This is page 14 of 15. Use http://codebase.md/genomoncology/biomcp?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:
--------------------------------------------------------------------------------
```
Took: 4
Total: 1
Max Score: 26.326775
# Hits
Id: chr7:g.140453136A>T
Score: 26.326775
Chrom: 7
Observed: True
## Cadd
License: http://bit.ly/2TIuab9
Alt: T
Anc: A
Annotype: CodingTranscript
Bstatistic: 570
Chrom: 7
Consdetail: missense
Consequence: NON_SYNONYMOUS
Consscore: 7
Cpg: 0.01
Exon: 15/18
Fitcons: 0.666978
Gc: 0.4
Grantham: 121
Isderived: TRUE
Isknownvariant: FALSE
Istv: TRUE
Length: 0
Min Dist Tse: 18739
Min Dist Tss: 876
Mutindex: -13
Naa: E
Oaa: V
Phred: 32
Pos: 140453136
Rawscore: 6.641785
Ref: A
Segway: GE1
Type: SNV
### Chmm
Bivflnk: 0.0
Enh: 0.0
Enhbiv: 0.0
Het: 0.0
Quies: 0.102
Reprpc: 0.0
Reprpcwk: 0.0
Tssa: 0.0
Tssaflnk: 0.0
Tssbiv: 0.0
Tx: 0.11
Txflnk: 0.0
Txwk: 0.78
Znfrpts: 0.0
### Dna
Helt: -0.55
Mgw: 0.7
Prot: 3.19
Roll: 8.98
### Encode
Exp: 21.94
H3k27ac: 6.0
H3k4me1: 17.72
H3k4me3: 4.08
Nucleo: 1.6
### Gene
Ccds Id: CCDS5863.1
Feature Id: ENST00000288602
Gene Id: ENSG00000157764
Genename: BRAF
#### Cds
Cdna Pos: 1860
Cds Pos: 1799
Rel Cdna Pos: 0.75
Rel Cds Pos: 0.78
#### Prot
Domain: ndomain
Protpos: 600
Rel Prot Pos: 0.78
### Gerp
N: 5.65
Rs: 771
Rs Pval: 4.53805e-225
S: 5.65
### Mapability
20bp: 1
35bp: 1
### Phast Cons
Mammalian: 1.0
Primate: 0.998
Vertebrate: 1.0
### Phylop
Mammalian: 2.167
Primate: 0.525
Vertebrate: 5.101
### Polyphen
Cat: probably_damaging
Val: 0.967
### Sift
Cat: deleterious
Val: 0
## Civic
License: http://bit.ly/2FqS871
Allele Registry Id: CA123643
Deprecated: False
Id: 12
Mane Select Transcript: ENST00000646891.2:c.1799T>A
Name: V600E
Open Cravat Url:
https://run.opencravat.org/webapps/variantreport/index.html?alt_base=T&c
hrom=chr7&pos=140753336&ref_base=A
Open Revision Count: 0
### Comments
Total Count: 1
### Contributors
#### Curators
Last Action Date: 2015-09-08T19:54:43Z
Total Action Count: 1
##### User
Id: 70
##### Unique Actions
Action: REVISION_SUGGESTED
Count: 1
#### Curators
Last Action Date: 2016-02-18T22:19:46Z
Total Action Count: 3
##### User
Id: 41
##### Unique Actions
Action: REVISION_SUGGESTED
Count: 3
#### Curators
Last Action Date: 2016-03-24T02:17:27Z
Total Action Count: 2
##### User
Id: 3
##### Unique Actions
Action: REVISION_SUGGESTED
Count: 2
#### Curators
Last Action Date: 2019-05-17T00:23:44Z
Total Action Count: 3
##### User
Id: 6
##### Unique Actions
Action: REVISION_SUGGESTED
Count: 2
##### Unique Actions
Action: VARIANT_CREATED
Count: 1
#### Curators
Last Action Date: 2017-04-29T15:22:52Z
Total Action Count: 4
##### User
Id: 83
##### Unique Actions
Action: REVISION_SUGGESTED
Count: 4
#### Curators
Last Action Date: 2022-01-13T05:40:29Z
Total Action Count: 1
##### User
Id: 110
##### Unique Actions
Action: COMMENTED
Count: 1
#### Curators
Last Action Date: 2022-01-10T19:43:00Z
Total Action Count: 3
##### User
Id: 15
##### Unique Actions
Action: REVISION_SUGGESTED
Count: 3
#### Editors
Last Action Date: 2017-04-02T01:41:36Z
Total Action Count: 5
##### User
Id: 15
##### Unique Actions
Action: REVISION_ACCEPTED
Count: 5
#### Editors
Last Action Date: 2016-02-18T22:20:12Z
Total Action Count: 3
##### User
Id: 41
##### Unique Actions
Action: REVISION_ACCEPTED
Count: 3
#### Editors
Last Action Date: 2017-05-12T03:16:45Z
Total Action Count: 4
##### User
Id: 6
##### Unique Actions
Action: REVISION_ACCEPTED
Count: 3
##### Unique Actions
Action: REVISION_REJECTED
Count: 1
#### Editors
Last Action Date: 2017-05-14T03:50:30Z
Total Action Count: 4
##### User
Id: 3
##### Unique Actions
Action: REVISION_ACCEPTED
Count: 4
#### Editors
Last Action Date: 2020-05-30T00:13:47Z
Total Action Count: 1
##### User
Id: 968
##### Unique Actions
Action: REVISION_ACCEPTED
Count: 1
#### Editors
Last Action Date: 2022-01-13T05:39:29Z
Total Action Count: 1
##### User
Id: 110
##### Unique Actions
Action: REVISION_ACCEPTED
Count: 1
### Coordinates
Chromosome: 7
Coordinate Type: GENE_VARIANT_COORDINATE
Ensembl Version: 75
Reference Bases: A
Reference Build: GRCH37
Representative Transcript: ENST00000288602.6
Start: 140453136
Stop: 140453136
Variant Bases: T
### Creation Activity
Created At: 2015-06-21T16:49:42Z
#### User
Display Name: kkrysiak
Id: 6
Role: ADMIN
### Feature
Deprecated: False
Flagged: False
Id: 5
Link: /features/5
Name: BRAF
### Flags
Total Count: 0
### Last Accepted Revision Event
#### Originating User
Display Name: CamGrisdale
Id: 968
Role: EDITOR
### Last Submitted Revision Event
#### Originating User
Display Name: LynzeyKujan
Id: 83
Role: CURATOR
### Revisions
Total Count: 0
### Variant Types
Id: 47
Link: /variant-types/47
Name: Missense Variant
Soid: SO:0001583
Clinvar Ids: 13961, 376069
Hgvs Descriptions:
- NM_004333.4:c.1799T>A
- NP_004324.2:p.Val600Glu
- NC_000007.13:g.140453136A>T
- ENST00000288602.6:c.1799T>A
### Molecular Profiles
Id: 12
Molecular Profile Score: 1378.5
Name: BRAF V600E
#### Evidence Items
Description:
BRAF V600E is shown to be associated with the tall-cell variant of
papillary thyroid cancer.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: DIAGNOSTIC
Flagged: False
Id: 79
Name: EID79
Significance: POSITIVE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1781
Display Name: Thyroid Cancer
Doid: 1781
Id: 16
Link: /diseases/16
Name: Thyroid Cancer
##### My Disease Info
Do Def:
An endocrine gland cancer located in the thyroid gland located in the
neck below the thyroid cartilage.
Icd10: C73
Mesh: D013964
Mondo Id: MONDO:0002108
Ncit: C3414, C7510
Disease Aliases:
- Malignant Neoplasm Of Thyroid Gland
- Malignant Tumour Of Thyroid Gland
- Neoplasm Of Thyroid Gland
- Thyroid Gland Cancer
- Thyroid Gland Neoplasm
- Thyroid Neoplasm
##### Molecular Profile
Id: 12
##### Source
Abstract:
This study was designed to examine the aggressive features of BRAF-
positive papillary thyroid cancer (PTC) and association with age.We
compared the clinicopathologic parameters and BRAF V600E mutation status
of 121 elderly (age ≥65 years) PTC patients who underwent thyroidectomy
from January 2007 to December 2009 to a consecutive cohort of 98 younger
(age <65 years) PTC patients.Younger and elderly PTC patients had
similar incidences of BRAF-positive tumors (41% vs. 38%; p = 0.67). The
elderly cohort was more likely to have smaller tumors (mean 1.6 vs. 2.1
cm; p = 0.001), present with advanced TNM stage (36% vs. 19%; p =
0.008), and have persistent/recurrent disease (10% vs. 1%; p = 0.006).
BRAF-positive status was associated with PTC that were tall cell variant
(p < 0.001), had extrathyroidal extension (p < 0.001), lymph node
involvement (p = 0.008), advanced (III/IV) TNM stage (p < 0.001), and
disease recurrence (p < 0.001). Except for lymph node involvement, the
association between aggressive histology characteristics at presentation
and BRAF-positive PTC also was observed within the age-defined cohorts.
In short-term follow-up (mean, 18 months), persistent/recurrent PTC was
much more likely to occur in patients who were both BRAF-positive and
elderly (22%).BRAF mutations are equally present in younger and older
patients. Aggressive histology characteristics at presentation are
associated with BRAF-positive PTC, irrespective of age. However, the
well-established association of BRAF with recurrence is limited to older
(age ≥65 years) patients.
Author String:
Gina M Howell, Sally E Carty, Michaele J Armstrong, Shane O Lebeau,
Steven P Hodak, Christopher Coyne, Michael T Stang, Kelly L McCoy,
Marina N Nikiforova, Yuri E Nikiforov, Linwah Yip
Citation: Howell et al., 2011
Citation Id: 21594703
Id: 93
Journal: Ann Surg Oncol
Link: /sources/93
Name: PubMed: Howell et al., 2011
Open Access: False
Publication Date: 2011-12
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21594703
Title:
Both BRAF V600E mutation and older age (≥ 65 years) are associated with
recurrent papillary thyroid cancer.
#### Evidence Items
Description:
Dabrafenib with trametinib provides higher response rate and lower
toxicity (as compared to chemotherapy) in patients with melanoma.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 5
Evidence Type: PREDICTIVE
Flagged: False
Id: 95
Name: EID95
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Dabrafenib and trametinib were approved for use as monotherapies in
BRAF-mutant metastatic melanoma by the U.S. Food and Drug Administration
(FDA) in 2013, and most recently, their use in combination has received
accelerated FDA approval. Both drugs target the mitogen-activated
protein kinase (MAPK) pathway: dabrafenib selectively inhibits mutant
BRAF that constitutively activates the pathway, and trametinib
selectively inhibits MEK1 and MEK2 proteins activated by RAF kinases.
The phase III study of dabrafenib in BRAF(V600E) metastatic melanoma
reported rapid tumor regression in most patients and a 59% objective
RECIST response rate. The median progression-free survival (PFS) and
overall survival (OS) were improved compared with dacarbazine.
Toxicities were well tolerated and different from those reported for
vemurafenib, the first FDA-approved BRAF inhibitor. Efficacy has been
demonstrated in other BRAF-mutant genotypes. The phase III study of
trametinib in BRAF inhibitor-naïve patients with BRAF(V600E) or
BRAF(V600K) also showed benefit with a prolonged median PFS and OS
compared with chemotherapy. Trametinib is ineffective in patients who
have progressed on BRAF inhibitors. A phase II trial of combined
dabrafenib and trametinib demonstrated higher response rates and longer
median PFS than dabrafenib monotherapy, with less cutaneous toxicity.
Here, we review the clinical development of both drugs as monotherapies
and in combination, and discuss their role in the management of BRAF-
mutant melanoma.
Author String: Alexander M Menzies, Georgina V Long
Citation: Menzies et al., 2014
Citation Id: 24583796
Id: 105
Journal: Clin Cancer Res
Link: /sources/105
Name: PubMed: Menzies et al., 2014
Open Access: False
Publication Date: 2014-4-15
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24583796
Title:
Dabrafenib and trametinib, alone and in combination for BRAF-mutant
metastatic melanoma.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
BRAF V600E is correlated with shorter disease-free and overall Survival
in a Spanish cohort of melanoma patients.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PROGNOSTIC
Flagged: False
Id: 104
Name: EID104
Significance: POOR_OUTCOME
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
BRAF mutations are frequent in melanoma but their prognostic
significance remains unclear.We sought to further evaluate the
prognostic value of BRAF mutations in localized cutaneous melanoma.We
undertook an observational retrospective study of 147 patients with
localized invasive (stages I and II) cutaneous melanomas to determine
the prognostic value of BRAF mutation status.After a median follow-up of
48 months, patients with localized melanomas with BRAF-mutant melanomas
exhibited poorer disease-free survival than those with BRAF-wt genotype
(hazard ratio 2.2, 95% confidence interval 1.1-4.3) even after
adjustment for Breslow thickness, tumor ulceration, location, age, sex,
and tumor mitotic rate.The retrospective design and the small number of
events are limitations.Our findings suggest that reappraisal of clinical
treatment approaches for patients with localized melanoma harboring
tumors with BRAF mutation might be warranted.
Author String:
Eduardo Nagore, Celia Requena, Víctor Traves, Carlos Guillen, Nicholas K
Hayward, David C Whiteman, Elke Hacker
Citation: Nagore et al., 2014
Citation Id: 24388723
Id: 111
Journal: J Am Acad Dermatol
Link: /sources/111
Name: PubMed: Nagore et al., 2014
Open Access: False
Publication Date: 2014-5
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24388723
Title: Prognostic value of BRAF mutations in localized cutaneous melanoma.
#### Evidence Items
Description:
In the setting of BRAF(V600E), NF1 loss resulted in elevated activation
of RAS-GTP and resistance to RAF inhibitors.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 90
Name: EID90
Significance: RESISTANCE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Melanoma is a disease characterized by lesions that activate ERK.
Although 70% of cutaneous melanomas harbor activating mutations in the
BRAF and NRAS genes, the alterations that drive tumor progression in the
remaining 30% are largely undefined. Vemurafenib, a selective inhibitor
of RAF kinases, has clinical utility restricted to BRAF-mutant tumors.
MEK inhibitors, which have shown clinical activity in NRAS-mutant
melanoma, may be effective in other ERK pathway-dependent settings.
Here, we investigated a panel of melanoma cell lines wild type for BRAF
and NRAS to determine the genetic alteration driving their
transformation and their dependence on ERK signaling in order to
elucidate a candidate set for MEK inhibitor treatment. A cohort of the
BRAF/RAS wild type cell lines with high levels of RAS-GTP had loss of
NF1, a RAS GTPase activating protein. In these cell lines, the MEK
inhibitor PD0325901 inhibited ERK phosphorylation, but also relieved
feedback inhibition of RAS, resulting in induction of pMEK and a rapid
rebound in ERK signaling. In contrast, the MEK inhibitor trametinib
impaired the adaptive response of cells to ERK inhibition, leading to
sustained suppression of ERK signaling and significant antitumor
effects. Notably, alterations in NF1 frequently co-occurred with RAS and
BRAF alterations in melanoma. In the setting of BRAF(V600E), NF1 loss
abrogated negative feedback on RAS activation, resulting in elevated
activation of RAS-GTP and resistance to RAF, but not MEK, inhibitors. We
conclude that loss of NF1 is common in cutaneous melanoma and is
associated with RAS activation, MEK-dependence, and resistance to RAF
inhibition.
Author String:
Moriah H Nissan, Christine A Pratilas, Alexis M Jones, Ricardo Ramirez,
Helen Won, Cailian Liu, Shakuntala Tiwari, Li Kong, Aphrothiti J
Hanrahan, Zhan Yao, Taha Merghoub, Antoni Ribas, Paul B Chapman, Rona
Yaeger, Barry S Taylor, Nikolaus Schultz, Michael F Berger, Neal Rosen,
David B Solit
Citation: Nissan et al., 2014
Citation Id: 24576830
Id: 98
Journal: Cancer Res
Link: /sources/98
Name: PubMed: Nissan et al., 2014
Open Access: True
Pmc Id: PMC4005042
Publication Date: 2014-4-15
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24576830
Title:
Loss of NF1 in cutaneous melanoma is associated with RAS activation and
MEK dependence.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
BRAF V600E is correlated with poor prognosis in papillary thyroid cancer
in a study of 187 patients with PTC and other thyroid diseases.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PROGNOSTIC
Flagged: False
Id: 106
Name: EID106
Significance: POOR_OUTCOME
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3969
Display Name: Papillary Thyroid Carcinoma
Doid: 3969
Id: 156
Link: /diseases/156
Name: Papillary Thyroid Carcinoma
##### My Disease Info
Do Def:
A differentiated thyroid gland carcinoma that is characterized by the
small mushroom shape of the tumor which has a stem attached to the
epithelial layer and arises from the follicular cells of the thyroid
gland.
Icdo: 8260/3
Mesh: D000077273
Mondo Id: MONDO:0005075
Ncit: C4035
Disease Aliases:
- Papillary Carcinoma Of The Thyroid Gland
- Papillary Carcinoma Of Thyroid
- Thyroid Gland Papillary Carcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
The aim of the present study was to investigate the prevalence of the
BRAF V600E mutation in papillary thyroid carcinoma (PTC) and to
determine the correlation between this mutation and indicators of poor
prognosis and outcome in patients with PTC. The BRAF V600E mutation
status was analyzed in 187 tumor samples using the multiplex allele-
specific PCR method. Univariate and multivariate analyses were performed
to investigate the association of the BRAF V600E mutation with clinical
features and patient outcome. The sensitivity of the multiplex allele-
specific PCR combined with denaturing high-performance liquid
chromatography reached ~1%. The BRAF V600E mutation was observed in
63.6% (119/187) of tumor tissues, predominantly in PTC specimens, and no
BRAF mutation was identified in other benign-type thyroid diseases. The
univariate analysis indicated that the BRAF V600E mutation was
associated with age, tumor stage and prognosis (P<0.05). In addition,
the frequency of the BRAF V600E mutation was significantly different in
the central (75.3%) and lateral neck (49.3%) lymph nodes of patients
with lymph node metastasis. Multivariate logistic regression analysis
showed that the BRAF V600E mutation (HR, 2.471; 95% CI, 1.149-5.312) and
lymph node metastasis (HR, 3.003; 95% CI, 1.027-8.771) are independent
factors that predict tumor prognosis. Thus, the BRAF V600E mutation is
an independent risk factor that may be used to predict thyroid cancer
persistence/recurrence.
Author String: Guoping He, Baojian Zhao, Xu Zhang, Rixiang Gong
Citation: He et al., 2014
Citation Id: 24396464
Id: 112
Journal: Oncol Lett
Link: /sources/112
Name: PubMed: He et al., 2014
Open Access: True
Pmc Id: PMC3881916
Publication Date: 2014-2
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24396464
Title:
Prognostic value of the BRAF V600E mutation in papillary thyroid
carcinoma.
#### Evidence Items
Description:
V600E is correlated with disease recurrence in both age cohorts (>65 and
<65 yo).
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PROGNOSTIC
Flagged: False
Id: 107
Name: EID107
Significance: POOR_OUTCOME
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3969
Display Name: Papillary Thyroid Carcinoma
Doid: 3969
Id: 156
Link: /diseases/156
Name: Papillary Thyroid Carcinoma
##### My Disease Info
Do Def:
A differentiated thyroid gland carcinoma that is characterized by the
small mushroom shape of the tumor which has a stem attached to the
epithelial layer and arises from the follicular cells of the thyroid
gland.
Icdo: 8260/3
Mesh: D000077273
Mondo Id: MONDO:0005075
Ncit: C4035
Disease Aliases:
- Papillary Carcinoma Of The Thyroid Gland
- Papillary Carcinoma Of Thyroid
- Thyroid Gland Papillary Carcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
This study was designed to examine the aggressive features of BRAF-
positive papillary thyroid cancer (PTC) and association with age.We
compared the clinicopathologic parameters and BRAF V600E mutation status
of 121 elderly (age ≥65 years) PTC patients who underwent thyroidectomy
from January 2007 to December 2009 to a consecutive cohort of 98 younger
(age <65 years) PTC patients.Younger and elderly PTC patients had
similar incidences of BRAF-positive tumors (41% vs. 38%; p = 0.67). The
elderly cohort was more likely to have smaller tumors (mean 1.6 vs. 2.1
cm; p = 0.001), present with advanced TNM stage (36% vs. 19%; p =
0.008), and have persistent/recurrent disease (10% vs. 1%; p = 0.006).
BRAF-positive status was associated with PTC that were tall cell variant
(p < 0.001), had extrathyroidal extension (p < 0.001), lymph node
involvement (p = 0.008), advanced (III/IV) TNM stage (p < 0.001), and
disease recurrence (p < 0.001). Except for lymph node involvement, the
association between aggressive histology characteristics at presentation
and BRAF-positive PTC also was observed within the age-defined cohorts.
In short-term follow-up (mean, 18 months), persistent/recurrent PTC was
much more likely to occur in patients who were both BRAF-positive and
elderly (22%).BRAF mutations are equally present in younger and older
patients. Aggressive histology characteristics at presentation are
associated with BRAF-positive PTC, irrespective of age. However, the
well-established association of BRAF with recurrence is limited to older
(age ≥65 years) patients.
Author String:
Gina M Howell, Sally E Carty, Michaele J Armstrong, Shane O Lebeau,
Steven P Hodak, Christopher Coyne, Michael T Stang, Kelly L McCoy,
Marina N Nikiforova, Yuri E Nikiforov, Linwah Yip
Citation: Howell et al., 2011
Citation Id: 21594703
Id: 93
Journal: Ann Surg Oncol
Link: /sources/93
Name: PubMed: Howell et al., 2011
Open Access: False
Publication Date: 2011-12
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21594703
Title:
Both BRAF V600E mutation and older age (≥ 65 years) are associated with
recurrent papillary thyroid cancer.
#### Evidence Items
Description:
BRAF mutation correlated with poor prognosis in papillary thyroid cancer
in both older (>65 yo) and younger (<65 yo) cohorts.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PROGNOSTIC
Flagged: False
Id: 105
Name: EID105
Significance: POOR_OUTCOME
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3969
Display Name: Papillary Thyroid Carcinoma
Doid: 3969
Id: 156
Link: /diseases/156
Name: Papillary Thyroid Carcinoma
##### My Disease Info
Do Def:
A differentiated thyroid gland carcinoma that is characterized by the
small mushroom shape of the tumor which has a stem attached to the
epithelial layer and arises from the follicular cells of the thyroid
gland.
Icdo: 8260/3
Mesh: D000077273
Mondo Id: MONDO:0005075
Ncit: C4035
Disease Aliases:
- Papillary Carcinoma Of The Thyroid Gland
- Papillary Carcinoma Of Thyroid
- Thyroid Gland Papillary Carcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
This study was designed to examine the aggressive features of BRAF-
positive papillary thyroid cancer (PTC) and association with age.We
compared the clinicopathologic parameters and BRAF V600E mutation status
of 121 elderly (age ≥65 years) PTC patients who underwent thyroidectomy
from January 2007 to December 2009 to a consecutive cohort of 98 younger
(age <65 years) PTC patients.Younger and elderly PTC patients had
similar incidences of BRAF-positive tumors (41% vs. 38%; p = 0.67). The
elderly cohort was more likely to have smaller tumors (mean 1.6 vs. 2.1
cm; p = 0.001), present with advanced TNM stage (36% vs. 19%; p =
0.008), and have persistent/recurrent disease (10% vs. 1%; p = 0.006).
BRAF-positive status was associated with PTC that were tall cell variant
(p < 0.001), had extrathyroidal extension (p < 0.001), lymph node
involvement (p = 0.008), advanced (III/IV) TNM stage (p < 0.001), and
disease recurrence (p < 0.001). Except for lymph node involvement, the
association between aggressive histology characteristics at presentation
and BRAF-positive PTC also was observed within the age-defined cohorts.
In short-term follow-up (mean, 18 months), persistent/recurrent PTC was
much more likely to occur in patients who were both BRAF-positive and
elderly (22%).BRAF mutations are equally present in younger and older
patients. Aggressive histology characteristics at presentation are
associated with BRAF-positive PTC, irrespective of age. However, the
well-established association of BRAF with recurrence is limited to older
(age ≥65 years) patients.
Author String:
Gina M Howell, Sally E Carty, Michaele J Armstrong, Shane O Lebeau,
Steven P Hodak, Christopher Coyne, Michael T Stang, Kelly L McCoy,
Marina N Nikiforova, Yuri E Nikiforov, Linwah Yip
Citation: Howell et al., 2011
Citation Id: 21594703
Id: 93
Journal: Ann Surg Oncol
Link: /sources/93
Name: PubMed: Howell et al., 2011
Open Access: False
Publication Date: 2011-12
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21594703
Title:
Both BRAF V600E mutation and older age (≥ 65 years) are associated with
recurrent papillary thyroid cancer.
#### Evidence Items
Description:
In patients with multiple myeloma, those with BRAF V600E had shorter
overall survival than wild-type.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PROGNOSTIC
Flagged: False
Id: 463
Name: EID463
Significance: POOR_OUTCOME
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9538
Display Name: Multiple Myeloma
Doid: 9538
Id: 41
Link: /diseases/41
Name: Multiple Myeloma
##### My Disease Info
Do Def: A myeloid neoplasm that is located_in the plasma cells in bone marrow.
Icd10: C90.0
Mesh: D009101
Mondo Id: MONDO:0009693
Ncit: C3242
Disease Aliases: Myeloma
##### Molecular Profile
Id: 12
##### Source
Abstract:
In multiple myeloma, there has been little progress in the specific
therapeutic targeting of oncogenic mutations. Whole-genome sequencing
data have recently revealed that a subset of patients carry an
activating mutation (V600E) in the BRAF kinase. To uncover the clinical
relevance of this mutation in multiple myeloma, we correlated the
mutation status in primary tumor samples from 379 patients with myeloma
with disease outcome. We found a significantly higher incidence of
extramedullary disease and a shorter overall survival in mutation
carriers when compared with controls. Most importantly, we report on a
patient with confirmed BRAF V600E mutation and relapsed myeloma with
extensive extramedullary disease, refractory to all approved therapeutic
options, who has rapidly and durably responded to low doses of the
mutation-specific BRAF inhibitor vermurafenib. Collectively, we provide
evidence for the development of the BRAF V600E mutation in the context
of clonal evolution and describe the prognostic and therapeutic
relevance of this targetable mutation.
Author String:
Mindaugas Andrulis, Nicola Lehners, David Capper, Roland Penzel,
Christoph Heining, Jennifer Huellein, Thorsten Zenz, Andreas von
Deimling, Peter Schirmacher, Anthony D Ho, Hartmut Goldschmidt, Kai
Neben, Marc S Raab
Citation: Andrulis et al., 2013
Citation Id: 23612012
Id: 278
Journal: Cancer Discov
Link: /sources/278
Name: PubMed: Andrulis et al., 2013
Open Access: False
Publication Date: 2013-8
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23612012
Title: Targeting the BRAF V600E mutation in multiple myeloma.
#### Evidence Items
Description:
An inducible BRAF-V600E mouse melanoma model has shown a tight
correlation between activated BRAF and disease progression.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 2123
Name: EID2123
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
The usual paradigm for developing kinase inhibitors in oncology is to
use a high-affinity proof-of-concept inhibitor with acceptable metabolic
properties for key target validation experiments. This approach requires
substantial medicinal chemistry and can be confounded by drug toxicity
and off-target activities of the test molecule. As a better alternative,
we have developed inducible short-hairpin RNA xenograft models to
examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results
show that tumor regression resulting from BRAF suppression is inducible,
reversible, and tightly regulated in these models. Analysis of
regressing tumors showed the primary mechanism of action for BRAF to be
increased tumor cell proliferation and survival. In a metastatic
melanoma model, conditional BRAF suppression slowed systemic tumor
growth as determined by in vivo bioluminescence imaging. Taken together,
gain-of-function BRAF signaling is strongly associated with in vivo
tumorigenicity, confirming BRAF as an important target for small-
molecule and RNA interference-based therapeutics.
Author String:
Klaus P Hoeflich, Daniel C Gray, Michael T Eby, Janet Y Tien, Leo Wong,
Janeko Bower, Alvin Gogineni, Jiping Zha, Mary J Cole, Howard M Stern,
Lesley J Murray, David P Davis, Somasekar Seshagiri
Citation: Hoeflich et al., 2006
Citation Id: 16424035
Id: 1485
Journal: Cancer Res
Link: /sources/1485
Name: PubMed: Hoeflich et al., 2006
Open Access: False
Publication Date: 2006-1-15
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16424035
Title:
Oncogenic BRAF is required for tumor growth and maintenance in melanoma
models.
##### Therapies
Deprecated: False
Id: 6
Link: /therapies/6
Name: Sorafenib
#### Evidence Items
Description:
An inducible BRAF-V600E mouse melanoma model shows a tight correlation
between activated BRAF and disease progression.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 2128
Name: EID2128
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
The usual paradigm for developing kinase inhibitors in oncology is to
use a high-affinity proof-of-concept inhibitor with acceptable metabolic
properties for key target validation experiments. This approach requires
substantial medicinal chemistry and can be confounded by drug toxicity
and off-target activities of the test molecule. As a better alternative,
we have developed inducible short-hairpin RNA xenograft models to
examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results
show that tumor regression resulting from BRAF suppression is inducible,
reversible, and tightly regulated in these models. Analysis of
regressing tumors showed the primary mechanism of action for BRAF to be
increased tumor cell proliferation and survival. In a metastatic
melanoma model, conditional BRAF suppression slowed systemic tumor
growth as determined by in vivo bioluminescence imaging. Taken together,
gain-of-function BRAF signaling is strongly associated with in vivo
tumorigenicity, confirming BRAF as an important target for small-
molecule and RNA interference-based therapeutics.
Author String:
Klaus P Hoeflich, Daniel C Gray, Michael T Eby, Janet Y Tien, Leo Wong,
Janeko Bower, Alvin Gogineni, Jiping Zha, Mary J Cole, Howard M Stern,
Lesley J Murray, David P Davis, Somasekar Seshagiri
Citation: Hoeflich et al., 2006
Citation Id: 16424035
Id: 1485
Journal: Cancer Res
Link: /sources/1485
Name: PubMed: Hoeflich et al., 2006
Open Access: False
Publication Date: 2006-1-15
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16424035
Title:
Oncogenic BRAF is required for tumor growth and maintenance in melanoma
models.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
#### Evidence Items
Description:
In the setting of BRAF(V600E), NF1 loss resulted in elevated activation
of RAS-GTP but does not show resistance to MEK inhibitors.
Evidence Direction: DOES_NOT_SUPPORT
Evidence Level: D
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 86
Name: EID86
Significance: RESISTANCE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Melanoma is a disease characterized by lesions that activate ERK.
Although 70% of cutaneous melanomas harbor activating mutations in the
BRAF and NRAS genes, the alterations that drive tumor progression in the
remaining 30% are largely undefined. Vemurafenib, a selective inhibitor
of RAF kinases, has clinical utility restricted to BRAF-mutant tumors.
MEK inhibitors, which have shown clinical activity in NRAS-mutant
melanoma, may be effective in other ERK pathway-dependent settings.
Here, we investigated a panel of melanoma cell lines wild type for BRAF
and NRAS to determine the genetic alteration driving their
transformation and their dependence on ERK signaling in order to
elucidate a candidate set for MEK inhibitor treatment. A cohort of the
BRAF/RAS wild type cell lines with high levels of RAS-GTP had loss of
NF1, a RAS GTPase activating protein. In these cell lines, the MEK
inhibitor PD0325901 inhibited ERK phosphorylation, but also relieved
feedback inhibition of RAS, resulting in induction of pMEK and a rapid
rebound in ERK signaling. In contrast, the MEK inhibitor trametinib
impaired the adaptive response of cells to ERK inhibition, leading to
sustained suppression of ERK signaling and significant antitumor
effects. Notably, alterations in NF1 frequently co-occurred with RAS and
BRAF alterations in melanoma. In the setting of BRAF(V600E), NF1 loss
abrogated negative feedback on RAS activation, resulting in elevated
activation of RAS-GTP and resistance to RAF, but not MEK, inhibitors. We
conclude that loss of NF1 is common in cutaneous melanoma and is
associated with RAS activation, MEK-dependence, and resistance to RAF
inhibition.
Author String:
Moriah H Nissan, Christine A Pratilas, Alexis M Jones, Ricardo Ramirez,
Helen Won, Cailian Liu, Shakuntala Tiwari, Li Kong, Aphrothiti J
Hanrahan, Zhan Yao, Taha Merghoub, Antoni Ribas, Paul B Chapman, Rona
Yaeger, Barry S Taylor, Nikolaus Schultz, Michael F Berger, Neal Rosen,
David B Solit
Citation: Nissan et al., 2014
Citation Id: 24576830
Id: 98
Journal: Cancer Res
Link: /sources/98
Name: PubMed: Nissan et al., 2014
Open Access: True
Pmc Id: PMC4005042
Publication Date: 2014-4-15
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24576830
Title:
Loss of NF1 in cutaneous melanoma is associated with RAS activation and
MEK dependence.
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
##### Therapies
Deprecated: False
Id: 29
Link: /therapies/29
Name: Mirdametinib
#### Evidence Items
Description:
In a mouse in vivo study of MEK protein inhibitor, PD-0325901, was able
to suppress growth of SKMEL28 BRAF-V600E xenograft tumors (P<0.01). The
reduction of growth was associated with loss of D-cyclin expression and
induction of p27.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 2124
Name: EID2124
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
The kinase pathway comprising RAS, RAF, mitogen-activated protein kinase
kinase (MEK) and extracellular signal regulated kinase (ERK) is
activated in most human tumours, often through gain-of-function
mutations of RAS and RAF family members. Using small-molecule inhibitors
of MEK and an integrated genetic and pharmacologic analysis, we find
that mutation of BRAF is associated with enhanced and selective
sensitivity to MEK inhibition when compared to either 'wild-type' cells
or cells harbouring a RAS mutation. This MEK dependency was observed in
BRAF mutant cells regardless of tissue lineage, and correlated with both
downregulation of cyclin D1 protein expression and the induction of G1
arrest. Pharmacological MEK inhibition completely abrogated tumour
growth in BRAF mutant xenografts, whereas RAS mutant tumours were only
partially inhibited. These data suggest an exquisite dependency on MEK
activity in BRAF mutant tumours, and offer a rational therapeutic
strategy for this genetically defined tumour subtype.
Author String:
David B Solit, Levi A Garraway, Christine A Pratilas, Ayana Sawai, Gad
Getz, Andrea Basso, Qing Ye, Jose M Lobo, Yuhong She, Iman Osman, Todd R
Golub, Judith Sebolt-Leopold, William R Sellers, Neal Rosen
Citation: Solit et al., 2006
Citation Id: 16273091
Id: 1487
Journal: Nature
Link: /sources/1487
Name: PubMed: Solit et al., 2006
Open Access: True
Pmc Id: PMC3306236
Publication Date: 2006-1-19
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16273091
Title: BRAF mutation predicts sensitivity to MEK inhibition.
##### Therapies
Deprecated: False
Id: 29
Link: /therapies/29
Name: Mirdametinib
#### Evidence Items
Description:
An inducible BRAF-V600E mouse melanoma model shows a tight correlation
between activated BRAF and disease progression.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 2125
Name: EID2125
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
The usual paradigm for developing kinase inhibitors in oncology is to
use a high-affinity proof-of-concept inhibitor with acceptable metabolic
properties for key target validation experiments. This approach requires
substantial medicinal chemistry and can be confounded by drug toxicity
and off-target activities of the test molecule. As a better alternative,
we have developed inducible short-hairpin RNA xenograft models to
examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results
show that tumor regression resulting from BRAF suppression is inducible,
reversible, and tightly regulated in these models. Analysis of
regressing tumors showed the primary mechanism of action for BRAF to be
increased tumor cell proliferation and survival. In a metastatic
melanoma model, conditional BRAF suppression slowed systemic tumor
growth as determined by in vivo bioluminescence imaging. Taken together,
gain-of-function BRAF signaling is strongly associated with in vivo
tumorigenicity, confirming BRAF as an important target for small-
molecule and RNA interference-based therapeutics.
Author String:
Klaus P Hoeflich, Daniel C Gray, Michael T Eby, Janet Y Tien, Leo Wong,
Janeko Bower, Alvin Gogineni, Jiping Zha, Mary J Cole, Howard M Stern,
Lesley J Murray, David P Davis, Somasekar Seshagiri
Citation: Hoeflich et al., 2006
Citation Id: 16424035
Id: 1485
Journal: Cancer Res
Link: /sources/1485
Name: PubMed: Hoeflich et al., 2006
Open Access: False
Publication Date: 2006-1-15
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16424035
Title:
Oncogenic BRAF is required for tumor growth and maintenance in melanoma
models.
##### Therapies
Deprecated: False
Id: 29
Link: /therapies/29
Name: Mirdametinib
#### Evidence Items
Description:
Acquired resistance to vemurafenib in BRAF-V600E positive melanomas
frequently confound vemurafenib therapy.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 2127
Name: EID2127
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
The identification of somatic mutations in the gene encoding the serine-
threonine protein kinase B-RAF (BRAF) in the majority of melanomas
offers an opportunity to test oncogene-targeted therapy for this
disease.We conducted a multicenter, phase 1, dose-escalation trial of
PLX4032 (also known as RG7204), an orally available inhibitor of mutated
BRAF, followed by an extension phase involving the maximum dose that
could be administered without adverse effects (the recommended phase 2
dose). Patients received PLX4032 twice daily until they had disease
progression. Pharmacokinetic analysis and tumor-response assessments
were conducted in all patients. In selected patients, tumor biopsy was
performed before and during treatment to validate BRAF inhibition.A
total of 55 patients (49 of whom had melanoma) were enrolled in the
dose-escalation phase, and 32 additional patients with metastatic
melanoma who had BRAF with the V600E mutation were enrolled in the
extension phase. The recommended phase 2 dose was 960 mg twice daily,
with increases in the dose limited by grade 2 or 3 rash, fatigue, and
arthralgia. In the dose-escalation cohort, among the 16 patients with
melanoma whose tumors carried the V600E BRAF mutation and who were
receiving 240 mg or more of PLX4032 twice daily, 10 had a partial
response and 1 had a complete response. Among the 32 patients in the
extension cohort, 24 had a partial response and 2 had a complete
response. The estimated median progression-free survival among all
patients was more than 7 months.Treatment of metastatic melanoma with
PLX4032 in patients with tumors that carry the V600E BRAF mutation
resulted in complete or partial tumor regression in the majority of
patients. (Funded by Plexxikon and Roche Pharmaceuticals.)
Author String:
Keith T Flaherty, Igor Puzanov, Kevin B Kim, Antoni Ribas, Grant A
McArthur, Jeffrey A Sosman, Peter J O'Dwyer, Richard J Lee, Joseph F
Grippo, Keith Nolop, Paul B Chapman
Citation: Flaherty et al., 2010
Citation Id: 20818844
Id: 352
Journal: N Engl J Med
Link: /sources/352
Name: PubMed: Flaherty et al., 2010
Open Access: True
Pmc Id: PMC3724529
Publication Date: 2010-8-26
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/20818844
Title: Inhibition of mutated, activated BRAF in metastatic melanoma.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
#### Evidence Items
Description:
Acquired resistance to vemurafenib in BRAF-V600E positive melanomas
frequently confound vemurafenib therapy.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 2133
Name: EID2133
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Oncogenic mutations in the serine/threonine kinase B-RAF (also known as
BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies
have demonstrated that the B-RAF(V600E) mutation predicts a dependency
on the mitogen-activated protein kinase (MAPK) signalling cascade in
melanoma-an observation that has been validated by the success of RAF
and MEK inhibitors in clinical trials. However, clinical responses to
targeted anticancer therapeutics are frequently confounded by de novo or
acquired resistance. Identification of resistance mechanisms in a manner
that elucidates alternative 'druggable' targets may inform effective
long-term treatment strategies. Here we expressed ∼600 kinase and
kinase-related open reading frames (ORFs) in parallel to interrogate
resistance to a selective RAF kinase inhibitor. We identified MAP3K8
(the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives
resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates
ERK primarily through MEK-dependent mechanisms that do not require RAF
signalling. Moreover, COT expression is associated with de novo
resistance in B-RAF(V600E) cultured cell lines and acquired resistance
in melanoma cells and tissue obtained from relapsing patients following
treatment with MEK or RAF inhibitors. We further identify combinatorial
MAPK pathway inhibition or targeting of COT kinase activity as possible
therapeutic strategies for reducing MAPK pathway activation in this
setting. Together, these results provide new insights into resistance
mechanisms involving the MAPK pathway and articulate an integrative
approach through which high-throughput functional screens may inform the
development of novel therapeutic strategies.
Author String:
Cory M Johannessen, Jesse S Boehm, So Young Kim, Sapana R Thomas, Leslie
Wardwell, Laura A Johnson, Caroline M Emery, Nicolas Stransky,
Alexandria P Cogdill, Jordi Barretina, Giordano Caponigro, Haley
Hieronymus, Ryan R Murray, Kourosh Salehi-Ashtiani, David E Hill, Marc
Vidal, Jean J Zhao, Xiaoping Yang, Ozan Alkan, Sungjoon Kim, Jennifer L
Harris, Christopher J Wilson, Vic E Myer, Peter M Finan, David E Root,
Thomas M Roberts, Todd Golub, Keith T Flaherty, Reinhard Dummer, Barbara
L Weber, William R Sellers, Robert Schlegel, Jennifer A Wargo, William C
Hahn, Levi A Garraway
Citation: Johannessen et al., 2010
Citation Id: 21107320
Id: 1492
Journal: Nature
Link: /sources/1492
Name: PubMed: Johannessen et al., 2010
Open Access: True
Pmc Id: PMC3058384
Publication Date: 2010-12-16
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21107320
Title:
COT drives resistance to RAF inhibition through MAP kinase pathway
reactivation.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
#### Evidence Items
Description:
In a mouse in vivo study, the MEK protein inhibitor selumetinib
suppressed the growth of 1205Lu xenograft tumors, which contains the
BRAF-V600Emutation (0.91 +/- 0.10-fold volume increase vs. 9.47 +/-
2.14-fold for non-treated mice). These tumors had a concomitant
reduction of BrdU positive cells (P=0.009) but no increase in apoptosis.
Selumetinib, in combination with docetaxel, a chemotherapeutic agent,
produced cycle arrest and elevated apoptosis.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 2129
Name: EID2129
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Disseminated melanoma is highly therapy resistant. The finding that 66%
of melanomas harbor the activating BRAF(V600E) mutation has raised
expectations for targeting the Ras/RAF/mitogen-activated protein
(MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK
pathway in melanoma. This study addresses the anti-melanoma activity of
the MEK inhibitor AZD6244 (ARRY-142886).We recently have shown that
growing melanoma cells as three-dimensional collagen-implanted spheroids
enhances resistance to the MEK inhibitor U0126. Here, we investigated
the anti-melanoma activity of AZD6244 in two-dimensional cell culture,
the three-dimensional spheroid model, and an in vivo model.In two-
dimensional cell culture, AZD6244 was cytostatic and reduced the growth
of melanoma cells in a concentration-dependent fashion through the
induction of G(1)-phase cell cycle arrest. In our three-dimensional
spheroid model, the effects of AZD6244 were largely cytostatic and
reversible, with drug washout leading to spheroid regrowth. Finally,
1205Lu cells were grown as tumor xenografts in severe combined
immunodeficient mice. After tumor establishment, mice were dosed twice
daily with 0, 10, or 30 mg/kg AZD6244 p.o. AZD6244 treatment decreased
phospho-ERK in the tumors and significantly suppressed tumor growth. The
original tumors remained viable, suggesting that AZD6244 monotherapy was
largely cytostatic, and not proapoptotic in this model. Further studies
showed that co-administration of AZD6244 (30 mg/kg) with docetaxel (15
mg/kg) led to tumor regression, indicating the potential for MEK
inhibitor/chemotherapy drug combinations.Inhibition of MEK is cytostatic
as a monotherapy in melanoma, but cytotoxic when combined with
docetaxel.
Author String:
Nikolas K Haass, Katrin Sproesser, Thiennga K Nguyen, Rooha Contractor,
C Angelica Medina, Katherine L Nathanson, Meenhard Herlyn, Keiran S M
Smalley
Citation: Haass et al., 2008
Citation Id: 18172275
Id: 1489
Journal: Clin Cancer Res
Link: /sources/1489
Name: PubMed: Haass et al., 2008
Open Access: False
Publication Date: 2008-1-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/18172275
Title:
The mitogen-activated protein/extracellular signal-regulated kinase
kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma
cells and tumor regression when combined with docetaxel.
##### Therapies
Deprecated: False
Id: 63
Link: /therapies/63
Name: Selumetinib
#### Evidence Items
Description:
In this Phase II pilot study (NCT00405587) of BRAF V600 inhibitor
vemurafenib in 21 metastatic colorectal cancer (CRC) patients with BRAF
V600E, one patient had a durable 21 week partial response, and seven
patients had 8 week stable disease as best response. Median progression
free survival was 2.1 months and median overall survival was 7.7 months.
The authors conclude that single agent vemurafenib did not show
meaningful activity in V600E CRC, in contrast to the significant
vemurafenib activity against V600 in melanoma.
Evidence Direction: DOES_NOT_SUPPORT
Evidence Level: B
Evidence Rating: 4
Evidence Type: PREDICTIVE
Flagged: False
Id: 1405
Name: EID1405
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
BRAF V600E mutation is seen in 5% to 8% of patients with metastatic
colorectal cancer (CRC) and is associated with poor prognosis.
Vemurafenib, an oral BRAF V600 inhibitor, has pronounced activity in
patients with metastatic melanoma, but its activity in patients with
BRAF V600E-positive metastatic CRC was unknown.In this multi-
institutional, open-label study, patients with metastatic CRC with BRAF
V600 mutations were recruited to an expansion cohort at the previously
determined maximum-tolerated dose of 960 mg orally twice a day.Twenty-
one patients were enrolled, of whom 20 had received at least one prior
metastatic chemotherapy regimen. Grade 3 toxicities included
keratoacanthomas, rash, fatigue, and arthralgia. Of the 21 patients
treated, one patient had a confirmed partial response (5%; 95% CI, 1% to
24%) and seven other patients had stable disease by RECIST criteria.
Median progression-free survival was 2.1 months. Patterns of concurrent
mutations, microsatellite instability status, CpG island methylation
status, PTEN loss, EGFR expression, and copy number alterations were not
associated with clinical benefit. In contrast to prior expectations,
concurrent KRAS and NRAS mutations were detected at low allele frequency
in a subset of the patients' tumors (median, 0.21% allele frequency) and
were apparent mechanisms of acquired resistance in vemurafenib-sensitive
patient-derived xenograft models.In marked contrast to the results seen
in patients with BRAF V600E-mutant melanoma, single-agent vemurafenib
did not show meaningful clinical activity in patients with BRAF V600E
mutant CRC. Combination strategies are now under development and may be
informed by the presence of intratumor heterogeneity of KRAS and NRAS
mutations.
Author String:
Scott Kopetz, Jayesh Desai, Emily Chan, Joel Randolph Hecht, Peter J
O'Dwyer, Dipen Maru, Van Morris, Filip Janku, Arvind Dasari, Woonbook
Chung, Jean-Pierre J Issa, Peter Gibbs, Brian James, Garth Powis, Keith
B Nolop, Suman Bhattacharya, Leonard Saltz
Citation: Kopetz et al., 2015
Citation Id: 26460303
Id: 953
Journal: J Clin Oncol
Link: /sources/953
Name: PubMed: Kopetz et al., 2015
Open Access: True
Pmc Id: PMC4669589
Publication Date: 2015-12-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26460303
Title:
Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-
Mutated Colorectal Cancer.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
An inducible BRAF-V600E mouse melanoma model shows a tight correlation
between activated BRAF and disease progression.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 2131
Name: EID2131
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
The usual paradigm for developing kinase inhibitors in oncology is to
use a high-affinity proof-of-concept inhibitor with acceptable metabolic
properties for key target validation experiments. This approach requires
substantial medicinal chemistry and can be confounded by drug toxicity
and off-target activities of the test molecule. As a better alternative,
we have developed inducible short-hairpin RNA xenograft models to
examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results
show that tumor regression resulting from BRAF suppression is inducible,
reversible, and tightly regulated in these models. Analysis of
regressing tumors showed the primary mechanism of action for BRAF to be
increased tumor cell proliferation and survival. In a metastatic
melanoma model, conditional BRAF suppression slowed systemic tumor
growth as determined by in vivo bioluminescence imaging. Taken together,
gain-of-function BRAF signaling is strongly associated with in vivo
tumorigenicity, confirming BRAF as an important target for small-
molecule and RNA interference-based therapeutics.
Author String:
Klaus P Hoeflich, Daniel C Gray, Michael T Eby, Janet Y Tien, Leo Wong,
Janeko Bower, Alvin Gogineni, Jiping Zha, Mary J Cole, Howard M Stern,
Lesley J Murray, David P Davis, Somasekar Seshagiri
Citation: Hoeflich et al., 2006
Citation Id: 16424035
Id: 1485
Journal: Cancer Res
Link: /sources/1485
Name: PubMed: Hoeflich et al., 2006
Open Access: False
Publication Date: 2006-1-15
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16424035
Title:
Oncogenic BRAF is required for tumor growth and maintenance in melanoma
models.
