Association: Responsive
13496 | Cdna: c.1799T>A
13497 | Drug: Vemurafenib (BRAF inhibitor)
13498 | Evidence Level: Early trials
13499 | Gene: BRAF
13500 | Primary Tumor Type: Malignant astrocytoma
13501 | Protein Change: BRAF:V600E
13502 | Region: inside_[cds_in_exon_15]
13503 | Source: PMID:22586120
13504 | Transcript: ENST00000288602
13505 |
13506 | ## Cgi
13507 | License: http://bit.ly/2FqS871
13508 | Association: Resistant
13509 | Cdna: c.1799T>A
13510 | Drug: Panitumumab (EGFR mAb inhibitor)
13511 | Evidence Level: Late trials
13512 | Gene: BRAF
13513 | Primary Tumor Type: Colorectal adenocarcinoma
13514 | Protein Change: BRAF:V600E
13515 | Region: inside_[cds_in_exon_15]
13516 | Source: PMID:20619739;PMID:21163703;PMID:23325582
13517 | Transcript: ENST00000288602
13518 |
13519 | ## Cgi
13520 | License: http://bit.ly/2FqS871
13521 | Association: Responsive
13522 | Cdna: c.1799T>A
13523 | Drug: Dabrafenib (BRAF inhibitor)
13524 | Evidence Level: Case report
13525 | Gene: BRAF
13526 | Primary Tumor Type: Gastrointestinal stromal
13527 | Protein Change: BRAF:V600E
13528 | Region: inside_[cds_in_exon_15]
13529 | Source: PMID:23470635;PMID:22608338
13530 | Transcript: ENST00000288602
13531 |
13532 | ## Cgi
13533 | License: http://bit.ly/2FqS871
13534 | Association: Responsive
13535 | Cdna: c.1799T>A
13536 | Drug: Vemurafenib (BRAF inhibitor)
13537 | Evidence Level: NCCN guidelines
13538 | Gene: BRAF
13539 | Primary Tumor Type:
13540 | Non-small cell lung;Lagerhans cell histiocytosis;Erdheim-Chester
13541 | histiocytosis
13542 | Protein Change: BRAF:V600E
13543 | Region: inside_[cds_in_exon_15]
13544 | Source: PMID:26287849
13545 | Transcript: ENST00000288602
13546 |
13547 | ## Cgi
13548 | License: http://bit.ly/2FqS871
13549 | Association: Responsive
13550 | Cdna: c.1799T>A
13551 | Drug: Dabrafenib + Trametinib (BRAF inhibitor + MEK inhibitor)
13552 | Evidence Level: FDA guidelines
13553 | Gene: BRAF
13554 | Primary Tumor Type: Cutaneous melanoma
13555 | Protein Change: BRAF:V600E
13556 | Region: inside_[cds_in_exon_15]
13557 | Source: FDA
13558 | Transcript: ENST00000288602
13559 |
13560 | ## Cgi
13561 | License: http://bit.ly/2FqS871
13562 | Association: Responsive
13563 | Cdna: c.1799T>A
13564 | Drug: ERK inhibitors
13565 | Evidence Level: Early trials
13566 | Gene: BRAF
13567 | Primary Tumor Type: Lung adenocarcinoma
13568 | Protein Change: BRAF:V600E
13569 | Region: inside_[cds_in_exon_15]
13570 | Source: ASCO 2017 (abstr 2508)
13571 | Transcript: ENST00000288602
13572 |
13573 | ## Cgi
13574 | License: http://bit.ly/2FqS871
13575 | Association: Responsive
13576 | Cdna: c.1799T>A
13577 | Drug: Dabrafenib (BRAF inhibitor)
13578 | Evidence Level: Early trials
13579 | Gene: BRAF
13580 | Primary Tumor Type: Lung adenocarcinoma;Thyroid
13581 | Protein Change: BRAF:V600E
13582 | Region: inside_[cds_in_exon_15]
13583 | Source:
13584 | PMID:23524406;PMID:22608338;ASCO 2013 (abstr 8009);ESMO 2014 (abstr
13585 | LBA38_PR);PMID:20818844;PMID:23489023;PMID:27080216
13586 | Transcript: ENST00000288602
13587 |
13588 | ## Cgi
13589 | License: http://bit.ly/2FqS871
13590 | Association: Responsive
13591 | Cdna: c.1799T>A
13592 | Drug: BRAF inhibitor + CDK2/4 inhibitors
13593 | Evidence Level: Pre-clinical
13594 | Gene: BRAF
13595 | Primary Tumor Type: Cutaneous melanoma
13596 | Protein Change: BRAF:V600E
13597 | Region: inside_[cds_in_exon_15]
13598 | Source: PMID:22997239
13599 | Transcript: ENST00000288602
13600 |
13601 | ## Cgi
13602 | License: http://bit.ly/2FqS871
13603 | Association: Responsive
13604 | Cdna: c.1799T>A
13605 | Drug: Vemurafenib (BRAF inhibitor)
13606 | Evidence Level: FDA guidelines
13607 | Gene: BRAF
13608 | Primary Tumor Type: Cutaneous melanoma
13609 | Protein Change: BRAF:V600E
13610 | Region: inside_[cds_in_exon_15]
13611 | Source: FDA
13612 | Transcript: ENST00000288602
13613 |
13614 | ## Cgi
13615 | License: http://bit.ly/2FqS871
13616 | Association: Responsive
13617 | Cdna: c.1799T>A
13618 | Drug: Dabrafenib (BRAF inhibitor)
13619 | Evidence Level: NCCN guidelines
13620 | Gene: BRAF