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
Proposed resistance mechanisms include PDGFRB upregulation or NRAS
mutations resulting in MAPK pathway reactivation, but not secondary
mutations in BRAF. MEK inhibitors may demonstrate clinical benefit in
vemurafenib-resistant melanoma patients.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 2132
Name: EID2132
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in
∼7% of human malignancies and ∼60% of melanomas. Early clinical
experience with a novel class I RAF-selective inhibitor, PLX4032,
demonstrated an unprecedented 80% anti-tumour response rate among
patients with B-RAF(V600E)-positive melanomas, but acquired drug
resistance frequently develops after initial responses. Hypotheses for
mechanisms of acquired resistance to B-RAF inhibition include secondary
mutations in B-RAF(V600E), MAPK reactivation, and activation of
alternative survival pathways. Here we show that acquired resistance to
PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB)
upregulation or N-RAS (also known as NRAS) mutations but not through
secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines
artificially derived from B-RAF(V600E)-positive melanoma cell lines and
validated key findings in PLX4032-resistant tumours and tumour-matched,
short-term cultures from clinical trial patients. Induction of PDGFRβ
RNA, protein and tyrosine phosphorylation emerged as a dominant feature
of acquired PLX4032 resistance in a subset of melanoma sub-lines,
patient-derived biopsies and short-term cultures. PDGFRβ-upregulated
tumour cells have low activated RAS levels and, when treated with
PLX4032, do not reactivate the MAPK pathway significantly. In another
subset, high levels of activated N-RAS resulting from mutations lead to
significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown
of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant
subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032
resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK
reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape
B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but
via receptor tyrosine kinase (RTK)-mediated activation of alternative
survival pathway(s) or activated RAS-mediated reactivation of the MAPK
pathway, suggesting additional therapeutic strategies.
Author String:
Ramin Nazarian, Hubing Shi, Qi Wang, Xiangju Kong, Richard C Koya, Hane
Lee, Zugen Chen, Mi-Kyung Lee, Narsis Attar, Hooman Sazegar, Thinle
Chodon, Stanley F Nelson, Grant McArthur, Jeffrey A Sosman, Antoni
Ribas, Roger S Lo
Citation: Nazarian et al., 2010
Citation Id: 21107323
Id: 1491
Journal: Nature
Link: /sources/1491
Name: PubMed: Nazarian et al., 2010
Open Access: True
Pmc Id: PMC3143360
Publication Date: 2010-12-16
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21107323
Title:
Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS
upregulation.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
#### Evidence Items
Description:
V600E is associated with adverse pathological features of colorectal
cancer. This can be concluded as a marker of poor prognosis.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 5
Evidence Type: PROGNOSTIC
Flagged: False
Id: 103
Name: EID103
Significance: POOR_OUTCOME
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
Colorectal cancer (CRC) is a heterogeneous disease with multiple
underlying causative genetic mutations. The B-type Raf proto-oncogene
(BRAF) plays an important role in the mitogen-activated protein kinase
(MAPK) signaling cascade during CRC. The presence of BRAFV600E mutation
can determine the response of a tumor to chemotherapy. However, the
association between the BRAFV600E mutation and the clinicopathological
features of CRC remains controversial. We performed a systematic review
and meta-analysis to estimate the effect of BRAFV600E mutation on the
clinicopathological characteristics of CRC.We identified studies that
examined the effect of BRAFV600E mutation on CRC within the PubMed, ISI
Science Citation Index, and Embase databases. The effect of BRAFV600E on
outcome parameters was estimated by odds ratios (ORs) with 95%
confidence intervals (CIs) for each study using a fixed effects or
random effects model.25 studies with a total of 11,955 CRC patients met
inclusion criteria. The rate of BRAFV600 was 10.8% (1288/11955). The
BRAFV600E mutation in CRC was associated with advanced TNM stage, poor
differentiation, mucinous histology, microsatellite instability (MSI),
CpG island methylator phenotype (CIMP). This mutation was also
associated with female gender, older age, proximal colon, and mutL
homolog 1 (MLH1) methylation.This meta-analysis demonstrated that
BRAFV600E mutation was significantly correlated with adverse
pathological features of CRC and distinct clinical characteristics.
These data suggest that BRAFV600E mutation could be used to supplement
standard clinical and pathological staging for the better management of
individual CRC patients, and could be considered as a poor prognostic
marker for CRC.
Author String:
Dong Chen, Jun-Fu Huang, Kai Liu, Li-Qun Zhang, Zhao Yang, Zheng-Ran
Chuai, Yun-Xia Wang, Da-Chuan Shi, Qing Huang, Wei-Ling Fu
Citation: Chen et al., 2014
Citation Id: 24594804
Id: 110
Journal: PLoS One
Link: /sources/110
Name: PubMed: Chen et al., 2014
Open Access: True
Pmc Id: PMC3940924
Publication Date: 2014
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24594804
Title:
BRAFV600E mutation and its association with clinicopathological features
of colorectal cancer: a systematic review and meta-analysis.
#### Evidence Items
Description:
BRAF mutations were identified in 9% of 108 cases of high-grade
colorectal neuroendocrine tumors (80% V600E). Two patients were treated
with a combination of BRAF and MEK inhibition and exhibited durable
response (beyond 7 and 9 months, respectively). Urinary BRAF V600E tumor
DNA correlated with disease response in one of the patients. BRAF and
MEK inhibition was either dabrafenib+trametinib (case 1) or
vemurafenib+trametinib (case 2).
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 1430
Name: EID1430
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:0050626
Display Name: Gastrointestinal Neuroendocrine Tumor
Doid: 0050626
Id: 53
Link: /diseases/53
Name: Gastrointestinal Neuroendocrine Tumor
##### My Disease Info
Do Def:
A gastrointestinal system cancer that has_material_basis_in
neuroendocrine cells.
Mondo Id: MONDO:0000386
Disease Aliases:
- Gastrointestinal Neuroendocrine Tumour
- Malignant Gastrointestinal Neuroendocrine Tumor
- Malignant Gastrointestinal Neuroendocrine Tumour
##### Molecular Profile
Id: 12
##### Source
Abstract:
Neuroendocrine tumors comprise a heterogeneous group of malignancies
with a broad spectrum of clinical behavior. Poorly differentiated tumors
follow an aggressive course with limited treatment options, and new
approaches are needed. Oncogenic BRAF V600E (BRAF(V600E)) substitutions
are observed primarily in melanoma, colon cancer, and non-small cell
lung cancer, but have been identified in multiple tumor types. Here, we
describe the first reported recurrent BRAF(V600E) mutations in advanced
high-grade colorectal neuroendocrine tumors and identify a BRAF
alteration frequency of 9% in 108 cases. Among these BRAF alterations,
80% were BRAF(V600E) Dramatic response to BRAF-MEK combination therapy
occurred in two cases of metastatic high-grade rectal neuroendocrine
carcinoma refractory to standard therapy. Urinary BRAF(V600E)
circulating tumor DNA monitoring paralleled disease response. Our series
represents the largest study of genomic profiling in colorectal
neuroendocrine tumors and provides strong evidence that BRAF(V600E) is
an oncogenic driver responsive to BRAF-MEK combination therapy in this
molecular subset.BRAF(V600E) is an established oncogenic driver, but
significant disparities in response exist among tumor types. Two
patients with treatment-refractory high-grade colorectal neuroendocrine
tumors harboring BRAF(V600E) exhibited rapid and durable response to
combined BRAF-MEK inhibition, providing the first clinical evidence of
efficacy in this aggressive tumor type. Cancer Discov; 6(6); 594-600.
©2016 AACR.This article is highlighted in the In This Issue feature, p.
561.
Author String:
Samuel J Klempner, Bruce Gershenhorn, Phu Tran, Thomas K Lee, Mark G
Erlander, Kyle Gowen, Alexa B Schrock, Deborah Morosini, Jeffrey S Ross,
Vincent A Miller, Philip J Stephens, Sai-Hong Ignatius Ou, Siraj M Ali
Citation: Klempner et al., 2016
Citation Id: 27048246
Id: 969
Journal: Cancer Discov
Link: /sources/969
Name: PubMed: Klempner et al., 2016
Open Access: True
Pmc Id: PMC5008024
Publication Date: 2016-6
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/27048246
Title:
BRAFV600E Mutations in High-Grade Colorectal Neuroendocrine Tumors May
Predict Responsiveness to BRAF-MEK Combination Therapy.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
The BRIM-3 Phase III trial NCT01006980 assessed BRAF inhibitor
vemurafenib versus dacarbazine in 598 patients with treatment naive
metastatic melanoma and confirmed V600E mutation. Significant
differences were seen in overall survival (13.3 months with vemurafenib
vs. 10.0 months with dacarbazine) and median progression free survival
(6.9 months with vemurafenib vs. 1.6 months with dacarbazine)
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 5
Evidence Type: PREDICTIVE
Flagged: False
Id: 1398
Name: EID1398
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
In the BRIM-3 trial, vemurafenib was associated with risk reduction
versus dacarbazine of both death and progression in patients with
advanced BRAF(V600) mutation-positive melanoma. We present an extended
follow-up analysis of the total population and in the BRAF(V600E) and
BRAF(V600K) mutation subgroups.Patients older than 18 years, with
treatment-naive metastatic melanoma and whose tumour tissue was positive
for BRAF(V600) mutations were eligible. Patients also had to have a life
expectancy of at least 3 months, an Eastern Cooperative Oncology Group
(ECOG) performance status of 0 or 1, and adequate haematological,
hepatic, and renal function. Patients were randomly assigned by
interactive voice recognition system to receive either vemurafenib (960
mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area
intravenously every 3 weeks). Coprimary endpoints were overall survival
and progression-free survival, analysed in the intention-to-treat
population (n=675), with data censored at crossover. A sensitivity
analysis was done. This trial is registered with ClinicalTrials.gov,
NCT01006980.675 eligible patients were enrolled from 104 centres in 12
countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were
randomly assigned to receive vemurafenib and 338 to receive dacarbazine.
Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5
months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially
randomly assigned to dacarbazine crossed over from dacarbazine to
vemurafenib. Median overall survival was significantly longer in the
vemurafenib group than in the dacarbazine group (13·6 months [95% CI
12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI
0·57-0·87]; p=0·0008), as was median progression-free survival (6·9
months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI
0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E)
disease, median overall survival in the vemurafenib group was 13·3
months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the
dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median
progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months
(1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the
57 (9%) patients with BRAF(V600K) disease, median overall survival in
the vemurafenib group was 14·5 months (95% CI 11·2-not estimable)
compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43
[95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9
months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30
[95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were
cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and
keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function
tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of
287 patients) in the dacarbazine group. Eight (2%) patients in the
vemurafenib group and seven (2%) in the dacarbazine group had grade 5
events.Inhibition of BRAF with vemurafenib improves survival in patients
with the most common BRAF(V600E) mutation and in patients with the less
common BRAF(V600K) mutation.F Hoffmann-La Roche-Genentech.
Author String:
Grant A McArthur, Paul B Chapman, Caroline Robert, James Larkin, John B
Haanen, Reinhard Dummer, Antoni Ribas, David Hogg, Omid Hamid, Paolo A
Ascierto, Claus Garbe, Alessandro Testori, Michele Maio, Paul Lorigan,
Celeste Lebbé, Thomas Jouary, Dirk Schadendorf, Stephen J O'Day, John M
Kirkwood, Alexander M Eggermont, Brigitte Dréno, Jeffrey A Sosman, Keith
T Flaherty, Ming Yin, Ivor Caro, Suzanne Cheng, Kerstin Trunzer, Axel
Hauschild
Citation: McArthur et al., 2014
Citation Id: 24508103
Id: 947
Journal: Lancet Oncol
Link: /sources/947
Name: PubMed: McArthur et al., 2014
Open Access: True
Pmc Id: PMC4382632
Publication Date: 2014-3
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24508103
Title:
Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K)
mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3,
randomised, open-label study.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
Phase 2 trial in 132 patients with previously treated metastatic
melanoma with BRAF V600E mutation.
Confirmed overall response rate was 53% (95% confidence interval [CI],
44 to 62; 6% with a complete response and 47% with a partial response),
median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and
median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1).
Median overall survival was 15.9 months (95% CI, 11.6 to 18.3).
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 1410
Name: EID1410
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:8923
Display Name: Skin Melanoma
Doid: 8923
Id: 206
Link: /diseases/206
Name: Skin Melanoma
##### My Disease Info
Do Def: A skin cancer that has_material_basis_in melanocytes.
Icd10: C43.9
Mesh: C562393
Mondo Id: MONDO:0005012
Ncit: C3510
Disease Aliases:
- Cutaneous Melanoma
- Malignant Ear Melanoma
- Malignant Lip Melanoma
- Malignant Lower Limb Melanoma
- Malignant Melanoma Of Ear And/or External Auricular Canal
- Malignant Melanoma Of Skin Of Lower Limb
- Malignant Melanoma Of Skin Of Trunk Except Scrotum
- Malignant Melanoma Of Skin Of Upper Limb
- Malignant Neck Melanoma
- Malignant Scalp Melanoma
- Malignant Trunk Melanoma
- Malignant Upper Limb Melanoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Approximately 50% of melanomas harbor activating (V600) mutations in the
serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor
vemurafenib (PLX4032) frequently produced tumor regressions in patients
with BRAF V600-mutant metastatic melanoma in a phase 1 trial and
improved overall survival in a phase 3 trial.We designed a multicenter
phase 2 trial of vemurafenib in patients with previously treated BRAF
V600-mutant metastatic melanoma to investigate the efficacy of
vemurafenib with respect to overall response rate (percentage of treated
patients with a tumor response), duration of response, and overall
survival. The primary end point was the overall response rate as
ascertained by the independent review committee; overall survival was a
secondary end point.A total of 132 patients had a median follow-up of
12.9 months (range, 0.6 to 20.1). The confirmed overall response rate
was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete
response and 47% with a partial response), the median duration of
response was 6.7 months (95% CI, 5.6 to 8.6), and the median
progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary
progression was observed in only 14% of patients. Some patients had a
response after receiving vemurafenib for more than 6 months. The median
overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common
adverse events were grade 1 or 2 arthralgia, rash, photosensitivity,
fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority,
keratoacanthoma type) were diagnosed in 26% of patients.Vemurafenib
induces clinical responses in more than half of patients with previously
treated BRAF V600-mutant metastatic melanoma. In this study with a long
follow-up, the median overall survival was approximately 16 months.
(Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.).
Author String:
Jeffrey A Sosman, Kevin B Kim, Lynn Schuchter, Rene Gonzalez, Anna C
Pavlick, Jeffrey S Weber, Grant A McArthur, Thomas E Hutson, Stergios J
Moschos, Keith T Flaherty, Peter Hersey, Richard Kefford, Donald
Lawrence, Igor Puzanov, Karl D Lewis, Ravi K Amaravadi, Bartosz
Chmielowski, H Jeffrey Lawrence, Yu Shyr, Fei Ye, Jiang Li, Keith B
Nolop, Richard J Lee, Andrew K Joe, Antoni Ribas
Citation: Sosman et al., 2012
Citation Id: 22356324
Id: 354
Journal: N Engl J Med
Link: /sources/354
Name: PubMed: Sosman et al., 2012
Open Access: True
Pmc Id: PMC3724515
Publication Date: 2012-2-23
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22356324
Title: Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
Thyroid cancer cell lines with BRAF V600E mutations were more sensitive
to the MEK inhibitor RDEA119 than those with wildtype BRAF (IC50:
0.034-0.217 uM vs. 1.413-34.120 uM).
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 2139
Name: EID2139
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1781
Display Name: Thyroid Cancer
Doid: 1781
Id: 16
Link: /diseases/16
Name: Thyroid Cancer
##### My Disease Info
Do Def:
An endocrine gland cancer located in the thyroid gland located in the
neck below the thyroid cartilage.
Icd10: C73
Mesh: D013964
Mondo Id: MONDO:0002108
Ncit: C3414, C7510
Disease Aliases:
- Malignant Neoplasm Of Thyroid Gland
- Malignant Tumour Of Thyroid Gland
- Neoplasm Of Thyroid Gland
- Thyroid Gland Cancer
- Thyroid Gland Neoplasm
- Thyroid Neoplasm
##### Molecular Profile
Id: 12
##### Source
Abstract:
We examined the therapeutic potential of a novel MEK inhibitor, RDEA119,
and its synergism with the mTOR inhibitor, temsirolimus, in thyroid
cancer cell lines. RDEA119 potently inhibited the proliferation of the 4
cell lines that harbored BRAF mutation but had no or modest effects on
the other 4 cells that harbored wild-type BRAF (IC(50) of 0.034-0.217 μM
vs. 1.413-34.120 μM). This inhibitory effect of RDEA119 in selected cell
lines OCUT1 (BRAF V600E(+), PIK3CA H1047R(+)) and SW1376 (BRAF V600E(+))
was enhanced by combination with the mTOR inhibitor, temsirolimus. The
PTEN-deficient cell FTC133 was highly sensitive to temsirolimus but
insensitive to RDEA119, and simultaneous treatment with the latter
enhanced the sensitivity of the cell to the former. The KAT18 (wild-
type) cell was not sensitive to either drug alone but became sensitive
to the combination of the 2 drugs. The drug synergy was confirmed by
combination index and isobologram analyses. RDEA119 and temsirolimus
also showed synergistic effects on autophagic death of OCUT1 and KAT18
cells selectively tested. Dramatic synergistic effects of the 2 drugs
were also seen on the growth of FTC133 xenograft tumors in nude mice.
Overall, the effects of the 2 drugs on cell proliferation or autophagic
death, either alone or in combination, were more pronounced in cells
that harbored genetic alterations in the MAP kinase and PI3K/Akt
pathways. Thus, these results demonstrated the important therapeutic
potential of the novel MEK inhibitor RDEA119 and its synergism with
temsirolimus in thyroid cancer.
Author String: Dingxie Liu, Joanna Xing, Barry Trink, Mingzhao Xing
Citation: Liu et al., 2010
Citation Id: 21351275
Id: 1496
Journal: Int J Cancer
Link: /sources/1496
Name: PubMed: Liu et al., 2010
Open Access: True
Pmc Id: PMC2916062
Publication Date: 2010-12-15
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21351275
Title:
BRAF mutation-selective inhibition of thyroid cancer cells by the novel
MEK inhibitor RDEA119 and genetic-potentiated synergism with the mTOR
inhibitor temsirolimus.
##### Therapies
Deprecated: False
Id: 463
Link: /therapies/463
Name: RDEA 119
#### Evidence Items
Description:
Two clinical trials evaluated the effects of vemurafenib in 54 patients
with BRAF (V600E) positive hairy-cell leukemia. The overall response
rate was 98% with 19/54 having a complete response and 34/54 having a
partial response. In the Italian study (n=25), the median relapse-free
survival was 9 months and in the U.S. study (n=24), rate of progression-
free survival was 73% with overall survival rate of 91%.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 2
Evidence Type: PREDICTIVE
Flagged: False
Id: 1579
Name: EID1579
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:285
Display Name: Hairy Cell Leukemia
Doid: 285
Id: 665
Link: /diseases/665
Name: Hairy Cell Leukemia
##### My Disease Info
Do Def:
A chronic lymphocytic leukemia that is characterized by over production
of B cells (lymphocytes) by the bone marrow where the B cells appear
hairy under a microscope.
Icd10: C91.4
Icdo: 9940/3
Mesh: D007943
Mondo Id: MONDO:0018935
Ncit: C7402
##### Molecular Profile
Id: 12
##### Source
Abstract:
BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We
assessed the safety and activity of the oral BRAF inhibitor vemurafenib
in patients with hairy-cell leukemia that had relapsed after treatment
with a purine analogue or who had disease that was refractory to purine
analogues.We conducted two phase 2, single-group, multicenter studies of
vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in
the United States. The therapy was administered for a median of 16 weeks
in the Italian study and 18 weeks in the U.S. study. Primary end points
were the complete response rate (in the Italian trial) and the overall
response rate (in the U.S. trial). Enrollment was completed (28
patients) in the Italian trial in April 2013 and is still open (26 of 36
planned patients) in the U.S. trial.The overall response rates were 96%
(25 of 26 patients who could be evaluated) after a median of 8 weeks in
the Italian study and 100% (24 of 24) after a median of 12 weeks in the
U.S. study. The rates of complete response were 35% (9 of 26 patients)
and 42% (10 of 24) in the two trials, respectively. In the Italian
trial, after a median follow-up of 23 months, the median relapse-free
survival was 19 months among patients with a complete response and 6
months among those with a partial response; the median treatment-free
survival was 25 months and 18 months, respectively. In the U.S. trial,
at 1 year, the progression-free survival rate was 73% and the overall
survival rate was 91%. Drug-related adverse events were usually of grade
1 or 2, and the events most frequently leading to dose reductions were
rash and arthralgia or arthritis. Secondary cutaneous tumors (treated
with simple excision) developed in 7 of 50 patients. The frequent
persistence of phosphorylated ERK-positive leukemic cells in bone marrow
at the end of treatment suggests bypass reactivation of MEK and ERK as a
resistance mechanism.A short oral course of vemurafenib was highly
effective in patients with relapsed or refractory hairy-cell leukemia.
(Funded by the Associazione Italiana per la Ricerca sul Cancro and
others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number
NCT01711632.).
Author String:
Enrico Tiacci, Jae H Park, Luca De Carolis, Stephen S Chung, Alessandro
Broccoli, Sasinya Scott, Francesco Zaja, Sean Devlin, Alessandro
Pulsoni, Young R Chung, Michele Cimminiello, Eunhee Kim, Davide Rossi,
Richard M Stone, Giovanna Motta, Alan Saven, Marzia Varettoni, Jessica K
Altman, Antonella Anastasia, Michael R Grever, Achille Ambrosetti, Kanti
R Rai, Vincenzo Fraticelli, Mario E Lacouture, Angelo M Carella, Ross L
Levine, Pietro Leoni, Alessandro Rambaldi, Franca Falzetti, Stefano
Ascani, Monia Capponi, Maria P Martelli, Christopher Y Park, Stefano A
Pileri, Neal Rosen, Robin Foà, Michael F Berger, Pier L Zinzani, Omar
Abdel-Wahab, Brunangelo Falini, Martin S Tallman
Citation: Tiacci et al., 2015
Citation Id: 26352686
Id: 1043
Journal: N Engl J Med
Link: /sources/1043
Name: PubMed: Tiacci et al., 2015
Open Access: True
Pmc Id: PMC4811324
Publication Date: 2015-10-29
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26352686
Title: Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
A 65-year-old man presented with stage II myeloma. He was initially
treated with chemotherapy and he received an autologous stem cell
transplant. Sequencing of the recurrent tumor harbored BRAF V600E
mutation and he was treated with vemurafenib. After 7 weeks of
treatment, the patient relapsed and died.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 1698
Name: EID1698
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9538
Display Name: Multiple Myeloma
Doid: 9538
Id: 41
Link: /diseases/41
Name: Multiple Myeloma
##### My Disease Info
Do Def: A myeloid neoplasm that is located_in the plasma cells in bone marrow.
Icd10: C90.0
Mesh: D009101
Mondo Id: MONDO:0009693
Ncit: C3242
Disease Aliases: Myeloma
##### Molecular Profile
Id: 12
##### Source
Author String:
J P Sharman, J Chmielecki, D Morosini, G A Palmer, J S Ross, P J
Stephens, J Stafl, V A Miller, S M Ali
Citation: Sharman et al., 2014
Citation Id: 24997557
Id: 1147
Journal: Clin Lymphoma Myeloma Leuk
Link: /sources/1147
Name: PubMed: Sharman et al., 2014
Open Access: False
Publication Date: 2014-10
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24997557
Title:
Vemurafenib response in 2 patients with posttransplant refractory BRAF
V600E-mutated multiple myeloma.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
Phase 1b study of vemurafenib, cetuximab and irinotecan in 19 patients
with colorectal cancer (1 with appendiceal cancer). Six of 17 evaluable
patients achieved an objective response, 15 patients total had either
stable disease or radiographic response (the patient with appendiceal
cancer had disease progression). Estimated median PFS was 7.7 months.
Effect of the combined treatment was also observed in xenograft and cell
line studies.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 4
Evidence Type: PREDICTIVE
Flagged: False
Id: 1902
Name: EID1902
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
In vitro, EGFR inhibition, combined with the BRAF inhibitor vemurafenib,
causes synergistic cytotoxicity for BRAFV600E metastatic colorectal
cancer, further augmented by irinotecan. The safety and efficacy of
vemurafenib, irinotecan, and cetuximab in BRAF-mutated malignancies are
not defined. In this 3+3 phase I study, patients with BRAFV600E-advanced
solid cancers received cetuximab and irinotecan with escalating doses of
vemurafenib. Nineteen patients (18 with metastatic colorectal cancer and
1 with appendiceal cancer) were enrolled. Three patients experienced
dose-limiting toxicities. The MTD of vemurafenib was 960 mg twice daily.
Six of 17 evaluable patients (35%) achieved a radiographic response by
Response Evaluation Criteria in Solid Tumors 1.1 criteria, consistent
with in vivo models demonstrating tumor regressions with the triplet
regimen. Median progression-free survival was 7.7 months. BRAFV600E
circulating cell-free DNA (cfDNA) trends correlated with radiographic
changes, and acquired mutations from cfDNA in genes reactivating MAPK
signaling were observed at progression.Vemurafenib, in combination with
irinotecan and cetuximab, was well tolerated in patients with
refractory, BRAF-mutated metastatic colorectal cancer, and both survival
outcomes and response rates exceeded prior reports for vemurafenib and
for irinotecan plus cetuximab in BRAFV600E metastatic colorectal cancer.
In vivo models demonstrated regressions with the triplet, in contrast
with vemurafenib and cetuximab alone. cfDNA predicted radiographic
response and identified mutations reactivating the MAPK pathway upon
progression. Cancer Discov; 6(12); 1352-65. ©2016 AACR.This article is
highlighted in the In This Issue feature, p. 1293.
Author String:
David S Hong, Van K Morris, Badi El Osta, Alexey V Sorokin, Filip Janku,
Siqing Fu, Michael J Overman, Sarina Piha-Paul, Vivek Subbiah, Bryan
Kee, Apostolia M Tsimberidou, David Fogelman, Jorge Bellido, Imad
Shureiqi, Helen Huang, Johnique Atkins, Gabi Tarcic, Nicolas Sommer,
Richard Lanman, Funda Meric-Bernstam, Scott Kopetz
Citation: Hong et al., 2016
Citation Id: 27729313
Id: 1336
Journal: Cancer Discov
Link: /sources/1336
Name: PubMed: Hong et al., 2016
Open Access: True
Pmc Id: PMC5562357
Publication Date: 2016-12
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/27729313
Title:
Phase IB Study of Vemurafenib in Combination with Irinotecan and
Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E
Mutation.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
##### Therapies
Deprecated: False
Id: 16
Link: /therapies/16
Name: Cetuximab
##### Therapies
Deprecated: False
Id: 101
Link: /therapies/101
Name: Irinotecan
#### Evidence Items
Description:
Cetuximab or panitumumab may be ineffective in patients with BRAF
mutation unless BRAF inhibitor such as Sorafenib is introduced.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 2894
Name: EID2894
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
PURPOSE Cetuximab or panitumumab are effective in 10% to 20% unselected
metastatic colorectal cancer (CRC) patients. KRAS mutations account for
approximately 30% to 40% patients who are not responsive. The serine-
threonine kinase BRAF is the principal effector of KRAS. We hypothesized
that, in KRAS wild-type patients, BRAF mutations could have a
predictive/prognostic value. PATIENTS AND METHODS We retrospectively
analyzed objective tumor responses, time to progression, overall
survival (OS), and the mutational status of KRAS and BRAF in 113 tumors
from cetuximab- or panitumumab-treated metastatic CRC patients. The
effect of the BRAF V600E mutation on cetuximab or panitumumab response
was also assessed using cellular models of CRC. Results KRAS mutations
were present in 30% of the patients and were associated with resistance
to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was
detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-
mutated patients responded to treatment, whereas none of the responders
carried BRAF mutations (P = .029). BRAF-mutated patients had
significantly shorter progression-free survival (P = .011) and OS (P <
.0001) than wild-type patients. In CRC cells, the introduction of BRAF
V600E allele impaired the therapeutic effect of cetuximab or
panitumumab. Treatment with the BRAF inhibitor sorafenib restored
sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E
allele. CONCLUSION BRAF wild-type is required for response to
panitumumab or cetuximab and could be used to select patients who are
eligible for the treatment. Double-hit therapies aimed at simultaneous
inhibition of epidermal growth factor receptor and BRAF warrant
exploration in CRC patients carrying the V600E oncogenic mutation.
Author String:
Federica Di Nicolantonio, Miriam Martini, Francesca Molinari, Andrea
Sartore-Bianchi, Sabrina Arena, Piercarlo Saletti, Sara De Dosso, Luca
Mazzucchelli, Milo Frattini, Salvatore Siena, Alberto Bardelli
Citation: Di Nicolantonio et al., 2008
Citation Id: 19001320
Id: 100
Journal: J Clin Oncol
Link: /sources/100
Name: PubMed: Di Nicolantonio et al., 2008
Open Access: False
Publication Date: 2008-12-10
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19001320
Title:
Wild-type BRAF is required for response to panitumumab or cetuximab in
metastatic colorectal cancer.
##### Therapies
Deprecated: False
Id: 6
Link: /therapies/6
Name: Sorafenib
##### Therapies
Deprecated: False
Id: 16
Link: /therapies/16
Name: Cetuximab
#### Evidence Items
Description:
In a clinical study of 122 cancer patients, including 37 previously
treated colorectal cancer patients harboring BRAF V600 (V600E=32; V600
unknown=5) mutations, stable disease and progressive disease were
reported in 50% of patients (n=5/10) treated with vemurafenib
monotherapy, respectively.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3742
Name: EID3742
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
BRAF V600 mutations occur in various nonmelanoma cancers. We undertook a
histology-independent phase 2 "basket" study of vemurafenib in BRAF V600
mutation-positive nonmelanoma cancers.We enrolled patients in six
prespecified cancer cohorts; patients with all other tumor types were
enrolled in a seventh cohort. A total of 122 patients with BRAF V600
mutation-positive cancer were treated, including 27 patients with
colorectal cancer who received vemurafenib and cetuximab. The primary
end point was the response rate; secondary end points included
progression-free and overall survival.In the cohort with non-small-cell
lung cancer, the response rate was 42% (95% confidence interval [CI], 20
to 67) and median progression-free survival was 7.3 months (95% CI, 3.5
to 10.8). In the cohort with Erdheim-Chester disease or Langerhans'-cell
histiocytosis, the response rate was 43% (95% CI, 18 to 71); the median
treatment duration was 5.9 months (range, 0.6 to 18.6), and no patients
had disease progression during therapy. There were anecdotal responses
among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid
cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and
clear-cell sarcoma and among patients with colorectal cancer who
received vemurafenib and cetuximab. Safety was similar to that in prior
studies of vemurafenib for melanoma.BRAF V600 appears to be a targetable
oncogene in some, but not all, nonmelanoma cancers. Preliminary
vemurafenib activity was observed in non-small-cell lung cancer and in
Erdheim-Chester disease and Langerhans'-cell histiocytosis. The
histologic context is an important determinant of response in BRAF
V600-mutated cancers. (Funded by F. Hoffmann-La Roche/Genentech;
ClinicalTrials.gov number, NCT01524978.).
Author String:
David M Hyman, Igor Puzanov, Vivek Subbiah, Jason E Faris, Ian Chau,
Jean-Yves Blay, Jürgen Wolf, Noopur S Raje, Eli L Diamond, Antoine
Hollebecque, Radj Gervais, Maria Elena Elez-Fernandez, Antoine Italiano,
Ralf-Dieter Hofheinz, Manuel Hidalgo, Emily Chan, Martin Schuler, Susan
Frances Lasserre, Martina Makrutzki, Florin Sirzen, Maria Luisa
Veronese, Josep Tabernero, José Baselga
Citation: Hyman et al., 2015
Citation Id: 26287849
Id: 1040
Journal: N Engl J Med
Link: /sources/1040
Name: PubMed: Hyman et al., 2015
Open Access: True
Pmc Id: PMC4971773
Publication Date: 2015-8-20
Retracted: True
Retraction Date: 2018-10-18T00:00:00Z
Retraction Nature: Correction
Retraction Reasons: +Conflict of Interest;
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26287849
Title: Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In a retrospective study of 53, KRAS exon 2 wild-type, metastatic
colorectal cancer patients, patients harboring BRAF G466A (n=1), G469A
(n=2), D594G (n=1), or V600E (n=2) mutations were reported to be non-
responders to cetuximab in combination with irinotecan, (BRAF mutation
positive: responders vs. non-responders = 0 vs. 6; BRAF wild-type:
responders vs. non-responders 30 vs. 17; P=0.004), as compared to
patients with wild-type BRAF.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3740
Name: EID3740
Significance: RESISTANCE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
Approximately 45% of metastatic colorectal cancer (mCRC) patients with
wild-type KRAS exon 2 are resistant to cetuximab treatment. We set out
to identify additional genetic markers that might predict the response
to cetuximab treatment. Fifty-three wild-type KRAS exon 2 mCRC patients
were treated with cetuximab/irinotecan-based chemotherapy as a first- or
third-line therapy. The mutational statuses of 10 EGFR pathway genes
were analyzed in primary tumors using next-generation sequencing. BRAF,
PIK3CA, KRAS (exons 3 and 4), NRAS, PTEN, and AKT1 mutations were
detected in 6, 6, 5, 4, 1, and 1 patient, respectively. Four of the BRAF
mutations were non-V600 variants. Four tumors harbored multiple co-
existing (complex) mutations. All patients with BRAF mutations or
complex mutation patterns were cetuximab non-responders. All patients
but one harboring KRAS, NRAS, or BRAF mutations were non-responders.
Mutations in any one of these three genes were associated with a poor
response rate (7.1%) and reduced survival (PFS = 8.0 months) compared to
wild-type patients (74.4% and 11.6 months). Our data suggest that KRAS,
NRAS, and BRAF mutations predict response to cetuximab treatment in mCRC
patients.
Author String:
Hung-Chih Hsu, Tan Kien Thiam, Yen-Jung Lu, Chien Yuh Yeh, Wen-Sy Tsai,
Jeng Fu You, Hsin Yuan Hung, Chi-Neu Tsai, An Hsu, Hua-Chien Chen, Shu-
Jen Chen, Tsai-Sheng Yang
Citation: Hsu et al., 2016
Citation Id: 26989027
Id: 1946
Journal: Oncotarget
Link: /sources/1946
Name: PubMed: Hsu et al., 2016
Open Access: True
Pmc Id: PMC5008360
Publication Date: 2016-4-19
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26989027
Title:
Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic
colorectal cancer patients.
##### Therapies
Deprecated: False
Id: 16
Link: /therapies/16
Name: Cetuximab
#### Evidence Items
Description:
Acquired resistance to vemurafenib in BRAF V600E-positive melanomas
frequently confound vemurafenib therapy. Proposed resistance mechanisms
include PDGFRB upregulation or NRAS mutations resulting in MAPK pathway
reactivation but not secondary mutations in BRAF. MEK inhibitors may
demonstrate clinical benefit in vemurafenib resistant melanoma patients.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 3745
Name: EID3745
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Oncogenic mutations in the serine/threonine kinase B-RAF (also known as
BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies
have demonstrated that the B-RAF(V600E) mutation predicts a dependency
on the mitogen-activated protein kinase (MAPK) signalling cascade in
melanoma-an observation that has been validated by the success of RAF
and MEK inhibitors in clinical trials. However, clinical responses to
targeted anticancer therapeutics are frequently confounded by de novo or
acquired resistance. Identification of resistance mechanisms in a manner
that elucidates alternative 'druggable' targets may inform effective
long-term treatment strategies. Here we expressed ∼600 kinase and
kinase-related open reading frames (ORFs) in parallel to interrogate
resistance to a selective RAF kinase inhibitor. We identified MAP3K8
(the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives
resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates
ERK primarily through MEK-dependent mechanisms that do not require RAF
signalling. Moreover, COT expression is associated with de novo
resistance in B-RAF(V600E) cultured cell lines and acquired resistance
in melanoma cells and tissue obtained from relapsing patients following
treatment with MEK or RAF inhibitors. We further identify combinatorial
MAPK pathway inhibition or targeting of COT kinase activity as possible
therapeutic strategies for reducing MAPK pathway activation in this
setting. Together, these results provide new insights into resistance
mechanisms involving the MAPK pathway and articulate an integrative
approach through which high-throughput functional screens may inform the
development of novel therapeutic strategies.
Author String:
Cory M Johannessen, Jesse S Boehm, So Young Kim, Sapana R Thomas, Leslie
Wardwell, Laura A Johnson, Caroline M Emery, Nicolas Stransky,
Alexandria P Cogdill, Jordi Barretina, Giordano Caponigro, Haley
Hieronymus, Ryan R Murray, Kourosh Salehi-Ashtiani, David E Hill, Marc
Vidal, Jean J Zhao, Xiaoping Yang, Ozan Alkan, Sungjoon Kim, Jennifer L
Harris, Christopher J Wilson, Vic E Myer, Peter M Finan, David E Root,
Thomas M Roberts, Todd Golub, Keith T Flaherty, Reinhard Dummer, Barbara
L Weber, William R Sellers, Robert Schlegel, Jennifer A Wargo, William C
Hahn, Levi A Garraway
Citation: Johannessen et al., 2010
Citation Id: 21107320
Id: 1492
Journal: Nature
Link: /sources/1492
Name: PubMed: Johannessen et al., 2010
Open Access: True
Pmc Id: PMC3058384
Publication Date: 2010-12-16
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21107320
Title:
COT drives resistance to RAF inhibition through MAP kinase pathway
reactivation.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In an in vitro study, cell lines (including YUHUY and YUSAC2) expressing
BRAF V600E were associated with increased sensitivity to vemurafenib
(PLX4032) treatment, as compared to cell lines expressing wild-type
BRAF. Sensitive was determined by assessing cellular proliferation, and
ERK and MEK phosphorylation.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 3747
Name: EID3747
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
BRAF(V600E/K) is a frequent mutationally active tumor-specific kinase in
melanomas that is currently targeted for therapy by the specific
inhibitor PLX4032. Our studies with melanoma tumor cells that are
BRAF(V600E/K) and BRAF(WT) showed that, paradoxically, while PLX4032
inhibited ERK1/2 in the highly sensitive BRAF(V600E/K), it activated the
pathway in the resistant BRAF(WT) cells, via RAF1 activation, regardless
of the status of mutations in NRAS or PTEN. The persistently active
ERK1/2 triggered downstream effectors in BRAF(WT) melanoma cells and
induced changes in the expression of a wide-spectrum of genes associated
with cell cycle control. Furthermore, PLX4032 increased the rate of
proliferation of growth factor-dependent NRAS Q61L mutant primary
melanoma cells, reduced cell adherence and increased mobility of cells
from advanced lesions. The results suggest that the drug can confer an
advantage to BRAF(WT) primary and metastatic tumor cells in vivo and
provide markers for monitoring clinical responses.
Author String:
Ruth Halaban, Wengeng Zhang, Antonella Bacchiocchi, Elaine Cheng, Fabio
Parisi, Stephan Ariyan, Michael Krauthammer, James P McCusker, Yuval
Kluger, Mario Sznol
Citation: Halaban et al., 2010
Citation Id: 20149136
Id: 1482
Journal: Pigment Cell Melanoma Res
Link: /sources/1482
Name: PubMed: Halaban et al., 2010
Open Access: True
Pmc Id: PMC2848976
Publication Date: 2010-4
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/20149136
Title:
PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK
pathway and enhances cell migration and proliferation of BRAF melanoma
cells.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In NCI-MATCH trial, patients with advanced solid tumors, lymphoma or
multiple myeloma harboring BRAF V600E mutation were treated with
dabrafenib and trametinib.
Patients with melanoma, thyroid carcinoma, colorectal cancer or NSCLC
were excluded.
The response rate was 100% (4/4) in patients cholangiocarcinoma and 83%
(5/6) in patients with low-grade papillary serous adenocarcinoma of the
ovary or mucinous-papillary serous adenocarcinoma of the peritoneum.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 7454
Name: EID7454
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:2394
Display Name: Ovarian Cancer
Doid: 2394
Id: 20
Link: /diseases/20
Name: Ovarian Cancer
##### My Disease Info
Do Def: A female reproductive organ cancer that is located_in the ovary.
Icd10: C56
Mesh: D010051
Mondo Id: MONDO:0008170
Ncit: C4984, C7431
Disease Aliases:
- Malignant Ovarian Tumor
- Malignant Tumour Of Ovary
- Ovarian Neoplasm
- Ovary Neoplasm
- Primary Ovarian Cancer
- Tumor Of The Ovary
##### Molecular Profile
Id: 12
##### Source
Abstract:
Background: The NCI-MATCH precision medicine trial assigns patients
(pts) with solid tumors, lymphomas, or multiple myeloma with progression
on prior treatment to a targeted therapy based on genetic alterations
identified in pre-treatment biopsies. Arm H (EAY131-H) evaluated the
combination of the BRAF inhibitor (inh) dabrafenib (DAB), and the MEK
inh, trametinib (TRM), in pts with BRAF V600E/K mutations. Methods: Pts
with melanoma, thyroid, or colorectal cancer were excluded. Pts with
NSCLC were excluded after the U.S. Food and Drug Administration (FDA)
approved DAB/TRM for this indication. Pts received DAB 150 mg po BID and
TRM 2 mg PO daily on 28 day cycles until disease progression or
intolerable toxicity; restaging was performed every 2 cycles. The
primary endpoint was objective response rate (ORR); secondary endpoints
included progression-free survival (PFS), 6-month PFS, and overall
survival (OS). Results: A total of 35 pts were enrolled from
1/2016-2/2018; 2 were ineligible (CrCl below criteria; labs out of
window). Over 17 distinct tumor histologies were represented. 58% of pts
were female, median age was 63 (range 21-85), 94% were Caucasian, and
48% of pts had received at least 3 prior therapies (range 1- 8). The
confirmed ORR was 33.3% (90% CI 19.9%, 49.1%), with a median duration of
response (DoR) of 12 months (mon). Varied histologies had a DoR of > 12
mon: histiocytic sarcoma, cholangiocarcinoma and mixed
adenoneuroendocrine carcinoma of unknown primary, among others. Median
PFS was 9.4 mon; the 6 mon PFS rate was 70.6% (90% CI 58.2%-85.5%), and
an additional 10 pts had a PFS > 5.5 mon. Median OS has not been
reached. At the time of data cutoff (12/2018) 11 pts continue on
treatment. Adverse events (AE) were comparable to previously reported
profiles of DAB/TRM; no new AEs were identified. The most frequent grade
3 AEs were fatigue, neutropenia, hyponatremia, hypophosphatemia, and
urinary tract infection; there was 1 grade 4 sepsis; no grade 5 AEs.
Conclusions: In this pre-treated, mixed histology cohort, DAB and TRM
showed promising activity outside of currently approved FDA indications
warranting further investigations. Correlative analyses are planned.
Clinical trial information: NCT02465060
Author String: April K.S. Salama
Citation: April K.S. Salama, 2019, ASCO Annual Meeting, Abstract 3002
Citation Id: 172039
Id: 2954
Journal: J Clin Oncol 37, 2019 (suppl; abstr 3002)
Link: /sources/2954
Name: ASCO: April K.S. Salama, 2019, ASCO Annual Meeting, Abstract 3002
Open Access: False
Publication Date: 2019-6
Retracted: False
Source Type: ASCO
Source Url: https://meetinglibrary.asco.org/record/172039/abstract
Title:
Dabrafenib and trametinib in patients with tumors with BRAF V600E/K
mutations: Results from the molecular analysis for therapy choice
(MATCH) Arm H.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
An inducible BRAF-V600E mouse melanoma model shows a tight correlation
between activated BRAF and disease progression.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 3748
Name: EID3748
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
The usual paradigm for developing kinase inhibitors in oncology is to
use a high-affinity proof-of-concept inhibitor with acceptable metabolic
properties for key target validation experiments. This approach requires
substantial medicinal chemistry and can be confounded by drug toxicity
and off-target activities of the test molecule. As a better alternative,
we have developed inducible short-hairpin RNA xenograft models to
examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results
show that tumor regression resulting from BRAF suppression is inducible,
reversible, and tightly regulated in these models. Analysis of
regressing tumors showed the primary mechanism of action for BRAF to be
increased tumor cell proliferation and survival. In a metastatic
melanoma model, conditional BRAF suppression slowed systemic tumor
growth as determined by in vivo bioluminescence imaging. Taken together,
gain-of-function BRAF signaling is strongly associated with in vivo
tumorigenicity, confirming BRAF as an important target for small-
molecule and RNA interference-based therapeutics.
Author String:
Klaus P Hoeflich, Daniel C Gray, Michael T Eby, Janet Y Tien, Leo Wong,
Janeko Bower, Alvin Gogineni, Jiping Zha, Mary J Cole, Howard M Stern,
Lesley J Murray, David P Davis, Somasekar Seshagiri
Citation: Hoeflich et al., 2006
Citation Id: 16424035
Id: 1485
Journal: Cancer Res
Link: /sources/1485
Name: PubMed: Hoeflich et al., 2006
Open Access: False
Publication Date: 2006-1-15
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16424035
Title:
Oncogenic BRAF is required for tumor growth and maintenance in melanoma
models.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In a retrospective study of 30 metastatic melanoma patients with
progressing metastases, patients with BRAF V600E mutation (n=8) treated
with vemurafenib monotherapy achieved a partial response (n=5) and
stable disease (n=1).
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3749
Name: EID3749
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Multiple BRAF inhibitor resistance mechanisms have been described,
however, their relative frequency, clinical correlates, and effect on
subsequent therapy have not been assessed in patients with metastatic
melanoma.Fifty-nine BRAF(V600)-mutant melanoma metastases from patients
treated with dabrafenib or vemurafenib were analyzed. The genetic
profile of resistance mechanisms and tumor signaling pathway activity
was correlated with clinicopathologic features and therapeutic
outcomes.Resistance mechanisms were identified in 58% progressing tumors
and BRAF alterations were common. Gene expression analysis revealed that
mitogen-activated protein kinase (MAPK) activity remained inhibited in
21% of resistant tumors, and the outcomes of patients with these tumors
were poor. Resistance mechanisms also occurred in pretreatment biopsies
and heterogeneity of resistance mechanisms occurred within patients and
within tumors. There were no responses to subsequent targeted therapy,
even when a progressing tumor had a resistance mechanism predicted to be
responsive.Selecting sequential drugs based on the molecular
characteristics of a single progressing biopsy is unlikely to provide
improved responses, and first-line therapies targeting multiple pathways
will be required.
Author String:
Helen Rizos, Alexander M Menzies, Gulietta M Pupo, Matteo S Carlino,
Carina Fung, Jessica Hyman, Lauren E Haydu, Branka Mijatov, Therese M
Becker, Suzanah C Boyd, Julie Howle, Robyn Saw, John F Thompson, Richard
F Kefford, Richard A Scolyer, Georgina V Long
Citation: Rizos et al., 2014
Citation Id: 24463458
Id: 1951
Journal: Clin Cancer Res
Link: /sources/1951
Name: PubMed: Rizos et al., 2014
Open Access: False
Publication Date: 2014-4-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24463458
Title:
BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum
and clinical impact.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In an in vitro study, BRAF V600E expressing cell lines (COLO205, A375
and COLO829) demonstrated improved sensitivity to vemurafenib treatment,
compared to BRAF wild-type expressing cells. Sensitivity was determined
by assessing cell proliferation (COLO205, GI50: 0.31uM; A375, GI50: 0.50
uM; COLO829, GI50: 1.7 uM vs. BRAF expressing cells (n=9) GI50: 10-41uM)
and ERK phosphorylation.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 3751
Name: EID3751
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
BRAF(V600E) is the most frequent oncogenic protein kinase mutation
known. Furthermore, inhibitors targeting "active" protein kinases have
demonstrated significant utility in the therapeutic repertoire against
cancer. Therefore, we pursued the development of specific kinase
inhibitors targeting B-Raf, and the V600E allele in particular. By using
a structure-guided discovery approach, a potent and selective inhibitor
of active B-Raf has been discovered. PLX4720, a 7-azaindole derivative
that inhibits B-Raf(V600E) with an IC(50) of 13 nM, defines a class of
kinase inhibitor with marked selectivity in both biochemical and
cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E)
kinase compared with a broad spectrum of other kinases, and potent
cytotoxic effects are also exclusive to cells bearing the V600E allele.
Consistent with the high degree of selectivity, ERK phosphorylation is
potently inhibited by PLX4720 in B-Raf(V600E)-bearing tumor cell lines
but not in cells lacking oncogenic B-Raf. In melanoma models, PLX4720
induces cell cycle arrest and apoptosis exclusively in
B-Raf(V600E)-positive cells. In B-Raf(V600E)-dependent tumor xenograft
models, orally dosed PLX4720 causes significant tumor growth delays,
including tumor regressions, without evidence of toxicity. The work
described here represents the entire discovery process, from initial
identification through structural and biological studies in animal
models to a promising therapeutic for testing in cancer patients bearing
B-Raf(V600E)-driven tumors.
Author String:
James Tsai, John T Lee, Weiru Wang, Jiazhong Zhang, Hanna Cho, Shumeye
Mamo, Ryan Bremer, Sam Gillette, Jun Kong, Nikolas K Haass, Katrin
Sproesser, Ling Li, Keiran S M Smalley, Daniel Fong, Yong-Liang Zhu,
Adhirai Marimuthu, Hoa Nguyen, Billy Lam, Jennifer Liu, Ivana Cheung,
Julie Rice, Yoshihisa Suzuki, Catherine Luu, Calvin Settachatgul, Rafe
Shellooe, John Cantwell, Sung-Hou Kim, Joseph Schlessinger, Kam Y J
Zhang, Brian L West, Ben Powell, Gaston Habets, Chao Zhang, Prabha N
Ibrahim, Peter Hirth, Dean R Artis, Meenhard Herlyn, Gideon Bollag
Citation: Tsai et al., 2008
Citation Id: 18287029
Id: 1952
Journal: Proc Natl Acad Sci U S A
Link: /sources/1952
Name: PubMed: Tsai et al., 2008
Open Access: True
Pmc Id: PMC2268581
Publication Date: 2008-2-26
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/18287029
Title:
Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent
antimelanoma activity.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In an in vitro study, a MBA72 cell line expressing BRAF V600E
demonstrated improved sensitivity to vemurafenib treatment, compared to
LND-1 cells expression BRAF wild-type. Sensitivity was determined by
assessing cell proliferation (MBA72, IC50: 3.2uM; vs. LND-1, IC50: 32.2
uM).
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 3752
Name: EID3752
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
BRAF G469A is a missense mutation within exon 11 of the BRAF gene
resulting in a constitutively activated enzyme frequently associated
with MAP kinase cascade signaling activation. No evidence currently
exists about its role in determining sensitivity/resistance to BRAF
inhibitors, utilized in the treatment of patients carrying BRAF V600
mutations, and to chemotherapy. The newly established metastatic
melanoma (MM) cell line MO-1 was characterized for its sensitivity to
vemurafenib and nab-paclitaxel, both already utilized for the treatment
of MM.All analyses were carried out by comparing results with those
found in MM cells wild type for BRAF or mutated in V600. In addition,
cellular effectors were investigated by ELISA kits, western blotting and
flow cytometry.The exposure to vemurafenib inhibited MO-1 cell
proliferation at concentrations similar to those obtained in
vemurafenib-resistant melanoma models, and an explanation of this
sensitivity is the strong activation of Erk1/2 and the low expression of
MITF. Nab-paclitaxel strongly reduced proliferation of MO-1 cells
perhaps for the very low expression level of PMEL17, transcriptionally
regulated by MITF and negatively involved in determining sensitivity to
taxanes.Thus, the mutation BRAF G469A in MM might be related to a weak
effectiveness of therapy with BRAF inhibitors and a promising
therapeutic approach may be with nab-paclitaxel.
Author String:
Letizia Porcelli, Gabriella Guida, Stefania Tommasi, Michele Guida,
Amalia Azzariti
Citation: Porcelli et al., 2015
Citation Id: 26070258
Id: 1953
Journal: Cancer Chemother Pharmacol
Link: /sources/1953
Name: PubMed: Porcelli et al., 2015
Open Access: False
Publication Date: 2015-8
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26070258
Title:
Metastatic melanoma cells with BRAF G469A mutation: nab-paclitaxel
better than vemurafenib?
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In a meta-analysis of 8 studies, papillary thyroid cancer patients with
BRAF V600E mutation had a higher frequency of recurrence and persistent
disease compared to those with wildtype BRAF (28.5% vs. 12.8% , Risk
ratio:2.14, 95%CI:1.67-2.74, P<0.00001).
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PROGNOSTIC
Flagged: False
Id: 2503
Name: EID2503
Significance: POOR_OUTCOME
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3969
Display Name: Papillary Thyroid Carcinoma
Doid: 3969
Id: 156
Link: /diseases/156
Name: Papillary Thyroid Carcinoma
##### My Disease Info
Do Def:
A differentiated thyroid gland carcinoma that is characterized by the
small mushroom shape of the tumor which has a stem attached to the
epithelial layer and arises from the follicular cells of the thyroid
gland.
Icdo: 8260/3
Mesh: D000077273
Mondo Id: MONDO:0005075
Ncit: C4035
Disease Aliases:
- Papillary Carcinoma Of The Thyroid Gland
- Papillary Carcinoma Of Thyroid
- Thyroid Gland Papillary Carcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
The effects of the BRAF(V600E) mutation on prognostic factors and poor
clinical outcomes in papillary thyroid cancer (PTC) have not been fully
quantified. The authors performed comprehensive meta-analysis to assess
the strength of associations between these conditions and the
BRAF(V600E) mutation.The authors identified the clinical studies that
examined the association of the BRAF(V600E) mutation in surgical
specimens with clinicopathologic outcomes between January 2003 and
October 2010 using the Medline database. One hundred thirty-one relevant
studies were hand-searched. The authors selected 27 studies that
included 5655 PTC patients. They calculated the pooled odds ratios (ORs)
or risk ratios with 95% confidence intervals (CIs) for each study using
a random effect model.The average prevalence rate of the BRAF(V600E)
mutation was 49.4%. In 26 studies, compared with the patients who had
the wild-type BRAF genes, the PTC patients with the BRAF(V600E) mutation
had increased ORs of an extrathyroidal invasion (OR, 2.14; 95% CI,
1.68-2.73), a lymph node metastasis (OR, 1.54; 95% CI, 1.21-1.97), and
an advanced TNM stage (OR, 2.00; 95% CI, 1.61-2.49). In 8 studies,
patients with the mutation had 2.14-fold increased risk of recurrent and
persistent disease (95% CI, 1.67-2.74). The associations were generally
consistent across the different study populations.This meta-analysis
demonstrates that the BRAF(V600E) mutation is closely related to the
high-risk clinicopathological factors and poorer outcome of PTC. The
results obtained here suggest that the BRAF(V600E) mutation should be
considered as a poor prognostic marker in PTC and may lead to better
management for individual patients.
Author String:
Tae Hyuk Kim, Young Joo Park, Jung Ah Lim, Hwa Young Ahn, Eun Kyung Lee,
You Jin Lee, Kyung Won Kim, Seo Kyung Hahn, Yeo Kyu Youn, Kwang Hyun
Kim, Bo Youn Cho, Do Joon Park
Citation: Kim et al., 2012
Citation Id: 21882184
Id: 1495
Journal: Cancer
Link: /sources/1495
Name: PubMed: Kim et al., 2012
Open Access: False
Publication Date: 2012-4-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21882184
Title:
The association of the BRAF(V600E) mutation with prognostic factors and
poor clinical outcome in papillary thyroid cancer: a meta-analysis.
#### Evidence Items
Description:
In an in vitro study, several cell lines (including MALME-3M, Colo829,
Colo38, A375 and SK-MEK28) expressing BRAF V600E were associated with
increased sensitivity to vemurafenib (RG7204) treatment, as compared to
cell lines expressing BRAF wild-type. Sensitivity was determined by
proliferation assay and by assessing MEK1/2 phosphorylation. Further, in
an in vivo study, LOX, Colo829 and A375 xenografts were reportedly
sensitive to vemurafenib treatment as assessed by tumor volume.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 3753
Name: EID3753
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
The BRAF(V600E) mutation is common in several human cancers, especially
melanoma. RG7204 (PLX4032) is a small-molecule inhibitor of BRAF(V600E)
kinase activity that is in phase II and phase III clinical testing.
Here, we report a preclinical characterization of the antitumor activity
of RG7204 using established in vitro and in vivo models of malignant
melanoma. RG7204 potently inhibited proliferation and mitogen-activated
protein/extracellular signal-regulated kinase (ERK) kinase and ERK
phosphorylation in a panel of tumor cell lines, including melanoma cell
lines expressing BRAF(V600E) or other mutant BRAF proteins altered at
codon 600. In contrast, RG7204 lacked activity in cell lines that
express wild-type BRAF or non-V600 mutations. In several tumor xenograft
models of BRAF(V600E)-expressing melanoma, we found that RG7204
treatment caused partial or complete tumor regressions and improved
animal survival, in a dose-dependent manner. There was no toxicity
observed in any dose group in any of the in vivo models tested. Our
findings offer evidence of the potent antitumor activity of RG7204
against melanomas harboring the mutant BRAF(V600E) gene.
Author String:
Hong Yang, Brian Higgins, Kenneth Kolinsky, Kathryn Packman, Zenaida Go,
Raman Iyer, Stanley Kolis, Sylvia Zhao, Richard Lee, Joseph F Grippo,
Kathleen Schostack, Mary Ellen Simcox, David Heimbrook, Gideon Bollag,
Fei Su
Citation: Yang et al., 2010
Citation Id: 20551065
Id: 351
Journal: Cancer Res
Link: /sources/351
Name: PubMed: Yang et al., 2010
Open Access: False
Publication Date: 2010-7-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/20551065
Title:
RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent
antitumor activity in preclinical melanoma models.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In an in vitro study of 27 melanoma cell lines, 18 out of 20 cell lines
expressing BRAF V600E mutation were associated with sensitivity to
vemurafenib treatment (IC50: 0.01-1�M). Sensitivity was determined by
assessing growth inhibition.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 3756
Name: EID3756
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
PLX4032/vemurafenib is a first-in-class small-molecule BRAF(V600E)
inhibitor with clinical activity in patients with BRAF mutant melanoma.
Nevertheless, drug resistance develops in treated patients, and
strategies to overcome primary and acquired resistance are required. To
explore the molecular mechanisms involved in primary resistance to
PLX4032, we investigated its effects on cell proliferation and signaling
in a panel of 27 genetically characterized patient-derived melanoma cell
lines. Cell sensitivity to PLX4032 was dependent on BRAF(V600E) and
independent from other gene alterations that commonly occur in melanoma
such as PTEN loss, BRAF, and MITF gene amplification. Two cell lines
lacking sensitivity to PLX4032 and harboring a different set of genetic
alterations were studied as models of primary resistance. Treatment with
the MEK inhibitor UO126 but not with PLX4032 inhibited cell growth and
ERK activation. Resistance to PLX4032 was maintained after CRAF down-
regulation by siRNA indicating alternative activation of MEK-ERK
signaling. Genetic characterization by multiplex ligation-dependent
probe amplification and analysis of phosphotyrosine signaling by MALDI-
TOF mass spectrometry analysis revealed the activation of MET and SRC
signaling, associated with the amplification of MET and of CTNNB1 and
CCND1 genes, respectively. The combination of PLX4032 with drugs or
siRNA targeting MET was effective in inhibiting cell growth and reducing
cell invasion and migration in melanoma cells with MET amplification;
similar effects were observed after targeting SRC in the other cell
line, indicating a role for MET and SRC signaling in primary resistance
to PLX4032. Our results support the development of classification of
melanoma in molecular subtypes for more effective therapies.
Author String:
Elisabetta Vergani, Viviana Vallacchi, Simona Frigerio, Paola Deho,
Piera Mondellini, Paola Perego, Giuliana Cassinelli, Cinzia Lanzi, Maria
Adele Testi, Licia Rivoltini, Italia Bongarzone, Monica Rodolfo
Citation: Vergani et al., 2011
Citation Id: 22241959
Id: 1956
Journal: Neoplasia
Link: /sources/1956
Name: PubMed: Vergani et al., 2011
Open Access: True
Pmc Id: PMC3257188
Publication Date: 2011-12
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22241959
Title:
Identification of MET and SRC activation in melanoma cell lines showing
primary resistance to PLX4032.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In an in vitro study, a melanoma cell line, A375, expressing the BRAF
V600E mutation was associated with resistance to dasatinib treatment,
comparable to melanoma MEWO cells expressing wild-type BRAF. Resistance
was determined by assessing cell viability.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 3759
Name: EID3759
Significance: RESISTANCE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Point mutations in the KIT receptor tyrosine kinase gene have recently
been identified in mucosal, acral lentiginous, and chronically sun-
damaged melanomas. We have identified the first human melanoma cell line
with an endogenous L576P mutation, the most common KIT mutation in
melanoma ( approximately 30-40%). In vitro testing showed that the cell
viability of the L576P mutant cell line was not reduced by imatinib,
nilotinib, or sorafenib small molecule KIT inhibitors effective in
nonmelanoma cells with other KIT mutations. However, the viability of
the mutant cells was reduced by dasatinib at concentrations as low as 10
nM (P = 0.004). Molecular modeling studies found that the L576P mutation
induces structural changes in KIT that reduce the affinity for imatinib
(DeltaDeltaGbind = -2.52 kcal/mol) but not for dasatinib
(DeltaDeltaGbind = +0.32 kcal/mol). Two metastatic melanoma patients
with the L576P KIT mutation were treated with dasatinib, including one
patient previously treated with imatinib. Both patients had marked
reduction (>50%) and elimination of tumor F18-fluorodeoxyglucose
(FDG)-avidity by positron emission tomography (PET) imaging after
dasatinib treatment. These data support the selective inhibitory effect
of dasatinib against cells harboring the most common KIT mutation in
melanoma, and thus has therapeutic implications for acrallentiginous,
chronic sun-damaged, and mucosal melanomas.
Author String:
Scott E Woodman, Jonathan C Trent, Katherine Stemke-Hale, Alexander J
Lazar, Sabrina Pricl, Giovanni M Pavan, Maurizio Fermeglia, Y N Vashisht
Gopal, Dan Yang, Donald A Podoloff, Doina Ivan, Kevin B Kim, Nicholas
Papadopoulos, Patrick Hwu, Gordon B Mills, Michael A Davies
Citation: Woodman et al., 2009
Citation Id: 19671763
Id: 74
Journal: Mol Cancer Ther
Link: /sources/74
Name: PubMed: Woodman et al., 2009
Open Access: True
Pmc Id: PMC3346953
Publication Date: 2009-8
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19671763
Title:
Activity of dasatinib against L576P KIT mutant melanoma: molecular,
cellular, and clinical correlates.
##### Therapies
Deprecated: False
Id: 20
Link: /therapies/20
Name: Dasatinib
#### Evidence Items
Description:
In a hairy cell leukemia patient harboring BRAF V600E mutation, BRAF
V600E mutation was associated with improved response to vemurafenib
treatment. The patient was treated with 3 lines of chemotherapy,
including 6 cycles of pentostatin and rituximab combination therapy, but
experience progressive disease; subsequently, the patient was treated
with vemurafenib monotherapy for 58 days and achieved a partial
response.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3768
Name: EID3768
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:285
Display Name: Hairy Cell Leukemia
Doid: 285
Id: 665
Link: /diseases/665
Name: Hairy Cell Leukemia
##### My Disease Info
Do Def:
A chronic lymphocytic leukemia that is characterized by over production
of B cells (lymphocytes) by the bone marrow where the B cells appear
hairy under a microscope.
Icd10: C91.4
Icdo: 9940/3
Mesh: D007943
Mondo Id: MONDO:0018935
Ncit: C7402
##### Molecular Profile
Id: 12
##### Source
Author String:
George A Follows, Hannah Sims, David M Bloxham, Thorsten Zenz, Melanie A
Hopper, Hongxiang Liu, Anthony Bench, Penny Wright, Mars B Van't Veer,
Mike A Scott
Citation: Follows et al., 2013
Citation Id: 23278307
Id: 1965
Journal: Br J Haematol
Link: /sources/1965
Name: PubMed: Follows et al., 2013
Open Access: False
Publication Date: 2013-4
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23278307
Title:
Rapid response of biallelic BRAF V600E mutated hairy cell leukaemia to
low dose vemurafenib.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
As a follow-up to a previous study (23300174), a hairy cell leukemia
patient harboring BRAF V600E mutation was associated with response to
vemurafenib monotherapy. The patient was previously treated with
vemurafenib and obtained a complete response, but then experienced
disease progression. Subsequently, the patient was re-treated with
vemurafenib and again achieved a complete hematological response.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3769
Name: EID3769
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:285
Display Name: Hairy Cell Leukemia
Doid: 285
Id: 665
Link: /diseases/665
Name: Hairy Cell Leukemia
##### My Disease Info
Do Def:
A chronic lymphocytic leukemia that is characterized by over production
of B cells (lymphocytes) by the bone marrow where the B cells appear
hairy under a microscope.
Icd10: C91.4
Icdo: 9940/3
Mesh: D007943
Mondo Id: MONDO:0018935
Ncit: C7402
##### Molecular Profile
Id: 12
##### Source
Abstract:
Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative
disorder that accounts for 2% of all leukemia. Recent identification of
the recurrent V600E BRAF mutation in a majority of HCL patients has led
some teams to evaluate the clinical potential of vemurafenib, a BRAF
V600 specific inhibitor in a limited number of refractory HCL patients.
Recently, we published the case of an HCL patient successfully treated
with a low dose of vemurafenib. Eight months after the ending of
treatment this patient relapsed. We present here the successful
retreatment of this patient with a second line of vemurafenib. Our data
suggest for the first time that vemurafenib at the dose of 240 mg once a
day could be sufficient to maintain a complete hematological remission
after an initial induction treatment with low-dose vemurafenib (2 × 240
mg) daily without inducing major toxicity.
Author String:
Caroline Bailleux, Guillaume Robert, Clémence Ginet, Daniel Re, Antoine
Thyss, Isabelle Sudaka, Isabelle Peyrottes, Paul Hofman, Patrick
Auberger, Frederic Peyrade
Citation: Bailleux et al., 2015
Citation Id: 25815361
Id: 1966
Journal: Oncoscience
Link: /sources/1966
Name: PubMed: Bailleux et al., 2015
Open Access: True
Pmc Id: PMC4341463
Publication Date: 2015
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25815361
Title:
Successful re-treatment of a relapsed V600E mutated HCL patient with
low-dose vemurafenib.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
A hairy cell leukemia patient with extensive CNS involvement patient
harboring BRAF V600E mutation was associated with complete response to
vemurafenib monotherapy. Upon identification of the BRAF V600E mutation,
the patient was treated with cytarabine, rituximab and methotrexate but
quickly progressed; subsequently, the patient was treated with 2 rounds
of vemurafenib and achieved complete response.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3770
Name: EID3770
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:285
Display Name: Hairy Cell Leukemia
Doid: 285
Id: 665
Link: /diseases/665
Name: Hairy Cell Leukemia
##### My Disease Info
Do Def:
A chronic lymphocytic leukemia that is characterized by over production
of B cells (lymphocytes) by the bone marrow where the B cells appear
hairy under a microscope.
Icd10: C91.4
Icdo: 9940/3
Mesh: D007943
Mondo Id: MONDO:0018935
Ncit: C7402
##### Molecular Profile
Id: 12
##### Source
Author String:
Michael M McDowell, Xiao Zhu, Nitin Agarwal, Marina N Nikiforova, Frank
S Lieberman, Jan Drappatz
Citation: McDowell et al., 2016
Citation Id: 27116997
Id: 1967
Journal: Leuk Lymphoma
Link: /sources/1967
Name: PubMed: McDowell et al., 2016
Open Access: False
Publication Date: 2016-12
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/27116997
Title:
Response of relapsed central nervous system hairy cell leukemia to
vemurafenib.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In a retrospective study of 17 papillary thyroid cancer patients,
patients with BRAF V600E mutation (n=6) were associated with a 47%
(7/15) partial response rate and a 53% (8/15) stable disease rate.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3773
Name: EID3773
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3969
Display Name: Papillary Thyroid Carcinoma
Doid: 3969
Id: 156
Link: /diseases/156
Name: Papillary Thyroid Carcinoma
##### My Disease Info
Do Def:
A differentiated thyroid gland carcinoma that is characterized by the
small mushroom shape of the tumor which has a stem attached to the
epithelial layer and arises from the follicular cells of the thyroid
gland.
Icdo: 8260/3
Mesh: D000077273
Mondo Id: MONDO:0005075
Ncit: C4035
Disease Aliases:
- Papillary Carcinoma Of The Thyroid Gland
- Papillary Carcinoma Of Thyroid
- Thyroid Gland Papillary Carcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Vemurafenib, a selective BRAF inhibitor, appears to have promising
clinical activity in patients with papillary thyroid cancer (PTC)
harboring the BRAF(V600E) mutation.To determine the efficacy and safety
of vemurafenib when used outside of a clinical trial.A retrospective
review at MD Anderson Cancer Center.The best responses were evaluated
using RECIST v1.1. A single radiologist reviewed all images. Adverse
events (AEs) were evaluated using CTCAE v.4.0.We identified 17 patients
with advanced PTC harboring the BRAF(V600E) mutation who were treated
with vemurafenib outside of a clinical trial. Median age at diagnosis
was 63 years, and 53% were male. At vemurafenib start, 3 (18%) patients
had disease confined to the neck, and 14 (72%) had distant metastases.
Tyrosine kinase inhibitors had been previously administered to 4 (24%)
patients. Two (12%) patients discontinued vemurafenib because of AEs
before restaging. Best response: partial response (PR) in 7/15 (47%) and
stable disease (SD) in 8/15(53%) patients. The rate of durable response
(PR plus SD ≥ 6 months) was 67%. Median time to treatment failure was 13
months. There was no association between change in thyroglobulin and
tumor size. Drug discontinuation, drug interruptions, and dose
reductions were needed in 5 (29%), 13 (76%), and 10 (59%) patients,
respectively. Most common AEs were fatigue (71%), weight loss (71%),
anorexia (65%), arthralgias (59%), hair loss (59%), rash (59%), hand-
foot syndrome (53%), calluses (47%), diarrhea (47%), fever (41%), dry
mouth (35%), nausea (35%), and verrucous keratosis (35%). Grade ≥ 3 AEs
were present in 8 (47%) patients.Vemurafenib is a potentially effective
and well-tolerated treatment strategy in patients with advanced PTC
harboring the BRAF(V600E) mutation. Our results are similar to those
reported in a phase II clinical trial and support the potential role of
vemurafenib in this patient population.
Author String:
Ramona Dadu, Komal Shah, Naifa L Busaidy, Steven G Waguespack, Mouhammad
A Habra, Anita K Ying, Mimi I Hu, Roland Bassett, Camilo Jimenez, Steven
I Sherman, Maria E Cabanillas
Citation: Dadu et al., 2015
Citation Id: 25353071
Id: 1970
Journal: J Clin Endocrinol Metab
Link: /sources/1970
Name: PubMed: Dadu et al., 2015
Open Access: True
Pmc Id: PMC4283003
Publication Date: 2015-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25353071
Title:
Efficacy and tolerability of vemurafenib in patients with BRAF(V600E)
-positive papillary thyroid cancer: M.D. Anderson Cancer Center off
label experience.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In a clinical trial (NCT01286753) of 55 cancer patients with BRAF V600E
mutation, patients with metastatic papillary thyroid cancer (n=3) were
associated with sensitivity to vemurafenib treatment. One patient
achieved partial response (31% reduction by RECIST) and two patients
achieved stable disease (9% and 16% reduction by RECIST criteria), the
time to progression for these three patients was 11.7, 13.2 and 11.4
months, and the overall survival was 15 months (patient was subsequently
treated with radiation therapy), at least 31.7 months (patient
subsequently underwent laryngectomy) and 24.9 months (patient was
subsequently treated with sorafenib, followed by sunitinib monotherapy),
respectively.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3774
Name: EID3774
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3969
Display Name: Papillary Thyroid Carcinoma
Doid: 3969
Id: 156
Link: /diseases/156
Name: Papillary Thyroid Carcinoma
##### My Disease Info
Do Def:
A differentiated thyroid gland carcinoma that is characterized by the
small mushroom shape of the tumor which has a stem attached to the
epithelial layer and arises from the follicular cells of the thyroid
gland.
Icdo: 8260/3
Mesh: D000077273
Mondo Id: MONDO:0005075
Ncit: C4035
Disease Aliases:
- Papillary Carcinoma Of The Thyroid Gland
- Papillary Carcinoma Of Thyroid
- Thyroid Gland Papillary Carcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Clinical benefit from cytotoxic chemotherapy for metastatic papillary
thyroid carcinoma (PTC) is disappointing, and effective therapeutic
approaches for these patients are urgently needed. Because kinase-
activating mutations in the BRAF proto-oncogene commonly occur in
advanced PTC, and inhibition of BRAF(V600E) has shown promising clinical
activity in melanoma, BRAF inhibitor therapy may be an effective
strategy to treat metastatic PTC.The dose escalation portion of a first-
in-human, phase I study of vemurafenib, a selective RAF inhibitor,
included three patients with metastatic PTC harboring the BRAF(V600E)
mutation. Vemurafenib was initially dosed at 240-360 mg twice a day,
later escalated to 720 mg twice a day. Response evaluation was performed
every 8 weeks per Response Evaluation Criteria in Solid Tumors
(RECIST).Among the three patients, one had a confirmed partial response
with reduction of pulmonary target lesions by 31%, and the duration of
response was 7.6 months before the disease progressed in the lungs and
the bones. The time to progression was 11.7 months. The other two
patients had stable disease, and the time to progression was 13.2 and
11.4 months, respectively.Vemurafenib appears to have a promising
clinical activity in patients with metastatic PTC, and our data suggest
that the BRAF(V600E) mutant kinase is a relevant target for therapy in
this patient population. Further investigation of inhibitors of mutated
BRAF kinase in patients with PTC in a phase II study is warranted.
Author String:
Kevin B Kim, Maria E Cabanillas, Alexander J Lazar, Michelle D Williams,
Deborah L Sanders, Joseph L Ilagan, Keith Nolop, Richard J Lee, Steven I
Sherman
Citation: Kim et al., 2013
Citation Id: 23489023
Id: 1971
Journal: Thyroid
Link: /sources/1971
Name: PubMed: Kim et al., 2013
Open Access: True
Pmc Id: PMC3967415
Publication Date: 2013-10
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23489023
Title:
Clinical responses to vemurafenib in patients with metastatic papillary
thyroid cancer harboring BRAF(V600E) mutation.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In an in vitro study, K2, a papillary thyroid carcinoma cell line
expressing the BRAFV600E mutation, was associated with sensitivity to
dasatinib treatment. Sensitivity was determined by assessing cell growth
inhibition. In an in vivo experiment, dasatinib also inhibited the
growth of K2 thyroid carcinoma xenografts in 7 of 13 mice.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 3775
Name: EID3775
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3969
Display Name: Papillary Thyroid Carcinoma
Doid: 3969
Id: 156
Link: /diseases/156
Name: Papillary Thyroid Carcinoma
##### My Disease Info
Do Def:
A differentiated thyroid gland carcinoma that is characterized by the
small mushroom shape of the tumor which has a stem attached to the
epithelial layer and arises from the follicular cells of the thyroid
gland.
Icdo: 8260/3
Mesh: D000077273
Mondo Id: MONDO:0005075
Ncit: C4035
Disease Aliases:
- Papillary Carcinoma Of The Thyroid Gland
- Papillary Carcinoma Of Thyroid
- Thyroid Gland Papillary Carcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Papillary thyroid carcinoma is the most common thyroid malignancy. Most
papillary thyroid carcinomas contain BRAF mutations or RET/PTC
rearrangements, thus providing targets for biologic therapy. Our
previous studies had suggested papillary thyroid carcinomas (PTCs) with
a BRAF mutation and the RET/PTC1 rearrangement have different
sensitivities to MEK1/2 inhibitors, suggesting different signaling
transduction pathways were involved.Src signaling transduction pathway
in PTC cells was examined using Src inhibitors (PP2, SU6656, or
dasatinib) and si-Src RNA in vitro by Western blot analysis and
proliferation analysis. An orthotopic xenograft mouse model was used for
the in vivo studies using dasatinib.In PTC cells, Src inhibitors
suppressed p-Src and p-FAK and inhibited cell growth. In addition,
significant suppression and extension of the p-ERK1/2 dephosphorylation
were detected in RET/PTC1-rearranged cells in combination with an MEK
inhibitor (CI-1040). The Src family kinase/ABL inhibitor, dasatinib,
significantly decreased tumor volume in mice inoculated with PTC cells
carrying the RET/PTC1 rearrangement. In BRAF-mutated PTC cells, Src
inhibitors effectively suppressed p-Src expression and dasatinib
significantly decreased tumor volume with twice daily treatment.Src
inhibitors effectively inhibited the Src signaling transduction pathway
in PTC cells in vitro and dasatinib suppressed tumor growth in vivo.
These results suggested that Src signaling transduction pathway plays an
important role in regulating growth in PTC cells. Combination of Src and
MEK1/2 inhibitors extended the dephosphorylation of extracellular
signal-regulated kinase (ERK)1/2 in PTCs carrying the RET/PTC1
rearrangement suggesting that combination therapy with complementary
inhibitors of other signaling transduction pathways may be needed to
effectively suppress growth and induce apoptosis in these cells.
Author String:
Ying C Henderson, Rafael Toro-Serra, Yunyun Chen, Junsun Ryu, Mitchell J
Frederick, Ge Zhou, Gary E Gallick, Stephen Y Lai, Gary L Clayman
Citation: Henderson et al., 2014
Citation Id: 23729178
Id: 1972
Journal: Head Neck
Link: /sources/1972
Name: PubMed: Henderson et al., 2014
Open Access: True
Pmc Id: PMC4401074
Publication Date: 2014-3
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23729178
Title: Src inhibitors in suppression of papillary thyroid carcinoma growth.
##### Therapies
Deprecated: False
Id: 20
Link: /therapies/20
Name: Dasatinib
#### Evidence Items
Description:
In an in vitro study, WiDr, HT-29 and RKO cell lines expressing BRAF
V600E mutation was associated with sensitivity to regorafenib treatment,
as compared to Caco-2 and KM12SM cells expressing wild-type BRAF.
Resistance was determined by assessing cell proliferation and migration.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 3776
Name: EID3776
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:219
Display Name: Colon Cancer
Doid: 219
Id: 119
Link: /diseases/119
Name: Colon Cancer
##### My Disease Info
Do Def: A colorectal cancer that is located_in the colon.
Icd10: C18
Mesh: D003110
Mondo Id: MONDO:0021063
Ncit: C9242
##### Molecular Profile
Id: 12
##### Source
Abstract:
Interaction between tumor cells and stromal cells plays an important
role in the growth and metastasis of colon cancer. We previously found
that carcinoma-associated fibroblasts (CAFs) expressed platelet-derived
growth factor receptor-β (PDGFR-β) and that PDGFR targeted therapy using
imatinib or nilotinib inhibited stromal reaction. Bone marrow-derived
mesenchymal stem cells (MSCs) migrate to tumor stroma and differentiate
into CAFs. A novel oral multikinase inhibitor regorafenib inhibits
receptor tyrosine kinases expressed on stromal cells (vascular
endothelial growth factor receptor 1-3, TIE2, PDGFR-β, and fibroblast
growth factors) and tumor cells (c-KIT, RET, and BRAF). These molecules
are involved in tumor growth, angiogenesis, lymphangiogenesis, and
stromal activation. Therefore, we examined whether regorafenib impaired
the tumor-promoting effect of CAFs/MSCs. KM12SM human colon cancer cells
alone or KM12SM cells with MSCs were transplanted into the cecal wall of
nude mice. Co-implantation of KM12SM cells with MSCs into the cecal wall
of nude mice produced tumors with abundant stromal component and
promoted tumor growth and lymph node metastasis. Single treatment with
regorafenib inhibited tumor growth and metastasis by inhibiting both
tumor cells and stromal reaction. This tumor-inhibitory effect of
regorafenib was more obvious in tumors developed by co-implanting KM12SM
cells with MSCs. Our data suggested that targeting of the tumor
microenvironment with regorafenib affected tumor cell-MSC interaction,
which in turn inhibited the growth and metastasis of colon cancer.
Author String:
Hidehiko Takigawa, Yasuhiko Kitadai, Kei Shinagawa, Ryo Yuge, Yukihito
Higashi, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama
Citation: Takigawa et al., 2016
Citation Id: 26865419
Id: 1973
Journal: Cancer Sci
Link: /sources/1973
Name: PubMed: Takigawa et al., 2016
Open Access: True
Pmc Id: PMC5001714
Publication Date: 2016-5
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26865419
Title:
Multikinase inhibitor regorafenib inhibits the growth and metastasis of
colon cancer with abundant stroma.
##### Therapies
Deprecated: False
Id: 27
Link: /therapies/27
Name: Regorafenib
#### Evidence Items
Description:
In a retrospective study of 35 lung adenocarcinoma patients (with
chemotherapy previously administered in 86% of patients), patients
harboring a BRAF V600E mutation and treated with vemurafenib monotherapy
(n=29) were associated with an improved response rate; an overall
survival (with 1st-line therapy) of 25.63 months, a 54% overall response
rate and a 95% disease control rate were reported.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Type: PREDICTIVE
Flagged: False
Id: 3782
Name: EID3782
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3910
Display Name: Lung Adenocarcinoma
Doid: 3910
Id: 30
Link: /diseases/30
Name: Lung Adenocarcinoma
##### My Disease Info
Do Def:
A lung non-small cell carcinoma that derives_from epithelial cells of
glandular origin.
Mesh: D000077192
Mondo Id: MONDO:0005061
Ncit: C27745, C3512
Disease Aliases:
- Bronchogenic Lung Adenocarcinoma
- Nonsmall Cell Adenocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Approximately 2% of lung adenocarcinomas have BRAF (v-Raf murine sarcoma
viral oncogene homolog B) mutations, including V600E and other types.
Vemurafenib, dabrafenib, and sorafenib as BRAF inhibitors are currently
tested in clinical trials, but access for patients is limited. The aim
of this study was to document the clinical course of patients treated
outside of clinical trials.We conducted a retrospective multicenter
cohort study in Europe of patients with advanced BRAF-mutant lung cancer
treated with known BRAF inhibitors. Data were anonymized and centrally
assessed for age, gender, smoking, histology, stage, local molecular
diagnostic results, systemic therapies, and survival. Best response was
assessed locally by RECIST1.1.We documented 35 patients treated in 17
centers with vemurafenib, dabrafenib, or sorafenib. Median age was 63
years (range 42-85); gender was balanced; 14 (40%) were never smokers;
all (100%) had adenocarcinoma; 29 (83%) had V600E; 6 (17%) had other
mutations; one of them had a concomitant KRAS mutation. Thirty (86%)
patients had chemotherapy in the first line. Overall survival with
first-line therapy was 25.3 months for V600E and 11.8 months for
non-V600E. Thirty-one patients received one BRAF inhibitor, and four
received a second inhibitor. Overall response rate with BRAF therapy was
53%, and disease control rate was 85%. Median progression-free survival
with BRAF therapy was 5.0 months, and overall survival was 10.8
months.These results confirm the activity of targeted therapy in
patients with BRAF-mutant lung adenocarcinoma. Further trials are
warranted to study combination therapies and drug resistance mechanisms.
Author String:
Oliver Gautschi, Julie Milia, Bastien Cabarrou, Marie-Virginia Bluthgen,
Benjamin Besse, Egbert F Smit, Juergen Wolf, Solange Peters, Martin
Früh, Dieter Koeberle, Youssouf Oulkhouir, Martin Schuler, Alessandra
Curioni-Fontecedro, Benjamin Huret, Mallorie Kerjouan, Sebastian
Michels, Georg Pall, Sacha Rothschild, Gerald Schmid-Bindert, Matthias
Scheffler, Rémi Veillon, Luciano Wannesson, Joachim Diebold, Gérard
Zalcman, Thomas Filleron, Julien Mazières
Citation: Gautschi et al., 2015
Citation Id: 26200454
Id: 1979
Journal: J Thorac Oncol
Link: /sources/1979
Name: PubMed: Gautschi et al., 2015
Open Access: False
Publication Date: 2015-10
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26200454
Title:
Targeted Therapy for Patients with BRAF-Mutant Lung Cancer: Results from
the European EURAF Cohort.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In a study of metastatic colorectal cancer patients who received 5-FU-
based first-line chemotherapy, those with BRAF V600E mutations had
reduced progression-free survival (4.3mo vs. 12.5mo, HR:4.9,
95%CI:2.7-9.0, P<0.0001, univariate analysis; HR:4.0, 95%CI:2.2-7.4,
P<0.0001, multivariate analysis) and reduced overall survival (10.9mo
vs. 40.5mo, HR:4.5, 95%CI:2.4-8.4, P<0.0001, univariate analysis;
HR:4.1, 95%CI:2.1-8.0, P<0.0001, multivariate analysis) compared to
those with wildtype BRAF.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PROGNOSTIC
Flagged: False
Id: 2116
Name: EID2116
Significance: POOR_OUTCOME
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
We address the prognostic and predictive value of KRAS, PIK3CA and BRAF
mutations for clinical outcomes in response to active agents in the
treatment of metastatic colorectal cancer (mCRC).We determined KRAS,
BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC
at two institutions. All patients received 5-FU-based first-line
chemotherapy and treatment outcome was analysed retrospectively.KRAS,
BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%)
cases, respectively. Multivariate analysis uncovered BRAF mutation as an
independent prognostic factor for decreased survival (hazard ratio (HR)
4.0, 95% confidence interval (CI) 2.1-7.6). In addition, patients with
BRAF-mutant tumours had significantly lower progression-free survival
(PFS: HR 4.0, 95% CI 2.2-7.4) than those whose tumors that carried wild-
type BRAF. Among 92 patients treated using chemotherapy and cetuximab as
salvage therapy, KRAS mutation was associated with lack of response
(P=0.002) and shorter PFS (P=0.09). BRAF (P=0.0005) and PIK3CA (P=0.01)
mutations also predicted reduced PFS in response to cetuximab salvage
therapy.These results underscore the potential of mutational profiling
to identify CRCs with different natural histories or treatment
responses. The adverse significance of BRAF mutation should inform
patient selection and stratification in clinical trials.
Author String:
J Souglakos, J Philips, R Wang, S Marwah, M Silver, M Tzardi, J Silver,
S Ogino, S Hooshmand, E Kwak, E Freed, J A Meyerhardt, Z Saridaki, V
Georgoulias, D Finkelstein, C S Fuchs, M H Kulke, R A Shivdasani
Citation: Souglakos et al., 2009
Citation Id: 19603024
Id: 1479
Journal: Br J Cancer
Link: /sources/1479
Name: PubMed: Souglakos et al., 2009
Open Access: True
Pmc Id: PMC2720232
Publication Date: 2009-8-4
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19603024
Title:
Prognostic and predictive value of common mutations for treatment
response and survival in patients with metastatic colorectal cancer.
#### Evidence Items
Description:
In a lung adenocarcinoma patient with brain metastases harboring BRAF
V600E mutation, BRAF V600E was associated with sensitivity to
vemurafenib treatment. Upon treatment with vemurafenib monotherapy, the
patient�s metastases demonstrated significant response and pleural right
effusion improvement was observed; however, at 4 months the patient�s
disease progressed resulting in death.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3780
Name: EID3780
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3910
Display Name: Lung Adenocarcinoma
Doid: 3910
Id: 30
Link: /diseases/30
Name: Lung Adenocarcinoma
##### My Disease Info
Do Def:
A lung non-small cell carcinoma that derives_from epithelial cells of
glandular origin.
Mesh: D000077192
Mondo Id: MONDO:0005061
Ncit: C27745, C3512
Disease Aliases:
- Bronchogenic Lung Adenocarcinoma
- Nonsmall Cell Adenocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Somatic BRAF mutations have been reported in 1-4% of non-small cell lung
cancer (NSCLC), primarily in adenocarcinomas with the BRAF (V600E)
mutation in about 50% of the cases. The role of BRAF mutation in NSCLC
and the treatment for tumors with such mutations is still evolving. Our
patient had metastatic NSCLC with metastases to her brain. Due to the
BRAF (V600E) mutation in her tumor and her poor functional status, we
offered her off-label treatment with vemurafenib, a BRAF inhibitor
approved for use in metastatic melanoma. Our patient's visceral disease
improved supporting vemurafenib's efficacy in the treatment of
metastatic BRAF-mutated NSCLC. The regression of intracranial disease
indicated vemurafenib was able to cross the blood-brain barrier and was
efficacious in treating brain metastases in this patient with lung
cancer.
Author String: Sara D Robinson, Joyce A O'Shaughnessy, C Lance Cowey, Kartik Konduri
Citation: Robinson et al., 2014
Citation Id: 24888229
Id: 1977
Journal: Lung Cancer
Link: /sources/1977
Name: PubMed: Robinson et al., 2014
Open Access: False
Publication Date: 2014-8
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24888229
Title:
BRAF V600E-mutated lung adenocarcinoma with metastases to the brain
responding to treatment with vemurafenib.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In an in vitro study, the BCPAP cell line expressing a BRAF V600E
mutation was associated with sensitivity to vemurafenib treatment.
Sensitivity was determined by assessing cell viability and apoptotic
cell death. However, the 8505C cell line expressing a BRAF V600E
mutation and high MET protein phosphorylation levels was reported to be
insensitive to vemurafenib treatment.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 3785
Name: EID3785
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3963
Display Name: Thyroid Gland Carcinoma
Doid: 3963
Id: 155
Link: /diseases/155
Name: Thyroid Gland Carcinoma
##### My Disease Info
Do Def: A thyroid gland cancer that has_material_basis_in epithelial cells.
Mesh: D013964
Mondo Id: MONDO:0015075
Ncit: C4815
Disease Aliases: Head And Neck Cancer, Thyroid, Thyroid Carcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
BRAF (V600E) mutation is the most commonly detected genetic alteration
in thyroid cancer. Unlike its high treatment response to selective BRAF
inhibitor (PLX4032) in metastatic melanoma, the treatment response in
thyroid cancer is reported to be low. The purpose of this study is to
investigate the resistance mechanism responsible for this low treatment
response to BRAF inhibitor in order to maximize the effect of targeted
therapy. We examined the expression of feedback regulation mechanisms
and alterations in the upper signal transduction pathway in thyroid
cancer cell lines harboring BRAF mutation. Also, we investigated the
effect of dual inhibition from combinatorial therapy. Two thyroid cancer
cell lines, 8505C (anaplastic thyroid cancer) and BCPAP (papillary
thyroid cancer) were selected and treated with PLX4032 and its drug
sensitivity were examined and compared. Further investigation on the
changes in signals responsible for the different treatment response to
PLX4032 was carried out and the same experiment was performed on
orthotopic xenograft mouse models. Unlike BCPAP cells, 8505C cells
presented drug resistance to PLX4032 treatment and this was mainly due
to increased expression of c-Met. Effective inhibitions of c-Met, p-AKT,
and p-ERK were achieved after dual treatment with BRAF inhibitor
(PLX4032) and c-Met inhibitor (PHA665752). Similar results were
confirmed by in vivo study with orthotopic xenograft mouse model. c-Met-
mediated reactivation of the PI3K/AKT pathway and MAPK pathway
contributes to the relative insensitivity of BRAF (V600E) mutant
anaplastic thyroid cancer cells to PLX4032. Dual inhibition of BRAF and
c-Met leads to sustained treatment response. © 2015 Wiley Periodicals,
Inc.
Author String:
Hyung Kwon Byeon, Hwi Jung Na, Yeon Ju Yang, Hyeong Ju Kwon, Jae Won
Chang, Myung Jin Ban, Won Shik Kim, Dong Yeob Shin, Eun Jig Lee, Yoon
Woo Koh, Joo-Heon Yoon, Eun Chang Choi
Citation: Byeon et al., 2016
Citation Id: 26456083
Id: 1982
Journal: Mol Carcinog
Link: /sources/1982
Name: PubMed: Byeon et al., 2016
Open Access: False
Publication Date: 2016-11
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26456083
Title:
c-Met-mediated reactivation of PI3K/AKT signaling contributes to
insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
An anaplastic pleomorphic xanthoastrocytoma patient harboring BRAF V600E
mutation was associated with improved response to vemurafenib treatment.
The patient was treated with radiation and temozolomide before
experiencing disease progression; subsequent treatment with vemurafenib
monotherapy, for a 12 week period, resulted in a near complete response.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3786
Name: EID3786
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:4852
Display Name: Pleomorphic Xanthoastrocytoma
Doid: 4852
Id: 1124
Link: /diseases/1124
Name: Pleomorphic Xanthoastrocytoma
##### My Disease Info
Do Def:
A low grade glioma that is characterized by pleomorphic and lipidized
cells expressing GFAP often surrounded by a reticulin network and
eosinophilic granular bodies.
Icdo: 9424/3
Mondo Id: MONDO:0016690
Ncit: C4323
Disease Aliases: Pleomorphic Xantho-astrocytoma
##### Molecular Profile
Id: 12
##### Source
Author String:
Eudocia Q Lee, Sandra Ruland, Nicole R LeBoeuf, Patrick Y Wen, Sandro
Santagata
Citation: Lee et al., 2016
Citation Id: 25092772
Id: 1983
Journal: J Clin Oncol
Link: /sources/1983
Name: PubMed: Lee et al., 2016
Open Access: False
Publication Date: 2016-4-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25092772
Title:
Successful Treatment of a Progressive BRAF V600E-Mutated Anaplastic
Pleomorphic Xanthoastrocytoma With Vemurafenib Monotherapy.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In a malignant peripheral nerve sheath tumor patient harboring a BRAF
V600E mutation, response to vemurafenib monotherapy was reported. Upon
identification of the BRAF V600E mutation, the patient was treated with
sorafenib monotherapy, but quickly progressed; subsequently, the patient
was treated with vemurafenib. 33 days after treatment was initiated,
tumor response was reported, as evident by the disappearance of chest
and abdominal skin lesions.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3788
Name: EID3788
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:5940
Display Name: Malignant Peripheral Nerve Sheath Tumor
Doid: 5940
Id: 326
Link: /diseases/326
Name: Malignant Peripheral Nerve Sheath Tumor
##### My Disease Info
Icdo: 9540/3
Mesh: D018319
Mondo Id: MONDO:0017827
Ncit: C3798
Disease Aliases: Malignant Neoplasm Of The Peripheral Nerve Sheath
##### Molecular Profile
Id: 12
##### Source
Abstract:
No effective systemic treatment exists for malignant peripheral nerve
sheath tumors (MPNSTs). These tumors have been reported to show
increased activity in the mitogen-activated protein kinase pathway from
the loss of neurofibromatosis-1 regulation and occasionally from BRAF
V600E mutation. A patient with sporadic metastatic MPNST and the BRAF
V600E mutation was treated with standard doses of sorafenib and later
vemurafenib and followed for response. The patient showed a rapid but
modest and transient response to sorafenib and a very dramatic response
to vemurafenib. This case represents the first report of successful
systemic treatment of MPNST with an inhibitor of the BRAF V600E
mutation. It will be important to define the general utility of this
approach and related therapies in this disease.
Author String: Henry G Kaplan
Citation: Kaplan, 2013
Citation Id: 24335681
Id: 1958
Journal: J Natl Compr Canc Netw
Link: /sources/1958
Name: PubMed: Kaplan, 2013
Open Access: False
Publication Date: 2013-12-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24335681
Title:
Vemurafenib treatment of BRAF V600E-mutated malignant peripheral nerve
sheath tumor.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
A primary central nervous system (CNS)-histiocytic sarcoma patient
harboring BRAF V600E mutation was associated with improved response to
vemurafenib treatment. The patient was treated with vemurafenib
monotherapy and obtained a clinical, biological and radiologic response;
subsequently, the patient developed progressive disease and died 6
months after initial treatment with vemurafenib.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3789
Name: EID3789
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:4231
Display Name: Histiocytoma
Doid: 4231
Id: 964
Link: /diseases/964
Name: Histiocytoma
##### My Disease Info
Icdo: 8831/0
Mesh: D051642
Mondo Id: MONDO:0005509
Ncit: C35765
##### Molecular Profile
Id: 12
##### Source
Author String:
Ahmed Idbaih, Karima Mokhtari, Jean-François Emile, Damien Galanaud,
Hayat Belaid, Simon de Bernard, Neila Benameur, Vlad-Ciprian Barlog,
Dimitri Psimaras, Jean Donadieu, Catherine Carpentier, Nadine Martin-
Duverneuil, Julien Haroche, Loic Feuvret, Noel Zahr, Jean-Yves Delattre,
Khê Hoang-Xuan
Citation: Idbaih et al., 2014
Citation Id: 25209580
Id: 1985
Journal: Neurology
Link: /sources/1985
Name: PubMed: Idbaih et al., 2014
Open Access: False
Publication Date: 2014-10-14
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25209580
Title:
Dramatic response of a BRAF V600E-mutated primary CNS histiocytic
sarcoma to vemurafenib.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In a conjunctival malignant melanoma patient harboring a BRAF V600E
mutation, BRAF V600E was associated with response to vemurafenib
treatment. Prior to identification of the BRAF V600E mutation, the
patient was treated with cryotherapy, standard chemotherapy and whole
brain radiotherapy; the patient achieved a 4 month progression free
survival with vemurafenib treatment prior to disease progression.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3790
Name: EID3790
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1751
Display Name: Malignant Conjunctival Melanoma
Doid: 1751
Id: 2605
Link: /diseases/2605
Name: Malignant Conjunctival Melanoma
##### My Disease Info
Mondo Id: MONDO:0002096
Ncit: C4550
Disease Aliases:
- Conjunctival Melanoma
- Malignant Melanoma Of Conjunctiva
##### Molecular Profile
Id: 12
##### Source
Abstract:
Conjunctival malignant melanoma (CMM) is a rare malignancy and in the
advanced setting there is no effective treatment. In contrast, half of
cutaneous melanomas have BRAF mutations and treatment with BRAF
inhibitors is established for patients with disseminated disease. The
most common form of ocular melanoma, uveal melanoma, lacks these
mutations, however, their presence has been reported for CMM.We used the
BRAF inhibitor vemurafenib to treat a 53 year-old female suffering from
a BRAF(V600E) mutated metastatic CMM. The patient benefited from the
treatment, a response was evident within a week and she experienced a
progression free survival of four months.To our knowledge, this is the
first described case of response to vemurafenib treatment in a patient
with ocular melanoma.