13621 | Primary Tumor Type: Non-small cell lung
13622 | Protein Change: BRAF:V600E
13623 | Region: inside_[cds_in_exon_15]
13624 | Source: NCCN
13625 | Transcript: ENST00000288602
13626 |
13627 | ## Cgi
13628 | License: http://bit.ly/2FqS871
13629 | Association: Responsive
13630 | Cdna: c.1799T>A
13631 | Drug: Dabrafenib + Trametinib (BRAF inhibitor + MEK inhibitor)
13632 | Evidence Level: Early trials
13633 | Gene: BRAF
13634 | Primary Tumor Type: Colorectal adenocarcinoma
13635 | Protein Change: BRAF:V600E
13636 | Region: inside_[cds_in_exon_15]
13637 | Source: PMID:26392102;ASCO 2015 (abstr 8006)
13638 | Transcript: ENST00000288602
13639 |
13640 | ## Cgi
13641 | License: http://bit.ly/2FqS871
13642 | Association: Responsive
13643 | Cdna: c.1799T>A
13644 | Drug: Selumetinib (MEK inhibitor)
13645 | Evidence Level: Early trials
13646 | Gene: BRAF
13647 | Primary Tumor Type: Pediatric glioma
13648 | Protein Change: BRAF:V600E
13649 | Region: inside_[cds_in_exon_15]
13650 | Source: NCT01089101
13651 | Transcript: ENST00000288602
13652 |
13653 | ## Cgi
13654 | License: http://bit.ly/2FqS871
13655 | Association: Responsive
13656 | Cdna: c.1799T>A
13657 | Drug: Dabrafenib + Trametinib (BRAF inhibitor + MEK inhibitor)
13658 | Evidence Level: Case report
13659 | Gene: BRAF
13660 | Primary Tumor Type: Neuroendocrine
13661 | Protein Change: BRAF:V600E
13662 | Region: inside_[cds_in_exon_15]
13663 | Source: PMID:27048246
13664 | Transcript: ENST00000288602
13665 |
13666 | ## Cgi
13667 | License: http://bit.ly/2FqS871
13668 | Association: Responsive
13669 | Cdna: c.1799T>A
13670 | Drug: Dabrafenib + Trametinib (BRAF inhibitor + MEK inhibitor)
13671 | Evidence Level: FDA guidelines
13672 | Gene: BRAF
13673 | Primary Tumor Type: Lung adenocarcinoma
13674 | Protein Change: BRAF:V600E
13675 | Region: inside_[cds_in_exon_15]
13676 | Source: PMID:27283860
13677 | Transcript: ENST00000288602
13678 |
13679 | ## Cgi
13680 | License: http://bit.ly/2FqS871
13681 | Association: Responsive
13682 | Cdna: c.1799T>A
13683 | Drug: MEK inhibitors
13684 | Evidence Level: Pre-clinical
13685 | Gene: BRAF
13686 | Primary Tumor Type: Ovary
13687 | Protein Change: BRAF:V600E
13688 | Region: inside_[cds_in_exon_15]
13689 | Source: PMID:19018267
13690 | Transcript: ENST00000288602
13691 |
13692 | ## Cgi
13693 | License: http://bit.ly/2FqS871
13694 | Association: Responsive
13695 | Cdna: c.1799T>A
13696 | Drug: BRAF inhibitor + HSP90 inhibitors
13697 | Evidence Level: Pre-clinical
13698 | Gene: BRAF
13699 | Primary Tumor Type: Cutaneous melanoma
13700 | Protein Change: BRAF:V600E
13701 | Region: inside_[cds_in_exon_15]
13702 | Source: PMID:22351686
13703 | Transcript: ENST00000288602
13704 |
13705 | ## Cgi
13706 | License: http://bit.ly/2FqS871
13707 | Association: Responsive
13708 | Cdna: c.1799T>A
13709 | Drug: Dabrafenib (BRAF inhibitor)
13710 | Evidence Level: FDA guidelines
13711 | Gene: BRAF
13712 | Primary Tumor Type: Cutaneous melanoma
13713 | Protein Change: BRAF:V600E
13714 | Region: inside_[cds_in_exon_15]
13715 | Source: FDA
13716 | Transcript: ENST00000288602
13717 |
13718 | ## Cgi
13719 | License: http://bit.ly/2FqS871
13720 | Association: Responsive
13721 | Cdna: c.1799T>A
13722 | Drug:
13723 | Panitumumab + Dabrafenib + Trametinib (EGFR mAb inhibitor + BRAF
13724 | inhibitor + MEK inhibitor)
13725 | Evidence Level: Early trials
13726 | Gene: BRAF
13727 | Primary Tumor Type: Colorectal adenocarcinoma
13728 | Protein Change: BRAF:V600E
13729 | Region: inside_[cds_in_exon_15]
13730 | Source: ASCO 2014 (abstr 3515);ASCO 2015 (abstr 103)
13731 | Transcript: ENST00000288602
13732 |
13733 | ## Cgi
13734 | License: http://bit.ly/2FqS871
13735 | Association: Responsive
13736 | Cdna: c.1799T>A
13737 | Drug: Vemurafenib (BRAF inhibitor)
13738 | Evidence Level: Case report
13739 | Gene: BRAF
13740 | Primary Tumor Type: Lung adenocarcinoma;Hairy-Cell leukemia;Myeloma
13741 | Protein Change: BRAF:V600E
13742 | Region: inside_[cds_in_exon_15]
13743 | Source: PMID:22743296;PMID:22621641;PMID:23612012
13744 | Transcript: ENST00000288602
13745 |
```