Author String: A Maleka, G Åström, P Byström, G J Ullenhag
Citation: Maleka et al., 2016
Citation Id: 27520988
Id: 1986
Journal: BMC Cancer
Link: /sources/1986
Name: PubMed: Maleka et al., 2016
Open Access: True
Pmc Id: PMC4983009
Publication Date: 2016-8-12
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/27520988
Title:
A case report of a patient with metastatic ocular melanoma who
experienced a response to treatment with the BRAF inhibitor vemurafenib.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
Chemotherapy-refractory, metastatic cholangiocarcinoma with CNS
involvement and a BRAF V600E mutation had a partial response at 8 weeks
to dabrafenib and trametinib combination with complete radiologic
regression at 12 weeks. At 6 months the patient was still on treatment.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 5902
Name: EID5902
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:4947
Display Name: Cholangiocarcinoma
Doid: 4947
Id: 29
Link: /diseases/29
Name: Cholangiocarcinoma
##### My Disease Info
Do Def:
A bile duct adenocarcinoma that has_material_basis_in bile duct
epithelial cells.
Icd10: C22.1
Icdo: 8160/3
Mesh: D018281
Mondo Id: MONDO:0019087
Ncit: C4436, C8265
Disease Aliases:
- Adult Primary Cholangiocarcinoma
- Adult Primary Cholangiocellular Carcinoma
- Cholangiosarcoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Since the prognosis of advanced cholangiocarcinoma (CCA) remains poor
with traditional chemotherapy, attention has shifted to molecularly
targeted agents. Results of available clinical studies reveal little or
no benefit of using targeted agents in advanced CCA. Limitations of
these trials could be the lack of comprehensive molecular and genetic
characterization of CCA samples in order to identify potential drug
targets. Here we report a case of a 59-year-old female with
chemotherapy-refractor, metastatic extrahepatic cholangiocarcinoma
(EHCCA). After failure of first-line chemotherapy with cisplatin plus
gemcitabine, next generation sequencing (NGS) based tumor molecular
profiling was performed on aspiration cytological sample, that revealed
BRAF V600E mutation. Multidisciplinary team decided on the initiation of
combined treatment with BRAF and MEK inhibitors. Dabrafenib was started
orally 150 mg twice a day, adding trametinib 2 mg once a day. Right from
the initiation of targeted therapy, significant clinical improvement had
been observed. Even though the first restaging computed tomography (CT)
scan at 8 weeks revealed spectacular decrease in all metastatic sites, a
new hepatic mass of 67 mm × 40 mm was identified and interpreted as new
metastatic lesion. As the clinical and radiological response was
contradictory, CT-guided biopsy was taken from the hepatic lesion while
the therapy was continued on. Histopathologic evaluation excluded the
hepatic lesion from being a metastasis, instead described it as a
fibrotic, inflammatory lesion. At 12 week, PET CT confirmed further
tumor regression with complete regression of the multiple cerebral
metastases. The therapy has been extremely well tolerated by the
patient. According to our knowledge, this is the first reported case on
a successful treatment of EHCCA with the combination of dabrafenib and
trametinib. Our case highlights the importance of molecular profiling in
CCA, in order to find potential actionable driver mutations for
personalised treatment.
Author String:
Judit Kocsis, Anita Árokszállási, Csilla András, Ingrid Balogh, Edit
Béres, Júlia Déri, István Peták, Levente Jánváry, Zsolt Horváth
Citation: Kocsis et al., 2017
Citation Id: 28480077
Id: 2381
Journal: J Gastrointest Oncol
Link: /sources/2381
Name: PubMed: Kocsis et al., 2017
Open Access: True
Pmc Id: PMC5401859
Publication Date: 2017-4
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/28480077
Title:
Combined dabrafenib and trametinib treatment in a case of chemotherapy-
refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic
clinical and radiological response with a confusing synchronic new liver
lesion.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
Two cases of patients with BRAF V600E positive, refractory intrahepatic
cholangiocarcinoma showed excellent clinical and radiographic response
to combination dabrafenib and trametinib treatment. One patient achieved
complete remission at 6 months with progression at 9 months and the
other partial remission at 2 months and no progression as of 5 months.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 5903
Name: EID5903
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:4928
Display Name: Intrahepatic Cholangiocarcinoma
Doid: 4928
Id: 1165
Link: /diseases/1165
Name: Intrahepatic Cholangiocarcinoma
##### My Disease Info
Do Def:
A cholangiocarcinoma that arises from the intrahepatic bile duct
epithelium in any site of the intrahepatic biliary tree.
Icd10: C22.1
Mesh: D018281
Mondo Id: MONDO:0003210
Ncit: C35417
Disease Aliases:
- Intrahepatic Bile Duct Carcinoma
- Peripheral Cholangiocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Intrahepatic cholangiocarcinoma (ICC) typically presents at an advanced
stage and is associated with a poor oncological outcome. The median
survival for metastatic ICC is less than 1 year with standard
chemotherapy. ICC is associated with distinct oncogenic drivers
including IDH (isocitrate dehydrogenase), HER-2 (human epidermal growth
factor 2), and BRAF (v-Raf murine sarcoma viral oncogene homolog B),
which may benefit from matching targeted therapies. Hereby we report 2
cases of BRAF V600E refractory ICC treated with dual BRAF and MEK
inhibitors (dabrafenib and trametinib) with excellent clinical and
radiological response to therapy and with protracted duration of disease
control. Our first patient achieved CR (complete remission) at 6 months
of treatment with ultimate disease progression at 9 months. The second
patient achieved a PR (partial response) at 2 months from starting
treatment and remains progression free at 5 months. Our results confirm
the activity of dual BRAF and MEK targeting in BRAF mutated ICC, adding
further support to 3 additional case-reports in the literature. Dual
targeting appears superior to other case reports with BRAF inhibition
alone and appear favorable to historic data with cytotoxic chemotherapy.
Given the poor outlook and refractoriness of BRAF mutant ICC, future
studies should focus on early integration of BRAF/MEK inhibition.
Author String: Viraj Lavingia, Marwan Fakih
Citation: Lavingia et al., 2016
Citation Id: 28078132
Id: 2380
Journal: J Gastrointest Oncol
Link: /sources/2380
Name: PubMed: Lavingia et al., 2016
Open Access: True
Pmc Id: PMC5177579
Publication Date: 2016-12
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/28078132
Title:
Impressive response to dual BRAF and MEK inhibition in patients with
BRAF mutant intrahepatic cholangiocarcinoma-2 case reports and a brief
review.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
Dabrafenib and trametinib combination showed durable response for a
patient with standard chemotherapy and radiation refractory, poorly
differentiated, intrahepatic cholangiocarcinoma harboring BRAF V600E. At
time of publication, 8.5 months, the patient was still on treatment.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 5904
Name: EID5904
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:4928
Display Name: Intrahepatic Cholangiocarcinoma
Doid: 4928
Id: 1165
Link: /diseases/1165
Name: Intrahepatic Cholangiocarcinoma
##### My Disease Info
Do Def:
A cholangiocarcinoma that arises from the intrahepatic bile duct
epithelium in any site of the intrahepatic biliary tree.
Icd10: C22.1
Mesh: D018281
Mondo Id: MONDO:0003210
Ncit: C35417
Disease Aliases:
- Intrahepatic Bile Duct Carcinoma
- Peripheral Cholangiocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
This is the case of a 47-year-old woman diagnosed with chemotherapy and
radiation-refractory BRAF V600E mutant, poorly differentiated
intrahepatic cholangiocarcinoma (ICC), with multiple metastatic lesions
within the liver, lungs, pleura, and bone, stage IV. Discussion of her
malignancy's next-generation sequencing genomic information at a
multidisciplinary molecular tumour board took place. The patient was
considered a suitable candidate for dual BRAF and MEK inhibition, with
the intent to prolong her survival and optimize the quality of life. We
report her excellent tolerance and exceptional response to dual therapy
with dabrafenib and trametinib, including symptomatic and sustained
near-complete radiological improvement. We also briefly review the
current knowledge of the genomics of cholangiocarcinoma with a focus on
BRAF mutations, and make a point of the importance of the establishment
of a molecular tumour board for personalized genomic medicine
approaches. To our knowledge, this is the first reported case of the use
of personalized genomic information for the successful management of a
patient with ICC, and it is also the first description of dual BRAF and
MEK targeted therapy in this malignancy, leading to what is considered
an exceptional response.
Author String:
Arturo Loaiza-Bonilla, Erica Clayton, Emma Furth, Mark O'Hara, Jennifer
Morrissette
Citation: Loaiza-Bonilla et al., 2014
Citation Id: 25435907
Id: 2379
Journal: Ecancermedicalscience
Link: /sources/2379
Name: PubMed: Loaiza-Bonilla et al., 2014
Open Access: True
Pmc Id: PMC4239128
Publication Date: 2014
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25435907
Title:
Dramatic response to dabrafenib and trametinib combination in a BRAF
V600E-mutated cholangiocarcinoma: implementation of a molecular tumour
board and next-generation sequencing for personalized medicine.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or
SHH alterations to treatment with pertuzumab plus trastuzumab,
erlotinib, vemurafenib, or vismodegib, respectively. Among 2 patients
with BRAF V600E mutant colorectal cancer, 1 had a partial response.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 2
Evidence Type: PREDICTIVE
Flagged: False
Id: 5960
Name: EID5960
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
Purpose Detection of specific molecular alterations in tumors guides the
selection of effective targeted treatment of patients with several types
of cancer. These molecular alterations may occur in other tumor types
for which the efficacy of targeted therapy remains unclear. The
MyPathway study evaluates the efficacy and safety of selected targeted
therapies in tumor types that harbor relevant genetic alterations but
are outside of current labeling for these treatments. Methods MyPathway
( ClinicalTrials.gov identifier: NCT02091141) is a multicenter,
nonrandomized, phase IIa multiple basket study. Patients with advanced
refractory solid tumors harboring molecular alterations in human
epidermal growth factor receptor-2, epidermal growth factor receptor,
v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway
are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or
vismodegib, respectively. The primary end point is investigator-assessed
objective response rate within each tumor-pathway cohort. Results
Between April 1, 2014 and November 1, 2016, 251 patients with 35
different tumor types received study treatment. The efficacy population
contains 230 treated patients who were evaluated for response or
discontinued treatment before evaluation. Fifty-two patients (23%) with
14 different tumor types had objective responses (complete, n = 4;
partial, n = 48). Tumor-pathway cohorts with notable objective response
rates included human epidermal growth factor
receptor-2-amplified/overexpressing colorectal (38% [14 of 37]; 95% CI,
23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1
V600-mutated non-small-cell lung cancer (43% [six of 14]; 95% CI, 18% to
71%). Conclusion The four currently approved targeted therapy regimens
in the MyPathway study produced meaningful responses when administered
without chemotherapy in several refractory solid tumor types not
currently labeled for these agents.
Author String:
John D Hainsworth, Funda Meric-Bernstam, Charles Swanton, Herbert
Hurwitz, David R Spigel, Christopher Sweeney, Howard Burris, Ron Bose,
Bongin Yoo, Alisha Stein, Mary Beattie, Razelle Kurzrock
Citation: Hainsworth et al., 2018
Citation Id: 29320312
Id: 2414
Journal: J Clin Oncol
Link: /sources/2414
Name: PubMed: Hainsworth et al., 2018
Open Access: False
Publication Date: 2018-2-20
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/29320312
Title:
Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular
Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple
Basket Study.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In this trial, 142 patients with metastatic, BRAF V600E mutant
colorectal cancer were randomized to receive either BRAF inhibitor
dabrafenib (D) + EGFR inhibitor panitumumab (P); or a triple therapy of
D + P and MEK inhibition with trametinib (T) or T + P. Confirmed
response rates for D+P (n=20), D+T+P (n=91), and T+P (n=31) were 10%,
21%, and 0%, respectively.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 4
Evidence Type: PREDICTIVE
Flagged: False
Id: 6123
Name: EID6123
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
Although BRAF inhibitor monotherapy yields response rates >50% in
BRAFV600-mutant melanoma, only approximately 5% of patients with
BRAFV600E colorectal cancer respond. Preclinical studies suggest that
the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive
feedback reactivation of MAPK signaling, often mediated by EGFR. This
clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) +
panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater
MAPK suppression and improved efficacy in 142 patients with BRAFV600E
colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were
10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired
pretreatment and on-treatment biopsies found that efficacy of D+T+P
correlated with increased MAPK suppression. Serial cell-free DNA
analysis revealed additional correlates of response and emergence of
KRAS and NRAS mutations on disease progression. Thus, targeting adaptive
feedback pathways in BRAFV600E colorectal cancer can improve efficacy,
but MAPK reactivation remains an important primary and acquired
resistance mechanism.Significance: This trial demonstrates that combined
BRAF + EGFR + MEK inhibition is tolerable, with promising activity in
patients with BRAFV600E colorectal cancer. Our findings highlight the
MAPK pathway as a critical target in BRAFV600E colorectal cancer and the
need to optimize strategies inhibiting this pathway to overcome both
primary and acquired resistance. Cancer Discov; 8(4); 428-43. ©2018
AACR.See related commentary by Janku, p. 389See related article by
Hazar-Rethinam et al., p. 417This article is highlighted in the In This
Issue feature, p. 371.
Author String:
Ryan B Corcoran, Thierry André, Chloe E Atreya, Jan H M Schellens,
Takayuki Yoshino, Johanna C Bendell, Antoine Hollebecque, Autumn J
McRee, Salvatore Siena, Gary Middleton, Kei Muro, Michael S Gordon,
Josep Tabernero, Rona Yaeger, Peter J O'Dwyer, Yves Humblet, Filip De
Vos, A Scott Jung, Jan C Brase, Savina Jaeger, Severine Bettinger,
Bijoyesh Mookerjee, Fatima Rangwala, Eric Van Cutsem
Citation: Corcoran et al., 2018
Citation Id: 29431699
Id: 2468
Journal: Cancer Discov
Link: /sources/2468
Name: PubMed: Corcoran et al., 2018
Open Access: True
Pmc Id: PMC5882509
Publication Date: 2018-4
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/29431699
Title:
Combined BRAF, EGFR, and MEK Inhibition in Patients with
BRAFV600E-Mutant Colorectal Cancer.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 28
Link: /therapies/28
Name: Panitumumab
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
Of metastatic colorectal cancer patients treated with bevacizumab-based
first-line therapy, those with BRAF V600E mutations had reduced
progression-free survival compared to those with wildtype BRAF (4.2mo
vs. 12.5mo, HR:5.1, 95%CI:2.4-11.1, P<0.0001).
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Type: PREDICTIVE
Flagged: False
Id: 2120
Name: EID2120
Significance: RESISTANCE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
We address the prognostic and predictive value of KRAS, PIK3CA and BRAF
mutations for clinical outcomes in response to active agents in the
treatment of metastatic colorectal cancer (mCRC).We determined KRAS,
BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC
at two institutions. All patients received 5-FU-based first-line
chemotherapy and treatment outcome was analysed retrospectively.KRAS,
BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%)
cases, respectively. Multivariate analysis uncovered BRAF mutation as an
independent prognostic factor for decreased survival (hazard ratio (HR)
4.0, 95% confidence interval (CI) 2.1-7.6). In addition, patients with
BRAF-mutant tumours had significantly lower progression-free survival
(PFS: HR 4.0, 95% CI 2.2-7.4) than those whose tumors that carried wild-
type BRAF. Among 92 patients treated using chemotherapy and cetuximab as
salvage therapy, KRAS mutation was associated with lack of response
(P=0.002) and shorter PFS (P=0.09). BRAF (P=0.0005) and PIK3CA (P=0.01)
mutations also predicted reduced PFS in response to cetuximab salvage
therapy.These results underscore the potential of mutational profiling
to identify CRCs with different natural histories or treatment
responses. The adverse significance of BRAF mutation should inform
patient selection and stratification in clinical trials.
Author String:
J Souglakos, J Philips, R Wang, S Marwah, M Silver, M Tzardi, J Silver,
S Ogino, S Hooshmand, E Kwak, E Freed, J A Meyerhardt, Z Saridaki, V
Georgoulias, D Finkelstein, C S Fuchs, M H Kulke, R A Shivdasani
Citation: Souglakos et al., 2009
Citation Id: 19603024
Id: 1479
Journal: Br J Cancer
Link: /sources/1479
Name: PubMed: Souglakos et al., 2009
Open Access: True
Pmc Id: PMC2720232
Publication Date: 2009-8-4
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19603024
Title:
Prognostic and predictive value of common mutations for treatment
response and survival in patients with metastatic colorectal cancer.
##### Therapies
Deprecated: False
Id: 33
Link: /therapies/33
Name: Bevacizumab
#### Evidence Items
Description:
In patients with papillary thyroid cancer harboring both BRAF V600E and
the TERT promotor mutation C228T (N=35), recurrence-free survival is
worse than in patients harboring one of these mutations (N=159 BRAF,
N=26 TERT promoter mutated) or no mutations in either gene
(N=287)(P<0.001).
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 5
Evidence Type: PROGNOSTIC
Flagged: False
Id: 656
Name: EID656
Significance: POOR_OUTCOME
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3969
Display Name: Papillary Thyroid Carcinoma
Doid: 3969
Id: 156
Link: /diseases/156
Name: Papillary Thyroid Carcinoma
##### My Disease Info
Do Def:
A differentiated thyroid gland carcinoma that is characterized by the
small mushroom shape of the tumor which has a stem attached to the
epithelial layer and arises from the follicular cells of the thyroid
gland.
Icdo: 8260/3
Mesh: D000077273
Mondo Id: MONDO:0005075
Ncit: C4035
Disease Aliases:
- Papillary Carcinoma Of The Thyroid Gland
- Papillary Carcinoma Of Thyroid
- Thyroid Gland Papillary Carcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
To investigate the prognostic value of the BRAF V600E mutation and the
recently identified TERT promoter mutation chr5:1,295,228C>T (C228T),
individually and in their coexistence, in papillary thyroid cancer
(PTC).We performed a retrospective study of the relationship of BRAF and
TERT C228T mutations with clinicopathologic outcomes of PTC in 507
patients (365 women and 142 men) age 45.9 ± 14.0 years (mean ± SD) with
a median follow-up of 24 months (interquartile range, 8 to 78
months).Coexisting BRAF V600E and TERT C228T mutations were more
commonly associated with high-risk clinicopathologic characteristics of
PTC than they were individually. Tumor recurrence rates were 25.8% (50
of 194;77.60 recurrences per 1,000 person-years; 95% CI, 58.81 to
102.38) versus 9.6% (30 of 313; 22.88 recurrences per 1,000 person-
years; 95% CI, 16.00 to 32.72) in BRAF mutation-positive versus
-negative patients (hazard ratio [HR], 3.22; 95% CI, 2.05 to 5.07) and
47.5% (29 of 61; 108.55 recurrences per 1,000 person-years; 95% CI,
75.43 to 156.20) versus 11.4% (51 of 446; 30.21 recurrences per 1,000
person-years; 95% CI, 22.96 to 39.74) in TERT mutation-positive versus
-negative patients (HR, 3.46; 95% CI, 2.19 to 5.45). Recurrence rates
were 68.6% (24 of 35; 211.76 recurrences per 1,000 person-years; 95% CI,
141.94 to 315.94) versus 8.7% (25 of 287; 21.60 recurrences per 1,000
person-years; 95% CI, 14.59 to 31.97) in patients harboring both
mutations versus patients harboring neither mutation (HR, 8.51; 95% CI,
4.84 to 14.97), which remained significant after clinicopathologic
cofactor adjustments. Disease-free patient survival curves displayed a
moderate decline with BRAF V600E or TERT C228T alone but a sharp decline
with two coexisting mutations.Coexisting BRAF V600E and TERT C228T
mutations form a novel genetic background that defines PTC with the
worst clinicopathologic outcomes, providing unique prognostic and
therapeutic implications.
Author String:
Mingzhao Xing, Rengyun Liu, Xiaoli Liu, Avaniyapuram Kannan Murugan,
Guangwu Zhu, Martha A Zeiger, Sara Pai, Justin Bishop
Citation: Xing et al., 2014
Citation Id: 25024077
Id: 413
Journal: J Clin Oncol
Link: /sources/413
Name: PubMed: Xing et al., 2014
Open Access: True
Pmc Id: PMC4145183
Publication Date: 2014-9-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25024077
Title:
BRAF V600E and TERT promoter mutations cooperatively identify the most
aggressive papillary thyroid cancer with highest recurrence.
#### Evidence Items
Description:
Thyroid nodule with BRAF V600E mutation is highly correlated with
papillary thyroid cancer.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 5
Evidence Type: DIAGNOSTIC
Flagged: False
Id: 80
Name: EID80
Significance: POSITIVE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3969
Display Name: Papillary Thyroid Carcinoma
Doid: 3969
Id: 156
Link: /diseases/156
Name: Papillary Thyroid Carcinoma
##### My Disease Info
Do Def:
A differentiated thyroid gland carcinoma that is characterized by the
small mushroom shape of the tumor which has a stem attached to the
epithelial layer and arises from the follicular cells of the thyroid
gland.
Icdo: 8260/3
Mesh: D000077273
Mondo Id: MONDO:0005075
Ncit: C4035
Disease Aliases:
- Papillary Carcinoma Of The Thyroid Gland
- Papillary Carcinoma Of Thyroid
- Thyroid Gland Papillary Carcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
BRAF(V600E) is the most frequent genetic mutation in papillary thyroid
cancer (PTC) and has been reported as an independent predictor of poor
prognosis of these patients. Current guidelines do not recommend the use
of BRAF(V600E) mutational analysis on cytologic specimens from fine
needle aspiration due to several reasons. Recently, immunohistochemistry
using VE1, a mouse anti-human BRAF(V600E) antibody, has been reported as
a highly reliable technique in detecting BRAF-mutated thyroid and
nonthyroid cancers. The aim of this study was to test the reliability of
VE1 immunohistochemistry on microhistologic samples from core needle
biopsy (CNB) in identifying BRAF-mutated PTC. A series of 30 nodules
(size ranging from 7 to 22 mm) from 30 patients who underwent surgery
following CNB were included in the study. All these lesions had had
inconclusive cytology. In all cases, both VE1 and BRAF(V600E) genotypes
were evaluated. After surgery, final histology demonstrated 21 cancers
and 9 benign lesions. CNB correctly diagnosed 20/20 PTC and 5/5
adenomatous nodules. One follicular thyroid cancer and 4 benign lesions
were assessed at CNB as uncertain follicular neoplasm. VE1
immunohistochemistry revealed 8 mutated PTC and 22 negative cases. A
100% agreement was found when positive and negative VE1 results were
compared with BRAF mutational status. These data are the first
demonstration that VE1 immunohistochemistry performed on thyroid CNB
samples perfectly matches with genetic analysis of BRAF status. Thus,
VE1 antibody can be used on thyroid microhistologic specimens to detect
BRAF(V600E)-mutated PTC before surgery.
Author String:
A Crescenzi, L Guidobaldi, N Nasrollah, S Taccogna, D D Cicciarella
Modica, L Turrini, G Nigri, F Romanelli, S Valabrega, L Giovanella, A
Onetti Muda, P Trimboli
Citation: Crescenzi et al., 2014
Citation Id: 24570209
Id: 94
Journal: Horm Metab Res
Link: /sources/94
Name: PubMed: Crescenzi et al., 2014
Open Access: False
Publication Date: 2014-5
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24570209
Title:
Immunohistochemistry for BRAF(V600E) antibody VE1 performed in core
needle biopsy samples identifies mutated papillary thyroid cancers.
#### Evidence Items
Description:
In this Phase III trial (NCT01584648 COMBI-d), previously untreated
patients with unresectable stage IIIC or IV melanoma with BRAF V600E
(359 patients) or V600K (61 patients) received dabrafenib and trametinib
or dabrafenib alone with primary endpoint of progression free survival
and secondary endpoints including disease response. The hazard ratio for
progression or death in the V600E group was 0.81 for dabrafenib-
trametinib vs dabrafenib-alone. Of 179 V600E patients in the dabrafenib-
trametinib group, 68% of patients had a response, which was 15
percentage points higher than in the dabrafenib-alone group (95% CI, 4
to 24; P=0.006).
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 5
Evidence Type: PREDICTIVE
Flagged: False
Id: 6938
Name: EID6938
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Combined BRAF and MEK inhibition, as compared with BRAF inhibition
alone, delays the emergence of resistance and reduces toxic effects in
patients who have melanoma with BRAF V600E or V600K mutations.In this
phase 3 trial, we randomly assigned 423 previously untreated patients
who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E
or V600K mutation to receive a combination of dabrafenib (150 mg orally
twice daily) and trametinib (2 mg orally once daily) or dabrafenib and
placebo. The primary end point was progression-free survival. Secondary
end points included overall survival, response rate, response duration,
and safety. A preplanned interim overall survival analysis was
conducted.The median progression-free survival was 9.3 months in the
dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group
(hazard ratio for progression or death in the dabrafenib-trametinib
group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The
overall response rate was 67% in the dabrafenib-trametinib group and 51%
in the dabrafenib-only group (P=0.002). At 6 months, the interim overall
survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib
alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02).
However, a specified efficacy-stopping boundary (two-sided P=0.00028)
was not crossed. Rates of adverse events were similar in the two groups,
although more dose modifications occurred in the dabrafenib-trametinib
group. The rate of cutaneous squamous-cell carcinoma was lower in the
dabrafenib-trametinib group than in the dabrafenib-only group (2% vs.
9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was
more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib
group.A combination of dabrafenib and trametinib, as compared with
dabrafenib alone, improved the rate of progression-free survival in
previously untreated patients who had metastatic melanoma with BRAF
V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical
Trials.gov number, NCT01584648.).
Author String:
Georgina V Long, Daniil Stroyakovskiy, Helen Gogas, Evgeny Levchenko,
Filippo de Braud, James Larkin, Claus Garbe, Thomas Jouary, Axel
Hauschild, Jean Jacques Grob, Vanna Chiarion Sileni, Celeste Lebbe,
Mario Mandalà, Michael Millward, Ana Arance, Igor Bondarenko, John B A G
Haanen, Johan Hansson, Jochen Utikal, Virginia Ferraresi, Nadezhda
Kovalenko, Peter Mohr, Volodymyr Probachai, Dirk Schadendorf, Paul
Nathan, Caroline Robert, Antoni Ribas, Douglas J DeMarini, Jhangir G
Irani, Michelle Casey, Daniele Ouellet, Anne-Marie Martin, Ngocdiep Le,
Kiran Patel, Keith Flaherty
Citation: Long et al., 2014
Citation Id: 25265492
Id: 2671
Journal: N Engl J Med
Link: /sources/2671
Name: PubMed: Long et al., 2014
Open Access: False
Publication Date: 2014-11-13
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25265492
Title:
Combined BRAF and MEK inhibition versus BRAF inhibition alone in
melanoma.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
In this trial, 19 patients with pediatric brain tumours (1 patient with
Astrocytoma, 1 with Fibrillary Astrocytoma, 10 with Pilocytic
Astrocytoma, 5 with Ganglioglioma and 2 with Pleomorphic
Xanthoastrocytoma) harbouring BRAF V600E were treated with vemurafenib.
The study reported a positive response to the treatment, with 1 complete
response, 5 partial responses, and 13 patients with stable disease.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 11770
Name: EID11770
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:0080829
Display Name: Low Grade Glioma
Doid: 0080829
Id: 3047
Link: /diseases/3047
Name: Low Grade Glioma
##### My Disease Info
Do Def:
A cell type benign neoplasm that has_material_basis_in glial cells
(astrocytes, oligodendrocytes or ependymocytes).
Mondo Id: MONDO:0021637
Ncit: C132067
Disease Aliases: Benign Glioma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Background: BRAFV600E mutation is present in a subset of pediatric brain
tumors. Vemurafenib is an oral, selective ATP-competitive inhibitor of
BRAFV600E kinase. The goal of this multi-center study conducted through
the Pacific Pediatric Neuro-Oncology Consortium (PNOC) was to determine
the recommended phase 2 dose (RP2D) and dose limiting toxicities (DLTs)
in children < 18 years with recurrent or progressive BRAFV600E mutant
brain tumors. Results: Nineteen eligible patients were enrolled. Eleven
patients had received three or more prior therapies. Data reported are
from the start of treatment for the first patient (April 30 2014)
through August 31 2019. The RP2D was defined as 550 mg/m2 twice daily
after DLT criteria adjustment for rash. Related grade ≥ 3 adverse events
included secondary keratoacanthoma (n = 1); rash (n =16); and fever (n =
5). Subjects received a median of 23 cycles (range 3-63). Four patients
remain on treatment. Centrally reviewed best radiographic responses
included 1 complete response, 5 partial responses, and 13 stable
disease. The steady-state area under the curve (AUC0-∞median) was 604
mg*h/L (range 329-1052). Methods: Vemurafenib was given starting at 550
mg/m2, twice daily which corresponds to the adult RP2D. Adverse events
were graded using the NIH Common Terminology Criteria for Adverse Events
(CTCAE) version 4.0. Central imaging review was performed.
Pharmacokinetic sampling was performed. Conclusions: Vemurafenib has
promising anti-tumor activity in recurrent BRAF V600E-positive brain
tumors with manageable toxicity. A phase 2 study is ongoing
(NCT01748149).
Author String:
Theodore Nicolaides, Kellie J Nazemi, John Crawford, Lindsay Kilburn,
Jane Minturn, Amar Gajjar, Karen Gauvain, Sarah Leary, Girish Dhall,
Mariam Aboian, Giles Robinson, Janel Long-Boyle, Hechuan Wang, Annette M
Molinaro, Sabine Mueller, Michael Prados
Citation: Nicolaides et al., 2020
Citation Id: 32523649
Id: 4902
Journal: Oncotarget
Link: /sources/4902
Name: PubMed: Nicolaides et al., 2020
Open Access: True
Pmc Id: PMC7260122
Publication Date: 2020-5-26
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/32523649
Title:
Phase I study of vemurafenib in children with recurrent or progressive
BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology
Consortium study (PNOC-002).
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
Patients with completely resected colorectal adenocarcinoma (Stage II-
III) were treated with fluorouracil and leucovorin +/- ironotecan. Of
the 1,307 FFPE samples tested, V600E was observed in 31 Stage II samples
(7.6%) and 72 Stage III samples (7.9%). V600E was prognostic for overall
survival, but not for relapse-free survival, in patients with stages II
and III combined, and in stage III alone. For all MSI low and stable
tumors, BRAF V600E positive samples had a hazard ratio (HR) of 2.19 (95%
CI, 1.43 to 3.37, P=0.00034). For all samples in the cohort (MSI-H and
MSI-L) BRAF V600E positive samples had a 1.66 HR (95% CI, 1.15 to 2.40,
P=0.0069). The authors note prognostic value for BRAF V600E, especially
in non-MSI high tumors.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 4
Evidence Type: PROGNOSTIC
Flagged: False
Id: 7156
Name: EID7156
Significance: POOR_OUTCOME
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
Mutations within the KRAS proto-oncogene have predictive value but are
of uncertain prognostic value in the treatment of advanced colorectal
cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278
patients with stage II to III colon cancer, to evaluate the prognostic
value of KRAS and BRAF tumor mutation status in this setting.Formalin-
fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively
collected and DNA was extracted from tissue sections from 1,404 cases.
Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed
by allele-specific real-time polymerase chain reaction. Survival
analyses were based on univariate and multivariate proportional hazard
regression models.KRAS and BRAF tumor mutation rates were 37.0% and
7.9%, respectively, and were not significantly different according to
tumor stage. In a multivariate analysis containing stage, tumor site,
nodal status, sex, age, grade, and microsatellite instability (MSI)
status, KRAS mutation was associated with grade (P = .0016), while BRAF
mutation was significantly associated with female sex (P = .017), and
highly significantly associated with right-sided tumors, older age, high
grade, and MSI-high tumors (all P < 10(-4)). In univariate and
multivariate analysis, KRAS mutations did not have a major prognostic
value regarding relapse-free survival (RFS) or overall survival (OS).
BRAF mutation was not prognostic for RFS, but was for OS, particularly
in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard
ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003).In stage II-III colon cancer,
the KRAS mutation status does not have major prognostic value. BRAF is
prognostic for OS in MS-L/S tumors.
Author String:
Arnaud D Roth, Sabine Tejpar, Mauro Delorenzi, Pu Yan, Roberto Fiocca,
Dirk Klingbiel, Daniel Dietrich, Bart Biesmans, György Bodoky, Carlo
Barone, Enrique Aranda, Bernard Nordlinger, Laura Cisar, Roberto
Labianca, David Cunningham, Eric Van Cutsem, Fred Bosman
Citation: Roth et al., 2010
Citation Id: 20008640
Id: 2783
Journal: J Clin Oncol
Link: /sources/2783
Name: PubMed: Roth et al., 2010
Open Access: False
Publication Date: 2010-1-20
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/20008640
Title:
Prognostic role of KRAS and BRAF in stage II and III resected colon
cancer: results of the translational study on the PETACC-3, EORTC 40993,
SAKK 60-00 trial.
#### Evidence Items
Description:
In a phase 2 trial, patients with radioiodine refractory papillary
thyroid carcinoma harboring BRAF mutation were treated with dabrafenib
alone or combination with trametinib. 94% of patients had BRAF V600E.
The response rate was 50% (11/22) for dabrafenib and 54% (13/24) for
dabrafenb and trametinib combination.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 7762
Name: EID7762
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3969
Display Name: Papillary Thyroid Carcinoma
Doid: 3969
Id: 156
Link: /diseases/156
Name: Papillary Thyroid Carcinoma
##### My Disease Info
Do Def:
A differentiated thyroid gland carcinoma that is characterized by the
small mushroom shape of the tumor which has a stem attached to the
epithelial layer and arises from the follicular cells of the thyroid
gland.
Icdo: 8260/3
Mesh: D000077273
Mondo Id: MONDO:0005075
Ncit: C4035
Disease Aliases:
- Papillary Carcinoma Of The Thyroid Gland
- Papillary Carcinoma Of Thyroid
- Thyroid Gland Papillary Carcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Background: BRAF mutations are present in ~44% of papillary thyroid
carcinoma (PTC) and its role in development of PTC is well established.
We hypothesized that dabrafenib (BRAF inhibitor) would have efficacy in
BRAF mutated PTC and that combining it with trametinib (MEK inhibitor)
would result in greater clinical efficacy than dabrafenib alone, through
vertical inhibition of the RAF/MAP/ERK pathway and mitigation of
potential mechanisms of resistance. Methods: Patients (pts) with BRAF
mutated radioiodine refractory PTC who had evidence of disease
progression within 13 months prior were randomized to Arm A (dabrafenib
150 mg PO BID) or Arm B (dabrafenib 150 mg PO BID + trametinib 2 mg PO
qd). Cross-over to Arm B was allowed at time of progression. Responses
were assessed by modified RECISTv1.1 every 2 months. Primary endpoint
was objective response rate (ORR) (complete-, partial- and minor-
response). With assumed true ORR of 15% vs 35%; and 90% power to
identify the correct regimen as most promising, 26 pts were to be
accrued in each Arm. Results: In this randomized phase 2 trial, 53 pts
(median age 63 years, 38 females) were enrolled; 25% of pts had 1-3
prior therapy with multi-kinase inhibitors. Median follow up was 13
months. Preliminary efficacy results are outlined in Table. The
treatment-related adverse events were similar to previously reported
phase III clinical trial of these drugs in melanoma. Conclusions: Single
agent dabrafenib, as well as combination of dabrafenib/trametinib are
well tolerated therapies that result in similar high objective response
rates with durable responses in pts with progressive BRAF-mutated PTC.
BRAF-pathway targeted therapies provide novel treatment options.
Clinical trial information: NCT01723202Arm A (n=26)DabrafenibArm B
(n=27)Dabrafenib + Trametinibp-valueAssessable pts (n)2224Partial
response109Minor response (MR)*14Objective Response11/22 (50%)13/24
(54%)0.78Stable ds910Progressive ds21Median Progression Free Survival
(months) (95% CI)11.4 (3.8 – NR)15.1 (11.7 –NR)0.27Median Duration of
response (months)(95% CI)15.6 (4.2 – NR)13.3 (9.7 – NR)0.87*MR was
defined as 20-29% decrease in the sum of diameters of target lesions;
NR=not reached
Author String: Manisha H. Shah
Citation: Manisha H. Shah, 2017, ASCO Annual Meeting, Abstract 6022
Citation Id: 145877
Id: 3096
Journal: J Clin Oncol 35, 2017 (suppl; abstr 6022)
Link: /sources/3096
Name: ASCO: Manisha H. Shah, 2017, ASCO Annual Meeting, Abstract 6022
Open Access: False
Publication Date: 2017-1-12
Retracted: False
Source Type: ASCO
Source Url: https://meetinglibrary.asco.org/record/145877/abstract
Title:
Results of randomized phase II trial of dabrafenib versus dabrafenib
plus trametinib in BRAF-mutated papillary thyroid carcinoma.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
This NCI-MATCH trial was conducted in 35 patients of which 29 were
included in the primary efficacy analysis with tumors with BRAF V600E
mutations, and treated with a combination of dabrafenib and trametinib.
The ORR was 37.9% (90% CI, 22.9-54.9). The median PFS and median OS were
11.4 months (90% CI, 8.4-16.3) and 28.6 months respectively. Meaningful
results were achieved with this treatment with an overall DCR of 75.9%.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 11672
Name: EID11672
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:162
Display Name: Cancer
Doid: 162
Id: 216
Link: /diseases/216
Name: Cancer
##### My Disease Info
Do Def: A cancer that is classified based on the organ it starts in.
Mesh: D009371
Mondo Id: MONDO:0004992
Disease Aliases: Malignant Neoplasm, Malignant Tumor, Primary Cancer
##### Molecular Profile
Id: 12
##### Source
Abstract:
BRAFV600 mutations are commonly found in melanoma and thyroid cancers
and to a lesser degree in other tumor types. Subprotocol H (EAY131-H) of
the NCI-MATCH platform trial sought to investigate the selective BRAF
inhibitor dabrafenib and the MEK1/2 inhibitor trametinib in patients
with solid tumors, lymphomas, or multiple myeloma whose tumors harbored
a BRAFV600 mutation.EAY131-H is an open-label, single-arm study.
Patients with melanoma, thyroid, or colorectal cancer were excluded;
patients with non-small-cell lung cancer were later excluded in an
amendment. Patients received dabrafenib 150 mg twice per day and
trametinib 2 mg per day continuously until disease progression or
intolerable toxicity. The primary end point was centrally assessed
objective response rate (ORR); secondary end points included
progression-free survival (PFS), 6-month PFS, and overall
survival.Thirty-five patients were enrolled, and 29 were included in the
primary efficacy analysis as prespecified in the protocol. Median age
was 59 years, and 45% of the patients had received ≥ 3 lines of therapy.
The confirmed ORR was 38% (90% CI, 22.9% to 54.9%) with P < .0001
against a null rate of 5%, and PFS was 11.4 months (90% CI, 8.4 to 16.3
months); responses were seen in 7 distinct tumor types. Seven patients
had a duration of response of > 12 months, including 4 patients with a
duration of response of > 24 months. An additional 8 patients had a PFS
> 6 months. The median overall survival was 28.6 months. Reported
adverse events were comparable to those noted in previously reported
profiles of dabrafenib and trametinib.This study met its primary end
point, with an ORR of 38% (P < .0001) in this mixed histology,
pretreated cohort. This promising activity warrants additional
investigations in BRAFV600-mutated tumors outside of currently approved
indications.
Author String:
April K S Salama, Shuli Li, Erin R Macrae, Jong-In Park, Edith P
Mitchell, James A Zwiebel, Helen X Chen, Robert J Gray, Lisa M McShane,
Larry V Rubinstein, David Patton, P Mickey Williams, Stanley R Hamilton,
Deborah K Armstrong, Barbara A Conley, Carlos L Arteaga, Lyndsay N
Harris, Peter J O'Dwyer, Alice P Chen, Keith T Flaherty
Citation: Salama et al., 2020
Citation Id: 32758030
Id: 4834
Journal: J Clin Oncol
Link: /sources/4834
Name: PubMed: Salama et al., 2020
Open Access: True
Pmc Id: PMC7676884
Publication Date: 2020-11-20
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/32758030
Title:
Dabrafenib and Trametinib in Patients With Tumors With BRAFV600E
Mutations: Results of the NCI-MATCH Trial Subprotocol H.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
This preclinical study examined vemurafenib efficacy on various
colorectal cancer cell lines and in mouse xenograft experiments. Of the
cell lines tested, six harbored BRAF V600E (and WT KRAS) and three
harbored BRAF WT (but mutant KRAS). Of the six BRAF V600E expressing
cell lines, four were sensitive to vemurafenib (IC50 ranging between
0.025 and 0.35 uM; HT29, Colo205, Colo741, LS411N). Cell lines
expressing the BRAF V600E mutation responded better to vemurafenib
treatment than cells wildtype for BRAF as measured by reduced cellular
proliferation and inhibition of MET and ERK phosphorylation (none of the
three BRAF wt cell lines had IC50s less than 10uM). Authors note that
one of the vemurafenib-resistant cell lines harboring BRAF V600E (RKO)
harbored a concurrent activating PIK3CA H1047R mutation. Nude, athymic
mice with HT29 xenografts treated with vemurafenib experienced
substantial tumor inhibition and increased lifespan at every dose
tested, though authors found 75 mg/kg twice daily to be optimal (95%
tumor growth inhibition, 90% increased lifespan compared to vehicle
treated controls).
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Rating: 2
Evidence Type: PREDICTIVE
Flagged: False
Id: 99
Name: EID99
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
The protein kinase BRAF is a key component of the RAS-RAF signaling
pathway which plays an important role in regulating cell proliferation,
differentiation, and survival. Mutations in BRAF at codon 600 promote
catalytic activity and are associated with 8% of all human (solid)
tumors, including 8% to 10% of colorectal cancers (CRC). Here, we report
the preclinical characterization of vemurafenib (RG7204; PLX4032;
RO5185426), a first-in-class, specific small molecule inhibitor of
BRAF(V600E) in BRAF-mutated CRC cell lines and tumor xenograft models.
As a single agent, vemurafenib shows dose-dependent inhibition of ERK
and MEK phosphorylation, thereby arresting cell proliferation in
BRAF(V600)-expressing cell lines and inhibiting tumor growth in
BRAF(V600E) bearing xenograft models. Because vemurafenib has shown
limited single-agent clinical activity in BRAF(V600E)-mutant metastatic
CRC, we therefore explored a range of combination therapies, with both
standard agents and targeted inhibitors in preclinical xenograft models.
In a BRAF-mutant CRC xenograft model with de novo resistance to
vemurafenib (RKO), tumor growth inhibition by vemurafenib was enhanced
by combining with an AKT inhibitor (MK-2206). The addition of
vemurafenib to capecitabine and/or bevacizumab, cetuximab and/or
irinotecan, or erlotinib resulted in increased antitumor activity and
improved survival in xenograft models. Together, our findings suggest
that the administration of vemurafenib in combination with standard-of-
care or novel targeted therapies may lead to enhanced and sustained
clinical antitumor efficacy in CRCs harboring the BRAF(V600E) mutation.
Author String:
Hong Yang, Brian Higgins, Kenneth Kolinsky, Kathryn Packman, William D
Bradley, Richard J Lee, Kathleen Schostack, Mary Ellen Simcox, Scott
Kopetz, David Heimbrook, Brian Lestini, Gideon Bollag, Fei Su
Citation: Yang et al., 2012
Citation Id: 22180495
Id: 108
Journal: Cancer Res
Link: /sources/108
Name: PubMed: Yang et al., 2012
Open Access: False
Publication Date: 2012-2-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22180495
Title:
Antitumor activity of BRAF inhibitor vemurafenib in preclinical models
of BRAF-mutant colorectal cancer.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
This in vivo study examined the efficacy of various treatments on
athymic nude mice xenografted with colorectal cancer HT29 cells, which
harbor BRAF V600E. The authors sought to understand whether the addition
of vemurafenib (a BRAF V600E inhibitor) to agents approved for the
treatment of metastatic colorectal cancer increased therapeutic
efficacy, and which combinations worked best. Erlotinib and vemurafenib
combination therapy resulted in >100% tumor growth inhibition (TGI) and
142% increased lifespan (ILS) compared to vehicle treated controls. Of
ten treated mice, 9 experienced partial response. Doublet therapy
produced a greater increase in TGI and ILS than either agent in
isolation.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 8507
Name: EID8507
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
The protein kinase BRAF is a key component of the RAS-RAF signaling
pathway which plays an important role in regulating cell proliferation,
differentiation, and survival. Mutations in BRAF at codon 600 promote
catalytic activity and are associated with 8% of all human (solid)
tumors, including 8% to 10% of colorectal cancers (CRC). Here, we report
the preclinical characterization of vemurafenib (RG7204; PLX4032;
RO5185426), a first-in-class, specific small molecule inhibitor of
BRAF(V600E) in BRAF-mutated CRC cell lines and tumor xenograft models.
As a single agent, vemurafenib shows dose-dependent inhibition of ERK
and MEK phosphorylation, thereby arresting cell proliferation in
BRAF(V600)-expressing cell lines and inhibiting tumor growth in
BRAF(V600E) bearing xenograft models. Because vemurafenib has shown
limited single-agent clinical activity in BRAF(V600E)-mutant metastatic
CRC, we therefore explored a range of combination therapies, with both
standard agents and targeted inhibitors in preclinical xenograft models.
In a BRAF-mutant CRC xenograft model with de novo resistance to
vemurafenib (RKO), tumor growth inhibition by vemurafenib was enhanced
by combining with an AKT inhibitor (MK-2206). The addition of
vemurafenib to capecitabine and/or bevacizumab, cetuximab and/or
irinotecan, or erlotinib resulted in increased antitumor activity and
improved survival in xenograft models. Together, our findings suggest
that the administration of vemurafenib in combination with standard-of-
care or novel targeted therapies may lead to enhanced and sustained
clinical antitumor efficacy in CRCs harboring the BRAF(V600E) mutation.
Author String:
Hong Yang, Brian Higgins, Kenneth Kolinsky, Kathryn Packman, William D
Bradley, Richard J Lee, Kathleen Schostack, Mary Ellen Simcox, Scott
Kopetz, David Heimbrook, Brian Lestini, Gideon Bollag, Fei Su
Citation: Yang et al., 2012
Citation Id: 22180495
Id: 108
Journal: Cancer Res
Link: /sources/108
Name: PubMed: Yang et al., 2012
Open Access: False
Publication Date: 2012-2-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22180495
Title:
Antitumor activity of BRAF inhibitor vemurafenib in preclinical models
of BRAF-mutant colorectal cancer.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
##### Therapies
Deprecated: False
Id: 15
Link: /therapies/15
Name: Erlotinib
#### Evidence Items
Description:
This study examined outcomes of 240 rectum cancer patients treated with
total mesorectal excision therapy. Tumor samples were obtained at the
time of surgery and genotyped for BRAF exon 15 mutations. BRAF V600E was
identified in 5 cases. The authors reported that no differences were
found in overall survival between patients with and without BRAF
mutations (P > 0.1).
Evidence Direction: DOES_NOT_SUPPORT
Evidence Level: C
Evidence Rating: 2
Evidence Type: PROGNOSTIC
Flagged: False
Id: 2362
Name: EID2362
Significance: POOR_OUTCOME
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
Identifying rectal cancer patients at risk for local recurrence would
allow for refinement in the selection of patients who would benefit from
preoperative radiotherapy. PIK3CA, KRAS, and BRAF mutations are commonly
found in colon cancers, but their prevalence has not been clearly
assessed in rectal cancer. In this study, we aim to determine the
mutation frequencies of PIK3CA, KRAS, and BRAF and to investigate
whether a mutation may be used as a prognostic parameter in rectal
cancer patients.We evaluated DNA mutations in PIK3CA, KRAS, and BRAF in
240 stage I to III rectal tumors obtained from nonirradiated patients
from the Dutch Total Mesorectal Excision trial.PIK3CA, KRAS, and BRAF
mutations were identified in 19 (7.9%), 81 (33.9%), and 5 (2.1%) rectal
cancers. Patients with PIK3CA mutations developed more local recurrences
(5-year risks, 27.8% versus 9.4%; P = 0.006) and tended to develop these
recurrences more rapidly after surgery (median local recurrence-free
interval since surgery: 7.9 versus 19.6 months; P = 0.07) than patients
without PIK3CA mutations. In multivariate analysis, PIK3CA mutations
remained as an independent predictor for the development of local
recurrences (hazard ratio, 3.4; 95% confidence interval, 1.2-9.2; P =
0.017), next to tumor-node-metastasis stage.PIK3CA mutations can be used
as a biomarker in identifying rectal cancer patients with an increased
risk for local recurrences. Currently, our findings suggest that
prospective evaluation of PIK3CA mutation status could reduce
overtreatment by preoperative radiotherapy for the low-risk patients who
might otherwise only experience the side effects.
Author String:
Youji He, Laura J Van't Veer, Izabela Mikolajewska-Hanclich, Marie-
Louise F van Velthuysen, Eliane C M Zeestraten, Iris D Nagtegaal,
Cornelis J H van de Velde, Corrie A M Marijnen
Citation: He et al., 2009
Citation Id: 19903786
Id: 1475
Journal: Clin Cancer Res
Link: /sources/1475
Name: PubMed: He et al., 2009
Open Access: False
Publication Date: 2009-11-15
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19903786
Title: PIK3CA mutations predict local recurrences in rectal cancer patients.
#### Evidence Items
Description:
In a study of metastatic colorectal cancer patients treated with
capecitabine, oxaliplatin, bevacizumab, and cetuximab those with BRAF
V600E mutations had reduced progression-free survival (6.6mo vs. 10.4mo,
P=0.01) and reduced overall survival (15.2mo vs. 21.5mo, P=0.001)
compared to those with wildtype BRAF.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 8646
Name: EID8646
Significance: RESISTANCE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Author String: Jolien Tol, Iris D Nagtegaal, Cornelis J A Punt
Citation: Tol et al., 2009
Citation Id: 19571295
Id: 1481
Journal: N Engl J Med
Link: /sources/1481
Name: PubMed: Tol et al., 2009
Open Access: False
Publication Date: 2009-7-2
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19571295
Title: BRAF mutation in metastatic colorectal cancer.
##### Therapies
Deprecated: False
Id: 16
Link: /therapies/16
Name: Cetuximab
##### Therapies
Deprecated: False
Id: 33
Link: /therapies/33
Name: Bevacizumab
##### Therapies
Deprecated: False
Id: 32
Link: /therapies/32
Name: Capecitabine
##### Therapies
Deprecated: False
Id: 237
Link: /therapies/237
Name: Oxaliplatin
#### Evidence Items
Description:
Multicenter, phase 1, dose-escalation trial of PLX4032 (Vemurafenib).
Treatment of metastatic melanoma with PLX4032 in patients with tumors
that carry the V600E BRAF mutation resulted in complete or partial tumor
regression in the majority of patients (N=37/48). Patients without the
V600E mutation had evidence of tumor regression.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 4
Evidence Type: PREDICTIVE
Flagged: False
Id: 1749
Name: EID1749
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
The identification of somatic mutations in the gene encoding the serine-
threonine protein kinase B-RAF (BRAF) in the majority of melanomas
offers an opportunity to test oncogene-targeted therapy for this
disease.We conducted a multicenter, phase 1, dose-escalation trial of
PLX4032 (also known as RG7204), an orally available inhibitor of mutated
BRAF, followed by an extension phase involving the maximum dose that
could be administered without adverse effects (the recommended phase 2
dose). Patients received PLX4032 twice daily until they had disease
progression. Pharmacokinetic analysis and tumor-response assessments
were conducted in all patients. In selected patients, tumor biopsy was
performed before and during treatment to validate BRAF inhibition.A
total of 55 patients (49 of whom had melanoma) were enrolled in the
dose-escalation phase, and 32 additional patients with metastatic
melanoma who had BRAF with the V600E mutation were enrolled in the
extension phase. The recommended phase 2 dose was 960 mg twice daily,
with increases in the dose limited by grade 2 or 3 rash, fatigue, and
arthralgia. In the dose-escalation cohort, among the 16 patients with
melanoma whose tumors carried the V600E BRAF mutation and who were
receiving 240 mg or more of PLX4032 twice daily, 10 had a partial
response and 1 had a complete response. Among the 32 patients in the
extension cohort, 24 had a partial response and 2 had a complete
response. The estimated median progression-free survival among all
patients was more than 7 months.Treatment of metastatic melanoma with
PLX4032 in patients with tumors that carry the V600E BRAF mutation
resulted in complete or partial tumor regression in the majority of
patients. (Funded by Plexxikon and Roche Pharmaceuticals.)
Author String:
Keith T Flaherty, Igor Puzanov, Kevin B Kim, Antoni Ribas, Grant A
McArthur, Jeffrey A Sosman, Peter J O'Dwyer, Richard J Lee, Joseph F
Grippo, Keith Nolop, Paul B Chapman
Citation: Flaherty et al., 2010
Citation Id: 20818844
Id: 352
Journal: N Engl J Med
Link: /sources/352
Name: PubMed: Flaherty et al., 2010
Open Access: True
Pmc Id: PMC3724529
Publication Date: 2010-8-26
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/20818844
Title: Inhibition of mutated, activated BRAF in metastatic melanoma.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In a retrospective study of 300 stage IV melanoma patients, patients
with BRAF V600E mutation (n=175) were associated with a 4.8% (8/167)
complete response, a 58.1% (97/167) partial response and stable disease
in 22.2% (37/167) of cases, while 15% (25/167) of patients harboring
BRAF V600E experienced progressive disease.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 3757
Name: EID3757
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Kinase inhibitors targeting the BRAF V600 mutation have become standard
in the treatment of metastatic melanoma. Albeit in wide clinical use,
the patterns associated with therapy outcome are not fully elucidated.
The present study was aimed to identify predictive factors of therapy
response and survival under the BRAF inhibitor vemurafenib.This
multicenter retrospective study analyzed patient, tumor, and
pretreatment characteristics collected in BRAF V600-mutated stage IV
melanoma patients before single-agent therapy with the BRAF inhibitor
vemurafenib.A total of 300 patients from 14 centers were included into
this study with a median follow-up time of 13.0 months. Median
progression-free survival (PFS) was 5.1 months; median overall survival
(OS) was 7.6 months. Best response under vemurafenib was associated with
serum lactate dehydrogenase (LDH; ≤ versus >upper normal limit; P =
0.0000001), Eastern Cooperative Oncology Group (ECOG) overall
performance status (OPS) (0 versus ≥ 1; P = 0.00089), and BRAF mutation
subtype (V600E versus V600K; P = 0.016). Multivariate analysis
identified ECOG OPS ≥ 1 [hazard ratio (HR) = 1.88; P = 0.00005],
immunotherapy pretreatment (HR = 0.53; P = 0.0067), elevated serum LDH
(HR = 1.45; P = 0.012), age >55 years (HR = 0.72; P = 0.019), and
chemotherapy pretreatment (HR = 1.39; P = 0.036) as independent
predictors of PFS. For OS, elevated serum LDH (HR = 1.99; P = 0.00012),
ECOG OPS ≥ 1 (HR = 1.90; P = 0.00063), age >55 years (HR = 0.65; P =
0.011), kinase inhibitor pretreatment (HR = 1.86; P = 0.014),
immunotherapy pretreatment (HR = 0.57; P = 0.025), chemotherapy
pretreatment (HR = 2.17; P = 0.039), and male gender (HR = 0.70; 95%
confidence interval 0.50-0.98; P = 0.039) were found as predictors.Our
data demonstrate that the type of pretreatment strongly influences the
outcome of vemurafenib therapy, with a precedent immunotherapy showing a
positive, and a prior chemotherapy and kinase inhibitors showing a
negative impact on survival, respectively. Moreover, we show that the
patient's OPS, serum LDH, age, and gender independently impact
vemurafenib therapy outcome. These findings should be taken into account
for the future design of therapy sequencing in BRAF V600 mutation-
positive melanoma patients.
Author String:
S Ugurel, C Loquai, K Kähler, J Hassel, C Berking, L Zimmer, I Haubitz,
I Satzger, T Müller-Brenne, N C Mikhaimer, J C Becker, K J Kilian, D
Schadendorf, L Heinzerling, M Kaatz, J Utikal, D Göppner, C Pföhler, A
Pflugfelder, R Mössner, R Gutzmer
Citation: Ugurel et al., 2015
Citation Id: 25524477
Id: 1957
Journal: Ann Oncol
Link: /sources/1957
Name: PubMed: Ugurel et al., 2015
Open Access: False
Publication Date: 2015-3
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25524477
Title:
A multicenter DeCOG study on predictors of vemurafenib therapy outcome
in melanoma: pretreatment impacts survival.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
A stage 4B, low-grade papillary serous ovarian adenocarcinoma patient,
harboring a BRAF V600E mutation was associated with response to
vemurafenib monotherapy. The patient was treated with standard
chemotherapy, hormone therapy and bevacizumab prior to the
identification of the BRAF V600E mutation; next, the patient was treated
with paclitaxel and an anti-HER3 antibody and finally with vemurafenib,
obtaining a partial response of greater than 1 year.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 3787
Name: EID3787
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:0050933
Display Name: Ovarian Serous Carcinoma
Doid: 0050933
Id: 87
Link: /diseases/87
Name: Ovarian Serous Carcinoma
##### My Disease Info
Do Def:
An ovarian carcinoma that has_material_basis_in the lining of the ovary
and produces a serum-like fluid.
Mondo Id: MONDO:0005211
##### Molecular Profile
Id: 12
##### Source
Abstract:
Low-grade serous ovarian adenocarcinomas (LGSOC) make up approximately
10 % of serous ovarian carcinomas. While rarely aggressive, this slow-
growing tumor is well known to respond poorly to chemotherapy. Specific
treatments for this ovarian subtype are lacking, with the same global
approaches used for high grade cases being applied for LGSOC patients.
LGSOCs have been reported to have a specific genetic profile, with
notable implication of the MAPK pathway. This has opened up
opportunities for novel therapeutic strategies, with in particular the
use of targeted therapies. We report here the case of a heavily
pretreated unresectable BRAF p.V600E-mutated LGSOC, which we treated
vemurafenib, a BRAF inhibitor specific for V600E mutations. We saw
impressive efficacy, with a long-term partial response along with CA125
reductions and symptom relief. Although this mutation is present in
LGSOC at very a low incidence, we recommend routine testing for BRAF and
other targetable mutations in this patient population, along with
further evaluation in the increasingly popular basket trial approach.
Author String:
Pierre Combe, Laure Chauvenet, Marie-Aude Lefrère-Belda, Hélène Blons,
Caroline Rousseau, Stéphane Oudard, Eric Pujade-Lauraine
Citation: Combe et al., 2015
Citation Id: 26490654
Id: 1984
Journal: Invest New Drugs
Link: /sources/1984
Name: PubMed: Combe et al., 2015
Open Access: False
Publication Date: 2015-12
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26490654
Title:
Sustained response to vemurafenib in a low grade serous ovarian cancer
with a BRAF V600E mutation.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
A 51 year old male anaplastic thyroid cancer patient harboring BRAF
V600E experienced rapid improvement in response to vemurafenib. The
patient was initially treated with paclitaxel and carboplatin but
experienced disease progression; subsequently, the patient was treated
concurrently with vemurafenib and radiation therapy and achieved near
complete regression of metastatic disease.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 3743
Name: EID3743
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:0080522
Display Name: Anaplastic Thyroid Carcinoma
Doid: 0080522
Id: 3040
Link: /diseases/3040
Name: Anaplastic Thyroid Carcinoma
##### My Disease Info
Do Def: A thyroid gland carcinoma that is composed of undifferentiated cells.
Mondo Id: MONDO:0006468
Ncit: C3878
Disease Aliases: Thyroid Gland Anaplastic Carcinoma
##### Molecular Profile
Id: 12
##### Source
Author String: Michael H Rosove, Parvin F Peddi, John A Glaspy
Citation: Rosove et al., 2013
Citation Id: 23406047
Id: 1948
Journal: N Engl J Med
Link: /sources/1948
Name: PubMed: Rosove et al., 2013
Open Access: False
Publication Date: 2013-2-14
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23406047
Title: BRAF V600E inhibition in anaplastic thyroid cancer.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
##### Therapies
Deprecated: False
Id: 360
Link: /therapies/360
Name: Radiation Therapy
#### Evidence Items
Description:
Using Sanger sequencing, BRAFV600E mutations were identified in 21 of
285 patients with PLGGs (7.4%). This mutation was enriched in
hemispheric tumors (p<0.007) and was associated with shorter
progression-free survival (p=0.011) and overall survival (p=0.032) [mt
(n=18) vs wt (n=166)].
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 4
Evidence Type: PROGNOSTIC
Flagged: False
Id: 7191
Name: EID7191
Significance: POOR_OUTCOME
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:0080830
Display Name: Childhood Low-grade Glioma
Doid: 0080830
Id: 3048
Link: /diseases/3048
Name: Childhood Low-grade Glioma
##### My Disease Info
Do Def:
A low-grade glioma that occurs in children and encompasses tumors of
astrocytic, oligodendroglial, and mixed glial-neuronal histology.
Mondo Id: MONDO:0859591
Disease Aliases: Pediatric Low-grade Glioma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Pediatric low-grade gliomas (PLGGs) consist of a number of entities with
overlapping histological features. PLGGs have much better prognosis than
the adult counterparts, but a significant proportion of PLGGs suffers
from tumor progression and recurrence. It has been shown that pediatric
and adult low-grade gliomas are molecularly distinct. Yet the clinical
significance of some of newer biomarkers discovered by genomic studies
has not been fully investigated. In this study, we evaluated in a large
cohort of 289 PLGGs a list of biomarkers and examined their clinical
relevance. TERT promoter (TERTp), H3F3A and BRAF V600E mutations were
detected by direct sequencing. ATRX nuclear loss was examined by
immunohistochemistry. CDKN2A deletion, KIAA1549-BRAF fusion, and MYB
amplification were determined by fluorescence in situ hybridization
(FISH). TERTp, H3F3A, and BRAF V600E mutations were identified in 2.5,
6.4, and 7.4% of PLGGs, respectively. ATRX loss was found in 4.9% of
PLGGs. CDKN2A deletion, KIAA1549-BRAF fusion and MYB amplification were
detected in 8.8, 32.0 and 10.6% of PLGGs, respectively. Survival
analysis revealed that TERTp mutation, H3F3A mutation, and ATRX loss
were significantly associated with poor PFS (p < 0.0001, p < 0.0001, and
p = 0.0002) and OS (p < 0.0001, p < 0.0001, and p < 0.0001). BRAF V600E
was associated with shorter PFS (p = 0.011) and OS (p = 0.032) in a
subset of PLGGs. KIAA1549-BRAF fusion was a good prognostic marker for
longer PFS (p = 0.0017) and OS (p = 0.0029). MYB amplification was also
a favorable marker for a longer PFS (p = 0.040). Importantly, we showed
that these molecular biomarkers can be used to stratify PLGGs into low-
(KIAA1549-BRAF fusion or MYB amplification), intermediate-I (BRAF V600E
and/or CDKN2A deletion), intermediate-II (no biomarker), and high-risk
(TERTp or H3F3A mutation or ATRX loss) groups with distinct PFS (p <
0.0001) and OS (p < 0.0001). This scheme should aid in clinical
decision-making.
Author String:
Rui Ryan Yang, Abudumijiti Aibaidula, Wei-Wei Wang, Aden Ka-Yin Chan,
Zhi-Feng Shi, Zhen-Yu Zhang, Danny Tat Ming Chan, Wai Sang Poon, Xian-
Zhi Liu, Wen-Cai Li, Rui-Qi Zhang, Yan-Xi Li, Nellie Yuk-Fei Chung, Hong
Chen, Jingsong Wu, Liangfu Zhou, Kay Ka-Wai Li, Ho-Keung Ng
Citation: Yang et al., 2018
Citation Id: 29948154
Id: 2816
Journal: Acta Neuropathol
Link: /sources/2816
Name: PubMed: Yang et al., 2018
Open Access: False
Publication Date: 2018-10
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/29948154
Title: Pediatric low-grade gliomas can be molecularly stratified for risk.
##### Phenotypes
Description:
Onset of disease manifestations before adulthood, defined here as before
the age of 16 years, but excluding neonatal or congenital onset.
Hpo Id: HP:0410280
Id: 15320
Link: /phenotypes/15320
Name: Pediatric onset
Url: https://hpo.jax.org/app/browse/term/HP:0410280
##### Phenotypes
Description:
Onset of disease at an age of greater than or equal to 16 to under 19
years.
Hpo Id: HP:0025708
Id: 16642
Link: /phenotypes/16642
Name: Early young adult onset
Url: https://hpo.jax.org/app/browse/term/HP:0025708
#### Evidence Items
Description:
Interim analysis of a basket trial evaluating the combination of
dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in previously
treated V600E-mutated patients showed 11/16 patients with anaplastic
thyroid carcinoma responded to treatment (overall response rate 69%; 95%
CI, 41% to 89%). Seven patients had ongoing responses. Median duration
of response, progression-free survival, and overall survival were not
reached after 120 weeks.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 4
Evidence Type: PREDICTIVE
Flagged: False
Id: 6975
Name: EID6975
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:0080522
Display Name: Anaplastic Thyroid Carcinoma
Doid: 0080522
Id: 3040
Link: /diseases/3040
Name: Anaplastic Thyroid Carcinoma
##### My Disease Info
Do Def: A thyroid gland carcinoma that is composed of undifferentiated cells.
Mondo Id: MONDO:0006468
Ncit: C3878
Disease Aliases: Thyroid Gland Anaplastic Carcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor)
and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated
anaplastic thyroid cancer, a rare, aggressive, and highly lethal
malignancy with poor patient outcomes and no systemic therapies with
clinical benefit. Methods In this phase II, open-label trial, patients
with predefined BRAF V600E-mutated malignancies received dabrafenib 150
mg twice daily and trametinib 2 mg once daily until unacceptable
toxicity, disease progression, or death. The primary end point was
investigator-assessed overall response rate. Secondary end points
included duration of response, progression-free survival, overall
survival, and safety. Results Sixteen patients with BRAF V600E-mutated
anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks;
range, 4 to 120 weeks). All patients had received prior radiation
treatment and/or surgery, and six had received prior systemic therapy.
The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to
89%), with seven ongoing responses. Median duration of response,
progression-free survival, and overall survival were not reached as a
result of a lack of events, with 12-month estimates of 90%, 79%, and
80%, respectively. The safety population was composed of 100 patients
who were enrolled with seven rare tumor histologies. Common adverse
events were fatigue (38%), pyrexia (37%), and nausea (35%). No new
safety signals were detected. Conclusion Dabrafenib plus trametinib is
the first regimen demonstrated to have robust clinical activity in BRAF
V600E-mutated anaplastic thyroid cancer and was well tolerated. These
findings represent a meaningful therapeutic advance for this orphan
disease.
Author String:
Vivek Subbiah, Robert J Kreitman, Zev A Wainberg, Jae Yong Cho, Jan H M
Schellens, Jean Charles Soria, Patrick Y Wen, Christoph Zielinski, Maria
E Cabanillas, Gladys Urbanowitz, Bijoyesh Mookerjee, Dazhe Wang, Fatima
Rangwala, Bhumsuk Keam
Citation: Subbiah et al., 2018
Citation Id: 29072975
Id: 2686
Journal: J Clin Oncol
Link: /sources/2686
Name: PubMed: Subbiah et al., 2018
Open Access: True
Pmc Id: PMC5791845
Publication Date: 2018-1-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/29072975
Title:
Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or
Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
Thirty-two patients with BRAF V600E positive metastatic colorectal
cancer (mCRC) and 7 patients with other cancers were treated with a
combination of BRAF-inhibitor vemurafenib (960 mg twice daily) and EGFR-
inhibitor erlotinib (150 mg daily) in a phase Ib/II trial. No dose-
limiting toxicities were observed. Overall response rates were 32%
[10/31, 16% (5/31) confirmed] in patients with mCRC and 43% (3/7) in
patients with other cancers, with clinical benefit rates of 65% and
100%, respectively. Early ctDNA dynamics were predictive of treatment
efficacy. Serial ctDNA monitoring revealed distinct patterns of acquired
treatment resistance. Convergent genomic evolution was observed with
frequent emergence of MAPK pathway alterations, including polyclonal
KRAS, NRAS, and MAP2K1 mutations, and MET amplification.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 11427
Name: EID11427
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
BRAF V600E mutant metastatic colorectal cancer represents a significant
clinical problem, with combination approaches being developed clinically
with oral BRAF inhibitors combined with EGFR-targeting antibodies. While
compelling preclinical data have highlighted the effectiveness of
combination therapy with vemurafenib and small-molecule EGFR inhibitors,
gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy
has not been investigated in clinical studies.We conducted a phase Ib/II
dose-escalation/expansion trial investigating the safety/efficacy of the
BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib.Thirty-two
patients with BRAF V600E positive metastatic colorectal cancer (mCRC)
and 7 patients with other cancers were enrolled. No dose-limiting
toxicities were observed in escalation, with vemurafenib 960 mg twice
daily with erlotinib 150 mg daily selected as the recommended phase II
dose. Among 31 evaluable patients with mCRC and 7 with other cancers,
overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43%
(3/7), respectively, with clinical benefit rates of 65% and 100%. Early
ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA
monitoring revealed distinct patterns of convergent genomic evolution
associated with acquired treatment resistance, with frequent emergence
of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1
mutations, and MET amplification.The Erlotinib and Vemurafenib In
Combination Trial study demonstrated a safe and novel combination of two
oral inhibitors targeting BRAF and EGFR. The dynamic assessment of
serial ctDNA was a useful measure of underlying genomic changes in
response to this combination and in understanding potential mechanisms
of resistance.
Author String:
Lavinia Tan, Ben Tran, Jeanne Tie, Ben Markman, Sumi Ananda, Niall C
Tebbutt, Michael Michael, Emma Link, Stephen Q Wong, Sushma
Chandrashekar, Jerick Guinto, David Ritchie, Rachel Koldej, Benjamin J
Solomon, Grant A McArthur, Rodney J Hicks, Peter Gibbs, Sarah-Jane
Dawson, Jayesh Desai
Citation: Tan et al., 2023
Citation Id: 36638198
Id: 4534
Journal: Clin Cancer Res
Link: /sources/4534
Name: PubMed: Tan et al., 2023
Open Access: True
Pmc Id: PMC10011885
Publication Date: 2023-3-14
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/36638198
Title:
A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in BRAF V600E
Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT
(Erlotinib and Vemurafenib In Combination Trial) Study.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
##### Therapies
Deprecated: False
Id: 15
Link: /therapies/15
Name: Erlotinib
#### Evidence Items
Description:
In this trial, 665 patients having metastatic colorectal cancer were
randomly assigned in 1:1:1 ratio to receive encorafenib plus cetuximab
plus binimetinib, encorafenib plus cetuximab, investigators' choice of
irinotecan plus cetuximab or FOLFIRI, this evidence item further shares
analysis of safety and efficacy data and concludes that encorafenib plus
cetuximab with or without binimetinib improved OS, PFS and ORR in
patients with BRAF-V600E mutated metastatic colorectal cancer. It also
concluded that encorafenib plus cetuximab doublet therapy could be used
as a standard care for previously treated patients with BRAF-V600E-mCRC
as OS efficacy was similar with or without binimetinib.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 5
Evidence Type: PREDICTIVE
Flagged: False
Id: 11436
Name: EID11436
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
BEACON CRC evaluated encorafenib plus cetuximab with or without
binimetinib versus investigators' choice of irinotecan or FOLFIRI plus
cetuximab in patients with BRAFV600E-mutant metastatic colorectal cancer
(mCRC), after progression on 1-2 prior regimens. In the previously
reported primary analysis, encorafenib, binimetinib plus cetuximab
(ENCO/BINI/CETUX; triplet) and encorafenib plus cetuximab (ENCO/CETUX;
doublet) regimens improved overall survival (OS) and objective response
rate (ORR; by blinded central review) versus standard of care. The
purpose of this analysis was to report updated efficacy and safety
data.In this open-label, phase III trial, 665 patients with BRAF
V600E-mutant mCRC were randomly assigned 1:1:1 to receive triplet,
doublet, or control. Primary end points were OS and independently
reviewed ORR comparing triplet to control. OS for doublet versus control
was a key secondary end point. Updated analyses include 6 months of
additional follow-up and ORR for all randomized patients.Patients
received triplet (n = 224), doublet (n = 220), or control (n = 221).
Median OS was 9.3 months (95% CI, 8.2 to 10.8) for triplet and 5.9
months (95% CI, 5.1 to 7.1) for control (hazard ratio [HR], 0.60 [95%
CI, 0.47 to 0.75]). Median OS for doublet was 9.3 months (95% CI, 8.0 to
11.3) (HR v control, 0.61 [95% CI, 0.48 to 0.77]). Confirmed ORR was
26.8% (95% CI, 21.1% to 33.1%) for triplet, 19.5% (95% CI, 14.5% to
25.4%) for doublet, and 1.8% (95% CI, 0.5% to 4.6%) for control. Adverse
events were consistent with the prior primary analysis, with grade ≥ 3
adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet, and
control, respectively.In the BEACON CRC study, encorafenib plus
cetuximab improved OS, ORR, and progression-free survival in previously
treated patients in the metastatic setting compared with standard
chemotherapy. Based on the primary and updated analyses, encorafenib
plus cetuximab is a new standard care regimen for previously treated
patients with BRAF V600E mCRC.
Author String:
Josep Tabernero, Axel Grothey, Eric Van Cutsem, Rona Yaeger, Harpreet
Wasan, Takayuki Yoshino, Jayesh Desai, Fortunato Ciardiello, Fotios
Loupakis, Yong Sang Hong, Neeltje Steeghs, Tormod Kyrre Guren, Hendrik-
Tobias Arkenau, Pilar Garcia-Alfonso, Elena Elez, Ashwin Gollerkeri,
Kati Maharry, Janna Christy-Bittel, Scott Kopetz
Citation: Tabernero et al., 2021
Citation Id: 33503393
Id: 3807
Journal: J Clin Oncol
Link: /sources/3807
Name: PubMed: Tabernero et al., 2021
Open Access: True
Pmc Id: PMC8078423
Publication Date: 2021-2-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/33503393
Title:
Encorafenib Plus Cetuximab as a New Standard of Care for Previously
Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival
Results and Subgroup Analyses from the BEACON Study.
##### Therapies
Deprecated: False
Id: 20589
Link: /therapies/20589
Name: Cetuximab/Encorafenib Regimen
#### Evidence Items
Description:
In an open-label, phase 3 randomized trial, 250 patients with either
previously untreated, stage IV or unresectable stage III BRAF V600E
mutation-positive melanoma were randomly assigned (3:1) to receive
dabrafenib 150 mg twice daily, orally or dacarbazine 1000 mg/m(2)
intravenously every 3 weeks. The median progression-free survival was
5.1 months for dabrafenib and 2.7 months for dacarbazine, with a hazard
ratio of 0.30 (95% CI: 0.18 – 0.51; p < 0.0001). Treatment-related
adverse events of grade 2 or greater occurred in 100/187 patients who
received dabrafenib and in 26/59 patients who received dacarbazine.
Evidence Direction: SUPPORTS
Evidence Level: A
Evidence Rating: 4
Evidence Type: PREDICTIVE
Flagged: False
Id: 11244
Name: EID11244
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a
manageable safety profile in studies of phase 1 and 2 in patients with
BRAF(V600)-mutated metastatic melanoma. We studied the efficacy of
dabrafenib in patients with BRAF(V600E)-mutated metastatic melanoma.We
enrolled patients in this open-label phase 3 trial between Dec 23, 2010,
and Sept 1, 2011. This report is based on a data cutoff date of Dec 19,
2011. Patients aged 18 years or older with previously untreated, stage
IV or unresectable stage III BRAF(V600E) mutation-positive melanoma were
randomly assigned (3:1) to receive dabrafenib (150 mg twice daily,
orally) or dacarbazine (1000 mg/m(2) intravenously every 3 weeks).
Patients were stratified according to American Joint Committee on Cancer
stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was
investigator-assessed progression-free survival and was analysed by
intention to treat; safety was assessed per protocol. This study is
registered with ClinicalTrials.gov, number NCT01227889.Of the 733
patients screened, 250 were randomly assigned to receive either
dabrafenib (187 patients) or dacarbazine (63 patients). Median
progression-free survival was 5·1 months for dabrafenib and 2·7 months
for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18-0·51;
p<0·0001). At data cutoff, 107 (57%) patients in the dabrafenib group
and 14 (22%) in the dacarbazine group remained on randomised treatment.
Treatment-related adverse events (grade 2 or higher) occurred in 100
(53%) of the 187 patients who received dabrafenib and in 26 (44%) of the
59 patients who received dacarbazine. The most common adverse events
with dabrafenib were skin-related toxic effects, fever, fatigue,
arthralgia, and headache. The most common adverse events with
dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia.
Grade 3-4 adverse events were uncommon in both groups.Dabrafenib
significantly improved progression-free survival compared with
dacarbazine.GlaxoSmithKline.
Author String:
Axel Hauschild, Jean-Jacques Grob, Lev V Demidov, Thomas Jouary, Ralf
Gutzmer, Michael Millward, Piotr Rutkowski, Christian U Blank, Wilson H
Miller, Eckhart Kaempgen, Salvador Martín-Algarra, Boguslawa
Karaszewska, Cornelia Mauch, Vanna Chiarion-Sileni, Anne-Marie Martin,
Suzanne Swann, Patricia Haney, Beloo Mirakhur, Mary E Guckert, Vicki
Goodman, Paul B Chapman
Citation: Hauschild et al., 2012
Citation Id: 22735384
Id: 1500
Journal: Lancet
Link: /sources/1500
Name: PubMed: Hauschild et al., 2012
Open Access: False
Publication Date: 2012-7-28
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22735384
Title:
Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-
label, phase 3 randomised controlled trial.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
#### Evidence Items
Description:
Five colorectal cancer (CRC) cell lines with BRAF V600E mutation were
resistant to treatment with the BRAF inhibitor vemurafenib. An RNAi
screen in the WiDr cell line (a V600E CRC line) identified EGFR as an
enhancer for survival when exposed to vemurafenib. Treatment with
vemurafenib and an EGFR inhibitor (cetuximab or gefitinib) in V600E CRC
cells (WiDr, VACO432 and KM20) showed inhibited growth as well as
induction of the cleaved PARP apoptotic marker.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 10328
Name: EID10328
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug
PLX4032 (vemurafenib) is highly effective in the treatment of melanoma.
However, colon cancer patients harbouring the same BRAF(V600E) oncogenic
lesion have poor prognosis and show only a very limited response to this
drug. To investigate the cause of the limited therapeutic effect of
PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-
interference-based genetic screen in human cells to search for kinases
whose knockdown synergizes with BRAF(V600E) inhibition. We report that
blockade of the epidermal growth factor receptor (EGFR) shows strong
synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E)
mutant colon cancers that inhibition of EGFR by the antibody drug
cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly
synergistic with BRAF(V600E) inhibition, both in vitro and in vivo.
Mechanistically, we find that BRAF(V600E) inhibition causes a rapid
feedback activation of EGFR, which supports continued proliferation in
the presence of BRAF(V600E) inhibition. Melanoma cells express low
levels of EGFR and are therefore not subject to this feedback
activation. Consistent with this, we find that ectopic expression of
EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Our
data suggest that BRAF(V600E) mutant colon cancers (approximately 8-10%
of all colon cancers), for which there are currently no targeted
treatment options available, might benefit from combination therapy
consisting of BRAF and EGFR inhibitors.
Author String:
Anirudh Prahallad, Chong Sun, Sidong Huang, Federica Di Nicolantonio,
Ramon Salazar, Davide Zecchin, Roderick L Beijersbergen, Alberto
Bardelli, René Bernards
Citation: Prahallad et al., 2012
Citation Id: 22281684
Id: 344
Journal: Nature
Link: /sources/344
Name: PubMed: Prahallad et al., 2012
Open Access: False
Publication Date: 2012-1-26
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22281684
Title:
Unresponsiveness of colon cancer to BRAF(V600E) inhibition through
feedback activation of EGFR.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
##### Therapies
Deprecated: False
Id: 14
Link: /therapies/14
Name: Gefitinib
#### Evidence Items
Description:
Five colorectal cancer (CRC) cell lines (VACO432, HT29, SNU-C5, KM20,
WiDr) with BRAF V600E mutation were resistant to treatment with the BRAF
inhibitor vemurafenib. An RNAi screen in the WiDr cell line (a V600E CRC
line) identified EGFR as an enhancer for survival when exposed to
vemurafenib. Treatment with vemurafenib and an EGFR inhibitor (cetuximab
or gefitinib) in V600E CRC cells (WiDr, VACO432 and KM20) showed
inhibited growth as well as induction of the cleaved PARP apoptotic
marker. Xenografts of WiDr and VACO432 cell lines showed similar tumour
growth when treated with vemurafenib or control treatment, suggesting
resistance to vemurafenib in vivo.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 10329
Name: EID10329
Significance: RESISTANCE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug
PLX4032 (vemurafenib) is highly effective in the treatment of melanoma.
However, colon cancer patients harbouring the same BRAF(V600E) oncogenic
lesion have poor prognosis and show only a very limited response to this
drug. To investigate the cause of the limited therapeutic effect of
PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-
interference-based genetic screen in human cells to search for kinases
whose knockdown synergizes with BRAF(V600E) inhibition. We report that
blockade of the epidermal growth factor receptor (EGFR) shows strong
synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E)
mutant colon cancers that inhibition of EGFR by the antibody drug
cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly
synergistic with BRAF(V600E) inhibition, both in vitro and in vivo.
Mechanistically, we find that BRAF(V600E) inhibition causes a rapid
feedback activation of EGFR, which supports continued proliferation in
the presence of BRAF(V600E) inhibition. Melanoma cells express low
levels of EGFR and are therefore not subject to this feedback
activation. Consistent with this, we find that ectopic expression of
EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Our
data suggest that BRAF(V600E) mutant colon cancers (approximately 8-10%
of all colon cancers), for which there are currently no targeted
treatment options available, might benefit from combination therapy
consisting of BRAF and EGFR inhibitors.
Author String:
Anirudh Prahallad, Chong Sun, Sidong Huang, Federica Di Nicolantonio,
Ramon Salazar, Davide Zecchin, Roderick L Beijersbergen, Alberto
Bardelli, René Bernards
Citation: Prahallad et al., 2012
Citation Id: 22281684
Id: 344
Journal: Nature
Link: /sources/344
Name: PubMed: Prahallad et al., 2012
Open Access: False
Publication Date: 2012-1-26
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22281684
Title:
Unresponsiveness of colon cancer to BRAF(V600E) inhibition through
feedback activation of EGFR.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In this case series, 11 patients with ECD or ECD/LCH (Seven had ECD and
four had overlapped ECD/LCH) were treated with single-agent dabrafenib
as initial histiocytosis therapy, following the failure of chemotherapy
or radiation, or following discontinuation of vemurafenib therapy
because of toxicity or intolerance were assessed. Dabrafenib monotherapy
was initially dosed from 50mg BID to 150mg twice daily. FDG-PET/CT scans
were performed prior to starting dabrafenib and in follow-up to measure
disease response in nearly all cases. For the five patients treated with
dabrafenib as initial therapy or following failure of conventional
therapy, three had a partial metabolic response and two had a complete
metabolic response by FDG-PET; all had a complete clinical response. In
three of these six patients, dabrafenib maintained their clinical and
metabolic response to vemurafenib; the sixth patient had been treated
with interferon-a with poor clinical response, and dabrafenib achieved a
sustained clinical and metabolic response. Two patients who stopped
vemurafenib for arthralgia or fatigue stopped dabrafenib for similar
intolerance after four and nine months, respectively.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 4
Evidence Type: PREDICTIVE
Flagged: False
Id: 11303
Name: EID11303
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:2571
Display Name: Langerhans-cell Histiocytosis
Doid: 2571
Id: 2136
Link: /diseases/2136
Name: Langerhans-cell Histiocytosis
##### My Disease Info
Do Def:
A histiocytosis that is characterized by clonal proliferation of
Langerhans cells.
Icd10: ["C96.0", "C96.6"]
Icdo: 9751/1
Mesh: ["C538636", "D006646"]
Mondo Id: MONDO:0018310
Ncit: C3107, C3160
Disease Aliases:
- Histiocytosis X
- Langerhan's Cell Histiocytosis
- Langerhans Cell Granulomatosis
- Letterer-Siwe Disease
- Letterer-Siwe Disease Involving Intra-abdominal Lymph Nodes
- Letterer-Siwe Disease Involving Intrapelvic Lymph Nodes
- Letterer-Siwe Disease Involving Intrathoracic Lymph Nodes
- Letterer-Siwe Disease Involving Lymph Nodes Of Axilla And Upper Limb
- Letterer-Siwe Disease Involving Lymph Nodes Of Head, Face And Neck
- Letterer-Siwe Disease Involving Lymph Nodes Of Head, Face, And Neck
- Letterer-Siwe Disease Involving Lymph Nodes Of Inguinal Region And Lower Limb
- Letterer-Siwe Disease Involving Lymph Nodes Of Multiple Sites
- Letterer-Siwe Disease Involving Spleen
- Letterer-Siwe Disease Of Intra-abdominal Lymph Nodes
- Letterer-Siwe Disease Of Intrapelvic Lymph Nodes
- Letterer-Siwe Disease Of Intrathoracic Lymph Nodes
- Letterer-Siwe Disease Of Lymph Nodes Of Axilla And Upper Limb
- Letterer-Siwe Disease Of Lymph Nodes Of Axilla And/or Upper Limb
- Letterer-Siwe Disease Of Lymph Nodes Of Head, Face And Neck
- Letterer-Siwe Disease Of Lymph Nodes Of Head, Face And/or Neck
- Letterer-Siwe Disease Of Lymph Nodes Of Inguinal Region Amd/or Lower Limb
- Letterer-Siwe Disease Of Lymph Nodes Of Inguinal Region And Lower Limb
- Letterer-Siwe Disease Of Lymph Nodes Of Inguinal Region And/or Lower Limb
- Letterer-Siwe Disease Of Lymph Nodes Of Multiple Sites
- Letterer-Siwe Disease Of Spleen
##### Molecular Profile
Id: 12
##### Source
Author String:
Ankush Bhatia, Gary Ulaner, Raajit Rampal, David M Hyman, Omar Abdel-
Wahab, Benjamin H Durham, Ahmet Dogan, Neval Ozkaya, Mario E Lacouture,
Julio Hajdenberg, Chezi Ganzel, Eli L Diamond
Citation: Bhatia et al., 2018
Citation Id: 29472347
Id: 4648
Journal: Haematologica
Link: /sources/4648
Name: PubMed: Bhatia et al., 2018
Open Access: True
Pmc Id: PMC5865413
Publication Date: 2018-4
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/29472347
Title: Single-agent dabrafenib for BRAFV600E-mutated histiocytosis.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
#### Evidence Items
Description:
In this case series, the authors assessed the efficacy and safety of
swapping cetuximab for panitumumab as some patients are unable to
tolerate treatment with the mouse/human chimeric monoclonal IgG1
antibody cetuximab. Panitumumab is a fully humanized IgG2 anti-EGFR
antibody that has a different binding site and also has a distinct
toxicity profile, causing fewer infusion reactions than cetuximab. Case
one was a 70-year-old female presenting with progressive metastatic
colorectal cancer after undergoing prior treatment with FOLFOX in 2016
and 2020 (2020 in combination with bevacizumab). Molecular profiling of
the patient’s tumour revealed a BRAF V600E mutation (KRAS-, NRAS wild-
type, MSS). Cetuximab and encorafenib were applied for three cycles
without any grade III/IV toxicities. However, the fourth infusion of
cetuximab had to be aborted due to a strong infusion reaction, which had
to be treated with dimenhydrinate and prednisone. The cetuximab was
swapped for panitumumab, and except for Grade I-II skin toxicity, no
panitumumab-related side effects occurred. After 15 months, the patient
is still stable under combination therapy with encorafenib plus
panitumumab. Case two is a 67-year-old male presenting for adjuvant
therapy after resection of rectal cancer. The patient progressed during
adjuvant treatment with capecitabine. Molecular characterization of the
malignancy revealed a BRAF V600E mutation (KRAS-, NRAS wild-type, MSS).
Treatment with FOLFOXIRI plus cetuximab was initiated, to which the
patient initially responded well. Due to progressive disease after about
10 months, second-line treatment with capecitabine plus bevacizumab was
initiated. Under this therapy, the patient developed multiple brain
metastases which were treated by surgical and radiotherapeutic
interventions. After switching to encorafenib and cetuximab, the first
infusion of cetuximab led to a severe allergic reaction with pronounced
respiratory symptoms. After the switch to panitumumab, no further
infusion reaction occurred, and besides grade I skin toxicity, no other
relevant side effects were apparent. The patient achieved a good partial
remission at three and six months. However, after ten months of
panitumumab and encorafenib, the patient progressed.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 2
Evidence Type: PREDICTIVE
Flagged: False
Id: 11309
Name: EID11309
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Author String:
Christian Rausch, Charlotte Schwicht, Daphne Doedens, Roswitha
Forstpointner, Christoph Benedikt Westphalen, Volker Heinemann
Citation: Rausch et al., 2022
Citation Id: 35970034
Id: 4650
Journal: Eur J Cancer
Link: /sources/4650
Name: PubMed: Rausch et al., 2022
Open Access: False
Publication Date: 2022-10
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/35970034
Title:
Panitumumab can safely and effectively be substituted for cetuximab in
the treatment of BRAF V600Emut metastatic colorectal cancer (mCRC) - A
case series.
##### Therapies
Deprecated: False
Id: 28
Link: /therapies/28
Name: Panitumumab
##### Therapies
Deprecated: False
Id: 483
Link: /therapies/483
Name: Encorafenib
#### Evidence Items
Description:
In this case study, a 32-year-old man, previously fit and well,
presented with a two-month history of vertigo, right visual disturbance,
dysphagia, and ataxia. Brain MRI revealed a large mixed solid and cystic
mass within the upper pons, with heterogeneous enhancement extending
along the left third cranial nerve root exit. The patient subsequently
underwent posterior fossa craniotomy and excisional biopsy of the
brainstem tumour. Histology showed a WHO grade 1 ganglioglioma with a
pilocytic glial component. After four years from the initial diagnosis,
MRI surveillance revealed progression in the cystic component of the
lesion, with worsening neurological symptoms including right sixth nerve
palsy, tongue fasciculations and right-sided hemi-anesthesia. Testing of
his initial biopsy specimen demonstrated a BRAF V600E mutation (Sequenom
OncoFOCUS Panel v3.0). The patient was started on vemurafenib 960 mg
twice daily and cobimetinib 60 mg daily. Treatment was complicated by a
grade 2 maculopapular rash and grade 2 ALT elevation and was withheld
until improvement of toxicities back to grade 1. The patient restarted
vemurafenib at 720 mg twice daily and cobimetinib at 60 mg daily. At 13
weeks post-commencement, restaging MRI demonstrated a partial response,
with a substantial reduction in the solid component of the lesion and a
lesser reduction in the cystic component. Objective clinical improvement
with the resolution of tongue fasciculations and subjective improvement
in sensory abnormalities and diplopia have been observed. At the time of
publication, the patient was in an ongoing partial response.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 1
Evidence Type: PREDICTIVE
Flagged: False
Id: 11310
Name: EID11310
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:5078
Display Name: Ganglioglioma
Doid: 5078
Id: 2604
Link: /diseases/2604
Name: Ganglioglioma
##### My Disease Info
Do Def: A cell type benign neoplasm that has_material_basis_in glial-type cells.
Icdo: 9505/1
Mesh: D018303
Mondo Id: MONDO:0016733
Ncit: C27362, C27363, C3788
Disease Aliases:
- Adult Ganglioglioma
- CNS Ganglioglioma
- Childhood Ganglioglioma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Post-surgical management of low grade gangliogliomas is controversial
with paucity of data for the use of chemotherapy. BRAF mutations are
present in a number of glioma subtypes and offer an opportunity for
treatment with targeted therapy.A 32-year-old man with an unresectable,
BRAF V600E mutant, WHO grade 1 ganglioglioma is commenced on combination
BRAF and MEK inhibition (vemurafenib and cobimetinib). Partial
radiological and clinical response was noted after 13 weeks of
treatment. Treatment complication with grade 2 skin and liver toxicity
was resolved with dose interruption and reduction.Combination BRAF and
MEK inhibition present a safe and feasible treatment strategy in
unresectable BRAF V600E mutant low grade ganglioglioma.
Author String: Wing Hing Yau, Malaka Ameratunga
Citation: Yau et al., 2020
Citation Id: 31985841
Id: 4651
Journal: J Clin Pharm Ther
Link: /sources/4651
Name: PubMed: Yau et al., 2020
Open Access: False
Publication Date: 2020-10
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/31985841
Title:
Combination of BRAF and MEK inhibition in BRAF V600E mutant low-grade
ganglioglioma.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
##### Therapies
Deprecated: False
Id: 342
Link: /therapies/342
Name: Cobimetinib
#### Evidence Items
Description:
In this case series, two patients with BRAF V600E mutant pleomorphic
xanthoastrocytoma were treated using the BRAF inhibitor dabrafenib and
trametinib in combination with the MEK inhibitor trametinib. Patient one
is a 48-year-old female with progressive anaplastic pleomorphic
xanthoastrocytoma (PXA). She initially presented with a seizure and
underwent a craniotomy and resection followed by adjuvant radiotherapy.
She remained in remission for 3 years. Subsequent relapses over 2 years
were treated with three further debulking surgeries, cyst drainage and
chemotherapy. Chemotherapy regimens included six cycles of procarbazine,
CCNU (lomustine), vincristine; six cycles of temozolomide and three
cycles of carboplatin. MRI after three cycles of carboplatin showed
tumour progression. Analysis of archival tumour tissue from an earlier
surgery identified a BRAF V600E mutation using DNA sequencing.
Histopathology showed glial tumour cells with significant nuclear
pleomorphism and abundant eosinophilic glassy cytoplasm, multiple giant
cells, brisk mitotic activity and necrosis. Immunohistochemistry for
BRAF V600E was strongly positive, while IDH1R132H was negative, and ATRX
was retained. The Ki67 proliferation index was 15%. She started
treatment with the BRAF inhibitor dabrafenib dosed at 150 mg twice daily
in combination with the MEK inhibitor trametinib dosed at 2 mg once
daily. MRI of the brain at this time showed a decrease in the bulk of
partially enhancing cystic/necrotic mass with a reduction of mass
effect. Subsequent interval MRI, 4 months following commencement of
dabrafenib and trametinib shows continued reduction in the size of both
solid and cystic disease. At the last review, 8 months following the
start of treatment, she was well, with a noted improvement in fatigue
and resolution of headaches. She continues on dabrafenib and trametinib.
Patient two was a previously treated patient that underwent successful
for relapsed BRAF V600E mutated anaplastic pleomorphic xanthoastrocytoma
with dabrafenib, following intolerance to vemurafenib. The patient
continued dabrafenib for 18 months, at which point she chose to stop
therapy and commence radiological surveillance. She had no visible
disease on MRI at this time. She subsequently had radiological
progression and now is undergoing subsequent treatment with a
combination therapy of dabrafenib and trametinib. Two months after
stopping dabrafenib, the first surveillance MRI demonstrated a new 8 mm
homogeneously enhancing nodular lesion on the posteromedial aspect of
the surgical cavity. The patient was re-started on dabrafenib at 150 mg
twice daily with the addition of trametinib at 2 mg once daily. Serial
MRIs demonstrated improvement with near complete response of the
enhancing nodule on the most recent MRI.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 2
Evidence Type: PREDICTIVE
Flagged: False
Id: 11311
Name: EID11311
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:4852
Display Name: Pleomorphic Xanthoastrocytoma
Doid: 4852
Id: 1124
Link: /diseases/1124
Name: Pleomorphic Xanthoastrocytoma
##### My Disease Info
Do Def:
A low grade glioma that is characterized by pleomorphic and lipidized
cells expressing GFAP often surrounded by a reticulin network and
eosinophilic granular bodies.
Icdo: 9424/3
Mondo Id: MONDO:0016690
Ncit: C4323
Disease Aliases: Pleomorphic Xantho-astrocytoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
BRAFV600E mutations have been identified in a number of glioma subtypes,
most frequently in pleomorphic xanthoastrocytoma, ganglioglioma,
pilocytic astrocytoma, and epithelioid glioblastoma. Although the
development of BRAF inhibitors has dramatically improved the clinical
outcome for patients with BRAFV600E mutant tumors, resistance develops
in a majority of patients due to reactivation of the MAPK pathway.
Addition of MEK inhibition to BRAF inhibition improves survival. Here we
report successful treatment of two patients with BRAFV600E mutant
pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in
combination with the MEK inhibitor trametinib.
Author String: Nicholas F Brown, Thomas Carter, Neil Kitchen, Paul Mulholland
Citation: Brown et al., 2017
Citation Id: 28984141
Id: 4652
Journal: CNS Oncol
Link: /sources/4652
Name: PubMed: Brown et al., 2017
Open Access: True
Pmc Id: PMC6004887
Publication Date: 2017-10
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/28984141
Title: Dabrafenib and trametinib in BRAFV600E mutated glioma.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
This study is part of an ongoing open-label, single-arm, phase 2 Rare
Oncology Agnostic Research (ROAR) basket trial enlisting 45 patients (31
with glioblastoma) into the high-grade glioma cohort (other patients had
anaplastic pleomorphic xanthoastrocytoma, anaplastic astrocytoma (n = 5
each), anaplastic ganglioglioma, anaplastic oligodendroglioma,
astroblastoma, and undifferentiated glioma (n = 1 each). Further, 13
patients were enrolled into the low-grade glioma cohort (ganglioglioma,
n = 4; diffuse astrocytoma, n = 2; pleomorphic xanthoastrocytoma, n = 2;
choroid plexus papilloma [gangliocytoma or ganglioglioma, localised
astrocytoma, pilocytic astrocytoma, and well differentiated astrocytoma,
n = 1 each]). Patients received oral dabrafenib at 150 mg orally, twice
daily and oral trametinib at 2 mg orally once daily. In the high-grade
glioma cohort, median follow-up was 12.7 months (IQR 5.4 – 32.3) and 15
(95% CI: 20 – 49) of 45 patients had an objective response, including
three complete responses and 12 partial responses. In the low-grade
glioma cohort, median follow-up was 32.2 months (IQR 25.1 – 47.8). Nine
(95% CI: 39 – 91) of 13 patients had an objective response, including
one complete response, six partial responses, and two minor responses.
Evidence Direction: SUPPORTS
Evidence Level: A
Evidence Rating: 1
Evidence Type: PREDICTIVE
Flagged: False
Id: 11312
Name: EID11312
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:4852
Display Name: Pleomorphic Xanthoastrocytoma
Doid: 4852
Id: 1124
Link: /diseases/1124
Name: Pleomorphic Xanthoastrocytoma
##### My Disease Info
Do Def:
A low grade glioma that is characterized by pleomorphic and lipidized
cells expressing GFAP often surrounded by a reticulin network and
eosinophilic granular bodies.
Icdo: 9424/3
Mondo Id: MONDO:0016690
Ncit: C4323
Disease Aliases: Pleomorphic Xantho-astrocytoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Effective treatments are needed to improve outcomes for high-grade
glioma and low-grade glioma. The activity and safety of dabrafenib plus
trametinib were evaluated in adult patients with recurrent or
progressive BRAFV600E mutation-positive high-grade glioma and low-grade
glioma.This study is part of an ongoing open-label, single-arm, phase 2
Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and
academic cancer centres in 13 countries (Austria, Belgium, Canada,
France, Germany, Italy, Japan, the Netherlands, Norway, South Korea,
Spain, Sweden, and the USA). The study enrolled patients aged 18 years
or older with an Eastern Cooperative Oncology Group performance status
of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade
glioma and low-grade glioma received dabrafenib 150 mg twice daily plus
trametinib 2 mg once daily orally until unacceptable toxicity, disease
progression, or death. In the high-grade glioma cohort, patients were
required to have measurable disease at baseline using the Response
Assessment in Neuro-Oncology high-grade glioma response criteria and
have been treated previously with radiotherapy and first-line
chemotherapy or concurrent chemoradiotherapy. Patients with low-grade
glioma were required to have measurable non-enhancing disease (except
pilocytic astrocytoma) at baseline using the Response Assessment in
Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the
evaluable intention-to-treat population, was investigator-assessed
objective response rate (complete response plus partial response for
high-grade glioma and complete response plus partial response plus minor
response for low-grade glioma). This trial is ongoing, but is closed for
enrolment, NCT02034110.Between April 17, 2014, and July 25, 2018, 45
patients (31 with glioblastoma) were enrolled into the high-grade glioma
cohort and 13 patients were enrolled into the low-grade glioma cohort.
The results presented here are based on interim analysis 16 (data cutoff
Sept 14, 2020). In the high-grade glioma cohort, median follow-up was
12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had
an objective response by investigator assessment, including three
complete responses and 12 partial responses. In the low-grade glioma
cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95%
CI 39-91) of 13 patients had an objective response by investigator
assessment, including one complete response, six partial responses, and
two minor responses. Grade 3 or worse adverse events were reported in 31
(53%) patients, the most common being fatigue (five [9%]), decreased
neutrophil count (five [9%]), headache (three [5%]), and neutropenia
(three [5%]).Dabrafenib plus trametinib showed clinically meaningful
activity in patients with BRAFV600E mutation-positive recurrent or
refractory high-grade glioma and low-grade glioma, with a safety profile
consistent with that in other indications. BRAFV600E testing could
potentially be adopted in clinical practice for patients with
glioma.Novartis.
Author String:
Patrick Y Wen, Alexander Stein, Martin van den Bent, Jacques De Greve,
Antje Wick, Filip Y F L de Vos, Nikolas von Bubnoff, Myra E van Linde,
Albert Lai, Gerald W Prager, Mario Campone, Angelica Fasolo, Jose A
Lopez-Martin, Tae Min Kim, Warren P Mason, Ralf-Dieter Hofheinz, Jean-
Yves Blay, Daniel C Cho, Anas Gazzah, Damien Pouessel, Jeffrey Yachnin,
Aislyn Boran, Paul Burgess, Palanichamy Ilankumaran, Eduard Gasal, Vivek
Subbiah
Citation: Wen et al., 2022
Citation Id: 34838156
Id: 4204
Journal: Lancet Oncol
Link: /sources/4204
Name: PubMed: Wen et al., 2022
Open Access: False
Publication Date: 2022-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/34838156
Title:
Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade
and high-grade glioma (ROAR): a multicentre, open-label, single-arm,
phase 2, basket trial.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
This study is part of an ongoing open-label, single-arm, phase 2 Rare
Oncology Agnostic Research (ROAR) basket trial enlisting 45 patients (31
with glioblastoma) into the high-grade glioma cohort (other patients had
anaplastic pleomorphic xanthoastrocytoma, anaplastic astrocytoma (n = 5
each), anaplastic ganglioglioma, anaplastic oligodendroglioma,
astroblastoma, and undifferentiated glioma (n = 1 each). Further, 13
patients were enrolled into the low-grade glioma cohort (ganglioglioma,
n = 4; diffuse astrocytoma, n = 2; pleomorphic xanthoastrocytoma, n = 2;
choroid plexus papilloma [gangliocytoma or ganglioglioma, localized
astrocytoma, pilocytic astrocytoma, and well-differentiated astrocytoma,
n = 1 each]). Patients received oral dabrafenib at 150 mg orally, twice
daily and oral trametinib at 2 mg orally once daily. In the high-grade
glioma cohort, median follow-up was 12.7 months (IQR 5.4 – 32.3) and 15
(95% CI: 20 – 49) of 45 patients had an objective response, including
three complete responses and 12 partial responses. In the low-grade
glioma cohort, the median follow-up was 32.2 months (IQR 25.1 – 47.8).
Nine (95% CI: 39 – 91) of 13 patients had an objective response,
including one complete response, six partial responses, and two minor
responses.
Evidence Direction: SUPPORTS
Evidence Level: A
Evidence Rating: 1
Evidence Type: PREDICTIVE
Flagged: False
Id: 11313
Name: EID11313
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:4851
Display Name: Pilocytic Astrocytoma
Doid: 4851
Id: 166
Link: /diseases/166
Name: Pilocytic Astrocytoma
##### My Disease Info
Do Def:
A childhood low-grade glioma that is characterized by cells that look
like fibers when viewed under a microscope and is located_in the brain.
Icdo: 9421/1
Mesh: D001254
Mondo Id: MONDO:0016691
Ncit: C4047
Disease Aliases: Grade I Astrocytic Tumor, Piloid Astrocytoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Effective treatments are needed to improve outcomes for high-grade
glioma and low-grade glioma. The activity and safety of dabrafenib plus
trametinib were evaluated in adult patients with recurrent or
progressive BRAFV600E mutation-positive high-grade glioma and low-grade
glioma.This study is part of an ongoing open-label, single-arm, phase 2
Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and
academic cancer centres in 13 countries (Austria, Belgium, Canada,
France, Germany, Italy, Japan, the Netherlands, Norway, South Korea,
Spain, Sweden, and the USA). The study enrolled patients aged 18 years
or older with an Eastern Cooperative Oncology Group performance status
of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade
glioma and low-grade glioma received dabrafenib 150 mg twice daily plus
trametinib 2 mg once daily orally until unacceptable toxicity, disease
progression, or death. In the high-grade glioma cohort, patients were
required to have measurable disease at baseline using the Response
Assessment in Neuro-Oncology high-grade glioma response criteria and
have been treated previously with radiotherapy and first-line
chemotherapy or concurrent chemoradiotherapy. Patients with low-grade
glioma were required to have measurable non-enhancing disease (except
pilocytic astrocytoma) at baseline using the Response Assessment in
Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the
evaluable intention-to-treat population, was investigator-assessed
objective response rate (complete response plus partial response for
high-grade glioma and complete response plus partial response plus minor
response for low-grade glioma). This trial is ongoing, but is closed for
enrolment, NCT02034110.Between April 17, 2014, and July 25, 2018, 45
patients (31 with glioblastoma) were enrolled into the high-grade glioma
cohort and 13 patients were enrolled into the low-grade glioma cohort.
The results presented here are based on interim analysis 16 (data cutoff
Sept 14, 2020). In the high-grade glioma cohort, median follow-up was
12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had
an objective response by investigator assessment, including three
complete responses and 12 partial responses. In the low-grade glioma
cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95%
CI 39-91) of 13 patients had an objective response by investigator
assessment, including one complete response, six partial responses, and
two minor responses. Grade 3 or worse adverse events were reported in 31
(53%) patients, the most common being fatigue (five [9%]), decreased
neutrophil count (five [9%]), headache (three [5%]), and neutropenia
(three [5%]).Dabrafenib plus trametinib showed clinically meaningful
activity in patients with BRAFV600E mutation-positive recurrent or
refractory high-grade glioma and low-grade glioma, with a safety profile
consistent with that in other indications. BRAFV600E testing could
potentially be adopted in clinical practice for patients with
glioma.Novartis.
Author String:
Patrick Y Wen, Alexander Stein, Martin van den Bent, Jacques De Greve,
Antje Wick, Filip Y F L de Vos, Nikolas von Bubnoff, Myra E van Linde,
Albert Lai, Gerald W Prager, Mario Campone, Angelica Fasolo, Jose A
Lopez-Martin, Tae Min Kim, Warren P Mason, Ralf-Dieter Hofheinz, Jean-
Yves Blay, Daniel C Cho, Anas Gazzah, Damien Pouessel, Jeffrey Yachnin,
Aislyn Boran, Paul Burgess, Palanichamy Ilankumaran, Eduard Gasal, Vivek
Subbiah
Citation: Wen et al., 2022
Citation Id: 34838156
Id: 4204
Journal: Lancet Oncol
Link: /sources/4204
Name: PubMed: Wen et al., 2022
Open Access: False
Publication Date: 2022-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/34838156
Title:
Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade
and high-grade glioma (ROAR): a multicentre, open-label, single-arm,
phase 2, basket trial.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
#### Evidence Items
Description:
In a genetic screen of 87 lung cancer cell lines, one MEK-dependent cell
line HCC364 contained a BRAF-V600E mutation. In growth assays, the MEK
inhibitor PD-0325901 reduced proliferation in growth assays of the
HCC364 cell line (IC50=3.2 nmol/L). Additionally, cells exposed to
PD-0325901 exhibited an increase in apoptosis, as measured by induction
of PARP cleavage.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 2143
Name: EID2143
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3908
Display Name: Lung Non-small Cell Carcinoma
Doid: 3908
Id: 8
Link: /diseases/8
Name: Lung Non-small Cell Carcinoma
##### My Disease Info
Do Def:
A lung carcinoma that is characterized as any type of epithelial lung
cancer other than small cell lung carcinoma.
Mesh: D002289
Mondo Id: MONDO:0005233
Ncit: C2926
Disease Aliases:
- Non-small Cell Lung Cancer
- Non-small Cell Lung Carcinoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Hyperactivated extracellular signal-regulated kinase (ERK) signaling is
common in human cancer and is often the result of activating mutations
in BRAF, RAS, and upstream receptor tyrosine kinases. To characterize
the mitogen-activated protein kinase/ERK kinase (MEK)/ERK dependence of
lung cancers harboring BRAF kinase domain mutations, we screened a large
panel of human lung cancer cell lines (n = 87) and tumors (n = 916) for
BRAF mutations. We found that non-small cell lung cancers (NSCLC) cells
with both V600E and non-V600E BRAF mutations were selectively sensitive
to MEK inhibition compared with those harboring mutations in epidermal
growth factor receptor (EGFR), KRAS, or ALK and ROS kinase fusions.
Supporting its classification as a "driver" mutation in the cells in
which it is expressed, MEK inhibition in (V600E)BRAF NSCLC cells led to
substantial induction of apoptosis, comparable with that seen with EGFR
kinase inhibition in EGFR mutant NSCLC models. Despite high basal ERK
phosphorylation, EGFR mutant cells were uniformly resistant to MEK
inhibition. Conversely, BRAF mutant cell lines were resistant to EGFR
inhibition. These data, together with the nonoverlapping pattern of EGFR
and BRAF mutations in human lung cancer, suggest that these lesions
define distinct clinical entities whose treatment should be guided by
prospective real-time genotyping. To facilitate such an effort, we
developed a mass spectrometry-based genotyping method for the detection
of hotspot mutations in BRAF, KRAS, and EGFR. Using this assay, we
confirmed that BRAF mutations can be identified in a minority of NSCLC
tumors and that patients whose tumors harbor BRAF mutations have a
distinct clinical profile compared with those whose tumors harbor kinase
domain mutations in EGFR.
Author String:
Christine A Pratilas, Aphrothiti J Hanrahan, Ensar Halilovic, Yogindra
Persaud, Junichi Soh, Dhananjay Chitale, Hisayuki Shigematsu, Hiromasa
Yamamoto, Ayana Sawai, Manickam Janakiraman, Barry S Taylor, William
Pao, Shinichi Toyooka, Marc Ladanyi, Adi Gazdar, Neal Rosen, David B
Solit
Citation: Pratilas et al., 2008
Citation Id: 19010912
Id: 341
Journal: Cancer Res
Link: /sources/341
Name: PubMed: Pratilas et al., 2008
Open Access: True
Pmc Id: PMC2649746
Publication Date: 2008-11-15
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/19010912
Title: Genetic predictors of MEK dependence in non-small cell lung cancer.
##### Therapies
Deprecated: False
Id: 29
Link: /therapies/29
Name: Mirdametinib
#### Evidence Items
Description:
In these two phase II studies (Italy and U.S. locations), BRAF
V600E-mutant hairy-cell leukemia was treated with vemurafenib at a dose
of 960 mg twice daily to investigate its efficacy. The overall response
rates were 96% (25 of 26 patients who could be evaluated) after a median
of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12
weeks in the U.S. study. The rates of complete response were 35% and 42%
in the two trials, respectively. In the Italian trial, the median
relapse-free survival was 9 months; the relapse-free survival was
significantly longer among patients who had a complete response than
among those who had a partial response (19 months vs. 6 months; HR,
0.26; 95% CI: 0.10 - 0.68; p = 0.006). The median treatment-free
survival was 21.5 months in all 26 patients who could be evaluated, and
it did not differ significantly between the group of patients who had a
complete response and the group of those who had a partial response (25
months and 18 months, respectively; p = 0.21). In the U.S. trial, at 1
year, the rate of progression-free survival was 73% (95% CI: 55 - 97)
and the rate of overall survival was 91% (95% CI: 79 - 99). Disease
progression occurred in 7 of 24 patients, including 3 patients who had
had a complete response and 4 who had had a partial response. At 1 year
after response, the cumulative incidence of relapse was 27% (95% CI: 7 -
51). Lastly, the frequent persistence of phosphorylated ERK–positive
leukemic cells in bone marrow at the end of treatment suggests bypass
reactivation of MEK and ERK as a resistance mechanism.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 11315
Name: EID11315
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:285
Display Name: Hairy Cell Leukemia
Doid: 285
Id: 665
Link: /diseases/665
Name: Hairy Cell Leukemia
##### My Disease Info
Do Def:
A chronic lymphocytic leukemia that is characterized by over production
of B cells (lymphocytes) by the bone marrow where the B cells appear
hairy under a microscope.
Icd10: C91.4
Icdo: 9940/3
Mesh: D007943
Mondo Id: MONDO:0018935
Ncit: C7402
##### Molecular Profile
Id: 12
##### Source
Abstract:
BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We
assessed the safety and activity of the oral BRAF inhibitor vemurafenib
in patients with hairy-cell leukemia that had relapsed after treatment
with a purine analogue or who had disease that was refractory to purine
analogues.We conducted two phase 2, single-group, multicenter studies of
vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in
the United States. The therapy was administered for a median of 16 weeks
in the Italian study and 18 weeks in the U.S. study. Primary end points
were the complete response rate (in the Italian trial) and the overall
response rate (in the U.S. trial). Enrollment was completed (28
patients) in the Italian trial in April 2013 and is still open (26 of 36
planned patients) in the U.S. trial.The overall response rates were 96%
(25 of 26 patients who could be evaluated) after a median of 8 weeks in
the Italian study and 100% (24 of 24) after a median of 12 weeks in the
U.S. study. The rates of complete response were 35% (9 of 26 patients)
and 42% (10 of 24) in the two trials, respectively. In the Italian
trial, after a median follow-up of 23 months, the median relapse-free
survival was 19 months among patients with a complete response and 6
months among those with a partial response; the median treatment-free
survival was 25 months and 18 months, respectively. In the U.S. trial,
at 1 year, the progression-free survival rate was 73% and the overall
survival rate was 91%. Drug-related adverse events were usually of grade
1 or 2, and the events most frequently leading to dose reductions were
rash and arthralgia or arthritis. Secondary cutaneous tumors (treated
with simple excision) developed in 7 of 50 patients. The frequent
persistence of phosphorylated ERK-positive leukemic cells in bone marrow
at the end of treatment suggests bypass reactivation of MEK and ERK as a
resistance mechanism.A short oral course of vemurafenib was highly
effective in patients with relapsed or refractory hairy-cell leukemia.
(Funded by the Associazione Italiana per la Ricerca sul Cancro and
others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number
NCT01711632.).
Author String:
Enrico Tiacci, Jae H Park, Luca De Carolis, Stephen S Chung, Alessandro
Broccoli, Sasinya Scott, Francesco Zaja, Sean Devlin, Alessandro
Pulsoni, Young R Chung, Michele Cimminiello, Eunhee Kim, Davide Rossi,
Richard M Stone, Giovanna Motta, Alan Saven, Marzia Varettoni, Jessica K
Altman, Antonella Anastasia, Michael R Grever, Achille Ambrosetti, Kanti
R Rai, Vincenzo Fraticelli, Mario E Lacouture, Angelo M Carella, Ross L
Levine, Pietro Leoni, Alessandro Rambaldi, Franca Falzetti, Stefano
Ascani, Monia Capponi, Maria P Martelli, Christopher Y Park, Stefano A
Pileri, Neal Rosen, Robin Foà, Michael F Berger, Pier L Zinzani, Omar
Abdel-Wahab, Brunangelo Falini, Martin S Tallman
Citation: Tiacci et al., 2015
Citation Id: 26352686
Id: 1043
Journal: N Engl J Med
Link: /sources/1043
Name: PubMed: Tiacci et al., 2015
Open Access: True
Pmc Id: PMC4811324
Publication Date: 2015-10-29
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/26352686
Title: Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
In a mouse xenograft model, tumors derived from pilocytic astrocytoma
cells that expressed BRAF V600E experienced a complete response to
treatment with selumetinib, whereas tumors derived from a wildtype BRAF
pilocytic astrocytoma cell line were resistant to selumetinib.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 2144
Name: EID2144
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3070
Display Name: High Grade Glioma
Doid: 3070
Id: 695
Link: /diseases/695
Name: High Grade Glioma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in glial cells and is located
in brain or located in spine.
Icdo: 9380/3
Mesh: D005910
Mondo Id: MONDO:0100342
Ncit: C3059, C4822
Disease Aliases:
- Glial Cell Tumor
- Glioma, Malignant
- Malignant Glioma
- Malignant Neuroglial Tumor
- Neuroglial Tumor
##### Molecular Profile
Id: 12
##### Source
Abstract:
AZD6244 (ARRY-142886) is a potent small molecule inhibitor of MEK1/2
that is in phase 2 clinical development.AZD6244 was tested against the
Pediatric Preclinical Testing Program (PPTP) in vitro panel (1 nM-10
microM). In vivo AZD6244 was tested at a dose of 100 mg/kg administered
orally twice daily 5 days per week for 6 weeks. Subsequently, AZD6244
was evaluated against two juvenile pilocytic astrocytoma (JPA)
xenografts using once and twice daily dosing schedules. Phosphorylation
of ERK1/2 was used as a surrogate for in vivo inhibition of MEK1/2 was
determined by immunoblotting.At the highest concentration used in vitro
(10 microM) AZD6244 only inhibited growth by 50% in 5 of the 23 cell
lines. Against the in vivo tumor panels, AZD6244 induced significant
differences in EFS distribution in 10 of 37 (27%) solid tumor models and
0 of 6 acute lymphoblastic leukemia (ALL) models. There were no
objective responses. Pharmacodynamic studies indicated at this dose and
schedule AZD6244 completely inhibited ERK1/2 phosphorylation. AZD6244
was evaluated against two JPA xenografts, BT-35 (wild-type BRAF) and
BT-40 (mutant [V600E] BRAF). BT-40 xenografts were highly sensitive to
AZD6244, whereas BT-35 xenografts progressed on AZD6244 treatment.At the
dose and schedule of administration used, AZD6244 as a single agent had
limited in vitro and in vivo activity against the PPTP tumor panels
despite inhibition of MEK1/2 activity. However, AZD6244 was highly
active against BT-40 JPA xenografts that harbor constitutively activated
BRAF, causing complete regressions.
Author String:
E Anders Kolb, Richard Gorlick, Peter J Houghton, Christopher L Morton,
Geoffrey Neale, Stephen T Keir, Hernan Carol, Richard Lock, Doris
Phelps, Min H Kang, C Patrick Reynolds, John M Maris, Catherine Billups,
Malcolm A Smith
Citation: Kolb et al., 2010
Citation Id: 20806365
Id: 1498
Journal: Pediatr Blood Cancer
Link: /sources/1498
Name: PubMed: Kolb et al., 2010
Open Access: True
Pmc Id: PMC3004092
Publication Date: 2010-10
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/20806365
Title:
Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric
Preclinical Testing Program.
##### Therapies
Deprecated: False
Id: 63
Link: /therapies/63
Name: Selumetinib
#### Evidence Items
Description:
Following treatment with sorafenib, thyroid cancer cell lines with BRAF
V600E mutations had severely reduced proliferation rates, but cells with
wildtype BRAF were insensitive (P<0.0001).
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Type: PREDICTIVE
Flagged: False
Id: 2142
Name: EID2142
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1781
Display Name: Thyroid Cancer
Doid: 1781
Id: 16
Link: /diseases/16
Name: Thyroid Cancer
##### My Disease Info
Do Def:
An endocrine gland cancer located in the thyroid gland located in the
neck below the thyroid cartilage.
Icd10: C73
Mesh: D013964
Mondo Id: MONDO:0002108
Ncit: C3414, C7510
Disease Aliases:
- Malignant Neoplasm Of Thyroid Gland
- Malignant Tumour Of Thyroid Gland
- Neoplasm Of Thyroid Gland
- Thyroid Gland Cancer
- Thyroid Gland Neoplasm
- Thyroid Neoplasm
##### Molecular Profile
Id: 12
##### Source
Abstract:
Oncogenic conversion of BRAF occurs in approximately 44% of papillary
thyroid carcinomas and 24% of anaplastic thyroid carcinomas. In
papillary thyroid carcinomas, this mutation is associated with an
unfavorable clinicopathologic outcome. Our aim was to exploit BRAF as a
potential therapeutic target for thyroid carcinoma.We used RNA
interference to evaluate the effect of BRAF knockdown in the human
anaplastic thyroid carcinoma cell lines FRO and ARO carrying the BRAF
V600E (V600EBRAF) mutation. We also exploited the effect of BAY 43-9006
[N-(3-trifluoromethyl-4-chlorophenyl)-N'-(4-(2-methylcarbamoyl
pyridin-4-yl)oxyphenyl)urea], a multikinase inhibitor able to inhibit
RAF family kinases in a panel of six (V600E)BRAF-positive thyroid
carcinoma cell lines and in nude mice bearing ARO cell xenografts.
Statistical tests were two sided.Knockdown of BRAF by small inhibitory
duplex RNA, but not control small inhibitory duplex RNA, inhibited the
mitogen-activated protein kinase signaling cascade and the growth of ARO
and FRO cells (P < 0.0001). These effects were mimicked by thyroid
carcinoma cell treatment with BAY 43-9006 (IC50 = 0.5-1 micromol/L; P <
0.0001), whereas the compound had negligible effects in normal
thyrocytes. ARO cell tumor xenografts were significantly (P < 0.0001)
smaller in nude mice treated with BAY 43-9006 than in control mice. This
inhibition was associated with suppression of phospho-mitogen-activated
protein kinase levels.BRAF provides signals crucial for proliferation of
thyroid carcinoma cells spontaneously harboring the (V600E)BRAF mutation
and, therefore, BRAF suppression might have therapeutic potential in
(V600E)BRAF-positive thyroid cancer.
Author String:
Giuliana Salvatore, Valentina De Falco, Paolo Salerno, Tito Claudio
Nappi, Stefano Pepe, Giancarlo Troncone, Francesca Carlomagno, Rosa
Marina Melillo, Scott M Wilhelm, Massimo Santoro
Citation: Salvatore et al., 2006
Citation Id: 16533790
Id: 1497
Journal: Clin Cancer Res
Link: /sources/1497
Name: PubMed: Salvatore et al., 2006
Open Access: False
Publication Date: 2006-3-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/16533790
Title: BRAF is a therapeutic target in aggressive thyroid carcinoma.
##### Therapies
Deprecated: False
Id: 6
Link: /therapies/6
Name: Sorafenib
#### Evidence Items
Description:
In a phase 2 clinical trial with 250 metastatic melanoma BRAF-V600E
patients, treatment groups were randomly assigned to either dabrafenib,
BRAF specific inhibitor, (n=187) or dacarbazine, a standard
chemotherapeutic agent (n=63). Patients treated with dabrafenib were
associated with improved progression-free survival (5.1mo vs. 2.7mo,
HR:0.30, 95% CI:0.18-0.51, P<0.0001) compared with patients undergoing
dacarbazine therapy.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Type: PREDICTIVE
Flagged: False
Id: 2146
Name: EID2146
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:8923
Display Name: Skin Melanoma
Doid: 8923
Id: 206
Link: /diseases/206
Name: Skin Melanoma
##### My Disease Info
Do Def: A skin cancer that has_material_basis_in melanocytes.
Icd10: C43.9
Mesh: C562393
Mondo Id: MONDO:0005012
Ncit: C3510
Disease Aliases:
- Cutaneous Melanoma
- Malignant Ear Melanoma
- Malignant Lip Melanoma
- Malignant Lower Limb Melanoma
- Malignant Melanoma Of Ear And/or External Auricular Canal
- Malignant Melanoma Of Skin Of Lower Limb
- Malignant Melanoma Of Skin Of Trunk Except Scrotum
- Malignant Melanoma Of Skin Of Upper Limb
- Malignant Neck Melanoma
- Malignant Scalp Melanoma
- Malignant Trunk Melanoma
- Malignant Upper Limb Melanoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a
manageable safety profile in studies of phase 1 and 2 in patients with
BRAF(V600)-mutated metastatic melanoma. We studied the efficacy of
dabrafenib in patients with BRAF(V600E)-mutated metastatic melanoma.We
enrolled patients in this open-label phase 3 trial between Dec 23, 2010,
and Sept 1, 2011. This report is based on a data cutoff date of Dec 19,
2011. Patients aged 18 years or older with previously untreated, stage
IV or unresectable stage III BRAF(V600E) mutation-positive melanoma were
randomly assigned (3:1) to receive dabrafenib (150 mg twice daily,
orally) or dacarbazine (1000 mg/m(2) intravenously every 3 weeks).
Patients were stratified according to American Joint Committee on Cancer
stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was
investigator-assessed progression-free survival and was analysed by
intention to treat; safety was assessed per protocol. This study is
registered with ClinicalTrials.gov, number NCT01227889.Of the 733
patients screened, 250 were randomly assigned to receive either
dabrafenib (187 patients) or dacarbazine (63 patients). Median
progression-free survival was 5·1 months for dabrafenib and 2·7 months
for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18-0·51;
p<0·0001). At data cutoff, 107 (57%) patients in the dabrafenib group
and 14 (22%) in the dacarbazine group remained on randomised treatment.
Treatment-related adverse events (grade 2 or higher) occurred in 100
(53%) of the 187 patients who received dabrafenib and in 26 (44%) of the
59 patients who received dacarbazine. The most common adverse events
with dabrafenib were skin-related toxic effects, fever, fatigue,
arthralgia, and headache. The most common adverse events with
dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia.
Grade 3-4 adverse events were uncommon in both groups.Dabrafenib
significantly improved progression-free survival compared with
dacarbazine.GlaxoSmithKline.
Author String:
Axel Hauschild, Jean-Jacques Grob, Lev V Demidov, Thomas Jouary, Ralf
Gutzmer, Michael Millward, Piotr Rutkowski, Christian U Blank, Wilson H
Miller, Eckhart Kaempgen, Salvador Martín-Algarra, Boguslawa
Karaszewska, Cornelia Mauch, Vanna Chiarion-Sileni, Anne-Marie Martin,
Suzanne Swann, Patricia Haney, Beloo Mirakhur, Mary E Guckert, Vicki
Goodman, Paul B Chapman
Citation: Hauschild et al., 2012
Citation Id: 22735384
Id: 1500
Journal: Lancet
Link: /sources/1500
Name: PubMed: Hauschild et al., 2012
Open Access: False
Publication Date: 2012-7-28
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/22735384
Title:
Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-
label, phase 3 randomised controlled trial.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
#### Evidence Items
Description:
A pediatric pilocytic astrocytoma patient harboring BRAF V600E mutation,
BRAF V600E mutation was associated with response to vemurafenib
monotherapy. The patient was treated with standard chemotherapy regimens
prior to the identification of the BRAF V600E mutation; subsequently,
vemurafenib was administered (initially in combination with standard
chemotherapy) and an overall regression achieved, with lack of disease
progression noted at 15 months of vemurafenib therapy.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Type: PREDICTIVE
Flagged: False
Id: 3772
Name: EID3772
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:4851
Display Name: Pilocytic Astrocytoma
Doid: 4851
Id: 166
Link: /diseases/166
Name: Pilocytic Astrocytoma
##### My Disease Info
Do Def:
A childhood low-grade glioma that is characterized by cells that look
like fibers when viewed under a microscope and is located_in the brain.
Icdo: 9421/1
Mesh: D001254
Mondo Id: MONDO:0016691
Ncit: C4047
Disease Aliases: Grade I Astrocytic Tumor, Piloid Astrocytoma
##### Molecular Profile
Id: 12
##### Source
Abstract:
The BRAF V600E missense mutation is known to be present in a subset of
central nervous system tumors. We report a patient with a BRAF V600E
mutated pilomyxoid astrocytoma who failed multiple conventional
chemotherapy regimens. Treatment with vemurafenib, a molecularly
targeted therapy against the mutant BRAF V600E kinase, combined with
vinblastine resulted in tumor regression. Furthermore, this patient
experienced almost immediate progression of disease after holding
vemurafenib for only 2-3 weeks, suggesting that the tumor response is
vemurafenib dependent. This population of patients may benefit from
targeted therapy and testing of individual tumors for BRAF mutations is
justified.
Author String: Mary Skrypek, Nicholas Foreman, Daniel Guillaume, Christopher Moertel
Citation: Skrypek et al., 2014
Citation Id: 24821190
Id: 1969
Journal: Pediatr Blood Cancer
Link: /sources/1969
Name: PubMed: Skrypek et al., 2014
Open Access: False
Publication Date: 2014-11
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24821190
Title: Pilomyxoid astrocytoma treated successfully with vemurafenib.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Evidence Items
Description:
Combined PI3K inhibitor GDC0941 and BRAF inhibitor PLX4720
administration to NSG mice subcutanousely injected with colorectal cell
lines with a BRAF V600E mutation effectively inhibited tumor growth and
reduced cellular proliferation.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 96
Name: EID96
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
We show that BRAF(V600E) initiates an alternative pathway to colorectal
cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma
sequence. This pathway underlies significant subsets of CRCs with
distinctive pathomorphologic/genetic/epidemiologic/clinical
characteristics. Genetic and functional analyses in mice revealed a
series of stage-specific molecular alterations driving different phases
of tumor evolution and uncovered mechanisms underlying this stage
specificity. We further demonstrate dose-dependent effects of oncogenic
signaling, with physiologic Braf(V600E) expression being sufficient for
hyperplasia induction, but later stage intensified Mapk-signaling
driving both tumor progression and activation of intrinsic tumor
suppression. Such phenomena explain, for example, the inability of p53
to restrain tumor initiation as well as its importance in invasiveness
control, and the late stage specificity of its somatic mutation.
Finally, systematic drug screening revealed sensitivity of this CRC
subtype to targeted therapeutics, including Mek or combinatorial
PI3K/Braf inhibition.
Author String:
Roland Rad, Juan Cadiñanos, Lena Rad, Ignacio Varela, Alexander Strong,
Lydia Kriegl, Fernando Constantino-Casas, Stefan Eser, Maren Hieber,
Barbara Seidler, Stacey Price, Mario F Fraga, Vincenzo Calvanese, Gary
Hoffman, Hannes Ponstingl, Günter Schneider, Kosuke Yusa, Carolyn Grove,
Roland M Schmid, Wei Wang, George Vassiliou, Thomas Kirchner, Ultan
McDermott, Pentao Liu, Dieter Saur, Allan Bradley
Citation: Rad et al., 2013
Citation Id: 23845441
Id: 106
Journal: Cancer Cell
Link: /sources/106
Name: PubMed: Rad et al., 2013
Open Access: True
Pmc Id: PMC3706745
Publication Date: 2013-7-8
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23845441
Title:
A genetic progression model of Braf(V600E)-induced intestinal
tumorigenesis reveals targets for therapeutic intervention.
##### Therapies
Deprecated: False
Id: 30
Link: /therapies/30
Name: PLX4720
##### Therapies
Deprecated: False
Id: 477
Link: /therapies/477
Name: Pictilisib Bismesylate
#### Evidence Items
Description:
Preclinical study analyzing the differential response to MEK inhibitors
in KRAS and BRAF mutant cancer cell lines and mouse xenografts.
Inhibition of active, phosphorylated MEK by GDC-0973 (cobimetinib) is
required for strong inhibition of the MAPK pathway in BRAF-mutant
tumours. This study provides mechanistic rationale for improved efficacy
of cobimetinib in BRAF-mutant models compared to MEK inhibitors acting
through an alternative mechanism (GDC-0623 and G-573).
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 1141
Name: EID1141
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:162
Display Name: Cancer
Doid: 162
Id: 216
Link: /diseases/216
Name: Cancer
##### My Disease Info
Do Def: A cancer that is classified based on the organ it starts in.
Mesh: D009371
Mondo Id: MONDO:0004992
Disease Aliases: Malignant Neoplasm, Malignant Tumor, Primary Cancer
##### Molecular Profile
Id: 12
##### Source
Abstract:
KRAS and BRAF activating mutations drive tumorigenesis through
constitutive activation of the MAPK pathway. As these tumours represent
an area of high unmet medical need, multiple allosteric MEK inhibitors,
which inhibit MAPK signalling in both genotypes, are being tested in
clinical trials. Impressive single-agent activity in BRAF-mutant
melanoma has been observed; however, efficacy has been far less robust
in KRAS-mutant disease. Here we show that, owing to distinct mechanisms
regulating MEK activation in KRAS- versus BRAF-driven tumours, different
mechanisms of inhibition are required for optimal antitumour activity in
each genotype. Structural and functional analysis illustrates that MEK
inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and
G-573, the former currently in phase I clinical trials) form a strong
hydrogen-bond interaction with S212 in MEK that is critical for blocking
MEK feedback phosphorylation by wild-type RAF. Conversely, potent
inhibition of active, phosphorylated MEK is required for strong
inhibition of the MAPK pathway in BRAF-mutant tumours, resulting in
superior efficacy in this genotype with GDC-0973 (also known as
cobimetinib), a MEK inhibitor currently in phase III clinical trials.
Our study highlights that differences in the activation state of MEK in
KRAS-mutant tumours versus BRAF-mutant tumours can be exploited through
the design of inhibitors that uniquely target these distinct activation
states of MEK. These inhibitors are currently being evaluated in
clinical trials to determine whether improvements in therapeutic index
within KRAS versus BRAF preclinical models translate to improved
clinical responses in patients.
Author String:
Georgia Hatzivassiliou, Jacob R Haling, Huifen Chen, Kyung Song, Steve
Price, Robert Heald, Joanne F M Hewitt, Mark Zak, Ariana Peck, Christine
Orr, Mark Merchant, Klaus P Hoeflich, Jocelyn Chan, Shiuh-Ming Luoh,
Daniel J Anderson, Mary J C Ludlam, Christian Wiesmann, Mark Ultsch,
Lori S Friedman, Shiva Malek, Marcia Belvin
Citation: Hatzivassiliou et al., 2013
Citation Id: 23934108
Id: 790
Journal: Nature
Link: /sources/790
Name: PubMed: Hatzivassiliou et al., 2013
Open Access: False
Publication Date: 2013-9-12
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23934108
Title:
Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus
BRAF-driven cancers.
##### Therapies
Deprecated: False
Id: 342
Link: /therapies/342
Name: Cobimetinib
#### Evidence Items
Description:
This meta-analysis of 7 randomized control trials evaluating overall
survival (OS) (8 for progression free survival) could not definitely
state that survival benefit of anti-EGFR monoclonal antibodies is
limited to patients with wild type BRAF. In other words, the authors
believe that there is insufficient data to justify the exclusion of
anti-EGFR monoclonal antibody therapy for patients with mutant BRAF. In
these studies, mutant BRAF specifically meant the V600E mutation.
Evidence Direction: DOES_NOT_SUPPORT
Evidence Level: B
Evidence Rating: 4
Evidence Type: PREDICTIVE
Flagged: False
Id: 816
Name: EID816
Significance: RESISTANCE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 12
##### Source
Abstract:
Metastatic colorectal cancer (mCRC) that harbours a BRAF V600E mutation
(BRAF MT) is associated with poorer outcomes. However, whether this
mutation is predictive of treatment benefit from anti-epidermal growth
factor receptor (EGFR) monoclonal antibodies (mAbs) is uncertain.We
conducted a systematic review and meta-analysis of randomised controlled
trials (RCTs) published up to July 2014 that evaluated the effect of
BRAF MT on the treatment benefit from anti-EGFR mAbs for mCRC.Seven RCTs
met the inclusion criteria for assessment of overall survival (OS),
whereas eight RCTs met the inclusion criteria for assessment of
progression-free survival (PFS). For RAS WT/BRAF MT tumours, the hazard
ratio for OS benefit with anti-EGFR mAbs was 0.97 (95% CI; 0.67-1.41),
whereas the hazard ratio was 0.81 (95% CI; 0.70-0.95) for RAS WT/BRAF WT
tumours. However, the test of interaction (P=0.43) was not statistically
significant, highlighting that the observed differences in the effect of
anti-EGFR mAbs on OS according to the BRAF mutation status may be due to
chance alone. Regarding PFS benefit with anti-EGFR mAbs, the hazard
ratio was 0.86 (95% CI; 0.61-1.21) for RAS WT/BRAF MT tumours as
compared with 0.62 (95% CI; 0.50-0.77) for RAS WT/BRAF WT tumours (test
of interaction, P=0.07).This meta-analysis demonstrates that there is
insufficient evidence to definitively state that RAS WT/BRAF MT
individuals attain a different treatment benefit from anti-EGFR mAbs for
mCRC compared with RAS WT/BRAF WT individuals. As such, there are
insufficient data to justify the exclusion of anti-EGFR mAb therapy for
patients with RAS WT/BRAF MT mCRC.
Author String:
A Rowland, M M Dias, M D Wiese, G Kichenadasse, R A McKinnon, C S
Karapetis, M J Sorich
Citation: Rowland et al., 2015
Citation Id: 25989278
Id: 548
Journal: Br J Cancer
Link: /sources/548
Name: PubMed: Rowland et al., 2015
Open Access: True
Pmc Id: PMC4580381
Publication Date: 2015-6-9
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/25989278
Title:
Meta-analysis of BRAF mutation as a predictive biomarker of benefit from
anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic
colorectal cancer.
##### Therapies
Deprecated: False
Id: 16
Link: /therapies/16
Name: Cetuximab
##### Therapies
Deprecated: False
Id: 28
Link: /therapies/28
Name: Panitumumab
#### Evidence Items
Description:
In 47 patients with Hairy Cell Leukemia, sequencing discovered a V600E
mutation in all 47 of the sequenced patients.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 4
Evidence Type: DIAGNOSTIC
Flagged: False
Id: 1127
Name: EID1127
Significance: POSITIVE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:285
Display Name: Hairy Cell Leukemia
Doid: 285
Id: 665
Link: /diseases/665
Name: Hairy Cell Leukemia
##### My Disease Info
Do Def:
A chronic lymphocytic leukemia that is characterized by over production
of B cells (lymphocytes) by the bone marrow where the B cells appear
hairy under a microscope.
Icd10: C91.4
Icdo: 9940/3
Mesh: D007943
Mondo Id: MONDO:0018935
Ncit: C7402
##### Molecular Profile
Id: 12
##### Source
Abstract:
Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity
whose underlying genetic lesion is still obscure.We searched for HCL-
associated mutations by performing massively parallel sequencing of the
whole exome of leukemic and matched normal cells purified from the
peripheral blood of an index patient with HCL. Findings were validated
by Sanger sequencing in 47 additional patients with HCL.Whole-exome
sequencing identified five missense somatic clonal mutations that were
confirmed on Sanger sequencing, including a heterozygous mutation in
BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is
oncogenic in other tumors, further analyses were focused on this genetic
lesion. The same BRAF mutation was noted in all the other 47 patients
with HCL who were evaluated by means of Sanger sequencing. None of the
195 patients with other peripheral B-cell lymphomas or leukemias who
were evaluated carried the BRAF V600E variant, including 38 patients
with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas
or leukemias. In immunohistologic and Western blot studies, HCL cells
expressed phosphorylated MEK and ERK (the downstream targets of the BRAF
kinase), indicating a constitutive activation of the RAF-MEK-ERK
mitogen-activated protein kinase pathway in HCL. In vitro incubation of
BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720,
a specific inhibitor of active BRAF, led to a marked decrease in
phosphorylated ERK and MEK. CONCLUSIONS; The BRAF V600E mutation was
present in all patients with HCL who were evaluated. This finding may
have implications for the pathogenesis, diagnosis, and targeted therapy
of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and
others.).
Author String:
Enrico Tiacci, Vladimir Trifonov, Gianluca Schiavoni, Antony Holmes,
Wolfgang Kern, Maria Paola Martelli, Alessandra Pucciarini, Barbara
Bigerna, Roberta Pacini, Victoria A Wells, Paolo Sportoletti, Valentina
Pettirossi, Roberta Mannucci, Oliver Elliott, Arcangelo Liso, Achille
Ambrosetti, Alessandro Pulsoni, Francesco Forconi, Livio Trentin,
Gianpietro Semenzato, Giorgio Inghirami, Monia Capponi, Francesco Di
Raimondo, Caterina Patti, Luca Arcaini, Pellegrino Musto, Stefano
Pileri, Claudia Haferlach, Susanne Schnittger, Giovanni Pizzolo, Robin
Foà, Laurent Farinelli, Torsten Haferlach, Laura Pasqualucci, Raul
Rabadan, Brunangelo Falini
Citation: Tiacci et al., 2011
Citation Id: 21663470
Id: 780
Journal: N Engl J Med
Link: /sources/780
Name: PubMed: Tiacci et al., 2011
Open Access: True
Pmc Id: PMC3689585
Publication Date: 2011-6-16
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21663470
Title: BRAF mutations in hairy-cell leukemia.
Molecular Profile Aliases: RS113488022, VAL600GLU, V640E, VAL640GLU
#### Variants
Id: 12
Link: /variants/12
Name: V600E
### Molecular Profiles
Id: 4170
Molecular Profile Score: 2.5
Name: BRAF V600E AND BRAF V600M
#### Evidence Items
Description:
A single 66-year old male patient with advanced melanoma thought to have
concomitant BRAF V600E and V600M mutations responded rapidly to
dabrafenib. His shoulder lesion reduced by 60% after 1 week of therapy
and was gone after 1 month.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 1
Evidence Type: PREDICTIVE
Flagged: False
Id: 73
Name: EID73
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 4170
##### Source
Abstract:
The recent findings brought the necessity of testing the mutational
status of a series of genes which had been already identified as
responsible for melanomas development and progression, such as BRAF,
CKIT and PTEN: the consequent results are, in fact, essential to guide
the assessment of the novel treatment protocols based on tailored
targeted therapies. We present here the case of a 66 year-old male
patient, diagnosed with an advanced melanoma in June 2011, and treated
with Dabrafenib for double mutant metastatic disease. The patient was
referred to our attention for a large exophytic malignant melanoma on
the left shoulder. After complete surgical excision and elective lymph
node dissection for presence of metastatic sentinel lymph node, the
patient has started high-dose interferon alfa-2b injections as adjuvant
therapy for a complete negative staging. The treatment was interrupted
in August 2011 due to the appearance of metastatic lymph nodes. Tumor
burden was rapidly growing reaching in few months the size of a tennis
ball for the tumor mass located in the shoulder. Mutational study of the
tumor revealed a double BRAF mutation on V-600E and V600M. This finding
incited us to enroll the patient in compassionate Dabrafenib clinical
trial. The therapy was started on may 2012 at 150 mg bid dosage. Almost
surprisingly for the rapidity of the effect, one week later the lesion
on the shoulder has reduced its size by 60% and one month later it has
completely disappeared from sight. CT scan of June 2012 documented the
astonishing clinical response.
Author String: Giovanni Ponti, Aldo Tomasi, Giovanni Pellacani
Citation: Ponti et al., 2012
Citation Id: 23031422
Id: 88
Journal: J Hematol Oncol
Link: /sources/88
Name: PubMed: Ponti et al., 2012
Open Access: True
Pmc Id: PMC3473234
Publication Date: 2012-10-2
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/23031422
Title:
Overwhelming response to Dabrafenib in a patient with double BRAF
mutation (V600E; V600M) metastatic malignant melanoma.
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
#### Variants
Id: 12
Link: /variants/12
Name: V600E
#### Variants
Id: 1405
Link: /variants/1405
Name: V600M
### Molecular Profiles
Id: 4173
Molecular Profile Score: 1.0
Name: BRAF V600E AND BRAF Amplification
#### Evidence Items
Description:
AURELIA trial indicated substantial improvement in progression-free
survival and overall survival in ovarian cancer patients with PD-L1
positive expression in response to bevacizumab plus single regime
chemotherapy (BC) treatment (p<0.05). In identifying the
clinicopathologic characteristics, over-expression of PD-L1 indicated
close association with low histological grade, advanced FIGO stage and
ascites volume >2,000 mL (p>0.05). These results are suggestive of over-
expression of PD-L1 being associative with more malignant epithelial
ovarian cancer phenotypes and expression of PD-L1 potentially
corresponding to BC treatment. Additionally combinational therapies of
bevacizumab with PD-L1 inhibitor atezolizumab in vivo elicited
synergistic effects greater than the control and each single treatment
(p<0.05).
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 1
Evidence Type: PREDICTIVE
Flagged: False
Id: 9885
Name: EID9885
Significance: SENSITIVITYRESPONSE
Variant Origin: NA
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:2152
Display Name: Epithelial Ovarian Cancer
Doid: 2152
Id: 225
Link: /diseases/225
Name: Epithelial Ovarian Cancer
##### My Disease Info
Do Def: An ovarian cancer that is derives_from ovarian surface epithelium.
Mondo Id: MONDO:0002229
Ncit: C4381
##### Molecular Profile
Id: 4173
##### Source
Abstract:
The AURELIA trial demonstrated that adding Bevacizumab to chemotherapy
significantly improved progression-free survival (PFS) for platinum
resistant recurrent ovarian cancer. Recently, immunotherapy also
presented potential anti-tumor effects in several malignant solid
tumors. This study aimed to investigate whether combining anti-PD-L1
Atezolizumab with BEV may have a synergistic effect and enhance the
efficacy of both treatments in cisplatin resistant epithelial ovarian
cancer (CREOC). We retrospectively analyzed 124 epithelial ovarian
cancer (EOC) patients from Gynecologic Oncology Department of Tianjin
Cancer Hospital between January 2013 and June 2018, who all were
diagnosed with cisplatin resistance due to progressing <6 months after
completing platinum-based therapy. Based on responding to at least 2
cycles of Bevacizumab-containing chemotherapy (BC), these Patients were
divided into BC response group and BC non-response group.
Immunohistochemistry was used to detect that PD-L1 expression and tumor
angiogenesis-related proteins (VEGF and Semaphorin4D) in tissues from
124 patients with CREOC. The positive expressions of PD-L1, VEGF, and
Semaphorin4D (SEMA4D) were found in 58.73, 50.79, and 71.43% of the 63
cases CREOC tissues with BC response, respectively, which were
significantly higher than that in the 61 cases BC non-response group (P
< 0.05). PD-L1 expression correlated with SEMA4D and VEGF positively (r
= 0.344 and 0.363, P < 0.001). Over-expressions of PD-L1, VEGF and
SEMA4D are associated with more malignant clinicopathologic
characteristics of CREOC Patients. In survival analysis, patients'
response to BC was the independent factor for evaluation of PFS and
overall survival (OS). Cell functional assays showed that Atezolizumab
in combination with Bevacizumab inhibited the proliferation, migration,
and invasion of cisplatin resistant ovarian cancer cell line A2780cis in
vitro synergistically, which maybe associate with Bevacizumab
suppressing the epithelial-mesenchymal transition (EMT) and PD-L1
expression by targeting STAT3. Furthermore, Bevacizumab and Atezolizumab
induced synergistic anti-tumor effect in vivo. These findings suggest a
novel therapeutic strategy for cisplatin resistant recurrent EOC and its
mechanism warrants further study.
Author String: Lei Zhang, Ying Chen, Fangxuan Li, Lewen Bao, Wenxin Liu
Citation: Zhang et al., 2019
Citation Id: 31105696
Id: 4206
Journal: Front Immunol
Link: /sources/4206
Name: PubMed: Zhang et al., 2019
Open Access: True
Pmc Id: PMC6498972
Publication Date: 2019
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/31105696
Title:
Atezolizumab and Bevacizumab Attenuate Cisplatin Resistant Ovarian
Cancer Cells Progression Synergistically via Suppressing Epithelial-
Mesenchymal Transition.
##### Therapies
Deprecated: False
Id: 261
Link: /therapies/261
Name: Atezolizumab
##### Therapies
Deprecated: False
Id: 33
Link: /therapies/33
Name: Bevacizumab
#### Evidence Items
Description:
COLO201 and COLO206F cells harboring BRAF V600E mutations were cloned to
be MEK inhibitor (AZD6244 [selumetinib]) resistant. The mechanism of
this resistance was shown to be amplification of the BRAF V600E gene.
BRAF V600E amplification was observed in 1/11 colorectal cancer patient
samples evaluated, indicating this subclone (28% of cells) would be MEK
inhibitor resistant.
Evidence Direction: SUPPORTS
Evidence Level: E
Evidence Rating: 4
Evidence Type: PREDICTIVE
Flagged: False
Id: 92
Name: EID92
Significance: RESISTANCE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 4173
##### Source
Abstract:
Oncogenic BRAF mutations are found in several tumor types, including
melanomas and colorectal cancers. Tumors with BRAF mutations have
increased mitogen-activated protein kinase pathway activity and
heightened sensitivity to BRAF and MEK (mitogen-activated or
extracellular signal-regulated protein kinase kinase) inhibitors. To
identify potential mechanisms of acquired drug resistance, we generated
clones resistant to the allosteric MEK inhibitor AZD6244 from two BRAF
V600E mutant colorectal cancer cell lines that are highly sensitive to
MEK or BRAF inhibition. These AZD6244-resistant (AR) clones, which
exhibited cross-resistance to BRAF inhibitors, acquired resistance
through amplification of the BRAF gene. A small percentage of treatment-
naïve parental cells showed preexisting BRAF amplification. We observed
similar amplification in a subset of cells in a BRAF-mutant colorectal
cancer. In cell lines, BRAF amplification increased the abundance of
phosphorylated MEK and impaired the ability of AZD6244 to inhibit ERK
(extracellular signal-regulated kinase) phosphorylation. The ability of
AZD6244 to inhibit ERK phosphorylation in AR cells was restored by
treatment with a BRAF inhibitor at low concentrations that reduced the
abundance of phosphorylated MEK to amounts observed in parental cells.
Combined MEK and BRAF inhibition fully overcame resistance to MEK or
BRAF inhibitors alone and was also more effective in parental cells
compared to treatment with either inhibitor alone. These findings
implicate BRAF amplification as a mechanism of resistance to both MEK
and BRAF inhibitors and suggest combined MEK and BRAF inhibition as a
clinical strategy to overcome, or possibly prevent, this mechanism of
resistance.
Author String:
Ryan B Corcoran, Dora Dias-Santagata, Kristin Bergethon, A John Iafrate,
Jeffrey Settleman, Jeffrey A Engelman
Citation: Corcoran et al., 2010
Citation Id: 21098728
Id: 102
Journal: Sci Signal
Link: /sources/102
Name: PubMed: Corcoran et al., 2010
Open Access: True
Pmc Id: PMC3372405
Publication Date: 2010-11-23
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21098728
Title:
BRAF gene amplification can promote acquired resistance to MEK
inhibitors in cancer cells harboring the BRAF V600E mutation.
##### Therapies
Deprecated: False
Id: 63
Link: /therapies/63
Name: Selumetinib
#### Variants
Id: 12
Link: /variants/12
Name: V600E
#### Variants
Id: 1269
Link: /variants/1269
Name: Amplification
### Molecular Profiles
Id: 4174
Molecular Profile Score: 10.0
Name: BRAF Amplification AND ( BRAF V600E OR BRAF V600K )
#### Evidence Items
Description:
In a retrospective study of 44 relapsed melanoma patients harboring BRAF
V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK
pathway reactivation mechanisms were implicated in acquired resistance
to BRAF inhibitor (vemurafenib or dabrafenib) monotherapy. The following
MAPK pathway variants were found in progressive tumors with patient
matched baseline tumors (some patients donated samples from multiple
geographically/temporally distinct progressive tumors): NRAS mutations
(G12D, G12R, G13R, Q61K, Q61R, Q61L) in 13/71 (18%) of progressive
tumors, KRAS mutations (G12C, G12R, Q61H) in 5/71 (7%) of progressive
tumors, mutant BRAF amplification (2-15 fold or 4-75 copies) in 11/57
(19%) of progressive tumors, mutant BRAF alternative splice variants
(novel exon boundaries between 1/9, 1/11, 3/9) in 6/48 (13%) of
progressive tumor RNA.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 2
Evidence Type: PREDICTIVE
Flagged: False
Id: 6262
Name: EID6262
Significance: RESISTANCE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1909
Display Name: Melanoma
Doid: 1909
Id: 7
Link: /diseases/7
Name: Melanoma
##### My Disease Info
Do Def:
A cell type cancer that has_material_basis_in abnormally proliferating
cells derives_from melanocytes which are found in skin, the bowel and
the eye.
Icdo: 8720/3
Mesh: D008545
Mondo Id: MONDO:0005105
Ncit: C3224
Disease Aliases: Malignant Melanoma, Naevocarcinoma
##### Molecular Profile
Id: 4174
##### Source
Abstract:
BRAF inhibitors elicit rapid antitumor responses in the majority of
patients with BRAF(V600)-mutant melanoma, but acquired drug resistance
is almost universal. We sought to identify the core resistance pathways
and the extent of tumor heterogeneity during disease progression. We
show that mitogen-activated protein kinase reactivation mechanisms were
detected among 70% of disease-progressive tissues, with RAS mutations,
mutant BRAF amplification, and alternative splicing being most common.
We also detected PI3K-PTEN-AKT-upregulating genetic alterations among
22% of progressive melanomas. Distinct molecular lesions in both core
drug escape pathways were commonly detected concurrently in the same
tumor or among multiple tumors from the same patient. Beyond harboring
extensively heterogeneous resistance mechanisms, melanoma regrowth
emerging from BRAF inhibitor selection displayed branched evolution
marked by altered mutational spectra/signatures and increased fitness.
Thus, melanoma genomic heterogeneity contributes significantly to BRAF
inhibitor treatment failure, implying upfront, cotargeting of two core
pathways as an essential strategy for durable responses.
Author String:
Hubing Shi, Willy Hugo, Xiangju Kong, Aayoung Hong, Richard C Koya,
Gatien Moriceau, Thinle Chodon, Rongqing Guo, Douglas B Johnson,
Kimberly B Dahlman, Mark C Kelley, Richard F Kefford, Bartosz
Chmielowski, John A Glaspy, Jeffrey A Sosman, Nicolas van Baren,
Georgina V Long, Antoni Ribas, Roger S Lo
Citation: Shi et al., 2014
Citation Id: 24265155
Id: 1941
Journal: Cancer Discov
Link: /sources/1941
Name: PubMed: Shi et al., 2014
Open Access: True
Pmc Id: PMC3936420
Publication Date: 2014-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/24265155
Title:
Acquired resistance and clonal evolution in melanoma during BRAF
inhibitor therapy.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
##### Therapies
Deprecated: False
Id: 22
Link: /therapies/22
Name: Dabrafenib
#### Variants
Id: 12
Link: /variants/12
Name: V600E
#### Variants
Id: 1269
Link: /variants/1269
Name: Amplification
#### Variants
Id: 563
Link: /variants/563
Name: V600K
### Molecular Profiles
Id: 4213
Molecular Profile Score: 0.0
Name: NOT KRAS Mutation AND ( BRAF V600E OR BRAF D594G )
#### Evidence Items
Description:
The Medical Research Council (MRC) COIN trial consisted of patients with
histologically confirmed adenocarcinoma of the colon or rectum,
inoperable metastatic or locoregional measurable disease, and who had
not received chemotherapy for metastatic disease.
In arm A patients were given oxaliplatin and fluoropyrimidine
chemotherapy.
In arm B patients were given the same chemotherapy with additional
cetuximab.
BRAF D594G was found in 12 patients (0.9%), and V600E was found in 90
(7% of patients).
Overall Survival in arm A was 10.0 months, and arm B was 7.2 months with
HR 1.18 (95% CI 0.76-1.81, p=0.46), indicating no sensitizing effect for
the presence of the BRAF mutations for cetuximab in KRAS WT patients.
Evidence Direction: DOES_NOT_SUPPORT
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 11060
Name: EID11060
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:0050861
Display Name: Colorectal Adenocarcinoma
Doid: 0050861
Id: 57
Link: /diseases/57
Name: Colorectal Adenocarcinoma
##### My Disease Info
Do Def:
A colorectal carcinoma that derives_from epithelial cells of glandular
origin.
Mondo Id: MONDO:0005008
Ncit: C5105
##### Molecular Profile
Id: 4213
##### Source
Abstract:
In the Medical Research Council (MRC) COIN trial, the epidermal growth
factor receptor (EGFR)-targeted antibody cetuximab was added to standard
chemotherapy in first-line treatment of advanced colorectal cancer with
the aim of assessing effect on overall survival.In this randomised
controlled trial, patients who were fit for but had not received
previous chemotherapy for advanced colorectal cancer were randomly
assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the
same combination plus cetuximab (arm B), or intermittent chemotherapy
(arm C). The choice of fluoropyrimidine therapy (capecitabine or infused
fluouroracil plus leucovorin) was decided before randomisation.
Randomisation was done centrally (via telephone) by the MRC Clinical
Trials Unit using minimisation. Treatment allocation was not masked. The
comparison of arms A and C is described in a companion paper. Here, we
present the comparison of arm A and B, for which the primary outcome was
overall survival in patients with KRAS wild-type tumours. Analysis was
by intention to treat. Further analyses with respect to NRAS, BRAF, and
EGFR status were done. The trial is registered, ISRCTN27286448.1630
patients were randomly assigned to treatment groups (815 to standard
therapy and 815 to addition of cetuximab). Tumour samples from 1316
(81%) patients were used for somatic molecular analyses; 565 (43%) had
KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367;
arm B, n=362), overall survival did not differ between treatment groups
(median survival 17·9 months [IQR 10·3-29·2] in the control group vs
17·0 months [9·4-30·1] in the cetuximab group; HR 1·04, 95% CI
0·87-1·23, p=0·67). Similarly, there was no effect on progression-free
survival (8·6 months [IQR 5·0-12·5] in the control group vs 8·6 months
[5·1-13·8] in the cetuximab group; HR 0·96, 0·82-1·12, p=0·60). Overall
response rate increased from 57% (n=209) with chemotherapy alone to 64%
(n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin
and gastrointestinal toxic effects were increased with cetuximab (14 vs
114 and 67 vs 97 patients in the control group vs the cetuximab group
with KRAS wild-type tumours, respectively). Overall survival differs by
somatic mutation status irrespective of treatment received: BRAF mutant,
8·8 months (IQR 4·5-27·4); KRAS mutant, 14·4 months (8·5-24·0); all
wild-type, 20·1 months (11·5-31·7).This trial has not confirmed a
benefit of addition of cetuximab to oxaliplatin-based chemotherapy in
first-line treatment of patients with advanced colorectal cancer.
Cetuximab increases response rate, with no evidence of benefit in
progression-free or overall survival in KRAS wild-type patients or even
in patients selected by additional mutational analysis of their tumours.
The use of cetuximab in combination with oxaliplatin and capecitabine in
first-line chemotherapy in patients with widespread metastases cannot be
recommended.Cancer Research UK, Cancer Research Wales, UK Medical
Research Council, Merck KGgA.
Author String:
Timothy S Maughan, Richard A Adams, Christopher G Smith, Angela M Meade,
Matthew T Seymour, Richard H Wilson, Shelley Idziaszczyk, Rebecca
Harris, David Fisher, Sarah L Kenny, Edward Kay, Jenna K Mitchell, Ayman
Madi, Bharat Jasani, Michelle D James, John Bridgewater, M John Kennedy,
Bart Claes, Diether Lambrechts, Richard Kaplan, Jeremy P Cheadle
Citation: Maughan et al., 2011
Citation Id: 21641636
Id: 2784
Journal: Lancet
Link: /sources/2784
Name: PubMed: Maughan et al., 2011
Open Access: True
Pmc Id: PMC3159415
Publication Date: 2011-6-18
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/21641636
Title:
Addition of cetuximab to oxaliplatin-based first-line combination
chemotherapy for treatment of advanced colorectal cancer: results of the
randomised phase 3 MRC COIN trial.
##### Therapies
Deprecated: False
Id: 16
Link: /therapies/16
Name: Cetuximab
##### Therapies
Deprecated: False
Id: 199
Link: /therapies/199
Name: Chemotherapy
#### Variants
Id: 611
Link: /variants/611
Name: D594G
#### Variants
Id: 12
Link: /variants/12
Name: V600E
#### Variants
Id: 336
Link: /variants/336
Name: Mutation
### Molecular Profiles
Id: 4241
Molecular Profile Score: 0.0
Name: BRAF V600E AND EZH2 Y646F
#### Evidence Items
Description:
Experiment with immunodeficient mice transplanted with melanoma cell
lines indicates EZH2 inhibitor JQEZ5 might be effective in combination
with a B-RAF inhibitor in RAF-mutant melanoma.
Evidence Direction: SUPPORTS
Evidence Level: D
Evidence Rating: 4
Evidence Type: PREDICTIVE
Flagged: False
Id: 6952
Name: EID6952
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:8923
Display Name: Skin Melanoma
Doid: 8923
Id: 206
Link: /diseases/206
Name: Skin Melanoma
##### My Disease Info
Do Def: A skin cancer that has_material_basis_in melanocytes.
Icd10: C43.9
Mesh: C562393
Mondo Id: MONDO:0005012
Ncit: C3510
Disease Aliases:
- Cutaneous Melanoma
- Malignant Ear Melanoma
- Malignant Lip Melanoma
- Malignant Lower Limb Melanoma
- Malignant Melanoma Of Ear And/or External Auricular Canal
- Malignant Melanoma Of Skin Of Lower Limb
- Malignant Melanoma Of Skin Of Trunk Except Scrotum
- Malignant Melanoma Of Skin Of Upper Limb
- Malignant Neck Melanoma
- Malignant Scalp Melanoma
- Malignant Trunk Melanoma
- Malignant Upper Limb Melanoma
##### Molecular Profile
Id: 4241
##### Source
Abstract:
B cell lymphoma and melanoma harbor recurrent mutations in the gene
encoding the EZH2 histone methyltransferase (EZH2), but the carcinogenic
role of these mutations is unclear. Here we describe a mouse model in
which the most common somatic Ezh2 gain-of-function mutation
(EZH2(Y646F) in human; Ezh2(Y641F) in mouse) is conditionally expressed.
Expression of Ezh2(Y641F) in mouse B cells or melanocytes caused high-
penetrance lymphoma or melanoma, respectively. Overexpression of the
anti-apoptotic protein Bcl2, but not the oncoprotein Myc, or loss of the
tumor suppressor protein p53 (encoded by Trp53 in mice) further
accelerated lymphoma progression. Expression of the mutant Braf but not
the mutant Nras oncoprotein further accelerated melanoma progression.
Although expression of Ezh2(Y641F) globally increased the abundance of
trimethylated Lys27 of histone H3 (H3K27me3), it also caused a
widespread redistribution of this repressive mark, including a loss of
H3K27me3 that was associated with increased transcription at many loci.
These results suggest that Ezh2(Y641F) induces lymphoma and melanoma
through a vast reorganization of chromatin structure, inducing both
repression and activation of polycomb-regulated loci.
Author String:
George P Souroullas, William R Jeck, Joel S Parker, Jeremy M Simon, Jie-
Yu Liu, Joshiawa Paulk, Jessie Xiong, Kelly S Clark, Yuri Fedoriw, Jun
Qi, Christin E Burd, James E Bradner, Norman E Sharpless
Citation: Souroullas et al., 2016
Citation Id: 27135738
Id: 2307
Journal: Nat Med
Link: /sources/2307
Name: PubMed: Souroullas et al., 2016
Open Access: True
Pmc Id: PMC4899144
Publication Date: 2016-6
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/27135738
Title:
An oncogenic Ezh2 mutation induces tumors through global redistribution
of histone 3 lysine 27 trimethylation.
##### Therapies
Deprecated: False
Id: 541
Link: /therapies/541
Name: JQEZ5
#### Variants
Id: 2989
Link: /variants/2989
Name: Y646F
#### Variants
Id: 12
Link: /variants/12
Name: V600E
### Molecular Profiles
Id: 4251
Molecular Profile Score: 0.0
Name: BRAF V600E AND EGFR L858R AND EGFR T790M
#### Evidence Items
Description:
A 42 year old man with non-smoking history presented with EGFR L858R
positive lung adenocarcinoma. He was given various treatments including
erlotinib and gefitinib and progressed four years later. biopsy revealed
EGFR T790M mutation, and osimertinib treatment was given. Partial
response was seen, and progression occurred after 13 months. BRAF V600E
mutation was found in progressed tumor cells, but was not reported
before osimertinib resistance.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 11098
Name: EID11098
Significance: RESISTANCE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:3910
Display Name: Lung Adenocarcinoma
Doid: 3910
Id: 30
Link: /diseases/30
Name: Lung Adenocarcinoma
##### My Disease Info
Do Def:
A lung non-small cell carcinoma that derives_from epithelial cells of
glandular origin.
Mesh: D000077192
Mondo Id: MONDO:0005061
Ncit: C27745, C3512
Disease Aliases:
- Bronchogenic Lung Adenocarcinoma
- Nonsmall Cell Adenocarcinoma
##### Molecular Profile
Id: 4251
##### Source
Author String: Alessandra Bearz, Elisa De Carlo, Roberto Doliana, Monica Schiappacassi
Citation: Bearz et al., 2017
Citation Id: 29074209
Id: 4545
Journal: J Thorac Oncol
Link: /sources/4545
Name: PubMed: Bearz et al., 2017
Open Access: False
Publication Date: 2017-11
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/29074209
Title:
Acquired BRAF V600E Mutation as Resistant Mechanism after Treatment with
Third-Generation EGFR Tyrosine Kinase Inhibitor.
##### Therapies
Deprecated: False
Id: 187
Link: /therapies/187
Name: Osimertinib
#### Variants
Id: 34
Link: /variants/34
Name: T790M
#### Variants
Id: 33
Link: /variants/33
Name: L858R
#### Variants
Id: 12
Link: /variants/12
Name: V600E
### Molecular Profiles
Id: 4452
Molecular Profile Score: 0.0
Name:
BRAF V600E AND CDKN2A Deletion AND CDKN2B Deletion AND TET2 E796K AND
BAX L76R AND AXIN2 P455K
#### Evidence Items
Description:
In this case study, a 28-year-old male with BRAF V600E-mutant anaplastic
ganglioglioma was started with vemurafenib at 960 mg twice daily in
March 2015 for tumour recurrence despite one surgical resection and
adjuvant radiation therapy. He had a partial response with a tumour
shrinkage up to 55% according to RANO (response assessment in neuro-
oncology) criteria that was observed after 4 cycles. However, the
response to vemurafenib only lasted for 14 cycles until May 2016 when
his brain MRI showed local recurrence. Whole-exome sequencing of matched
tumour and germline DNA and RNA sequencing was carried out and the BRAF
V600E mutation was confirmed, along with a focal homozygous deletion of
CDKN2A and CDKN2B at the 9p21 locus. No additional molecular alteration
in MAPK genes was found. Three other somatic variants were identified. A
TET2 (p.Glu796Lys) mutation was found in both tumours. Mutations of BAX
(p.Leu76Arg) and AXIN2 (p.Pro455Lys) were only detected in the recurrent
tumour. These 3 genetic variants were not previously reported in the
literature or in public databases, including ExAC, ClinVar, and COSMIC,
and were annotated as variants of unknown significance. The patient was
then started with combined vemurafenib at 960 mg twice daily and
cobimetinib at 60 mg daily, 21 days every 28 days in November 2016. A
complete response was observed after 3 months of combined treatment. At
the last follow-up, after 16 months of treatment, there is no evidence
of recurrence.
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 1
Evidence Type: PREDICTIVE
Flagged: False
Id: 11314
Name: EID11314
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:5078
Display Name: Ganglioglioma
Doid: 5078
Id: 2604
Link: /diseases/2604
Name: Ganglioglioma
##### My Disease Info
Do Def: A cell type benign neoplasm that has_material_basis_in glial-type cells.
Icdo: 9505/1
Mesh: D018303
Mondo Id: MONDO:0016733
Ncit: C27362, C27363, C3788
Disease Aliases:
- Adult Ganglioglioma
- CNS Ganglioglioma
- Childhood Ganglioglioma
##### Molecular Profile
Id: 4452
##### Source
Author String:
Mehdi Touat, Julie Gratieux, Stephanie Condette Auliac, Karine Sejean,
Sorin Aldea, Julien Savatovsky, Géraldine Perkins, Hélène Blons, Keith L
Ligon, Ahmed Idbaih, Antoine Hollebecque, Anne-Paule Gimenez-Roqueplo,
Pierre Laurent-Puig, Marc Sanson, Chiara Villa, Anna Luisa Di Stefano
Citation: Touat et al., 2018
Citation Id: 30120137
Id: 4653
Journal: Neurology
Link: /sources/4653
Name: PubMed: Touat et al., 2018
Open Access: True
Pmc Id: PMC9694795
Publication Date: 2018-9-11
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/30120137
Title:
Vemurafenib and cobimetinib overcome resistance to vemurafenib in BRAF-
mutant ganglioglioma.
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
##### Therapies
Deprecated: False
Id: 342
Link: /therapies/342
Name: Cobimetinib
#### Variants
Id: 4314
Link: /variants/4314
Name: Deletion
#### Variants
Id: 4476
Link: /variants/4476
Name: E796K
#### Variants
Id: 4477
Link: /variants/4477
Name: L76R
#### Variants
Id: 4478
Link: /variants/4478
Name: P455K
#### Variants
Id: 12
Link: /variants/12
Name: V600E
#### Variants
Id: 2654
Link: /variants/2654
Name: Deletion
### Molecular Profiles
Id: 4453
Molecular Profile Score: 0.0
Name: BRAF V600E OR KIAA1549::BRAF Fusion
#### Evidence Items
Description:
In this phase II trial on patients with pediatric low-grade glioma were
assigned to six unique strata according to histology, tumour location,
NF1 status, and BRAF aberration status. This study reports the results
of strata 1 and 3. Stratum 1 comprised patients with WHO grade I
pilocytic astrocytoma harbouring either one of the two most common BRAF
aberrations (KIAA1549–BRAF fusion or the BRAF V600E mutation. Stratum 3
comprised patients with any neurofibromatosis type 1 (NF1)-associated
pediatric low-grade glioma (WHO grades I and II). Selumetinib was dosed
at 25 mg/m2 twice daily in 28-day courses for up to 26 courses. In
stratum 1, nine of 25 patients achieved a sustained partial response
(95% CI: 18 – 57). The median follow-up for the 11 patients who had not
had a progression event by Aug 9, 2018, was 36.40 months (IQR 21.72 –
45.59). The 2-year progression-free survival was 70% (95% CI: 47 – 85).
In stratum 3, ten of 25 patients achieved a sustained partial response
(95% CI: 21 – 61). The median follow-up was 48.60 months (IQR 39.14 –
51.31) for the 17 patients without a progression event by Aug 9, 2018.
The 2-year progression-free survival was 96% (95% CI: 74 - 99).
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 11316
Name: EID11316
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:4851
Display Name: Pilocytic Astrocytoma
Doid: 4851
Id: 166
Link: /diseases/166
Name: Pilocytic Astrocytoma
##### My Disease Info
Do Def:
A childhood low-grade glioma that is characterized by cells that look
like fibers when viewed under a microscope and is located_in the brain.
Icdo: 9421/1
Mesh: D001254
Mondo Id: MONDO:0016691
Ncit: C4047
Disease Aliases: Grade I Astrocytic Tumor, Piloid Astrocytoma
##### Molecular Profile
Id: 4453
##### Source
Abstract:
Paediatric low-grade glioma is the most common CNS tumour of childhood.
Although overall survival is good, disease often recurs. No single
universally accepted treatment exists for these patients; however,
standard cytotoxic chemotherapies are generally used. We aimed to assess
the activity of selumetinib, a MEK1/2 inhibitor, in these patients.The
Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study
in patients with paediatric low-grade glioma in 11 hospitals in the USA.
Patients aged 3-21 years with a Lansky or Karnofsky performance score
greater than 60 and the presence of recurrent, refractory, or
progressive paediatric low-grade glioma after at least one standard
therapy were eligible for inclusion. Patients were assigned to six
unique strata according to histology, tumour location, NF1 status, and
BRAF aberration status; herein, we report the results of strata 1 and 3.
Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma
harbouring either one of the two most common BRAF aberrations
(KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3
comprised patients with any neurofibromatosis type 1 (NF1)-associated
paediatric low-grade glioma (WHO grades I and II). Selumetinib was
provided as capsules given orally at the recommended phase 2 dose of 25
mg/m2 twice daily in 28-day courses for up to 26 courses. The primary
endpoint was the proportion of patients with a stratum-specific
objective response (partial response or complete response), as assessed
by the local site and sustained for at least 8 weeks. All responses were
reviewed centrally. All eligible patients who initiated treatment were
evaluable for the activity and toxicity analyses. Although the trial is
ongoing in other strata, enrolment and planned follow-up is complete for
strata 1 and 3. This trial is registered with ClinicalTrials.gov, number
NCT01089101.Between July 25, 2013, and June 12, 2015, 25 eligible and
evaluable patients were accrued to stratum 1, and between Aug 28, 2013,
and June 25, 2015, 25 eligible and evaluable patients were accrued to
stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients
achieved a sustained partial response. The median follow-up for the 11
patients who had not had a progression event by Aug 9, 2018, was 36·40
months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients
achieved a sustained partial response; median follow-up was 48·60 months
(IQR 39·14-51·31) for the 17 patients without a progression event by Aug
9, 2018. The most frequent grade 3 or worse adverse events were elevated
creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]).
No treatment-realted deaths were reported.Selumetinib is active in
recurrent, refractory, or progressive pilocytic astrocytoma harbouring
common BRAF aberrations and NF1-associated paediatric low-grade glioma.
These results show that selumetinib could be an alternative to standard
chemotherapy for these subgroups of patients, and have directly led to
the development of two Children's Oncology Group phase 3 studies
comparing standard chemotherapy to selumetinib in patients with newly
diagnosed paediatric low-grade glioma both with and without NF1.National
Cancer Institute Cancer Therapy Evaluation Program, the American
Lebanese Syrian Associated Charities, and AstraZeneca.
Author String:
Jason Fangusaro, Arzu Onar-Thomas, Tina Young Poussaint, Shengjie Wu,
Azra H Ligon, Neal Lindeman, Anuradha Banerjee, Roger J Packer, Lindsay
B Kilburn, Stewart Goldman, Ian F Pollack, Ibrahim Qaddoumi, Regina I
Jakacki, Paul G Fisher, Girish Dhall, Patricia Baxter, Susan G
Kreissman, Clinton F Stewart, David T W Jones, Stefan M Pfister, Gilbert
Vezina, Jessica S Stern, Ashok Panigrahy, Zoltan Patay, Benita Tamrazi,
Jeremy Y Jones, Sofia S Haque, David S Enterline, Soonmee Cha, Michael J
Fisher, Laurence Austin Doyle, Malcolm Smith, Ira J Dunkel, Maryam
Fouladi
Citation: Fangusaro et al., 2019
Citation Id: 31151904
Id: 2973
Journal: Lancet Oncol
Link: /sources/2973
Name: PubMed: Fangusaro et al., 2019
Open Access: True
Pmc Id: PMC6628202
Publication Date: 2019-7
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/31151904
Title:
Selumetinib in paediatric patients with BRAF-aberrant or
neurofibromatosis type 1-associated recurrent, refractory, or
progressive low-grade glioma: a multicentre, phase 2 trial.
##### Therapies
Deprecated: False
Id: 63
Link: /therapies/63
Name: Selumetinib
#### Evidence Items
Description:
In this ongoing phase 2 trial (FIREFLY-1), 76 patients, aged 6 months to
25 years, with pediatric low-grade glioma harbouring BRAF alterations
(BRAF fusions or BRAF V600E mutations) were treated with tovorafenib
(DAY-101). The overall response rate according to the RAPNO-LGG criteria
was 51% (95% CI; 40-63) and the median PFS and DOR were 13.8 months (95%
CI; 8.3-16.9) and 13.8 months (95% CI; 11.3 - NR) respectively. All
patients experienced at least one adverse event which may be treatment-
emergent, and 63% of the patients experienced Grade ≥3 adverse events.
Evidence Direction: SUPPORTS
Evidence Level: A
Evidence Rating: 5
Evidence Type: PREDICTIVE
Flagged: False
Id: 12016
Name: EID12016
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:0080830
Display Name: Childhood Low-grade Glioma
Doid: 0080830
Id: 3048
Link: /diseases/3048
Name: Childhood Low-grade Glioma
##### My Disease Info
Do Def:
A low-grade glioma that occurs in children and encompasses tumors of
astrocytic, oligodendroglial, and mixed glial-neuronal histology.
Mondo Id: MONDO:0859591
Disease Aliases: Pediatric Low-grade Glioma
##### Molecular Profile
Id: 4453
##### Source
Abstract:
BRAF genomic alterations are the most common oncogenic drivers in
pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2
FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral,
selective, central nervous system-penetrant, type II RAF inhibitor
tovorafenib (420 mg m-2 once weekly; 600 mg maximum) in patients with
BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension
cohort, which provided treatment access for patients with RAF-altered
pLGG after arm 1 closure. Based on independent review, according to
Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG)
criteria, the overall response rate (ORR) of 67% met the arm 1
prespecified primary endpoint; median duration of response (DOR) was
16.6 months; and median time to response (TTR) was 3.0 months (secondary
endpoints). Other select arm 1 secondary endpoints included ORR, DOR and
TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-
Grade Glioma (RAPNO) criteria and safety (assessed in all treated
patients and the primary endpoint for arm 2, n = 137). The ORR according
to RAPNO criteria (including minor responses) was 51%; median DOR was
13.8 months; and median TTR was 5.3 months. The most common treatment-
related adverse events (TRAEs) were hair color changes (76%), elevated
creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred
in 42% of patients. Nine (7%) patients had TRAEs leading to
discontinuation of tovorafenib. These data indicate that tovorafenib
could be an effective therapy for BRAF-altered, relapsed/refractory
pLGG. ClinicalTrials.gov registration: NCT04775485 .
Author String:
Lindsay B Kilburn, Dong-Anh Khuong-Quang, Jordan R Hansford, Daniel
Landi, Jasper van der Lugt, Sarah E S Leary, Pablo Hernáiz Driever,
Simon Bailey, Sébastien Perreault, Geoffrey McCowage, Angela J Waanders,
David S Ziegler, Olaf Witt, Patricia A Baxter, Hyoung Jin Kang, Timothy
E Hassall, Jung Woo Han, Darren Hargrave, Andrea T Franson, Michal Yalon
Oren, Helen Toledano, Valérie Larouche, Cassie Kline, Mohamed S
Abdelbaki, Nada Jabado, Nicholas G Gottardo, Nicolas U Gerber, Nicholas
S Whipple, Devorah Segal, Susan N Chi, Liat Oren, Enrica E K Tan, Sabine
Mueller, Izzy Cornelio, Lisa McLeod, Xin Zhao, Ashley Walter, Daniel Da
Costa, Peter Manley, Samuel C Blackman, Roger J Packer, Karsten Nysom
Citation: Kilburn et al., 2024
Citation Id: 37978284
Id: 4991
Journal: Nat Med
Link: /sources/4991
Name: PubMed: Kilburn et al., 2024
Open Access: True
Pmc Id: PMC10803270
Publication Date: 2024-1
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/37978284
Title:
The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric
low-grade glioma: the phase 2 FIREFLY-1 trial.
##### Therapies
Deprecated: False
Id: 1071
Link: /therapies/1071
Name: Tovorafenib
#### Variants
Id: 618
Link: /variants/618
Name: Fusion
#### Variants
Id: 12
Link: /variants/12
Name: V600E
### Molecular Profiles
Id: 4707
Molecular Profile Score: 15.0
Name: BRAF V600E OR BRAF K601E
#### Evidence Items
Description:
This clinical study was conducted with 30 patients with colorectal
cancer harboring BRAF V600E (n = 29) or BRAF K601E (n=1) mutations,
treated with a combination of cobimetinib and vemurafenib. Of the 30
patients, only 27 were evaluable. An OR rate of 30% (95% CI; 14-50), and
DC rate of 52% (95% CI; 35-65) was noted. Eight patients had a partial
response with a median duration of 8.1 weeks (5.1-32.3 weeks) and six
patients had SD16+ with a median duration of 29.1 weeks (28.1-44.0
weeks). The reported PFS was 15.7 weeks (95% CI; 12.1-18.1) and OS was
38.9 weeks (95% CI; 26.1-49.4). In 43% of the cohort, grade 3 AEs or
SAEs were observed, likely associated with the treatment.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 11670
Name: EID11670
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:9256
Display Name: Colorectal Cancer
Doid: 9256
Id: 11
Link: /diseases/11
Name: Colorectal Cancer
##### My Disease Info
Do Def:
An intestinal cancer that effects the long, tube-like organ that is
connected to the small intestine at one end and the anus at the other.
Icd10: C18.9
Mondo Id: MONDO:0005575
Ncit: C4978
##### Molecular Profile
Id: 4707
##### Source
Abstract:
TAPUR is a phase II basket trial evaluating the antitumor activity of
commercially available targeted agents in patients with advanced cancer
and genomic alterations known to be drug targets. The results of a
cohort of patients with colorectal cancer (CRC) with BRAF mutations
treated with cobimetinib (C) plus vemurafenib (V) are reported.Eligible
patients had advanced CRC, no standard treatment options, measurable
disease (RECIST), Eastern Cooperative Oncology Group performance status
0-2, adequate organ function, tumors with BRAF V600E/D/K/R mutations,
and no MAP2K1/2, MEK1/2, or NRAS mutations. C was taken 60 mg orally
once daily for 21 days followed by seven days off, and V was taken 960
mg orally twice daily. Simon's two-stage design was used with a primary
study end point of objective response or stable disease of at least 16
weeks duration. Secondary end points were progression-free survival,
overall survival, and safety.Thirty patients were enrolled from August
2016 to August 2018; all had CRC with a BRAF V600E mutation except one
patient with a BRAF K601E mutation. Three patients were not evaluable
for efficacy. Eight patients with partial responses and six patients
with stable disease of at least 16 weeks duration were observed for
disease control and objective response rates of 52% (95% CI, 35 to 65)
and 30% (95% CI, 14 to 50), respectively. The null hypothesis of 15%
disease control rate was rejected (P < .0001). Thirteen patients had at
least one grade 3 adverse event or serious adverse event at least
possibly related to C + V: anemia, decreased lymphocytes, dyspnea,
diarrhea, elevated liver enzymes, fatigue, hypercalcemia,
hypophosphatemia, rash, photosensitivity, and upper gastrointestinal
hemorrhage.The combination of C + V has antitumor activity in heavily
pretreated patients with CRC with BRAF mutations.
Author String:
Kelsey A Klute, Michael Rothe, Elizabeth Garrett-Mayer, Pam K Mangat,
Reza Nazemzadeh, Kathleen J Yost, Herbert L Duvivier, Eugene R Ahn,
Timothy L Cannon, Olatunji B Alese, John C Krauss, Ramya Thota, Carmen J
Calfa, Crystal S Denlinger, Raegan O'Lone, Susan Halabi, Gina N
Grantham, Richard L Schilsky
Citation: Klute et al., 2022
Citation Id: 36409971
Id: 4832
Journal: JCO Precis Oncol
Link: /sources/4832
Name: PubMed: Klute et al., 2022
Open Access: False
Publication Date: 2022-11
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/36409971
Title:
Cobimetinib Plus Vemurafenib in Patients With Colorectal Cancer With
BRAF Mutations: Results From the Targeted Agent and Profiling
Utilization Registry (TAPUR) Study.
##### Therapies
Deprecated: False
Id: 342
Link: /therapies/342
Name: Cobimetinib
##### Therapies
Deprecated: False
Id: 4
Link: /therapies/4
Name: Vemurafenib
#### Variants
Id: 12
Link: /variants/12
Name: V600E
#### Variants
Id: 584
Link: /variants/584
Name: K601E
### Molecular Profiles
Id: 4715
Molecular Profile Score: 0.0
Name:
BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1
Mutation
#### Evidence Items
Description:
In this phase II study of the arm E of the NCI-COG pediatric MATCH
trial, 20 patients (median age: 14) were treated with Selumetinib. High-
grade glioma (n=7) and rhabdomyosarcoma (n=7) were the most common types
of cancers in this cohort. There was no objective response (PR or CR),
the best overall response being SD, in three patients. The 6-month PFS
rate was 15% (95% CI; 4-34). 25% of the patients had grade 3 or higher
AEs, possibly attributed to selumetinib treatment.
Evidence Direction: DOES_NOT_SUPPORT
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 11681
Name: EID11681
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:162
Display Name: Cancer
Doid: 162
Id: 216
Link: /diseases/216
Name: Cancer
##### My Disease Info
Do Def: A cancer that is classified based on the organ it starts in.
Mesh: D009371
Mondo Id: MONDO:0004992
Disease Aliases: Malignant Neoplasm, Malignant Tumor, Primary Cancer
##### Molecular Profile
Id: 4715
##### Source
Abstract:
The NCI-COG Pediatric MATCH trial assigns patients age 1-21 years with
relapsed or refractory solid tumors, lymphomas, and histiocytic
disorders to phase II studies of molecularly targeted therapies on the
basis of detection of predefined genetic alterations. Patients with
tumors harboring mutations or fusions driving activation of the mitogen-
activated protein kinase (MAPK) pathway were treated with the MEK
inhibitor selumetinib.Patients received selumetinib twice daily for
28-day cycles until disease progression or intolerable toxicity. The
primary end point was objective response rate; secondary end points
included progression-free survival and tolerability of
selumetinib.Twenty patients (median age: 14 years) were treated. All
were evaluable for response and toxicities. The most frequent diagnoses
were high-grade glioma (HGG; n = 7) and rhabdomyosarcoma (n = 7).
Twenty-one actionable mutations were detected: hotspot mutations in KRAS
(n = 8), NRAS (n = 3), and HRAS (n = 1), inactivating mutations in NF1
(n = 7), and BRAF V600E (n = 2). No objective responses were observed.
Three patients had a best response of stable disease including two
patients with HGG (NF1 mutation, six cycles; KRAS mutation, 12 cycles).
Six-month progression-free survival was 15% (95% CI, 4 to 34). Five
patients (25%) experienced a grade 3 or higher adverse event that was
possibly or probably attributable to study drug.A national histology-
agnostic molecular screening strategy was effective at identifying
children and young adults eligible for treatment with selumetinib in the
first Pediatric MATCH treatment arm to be completed. MEK inhibitors have
demonstrated promising responses in some pediatric tumors (eg, low-grade
glioma and plexiform neurofibroma). However, selumetinib in this cohort
with treatment-refractory tumors harboring MAPK alterations demonstrated
limited efficacy, indicating that pathway mutation status alone is
insufficient to predict response to selumetinib monotherapy for
pediatric cancers.
Author String:
Olive S Eckstein, Carl E Allen, P Mickey Williams, Sinchita Roy-
Chowdhuri, David R Patton, Brent Coffey, Joel M Reid, Jin Piao, Lauren
Saguilig, Todd A Alonzo, Stacey L Berg, Nilsa C Ramirez, Alok Jaju,
Joyce Mhlanga, Elizabeth Fox, Douglas S Hawkins, Margaret M Mooney,
Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, D
Williams Parsons
Citation: Eckstein et al., 2022
Citation Id: 35363510
Id: 4841
Journal: J Clin Oncol
Link: /sources/4841
Name: PubMed: Eckstein et al., 2022
Open Access: True
Pmc Id: PMC9273373
Publication Date: 2022-7-10
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/35363510
Title:
Phase II Study of Selumetinib in Children and Young Adults With Tumors
Harboring Activating Mitogen-Activated Protein Kinase Pathway Genetic
Alterations: Arm E of the NCI-COG Pediatric MATCH Trial.
##### Therapies
Deprecated: False
Id: 63
Link: /therapies/63
Name: Selumetinib
#### Variants
Id: 275
Link: /variants/275
Name: Mutation
#### Variants
Id: 12
Link: /variants/12
Name: V600E
#### Variants
Id: 587
Link: /variants/587
Name: Mutation
#### Variants
Id: 336
Link: /variants/336
Name: Mutation
#### Variants
Id: 208
Link: /variants/208
Name: Mutation
### Molecular Profiles
Id: 4748
Molecular Profile Score: 0.0
Name:
BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1
Inactivating Mutation
#### Evidence Items
Description:
In this Phase II study, 20 patients harboring activating RAS gene
mutations (KRAS = 8, NRAS = 3. HRAS = 1), BRAF V600E mutations, and NF1
inactivating mutations (n=7) were treated with Selumetinib. No objected
response was reported in these patients, and the six-month PFS was 15%
(95% CI; 4-34). 25% (n=5) of the patients experienced a grade 3 or
higher adverse effects, likely associated with selumetinib. Overall,
selumetinib had limited efficacy in this cohort.
Evidence Direction: DOES_NOT_SUPPORT
Evidence Level: B
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 11696
Name: EID11696
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:162
Display Name: Cancer
Doid: 162
Id: 216
Link: /diseases/216
Name: Cancer
##### My Disease Info
Do Def: A cancer that is classified based on the organ it starts in.
Mesh: D009371
Mondo Id: MONDO:0004992
Disease Aliases: Malignant Neoplasm, Malignant Tumor, Primary Cancer
##### Molecular Profile
Id: 4748
##### Source
Abstract:
The NCI-COG Pediatric MATCH trial assigns patients age 1-21 years with
relapsed or refractory solid tumors, lymphomas, and histiocytic
disorders to phase II studies of molecularly targeted therapies on the
basis of detection of predefined genetic alterations. Patients with
tumors harboring mutations or fusions driving activation of the mitogen-
activated protein kinase (MAPK) pathway were treated with the MEK
inhibitor selumetinib.Patients received selumetinib twice daily for
28-day cycles until disease progression or intolerable toxicity. The
primary end point was objective response rate; secondary end points
included progression-free survival and tolerability of
selumetinib.Twenty patients (median age: 14 years) were treated. All
were evaluable for response and toxicities. The most frequent diagnoses
were high-grade glioma (HGG; n = 7) and rhabdomyosarcoma (n = 7).
Twenty-one actionable mutations were detected: hotspot mutations in KRAS
(n = 8), NRAS (n = 3), and HRAS (n = 1), inactivating mutations in NF1
(n = 7), and BRAF V600E (n = 2). No objective responses were observed.
Three patients had a best response of stable disease including two
patients with HGG (NF1 mutation, six cycles; KRAS mutation, 12 cycles).
Six-month progression-free survival was 15% (95% CI, 4 to 34). Five
patients (25%) experienced a grade 3 or higher adverse event that was
possibly or probably attributable to study drug.A national histology-
agnostic molecular screening strategy was effective at identifying
children and young adults eligible for treatment with selumetinib in the
first Pediatric MATCH treatment arm to be completed. MEK inhibitors have
demonstrated promising responses in some pediatric tumors (eg, low-grade
glioma and plexiform neurofibroma). However, selumetinib in this cohort
with treatment-refractory tumors harboring MAPK alterations demonstrated
limited efficacy, indicating that pathway mutation status alone is
insufficient to predict response to selumetinib monotherapy for
pediatric cancers.
Author String:
Olive S Eckstein, Carl E Allen, P Mickey Williams, Sinchita Roy-
Chowdhuri, David R Patton, Brent Coffey, Joel M Reid, Jin Piao, Lauren
Saguilig, Todd A Alonzo, Stacey L Berg, Nilsa C Ramirez, Alok Jaju,
Joyce Mhlanga, Elizabeth Fox, Douglas S Hawkins, Margaret M Mooney,
Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, D
Williams Parsons
Citation: Eckstein et al., 2022
Citation Id: 35363510
Id: 4841
Journal: J Clin Oncol
Link: /sources/4841
Name: PubMed: Eckstein et al., 2022
Open Access: True
Pmc Id: PMC9273373
Publication Date: 2022-7-10
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/35363510
Title:
Phase II Study of Selumetinib in Children and Young Adults With Tumors
Harboring Activating Mitogen-Activated Protein Kinase Pathway Genetic
Alterations: Arm E of the NCI-COG Pediatric MATCH Trial.
##### Therapies
Deprecated: False
Id: 63
Link: /therapies/63
Name: Selumetinib
#### Variants
Id: 275
Link: /variants/275
Name: Mutation
#### Variants
Id: 4643
Link: /variants/4643
Name: Inactivating Mutation
#### Variants
Id: 12
Link: /variants/12
Name: V600E
#### Variants
Id: 336
Link: /variants/336
Name: Mutation
#### Variants
Id: 208
Link: /variants/208
Name: Mutation
### Molecular Profiles
Id: 4765
Molecular Profile Score: 0.0
Name: BRAF V600E AND ERBB2 Amplification AND SMAD4 LOSS AND TP53 V218E
#### Evidence Items
Description:
In this clinical trial, 18 patients with pancreatic cancer were
recruited. In this case, the patient (74 y/F) with pancreatic cancer
harboring, BRAF V600E, SMAD4 Loss, ERBB2 amplification, and, TP53 V218E,
was treated with Trametinib, Trastuzumab, Lapatinib, and, Bevacizumab.
The trial reported a progression-free survival (PFS) of 7.8 months and
an overall survival (OS) of 9.4 months for this individual. The study
concluded that the patient derived clinical benefit, defined as stable
disease (SD) lasting at least 6 months, partial remission (PR), or
complete remission (CR).
Evidence Direction: SUPPORTS
Evidence Level: C
Evidence Rating: 3
Evidence Type: PREDICTIVE
Flagged: False
Id: 11712
Name: EID11712
Significance: SENSITIVITYRESPONSE
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1793
Display Name: Pancreatic Cancer
Doid: 1793
Id: 556
Link: /diseases/556
Name: Pancreatic Cancer
##### My Disease Info
Do Def: An endocrine gland cancer located_in the pancreas.
Icd10: ["C25.0", "C25.1", "C25.2"]
Mesh: D010190
Mondo Id: MONDO:0009831
Ncit: C3305
Disease Aliases:
- Ca Body Of Pancreas
- Ca Head Of Pancreas
- Ca Tail Of Pancreas
- Malignant Neoplasm Of Body Of Pancreas
- Malignant Neoplasm Of Head Of Pancreas
- Malignant Neoplasm Of Tail Of Pancreas
- Pancreas Neoplasm
- Pancreatic Neoplasm
- Pancreatic Tumor
##### Molecular Profile
Id: 4765
##### Source
Abstract:
Despite progress, 2-year pancreatic cancer survival remains dismal. We
evaluated a biomarker-driven, combination/N-of-one strategy in 18
patients (advanced/metastatic pancreatic cancer) (from Molecular Tumor
Board). Targeted agents administered/patient = 2.5 (median) (range,
1-4); first-line therapy (N = 5); second line, (N = 13). Comparing
patients (high versus low degrees of matching) (matching score ≥50%
versus <50%; reflecting number of alterations matched to targeted agents
divided by number of pathogenic alterations), survival was significantly
longer (hazard ratio [HR] 0.24 (95% confidence interval [CI],
0.078-0.76, P = 0.016); clinical benefit rates (CBR) (stable disease ≥6
months/partial/complete response) trended higher (45.5 vs 0.0%, P =
0.10); progression-free survival, HR, 95% CI, 0.36 (0.12-1.10) (p =
0.075). First versus ≥2nd-line therapy had higher CBRs (80.0 vs 7.7%, P
= 0.008). No grade 3-4 toxicities occurred. The longest responder
achieved partial remission (17.5 months) by co-targeting MEK and CDK4/6
alterations (chemotherapy-free). Therefore, genomically matched targeted
agent combinations were active in these advanced pancreatic cancers.
Larger prospective trials are warranted.
Author String:
Justin Shaya, Shumei Kato, Jacob J Adashek, Hitendra Patel, Paul T
Fanta, Gregory P Botta, Jason K Sicklick, Razelle Kurzrock
Citation: Shaya et al., 2023
Citation Id: 36670111
Id: 4855
Journal: NPJ Genom Med
Link: /sources/4855
Name: PubMed: Shaya et al., 2023
Open Access: True
Pmc Id: PMC9860045
Publication Date: 2023-1-20
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/36670111
Title:
Personalized matched targeted therapy in advanced pancreatic cancer: a
pilot cohort analysis.
##### Therapies
Deprecated: False
Id: 19
Link: /therapies/19
Name: Trametinib
##### Therapies
Deprecated: False
Id: 84
Link: /therapies/84
Name: Trastuzumab
##### Therapies
Deprecated: False
Id: 45
Link: /therapies/45
Name: Lapatinib
##### Therapies
Deprecated: False
Id: 33
Link: /therapies/33
Name: Bevacizumab
#### Variants
Id: 306
Link: /variants/306
Name: Amplification
#### Variants
Id: 4657
Link: /variants/4657
Name: V218E
#### Variants
Id: 12
Link: /variants/12
Name: V600E
#### Variants
Id: 564
Link: /variants/564
Name: LOSS
### Molecular Profiles
Id: 5175
Molecular Profile Score: 0.0
Name: BRAF V600E AND MSI Low
#### Evidence Items
Description:
5577 colon carcinoma tumors were evaluated for BRAF, KRAS, and mismatch
repair status. From those successfully evaluated, 201 had microsatellite
instability (MSI or MSI-H) and BRAF V600E, 72 had MSI and KRAS exon 2
mutation, and 204 had MSI and no KRAS or BRAF mutation. In addition, 279
were microsatellite stable (MSS or MSI-L) and BRAF V600E, 1450 had MSI
and KRAS exon 2 mutation, and 2205 had MSI and no KRAS or BRAF mutation.
MSS patients with BRAF V600E were associated with shorter time to
recurrence (HR = 1.54, 95% CI = 1.23 to 1.92, P < .001).
Overall survival in MSS with BRAF V600E was poorer than wild-type (HR =
2.01, 95% CI = 1.56 to 2.57, P < .001).
This prognostic effect was not seen in BRAF or KRAS mutant patients that
had MSI tumors.
Evidence Direction: SUPPORTS
Evidence Level: B
Evidence Rating: 3
Evidence Type: PROGNOSTIC
Flagged: False
Id: 12072
Name: EID12072
Significance: POOR_OUTCOME
Variant Origin: SOMATIC
##### Disease
Disease Url: https://www.disease-ontology.org/?id=DOID:1520
Display Name: Colon Carcinoma
Doid: 1520
Id: 210
Link: /diseases/210
Name: Colon Carcinoma
##### My Disease Info
Do Def:
A colon cancer that has_material_basis_in abnormally proliferating cells
derives_from epithelial cells.
Mondo Id: MONDO:0002032
Ncit: C4910
Disease Aliases: Carcinoma Of Colon, Colonic Carcinoma
##### Molecular Profile
Id: 5175
##### Source
Abstract:
The prognostic value of BRAF and KRAS mutations within microsatellite-
unstable (MSI) and microsatellite-stable (MSS) subgroups of resected
colon carcinoma patients remains controversial. We examined this
question in prospectively collected biospecimens from stage III colon
cancer with separate analysis of MSI and MSS tumors from patients
receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy
trials.Three groups were defined: BRAF Mutant, KRAS Mutant, and double
wild-type. The analytic strategy involved estimation of study-specific
effects, assessment of homogeneity of results, and then analysis of
pooled data as no differences in patient outcome were found between
treatment arms in both trials. Associations of mutations with patient
outcome were analyzed, and multivariable models were adjusted for
treatment and relevant factors.Four thousand four hundred eleven tumors
were evaluable for BRAF and KRAS mutations and mismatch repair status;
3934 were MSS and 477 were MSI. In MSS patients, all BRAF V600E
mutations (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.23
to 1.92, P < .001), KRAS codon 12 alterations, and p.G13D mutations (HR
= 1.60, 95% CI = 1.40 to 1.83, P < .001) were associated with shorter
time to recurrence (TTR) and shorter survival after relapse (SAR; HR =
3.02 , 95% CI = 2.32 to 3.93, P < .001, and HR = 1.20, 95% CI = 1.01 to
1.44, P = .04, respectively). Overall survival (OS) in MSS patients was
poorer for BRAF-mutant patients (HR = 2.01, 95% CI = 1.56 to 2.57, P <
.001) and KRAS-mutant patients (HR = 1.62, 95% CI = 1.38 to 1.91, P <
.001) vs wild-type. No prognostic role of KRAS or BRAF mutations was
seen in MSI patients. Furthermore, no interaction was found between
treatment arm (with or without cetuximab) and KRAS and BRAF mutations
for TTR or OS in MSS patients.In a pooled analysis of resected stage III
colon cancer patients receiving adjuvant FOLFOX, BRAF or KRAS mutations
are independently associated with shorter TTR, SAR, and OS in patients
with MSS, but not MSI, tumors. Future clinical trials in the adjuvant
setting should consider these mutations as important stratification
factors.
Author String:
Julien Taieb, Karine Le Malicot, Qian Shi, Frédérique Penault-Llorca,
Olivier Bouché, Josep Tabernero, Enrico Mini, Richard M Goldberg, Gunnar
Folprecht, Jean Luc Van Laethem, Daniel J Sargent, Steven R Alberts,
Jean Francois Emile, Pierre Laurent Puig, Frank A Sinicrope
Citation: Taieb et al., 2017
Citation Id: 28040692
Id: 5048
Journal: J Natl Cancer Inst
Link: /sources/5048
Name: PubMed: Taieb et al., 2017
Open Access: True
Pmc Id: PMC6075212
Publication Date: 2017-5
Retracted: False
Source Type: PUBMED
Source Url: http://www.ncbi.nlm.nih.gov/pubmed/28040692
Title:
Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III
Colon Cancer.
#### Variants
Id: 12
Link: /variants/12
Name: V600E
#### Variants
Id: 4985
Link: /variants/4985
Name: Low
Variant Aliases: RS113488022, VAL600GLU, V640E, VAL640GLU
## Clinvar
License: http://bit.ly/2SQdcI0
Allele Id: 29000
Alt: T
Chrom: 7
Cytogenic: 7q34
Omim: 164757.0001
Ref: A
Rsid: rs113488022
Type: single nucleotide variant
Variant Id: 13961
### Gene
Id: 673
Symbol: BRAF
### Hg19
End: 140453136
Start: 140453136
### Hg38
End: 140753336
Start: 140753336
### Hgvs
Coding:
- LRG_299t1:c.1799T>A
- NM_001354609.2:c.1799T>A
- NM_001374244.1:c.1919T>A
- NM_001374258.1:c.1919T>A
- NM_001378467.1:c.1808T>A
- NM_001378468.1:c.1799T>A
- NM_001378469.1:c.1733T>A
- NM_001378470.1:c.1697T>A
- NM_001378471.1:c.1688T>A
- NM_001378472.1:c.1643T>A
- NM_001378473.1:c.1643T>A
- NM_001378474.1:c.1799T>A
- NM_001378475.1:c.1535T>A
- NM_004333.6:c.1799T>A
Genomic:
- LRG_299:g.176429T>A
- NC_000007.12:g.140099605A>T
- NC_000007.13:g.140453136A>T
- NC_000007.14:g.140753336A>T
- NG_007873.3:g.176429T>A
Protein:
- LRG_299p1:p.Val600Glu
- NP_001341538.1:p.Val600Glu
- NP_001361173.1:p.Val640Glu
- NP_001361187.1:p.Val640Glu
- NP_001365396.1:p.Val603Glu
- NP_001365397.1:p.Val600Glu
- NP_001365398.1:p.Val578Glu
- NP_001365399.1:p.Val566Glu
- NP_001365400.1:p.Val563Glu
- NP_001365401.1:p.Val548Glu
- NP_001365402.1:p.Val548Glu
- NP_001365403.1:p.Val600Glu
- NP_001365404.1:p.Val512Glu
- NP_004324.2:p.Val600Glu
- P15056:p.Val600Glu
- p.V600E
### Rcv
Accession: RCV000014992
Clinical Significance: Pathogenic
Last Evaluated: 2014-09-04
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Carcinoma of colon (CRC)
##### Identifiers
Medgen: C0699790
Mondo: MONDO:0002032
Synonyms: Colonic carcinoma, Colon carcinoma
### Rcv
Accession: RCV000014993
Clinical Significance: Pathogenic
Last Evaluated: 2014-09-04
Number Submitters: 2
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Papillary thyroid carcinoma
##### Identifiers
Human Phenotype Ontology: HP:0002895
Medgen: C0238463
Mesh: D000077273
Mondo: MONDO:0005075
Orphanet: 146
Synonyms:
- NONMEDULLARY THYROID CARCINOMA, PAPILLARY
- Thyroid carcinoma, papillary, somatic
- Thyroid gland papillary carcinoma
### Rcv
Accession: RCV000014994
Clinical Significance: Pathogenic
Last Evaluated: 2014-09-04
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Astrocytoma, low-grade, somatic
##### Identifiers
Medgen: C2674727
### Rcv
Accession: RCV000022677
Clinical Significance: Pathogenic
Last Evaluated: 2014-09-04
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Nongerminomatous germ cell tumor
##### Identifiers
Medgen: C1266158
Mondo: MONDO:0021656
Synonyms:
- NONSEMINOMATOUS GERM CELL TUMORS, SOMATIC
- Germ cell tumor, nonseminomatous
- Non-seminomatous germ-cell tumors
### Rcv
Accession: RCV000037936
Clinical Significance: Pathogenic
Last Evaluated: 2009-05-29
Number Submitters: 2
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Non-small cell lung carcinoma (NSCLC)
##### Identifiers
Human Phenotype Ontology: HP:0030358
Medgen: C0007131
Mesh: D002289
Mondo: MONDO:0005233
Synonyms: Non-small cell lung cancer
### Rcv
Accession: RCV000067669
Clinical Significance: Pathogenic
Last Evaluated: 2016-03-10
Number Submitters: 2
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Melanoma
##### Identifiers
Human Phenotype Ontology: HP:0007474
Medgen: C0025202
Mesh: D008545
Mondo: MONDO:0005105
### Rcv
Accession: RCV000080903
Clinical Significance: Pathogenic
Last Evaluated: 2014-07-11
Number Submitters: 4
Origin: germline
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: criteria provided, multiple submitters, no conflicts
#### Conditions
Name: not provided
##### Identifiers
Medgen: C3661900
Synonyms: none provided
### Rcv
Accession: RCV000208763
Clinical Significance: not provided
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion provided
#### Conditions
Name: Cardio-facio-cutaneous syndrome
##### Identifiers
Medgen: C1275081
Mondo: MONDO:0015280
Omim: PS115150
Orphanet: 1340
Synonyms: Cardiofaciocutaneous syndrome, CFC syndrome
### Rcv
Accession: RCV000417746
Clinical Significance: Likely pathogenic
Last Evaluated: 2016-05-31
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Malignant melanoma of skin (CMM)
##### Identifiers
Human Phenotype Ontology: HP:0012056
Medgen: C0151779
Mesh: C562393
Mondo: MONDO:0005012
Synonyms: Malignant melanoma, somatic, Cutaneous melanoma
### Rcv
Accession: RCV000420614
Clinical Significance: Likely pathogenic
Last Evaluated: 2015-07-14
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Colonic neoplasm
##### Identifiers
Human Phenotype Ontology: HP:0100273
Medgen: C0009375
Mesh: D003110
Mondo: MONDO:0005401
Synonyms: Colonic Neoplasms, Neoplasm of the colon
### Rcv
Accession: RCV000424470
Clinical Significance: Likely pathogenic
Last Evaluated: 2016-05-31
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Squamous cell carcinoma of the head and neck (HNSCC)
##### Identifiers
Medgen: C1168401
Mesh: D000077195
Mondo: MONDO:0010150
Omim: 275355
Orphanet: 67037
Synonyms:
- Head and neck squamous cell carcinoma
- Carcinoma, squamous cell of head and neck
- Squamous cell carcinoma, head and neck, somatic
### Rcv
Accession: RCV000425166
Clinical Significance: Likely pathogenic
Last Evaluated: 2016-05-31
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Brainstem glioma
##### Identifiers
Human Phenotype Ontology: HP:0010796
Medgen: C0677865
Mondo: MONDO:0002911
### Rcv
Accession: RCV000425847
Clinical Significance: Likely pathogenic
Last Evaluated: 2016-05-31
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Glioblastoma
##### Identifiers
Medgen: C0017636
Mesh: D005909
Mondo: MONDO:0018177
Synonyms:
- Giant cell glioblastoma (histologic variant)
- Gliosarcoma (histologic variant)
### Rcv
Accession: RCV000429915
Clinical Significance: Likely pathogenic
Last Evaluated: 2016-05-31
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Lung adenocarcinoma
##### Identifiers
Human Phenotype Ontology: HP:0030078
Medgen: C0152013
Mesh: D000077192
Mondo: MONDO:0005061
Synonyms: Adenocarcinoma of lung, Adenocarcinoma of lung, somatic
### Rcv
Accession: RCV000430562
Clinical Significance: Likely pathogenic
Last Evaluated: 2019-08-31
Number Submitters: 2
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Multiple myeloma (MM)
##### Identifiers
Human Phenotype Ontology: HP:0006775
Medgen: C0026764
Mesh: D009101
Mondo: MONDO:0009693
Omim: 254500
Orphanet: 85443
Synonyms:
- Plasma cell myeloma
- Kahler disease
- Myelomatosis
- Plasma cell dyscrasia
- Multiple myeloma, somatic
### Rcv
Accession: RCV000432628
Clinical Significance: Pathogenic
Last Evaluated: 2014-10-02
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Ovarian neoplasm
##### Identifiers
Human Phenotype Ontology: HP:0100615
Medgen: C0919267
Mesh: D010051
Mondo: MONDO:0021068
Synonyms: Neoplasm of ovary, Ovarian tumor, Ovarian Neoplasms
### Rcv
Accession: RCV000433305
Clinical Significance: Pathogenic
Last Evaluated: 2014-10-02
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Lung carcinoma
##### Identifiers
Medgen: C0684249
Mondo: MONDO:0005138
### Rcv
Accession: RCV000435441
Clinical Significance: Likely pathogenic
Last Evaluated: 2016-05-31
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Neoplasm of brain
##### Identifiers
Human Phenotype Ontology: HP:0030692
Medgen: C0006118
Mesh: D001932
Mondo: MONDO:0021211
Synonyms: Brain tumour, Brain neoplasm, Brain Neoplasms
### Rcv
Accession: RCV000440540
Clinical Significance: Pathogenic
Last Evaluated: 2014-10-02
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Gastrointestinal stromal tumor
##### Identifiers
Human Phenotype Ontology: HP:0100723
Medgen: C0238198
Mesh: D046152
Mondo: MONDO:0011719
Omim: 606764
Orphanet: 44890
Synonyms:
- Gastrointestinal Stromal Sarcoma
- Gastrointestinal stromal tumor, somatic
- Gastrointestinal stroma tumor
### Rcv
Accession: RCV000440802
Clinical Significance: Likely pathogenic
Last Evaluated: 2016-05-31
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Papillary renal cell carcinoma, sporadic
##### Identifiers
Medgen: C1336078
Mesh: C538614
### Rcv
Accession: RCV000443448
Clinical Significance: Likely pathogenic
Last Evaluated: 2016-05-13
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Neoplasm
##### Identifiers
Human Phenotype Ontology: HP:0006741
Medgen: C0027651
Mesh: D009369
Mondo: MONDO:0005070
Synonyms: Neoplasms, Neoplasm (disease)
### Rcv
Accession: RCV000443745
Clinical Significance: Pathogenic
Last Evaluated: 2016-05-31
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Neoplasm of the large intestine
##### Identifiers
Human Phenotype Ontology: HP:0100834
Medgen: C0009404
Mesh: D015179
Mondo: MONDO:0005335
Synonyms: Colorectal Neoplasms, Colorectal neoplasm
### Rcv
Accession: RCV000662278
Clinical Significance: Pathogenic
Last Evaluated: 2015-05-07
Number Submitters: 2
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name:
Cystic epithelial invagination containing papillae lined by columnar
epithelium
### Rcv
Accession: RCV000860020
Clinical Significance: Pathogenic
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Cerebral arteriovenous malformation (BAVM)
##### Identifiers
Human Phenotype Ontology: HP:0002408
Medgen: C0917804
Mondo: MONDO:0007154
Omim: 108010
Orphanet: 46724
Synonyms:
- CEREBRAL ARTERIOVENOUS MALFORMATIONS
- Arteriovenous malformations of the brain
### Rcv
Accession: RCV001248834
Clinical Significance: Pathogenic
Last Evaluated: 2019-02-15
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Nephroblastoma
##### Identifiers
Human Phenotype Ontology: HP:0000115
Medgen: C0027708
Mesh: D009396
Mondo: MONDO:0006058
Synonyms: Wilms tumor, Wilms' tumor
### Rcv
Accession: RCV001254874
Clinical Significance: Likely pathogenic
Number Submitters: 1
Origin: unknown
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Malignant neoplastic disease
##### Identifiers
Medgen: C0006826
Mondo: MONDO:0004992
Synonyms: Cancer
### Rcv
Accession: RCV002051586
Clinical Significance: Pathogenic
Last Evaluated: 2022-02-09
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: no assertion criteria provided
#### Conditions
Name: Lymphangioma
##### Identifiers
Human Phenotype Ontology: HP:0100764
Medgen: C0024221
Mondo: MONDO:0002013
### Rcv
Accession: RCV003458334
Clinical Significance: Pathogenic
Last Evaluated: 2023-10-22
Number Submitters: 1
Origin: somatic
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: criteria provided, single submitter
#### Conditions
Name: Vascular malformation
##### Identifiers
Medgen: C0158570
Mondo: MONDO:0024291
Synonyms: Vascular malformations
### Rcv
Accession: RCV004018627
Clinical Significance: Likely pathogenic
Last Evaluated: 2022-05-23
Number Submitters: 1
Origin: germline
Preferred Name: NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)
Review Status: criteria provided, single submitter
#### Conditions
Name: Cardiovascular phenotype
##### Identifiers
Medgen: CN230736
## Cosmic
License: http://bit.ly/2VMkY7R
Alt: A
Chrom: 7
Cosmic Id: COSM476
Mut Freq: 2.83
Mut Nt: T>A
Ref: T
Tumor Site: biliary_tract
### Hg19
End: 140453136
Start: 140453136
## Dbnsfp
License: http://bit.ly/2VLnQBz
Alt: T
Ancestral Allele: A
Chrom: 7
Ref: A
Reliability Index: 10
Rsid: rs113488022
Vep Canonical: YES
### Aa
Alt: E
Ref: V
Codon Degeneracy: 0
Codonpos: 2
Pos: 600, 640
Refcodon: GTG
### Alphamissense
Rankscore: 0.97238
Pred: P
Score: 0.9853, 0.9978, 0.9927, 0.9941
### Bayesdel
#### Add Af
Pred: D
Rankscore: 0.89859
Score: 0.399079
#### No Af
Pred: D
Rankscore: 0.89732
Score: 0.335473
### Bstatistic
Converted Rankscore: 0.46346
Score: 789.0
### Clinpred
Pred: D
Rankscore: 0.84315
Score: 0.993496775627136
### Clinvar
Clinvar Id: 13961
Hgvs: NC_000007.14:g.140753336A>T
Review: criteria_provided,_multiple_submitters,_no_conflicts
Clnsig: Pathogenic, drug_response, other
Medgen:
- C0025202
- C0027651
- C0027708
- C3661900
- C0158570
- C0024221
- C0017636
- C1275081
- C0346629
- C0006118
- C1266158
- C0238198
- C0238463
- C0151779
- C0684249
- C0919267
- C0917804
- C0026764
- C0007131
- C2674727
- C0677865
- C0006826
- C0152013
- C0009375
- C1336078
- C0009404
- C0699790
- C1168401
Omim: PS115150, 114500, 606764, 167000, 108010, 254500, 275355
Orphanet: 654, 2415, 360, 1340, 44890, 146, 46724, 29073, 85443, 67037
Trait:
- Melanoma
- Neoplasm
- Nephroblastoma
- not_provided
- Vascular_malformation
- Lymphangioma
- Glioblastoma
- Cardio-facio-cutaneous_syndrome
- Colorectal_cancer
- Neoplasm_of_brain
- Nongerminomatous_germ_cell_tumor
- Gastrointestinal_stromal_tumor
- Papillary_thyroid_carcinoma
- Malignant_melanoma_of_skin
- Lung_carcinoma
- Neoplasm_of_ovary
- Cerebral_arteriovenous_malformation
- Multiple_myeloma
- Non-small_cell_lung_carcinoma
- Astrocytoma,_low-grade,_somatic
- Brainstem_glioma
- Malignant_neoplastic_disease
- Lung_adenocarcinoma
- Cystic_epithelial_invagination_containing_papillae_lined_by_columnar_epithelium
- Colonic_neoplasm
- Papillary_renal_cell_carcinoma,_sporadic
- Neoplasm_of_the_large_intestine
- Carcinoma_of_colon
- Squamous_cell_carcinoma_of_the_head_and_neck
- Vemurafenib-Cobimetinib_Response
- Trametinib-Dabrafenib_Response
Var Source:
- ClinGen:CA123643
- Genetic_Testing_Registry_(GTR):GTR000522729
- Genetic_Testing_Registry_(GTR):GTR000575664
- Genetic_Testing_Registry_(GTR):GTR000575672
- Genetic_Testing_Registry_(GTR):GTR000575677
- OMIM:164757.0001
- UniProtKB:P15056#VAR_018629
### Dann
Rankscore: 0.42049
Score: 0.9848685552251786
### Deogen2
Pred: D
Rankscore: 0.95953
Score: 0.830668
### Eigen
Phred Coding: 4.637965
Raw Coding: 0.445381171133835
Raw Coding Rankscore: 0.63941
### Eigen-pc
Phred Coding: 5.634784
Raw Coding: 0.548689949287972
Raw Coding Rankscore: 0.71304
### Ensembl
Geneid: ENSG00000157764
Proteinid:
- ENSP00000419060
- ENSP00000496776
- ENSP00000493543
- ENSP00000288602
Transcriptid:
- ENST00000496384
- ENST00000644969
- ENST00000646891
- ENST00000288602
### Esm1b
Pred: D
Rankscore: 0.97691
Score: -15.954
### Eve
Class10 Pred: U
Class20 Pred: U
Class25 Pred: U
Class30 Pred: U
Class40 Pred: U
Class50 Pred: U
Class60 Pred: U
Class70 Pred: U
Class75 Pred: P
Class80 Pred: P
Class90 Pred: P
Rankscore: 0.71581
Score: 0.6445960741367582
### Exac
Ac: 2
Adj Ac: 2
Adj Af: 1.65e-05
Af: 1.647e-05
#### Afr
Ac: 0
Af: 0.0
#### Amr
Ac: 1
Af: 8.715e-05
#### Eas
Ac: 0
Af: 0.0
#### Fin
Ac: 0
Af: 0.0
#### Nfe
Ac: 0
Af: 0.0
#### Sas
Ac: 1
Af: 6.06e-05
### Exac Nonpsych
Ac: 2
Adj Ac: 2
Adj Af: 2.208e-05
Af: 2.204e-05
#### Afr
Ac: 0
Af: 0.0
#### Amr
Ac: 1
Af: 8.724e-05
#### Eas
Ac: 0
Af: 0.0
#### Fin
Ac: 0
Af: 0.0
#### Nfe
Ac: 0
Af: 0.0
#### Sas
Ac: 1
Af: 6.064e-05
### Exac Nontcga
Ac: 2
Adj Ac: 2
Adj Af: 1.886e-05
Af: 1.883e-05
#### Afr
Ac: 0
Af: 0.0
#### Amr
Ac: 1
Af: 8.998e-05
#### Eas
Ac: 0
Af: 0.0
#### Fin
Ac: 0
Af: 0.0
#### Nfe
Ac: 0
Af: 0.0
#### Sas
Ac: 1
Af: 6.098e-05
### Fathmm-mkl
Coding Group: AEFI
Coding Pred: D
Coding Rankscore: 0.83898
Coding Score: 0.98542
### Fathmm-xf
Coding Pred: D
Coding Rankscore: 0.87678
Coding Score: 0.914006
### Fitcons
#### Gm12878
Confidence Value: 0
Rankscore: 0.7944
Score: 0.708844
#### H1-hesc
Confidence Value: 0
Rankscore: 0.34648
Score: 0.602189
#### Huvec
Confidence Value: 0
Rankscore: 0.65921
Score: 0.6691
#### Integrated
Confidence Value: 0
Rankscore: 0.46895
Score: 0.6512
### Genocanyon
Rankscore: 0.74766
Score: 0.999999994558225
### Gerp++
Nr: 5.65
Rs: 5.65
Rs Rankscore: 0.86881
### Gmvp
Rankscore: 0.95276
Score: 0.9529287864278634
### Hg18
End: 140099605
Start: 140099605
### Hg19
End: 140453136
Start: 140453136
### Hg38
End: 140753336
Start: 140753336
### Interpro
Domain:
- Serine-threonine/tyrosine-protein kinase, catalytic domain|Protein kinase domain|Protein kinase domain
### List-s2
Rankscore: 0.29288
Pred: T
Score: 0.684632, 0.684232
### Lrt
Converted Rankscore: 0.8433
Omega: 0.0
Pred: D
Score: 0.0
### M-cap
Pred: D
Rankscore: 0.84885
Score: 0.171639
### Metalr
Pred: T
Rankscore: 0.6027
Score: 0.2357
### Metarnn
Rankscore: 0.87655
Pred: D
Score: 0.88336486
### Metasvm
Pred: T
Rankscore: 0.5694
Score: -0.7685
### Mpc
Rankscore: 0.98012
Score: 2.57041727597
### Mutationassessor
Pred: N
Rankscore: 0.16133
Score: 0.65
### Mutationtaster
Aae: V600E
Converted Rankscore: 0.81001
Model: simple_aae
Pred: D
Score: 1.0
### Mutformer
Rankscore: 0.99257
Score: 0.99925762
### Mutpred
Rankscore: 0.84872
Aa Change: V600E
Accession: P15056
#### Pred
Mechanism: Gain of disorder
P Val: 0.0057
Score: 0.713
### Mvp
Rankscore: 0.9862
Score: 0.986356512902
### Phactboost
Rankscore: 0.98361
Score: 0.999853239760113
### Phastcons
#### 100way Vertebrate
Rankscore: 0.71638
Score: 1.0
#### 17way Primate
Rankscore: 0.91618
Score: 0.999
#### 470way Mammalian
Rankscore: 0.68203
Score: 1.0
### Phylop
#### 100way Vertebrate
Rankscore: 0.94474
Score: 9.236
#### 17way Primate
Rankscore: 0.87069
Score: 0.75
#### 470way Mammalian
Rankscore: 0.89583
Score: 11.216
### Polyphen2
#### Hdiv
Pred: D
Rankscore: 0.57185
Score: 0.971
#### Hvar
Pred: D
Rankscore: 0.67921
Score: 0.943
### Primateai
Pred: D
Rankscore: 0.9559
Score: 0.892686009407
### Revel
Rankscore: 0.98378
Score: 0.931
### Siphy 29way
Logodds Rankscore: 0.79463
Logodds Score: 15.9326
#### Pi
A: 1.0
C: 0.0
G: 0.0
T: 0.0
### Varity
#### Er
Rankscore: 0.98206
Score: 0.94685084
#### Er Loo
Rankscore: 0.98903
Score: 0.9587261
#### R
Rankscore: 0.97515
Score: 0.9623422
#### R Loo
Rankscore: 0.97053
Score: 0.9577461
Appris: alternative2, principal2
Gencode Basic: Y
Genename: BRAF
Hgvsc: c.620T>A, c.1919T>A, c.1799T>A
Hgvsp: p.Val640Glu, p.Val207Glu, p.Val600Glu, p.V600E
Tsl: 5, 1
### Uniprot
Acc: H7C560
Entry: H7C560_HUMAN
### Uniprot
Acc: A0A2R8Y8E0
Entry: A0A2R8Y8E0_HUMAN
### Uniprot
Acc: P15056
Entry: BRAF_HUMAN
### Uniprot
Acc: A0A2U3TZI2
Entry: A0A2U3TZI2_HUMAN
## Dbsnp
License: http://bit.ly/2AqoLOc
Alt: T
Chrom: 7
Dbsnp Build: 156
Ref: A
Rsid: rs113488022
Vartype: snv
### Gene
Geneid: 673
Is Pseudo: False
Name: B-Raf proto-oncogene, serine/threonine kinase
Strand: -
Symbol: BRAF
#### Rnas
Hgvs: NM_001354609.2:c.1799=
Refseq: NM_001354609.2
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 2023
Seq Id: NM_001354609.2
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 599
Seq Id: NP_001341538.1
##### Protein Product
Refseq: NP_001341538.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: NM_001374244.1:c.1919=
Refseq: NM_001374244.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 2143
Seq Id: NM_001374244.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 639
Seq Id: NP_001361173.1
##### Protein Product
Refseq: NP_001361173.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: NM_001374258.1:c.1919=
Refseq: NM_001374258.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 2143
Seq Id: NM_001374258.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 639
Seq Id: NP_001361187.1
##### Protein Product
Refseq: NP_001361187.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: NM_001378467.1:c.1808=
Refseq: NM_001378467.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 2032
Seq Id: NM_001378467.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 602
Seq Id: NP_001365396.1
##### Protein Product
Refseq: NP_001365396.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: NM_001378468.1:c.1799=
Refseq: NM_001378468.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 2023
Seq Id: NM_001378468.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 599
Seq Id: NP_001365397.1
##### Protein Product
Refseq: NP_001365397.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: NM_001378469.1:c.1733=
Refseq: NM_001378469.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 1957
Seq Id: NM_001378469.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 577
Seq Id: NP_001365398.1
##### Protein Product
Refseq: NP_001365398.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: NM_001378470.1:c.1697=
Refseq: NM_001378470.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 1921
Seq Id: NM_001378470.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 565
Seq Id: NP_001365399.1
##### Protein Product
Refseq: NP_001365399.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: NM_001378471.1:c.1688=
Refseq: NM_001378471.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 1912
Seq Id: NM_001378471.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 562
Seq Id: NP_001365400.1
##### Protein Product
Refseq: NP_001365400.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: NM_001378472.1:c.1643=
Refseq: NM_001378472.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 1742
Seq Id: NM_001378472.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 547
Seq Id: NP_001365401.1
##### Protein Product
Refseq: NP_001365401.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: NM_001378473.1:c.1643=
Refseq: NM_001378473.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 1742
Seq Id: NM_001378473.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 547
Seq Id: NP_001365402.1
##### Protein Product
Refseq: NP_001365402.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: NM_001378474.1:c.1799=
Refseq: NM_001378474.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 2023
Seq Id: NM_001378474.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 599
Seq Id: NP_001365403.1
##### Protein Product
Refseq: NP_001365403.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: NM_001378475.1:c.1535=
Refseq: NM_001378475.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 1759
Seq Id: NM_001378475.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 511
Seq Id: NP_001365404.1
##### Protein Product
Refseq: NP_001365404.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: NM_004333.6:c.1799=
Refseq: NM_004333.6
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 2023
Seq Id: NM_004333.6
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 599
Seq Id: NP_004324.2
##### Protein Product
Refseq: NP_004324.2
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: XM_017012559.2:c.1919=
Refseq: XM_017012559.2
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 2143
Seq Id: XM_017012559.2
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 639
Seq Id: XP_016868048.1
##### Protein Product
Refseq: XP_016868048.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: XM_047420766.1:c.1763=
Refseq: XM_047420766.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 1862
Seq Id: XM_047420766.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 587
Seq Id: XP_047276722.1
##### Protein Product
Refseq: XP_047276722.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: XM_047420767.1:c.1919=
Refseq: XM_047420767.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 2143
Seq Id: XM_047420767.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 639
Seq Id: XP_047276723.1
##### Protein Product
Refseq: XP_047276723.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
#### Rnas
Hgvs: XM_047420768.1:c.1815-3918=
Refseq: XM_047420768.1
##### Protein Product
Refseq: XP_047276724.1
##### So
Accession: SO:0001627
Name: intron_variant
#### Rnas
Hgvs: XM_047420769.1:c.1695-3918=
Refseq: XM_047420769.1
##### Protein Product
Refseq: XP_047276725.1
##### So
Accession: SO:0001627
Name: intron_variant
#### Rnas
Hgvs: XM_047420770.1:c.1085=
Refseq: XM_047420770.1
##### Codon Aligned Transcript Change
Deleted Sequence: GTG
Inserted Sequence: GTG
Position: 1481
Seq Id: XM_047420770.1
##### Protein
##### Variant
##### Spdi
Deleted Sequence: V
Inserted Sequence: V
Position: 361
Seq Id: XP_047276726.1
##### Protein Product
Refseq: XP_047276726.1
##### So
Accession: SO:0001580
Name: coding_sequence_variant
### Hg19
End: 140453136
Start: 140453136
### Alleles
Allele: A
#### Freq
Exac: 1.0
Gnomad Exomes: 1.0
### Alleles
Allele: T
#### Freq
Exac: 0.0
Gnomad Exomes: 0.0
Citations:
- 12068308
- 12460918
- 12460919
- 12960123
- 14679157
- 15035987
- 19001320
- 19010912
- 19018267
- 19238210
- 19404918
- 19537845
- 19561230
- 20350999
- 20413299
- 20619739
- 20630094
- 20735442
- 20818844
- 21129611
- 21156289
- 21163703
- 21426297
- 21483012
- 21639808
- 21683865
- 21975775
- 22038996
- 22048237
- 22180495
- 22281684
- 22351686
- 22356324
- 22389471
- 22448344
- 22536370
- 22586120
- 22608338
- 22649091
- 22663011
- 22735384
- 22743296
- 22773810
- 22805292
- 22972589
- 22997239
- 23020132
- 23031422
- 23251002
- 23325582
- 23470635
- 23524406
- 23549875
- 23614898
- 23757202
- 23812671
- 23833300
- 23845441
- 23918947
- 24107445
- 24163374
- 24388723
- 24576830
- 24583796
- 24586605
- 24594804
- 25024077
- 25157968
- 25370471
- 25989278
- 26619011
- 26678033
## Docm
Aa Change: p.V600E
All Domains:
pfam_Ser-Thr/Tyr_kinase_cat_dom,pfam_Prot_kinase_dom,pfam_Raf-like_ras-
bd,pfam_Prot_Kinase_C-like_PE/DAG-bd,superfamily_Kinase-
like_dom,smart_Raf-like_ras-bd,smart_Prot_Kinase_C-like_PE/DAG-
bd,smart_Ser/Thr_dual-sp_kinase_dom,smart_Tyr_kinase_cat_dom,pfscan_Raf-
like_ras-bd,pfscan_Prot_Kinase_C-like_PE/DAG-
bd,pfscan_Prot_kinase_dom,prints_Ser-
Thr/Tyr_kinase_cat_dom,prints_DAG/PE-bd
Alt: T
C Position: c.1799
Chrom: 7
Default Gene Name: BRAF
Deletion Substructures: -
Disease: Thyroid Cancer
Doid: DOID:1781
Domain:
pfam_Ser-Thr/Tyr_kinase_cat_dom,pfam_Prot_kinase_dom,superfamily_Kinase-
like_dom,smart_Ser/Thr_dual-
sp_kinase_dom,smart_Tyr_kinase_cat_dom,pfscan_Prot_kinase_dom
Ensembl Gene Id: ENSG00000157764
Genename: BRAF
Genename Source: HGNC
Primary: 1
Pubmed Id:
20818844, 19255327, 19773371, 12068308, 18541894, 19255327, 20368568,
19773371
Ref: A
Source: MyCancerGenome
Strand: -1
Transcript Error: no_errors
Transcript Name: ENST00000288602
Transcript Source: ensembl
Transcript Species: human
Transcript Status: known
Transcript Version: 74_37
Trv Type: missense
Type: SNP
Ucsc Cons: 1
Url: http://www.mycancergenome.org/content/disease/thyroid-cancer/braf/54
### Hg19
End: 140453136
Start: 140453136
## Emv
License: http://bit.ly/2RieoY1
Egl Classification: Pathogenic
Egl Classification Date: 10/08/2013
Egl Protein: p.Val600Glu | p.V600E
Egl Variant: NM_004333.4:c.1799T>A
Exon: Ex15
Gene: BRAF
Variant Id: 15358
Hgvs:
- LRG_299t1:c.1799T>A
- NM_004333.4:c.1799T>A
- XM_005250045.1:c.1799T>A
- XM_005250046.1:c.1799T>A
- XM_005250047.1:c.1799T>A
## Exac
License: http://bit.ly/2H9c4hg
Af: 1.647e-05
Alleles: T
Alt: T
Baseqranksum: 1.1
Chrom: 7
Clippingranksum: -0.323
Culprit: FS
Fs: 0.0
Inbreedingcoeff: 0.0343
Ncc: 11
Pos: 140453136
Qd: 12.29
Readposranksum: 0.358
Ref: A
Type: snp
Vqslod: 4.08
### Ac
Ac: 2
Ac Adj: 2
Ac Afr: 0
Ac Amr: 1
Ac Eas: 0
Ac Female: 0
Ac Fin: 0
Ac Het: 2
Ac Hom: 0
Ac Male: 2
Ac Nfe: 0
Ac Oth: 0
Ac Sas: 1
### An
An: 121410
An Adj: 121220
An Afr: 10396
An Amr: 11474
An Eas: 8644
An Female: 54032
An Fin: 6610
An Male: 67188
An Nfe: 66688
An Oth: 906
An Sas: 16502
### Het
Het Afr: 0
Het Amr: 1
Het Eas: 0
Het Fin: 0
Het Nfe: 0
Het Oth: 0
Het Sas: 1
### Hom
Hom Afr: 0
Hom Amr: 0
Hom Eas: 0
Hom Fin: 0
Hom Nfe: 0
Hom Oth: 0
Hom Sas: 0
### Mq
Mq: 59.5
Mq0: 0
Mqranksum: -0.129
## Exac Nontcga
License: http://bit.ly/2H9c4hg
Af: 1.883e-05
Alleles: T
Alt: T
Baseqranksum: 1.1
Chrom: 7
Clippingranksum: -0.323
Culprit: FS
Fs: 0.0
Inbreedingcoeff: 0.0343
Ncc: 11
Pos: 140453136
Qd: 12.29
Readposranksum: 0.358
Ref: A
Type: snp
Vqslod: 4.08
### Ac
Ac: 2
Ac Adj: 2
Ac Afr: 0
Ac Amr: 1
Ac Eas: 0
Ac Female: 0
Ac Fin: 0
Ac Het: 2
Ac Hom: 0
Ac Male: 2
Ac Nfe: 0
Ac Oth: 0
Ac Sas: 1
### An
An: 106208
An Adj: 106034
An Afr: 9058
An Amr: 11114
An Eas: 7860
An Female: 45794
An Fin: 6610
An Male: 60240
An Nfe: 54302
An Oth: 692
An Sas: 16398
### Het
Het Afr: 0
Het Amr: 1
Het Eas: 0
Het Fin: 0
Het Nfe: 0
Het Oth: 0
Het Sas: 1
### Hom
Hom Afr: 0
Hom Amr: 0
Hom Eas: 0
Hom Fin: 0
Hom Nfe: 0
Hom Oth: 0
Hom Sas: 0
### Mq
Mq: 59.5
Mq0: 0
Mqranksum: -0.129
## Gnomad Exome
License: http://bit.ly/2I1cl1I
Alleles: T
Alt: T
Baseqranksum: 1.11
Chrom: 7
Clippingranksum: 0.007
Dp: 10269946
Fs: 0.0
Inbreedingcoeff: 0.06
Pab Max: 0.916129
Pos: 140453136
Qd: 14.92
Readposranksum: 0.421
Ref: A
Rf: 0.906237
Rsid: rs113488022
Sor: 0.739
Type: snp
Vqslod: 5.48
Vqsr Culprit: FS
### Ac
Ac: 1
Ac Afr: 0
Ac Afr Female: 0
Ac Afr Male: 0
Ac Amr: 0
Ac Amr Female: 0
Ac Amr Male: 0
Ac Asj: 0
Ac Asj Female: 0
Ac Asj Male: 0
Ac Eas: 0
Ac Eas Female: 0
Ac Eas Jpn: 0
Ac Eas Kor: 0
Ac Eas Male: 0
Ac Eas Oea: 0
Ac Female: 0
Ac Fin: 0
Ac Fin Female: 0
Ac Fin Male: 0
Ac Male: 1
Ac Nfe: 0
Ac Nfe Bgr: 0
Ac Nfe Est: 0
Ac Nfe Female: 0
Ac Nfe Male: 0
Ac Nfe Nwe: 0
Ac Nfe Onf: 0
Ac Nfe Seu: 0
Ac Nfe Swe: 0
Ac Oth: 0
Ac Oth Female: 0
Ac Oth Male: 0
Ac Sas: 1
Ac Sas Female: 0
Ac Sas Male: 1
### Af
Af: 3.97994e-06
Af Afr: 0.0
Af Afr Female: 0.0
Af Afr Male: 0.0
Af Amr: 0.0
Af Amr Female: 0.0
Af Amr Male: 0.0
Af Asj: 0.0
Af Asj Female: 0.0
Af Asj Male: 0.0
Af Eas: 0.0
Af Eas Female: 0.0
Af Eas Jpn: 0.0
Af Eas Kor: 0.0
Af Eas Male: 0.0
Af Eas Oea: 0.0
Af Female: 0.0
Af Fin: 0.0
Af Fin Female: 0.0
Af Fin Male: 0.0
Af Male: 7.3642e-06
Af Nfe: 0.0
Af Nfe Bgr: 0.0
Af Nfe Est: 0.0
Af Nfe Female: 0.0
Af Nfe Male: 0.0
Af Nfe Nwe: 0.0
Af Nfe Onf: 0.0
Af Nfe Seu: 0.0
Af Nfe Swe: 0.0
Af Oth: 0.0
Af Oth Female: 0.0
Af Oth Male: 0.0
Af Sas: 3.26669e-05
Af Sas Female: 0.0
Af Sas Male: 4.33501e-05
### An
An: 251260
An Afr: 16252
An Afr Female: 10070
An Afr Male: 6182
An Amr: 34528
An Amr Female: 20246
An Amr Male: 14282
An Asj: 10076
An Asj Female: 4900
An Asj Male: 5176
An Eas: 18392
An Eas Female: 9326
An Eas Jpn: 152
An Eas Kor: 3816
An Eas Male: 9066
An Eas Oea: 14424
An Female: 115468
An Fin: 21638
An Fin Female: 10364
An Fin Male: 11274
An Male: 135792
An Nfe: 113638
An Nfe Bgr: 2668
An Nfe Est: 240
An Nfe Female: 50102
An Nfe Male: 63536
An Nfe Nwe: 42154
An Nfe Onf: 30954
An Nfe Seu: 11496
An Nfe Swe: 26126
An Oth: 6124
An Oth Female: 2916
An Oth Male: 3208
An Sas: 30612
An Sas Female: 7544
An Sas Male: 23068
### Hom
Hom: 0
Hom Afr: 0
Hom Afr Female: 0
Hom Afr Male: 0
Hom Amr: 0
Hom Amr Female: 0
Hom Amr Male: 0
Hom Asj: 0
Hom Asj Female: 0
Hom Asj Male: 0
Hom Eas: 0
Hom Eas Female: 0
Hom Eas Jpn: 0
Hom Eas Kor: 0
Hom Eas Male: 0
Hom Eas Oea: 0
Hom Female: 0
Hom Fin: 0
Hom Fin Female: 0
Hom Fin Male: 0
Hom Male: 0
Hom Nfe: 0
Hom Nfe Bgr: 0
Hom Nfe Est: 0
Hom Nfe Female: 0
Hom Nfe Male: 0
Hom Nfe Nwe: 0
Hom Nfe Onf: 0
Hom Nfe Seu: 0
Hom Nfe Swe: 0
Hom Oth: 0
Hom Oth Female: 0
Hom Oth Male: 0
Hom Sas: 0
Hom Sas Female: 0
Hom Sas Male: 0
### Mq
Mq: 59.48
Mqranksum: 0.263
## Hg19
End: 140453136
Start: 140453136
## Mutdb
License: http://bit.ly/2SQ6fXA
Alt: A
Chrom: 7
Cosmic Id: 476, 1131
Mutpred Score: 0.705
Ref: T
Rsid: rs113488022
Strand: m
Uniprot Id: VAR_018629
### Hg19
End: 140453136
Start: 140453136
## Snpeff
License: http://bit.ly/2suyRKt
### Ann
Effect: missense_variant
Feature Id: NM_004333.4
Feature Type: transcript
Gene Id: BRAF
Genename: BRAF
Hgvs C: c.1799T>A
Hgvs P: p.Val600Glu
Putative Impact: MODERATE
Rank: 15
Total: 18
Transcript Biotype: protein_coding
#### Cdna
Length: 2946
Position: 1860
#### Cds
Length: 2301
Position: 1799
#### Protein
Length: 766
Position: 600
## Vcf
Alt: T
Position: 140453136
Ref: A
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: PLX4720 (BRAF inhibitor)
Evidence Level: Pre-clinical
Gene: BRAF
Primary Tumor Type: Malignant astrocytoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMC3638050
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: BRAF inhibitor + MEK inhibitors
Evidence Level: Early trials
Gene: BRAF
Primary Tumor Type: Thyroid
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: ASCO 2013 (abstr 9029)
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Pan-RAF inhibitors
Evidence Level: Early trials
Gene: BRAF
Primary Tumor Type: Cutaneous melanoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source:
ESMO 2015 (abstract 300);AACR 2016 (abstr CT005);AACR 2017 (abstr CT002)
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: BRAF inhibitors
Evidence Level: Case report
Gene: BRAF
Primary Tumor Type: Ovary
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:22608338
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Resistant
Cdna: c.1799T>A
Drug: EGFR TK inhibitors
Evidence Level: Case report
Gene: BRAF
Primary Tumor Type: Lung adenocarcinoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:22773810
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Trametinib (MEK inhibitor)
Evidence Level: FDA guidelines
Gene: BRAF
Primary Tumor Type: Cutaneous melanoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: FDA
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: BRAF inhibitors
Evidence Level: Pre-clinical
Gene: BRAF
Primary Tumor Type: Glioma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:22038996;PMID:22586120
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Vemurafenib + Cobimetinib (BRAF inhibitor + MEK inhibitor)
Evidence Level: FDA guidelines
Gene: BRAF
Primary Tumor Type: Cutaneous melanoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: FDA
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: BRAF inhibitor + PI3K pathway inhibitors
Evidence Level: Pre-clinical
Gene: BRAF
Primary Tumor Type: Cutaneous melanoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:22389471;PMID:21156289
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Resistant
Cdna: c.1799T>A
Drug: Cetuximab (EGFR mAb inhibitor)
Evidence Level: Late trials
Gene: BRAF
Primary Tumor Type: Colorectal adenocarcinoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:20619739;PMID:21163703;PMID:23325582
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: ERK inhibitors
Evidence Level: Pre-clinical
Gene: BRAF
Primary Tumor Type: Cutaneous melanoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:23614898;PMID:22997239
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: MEK inhibitors
Evidence Level: Early trials
Gene: BRAF
Primary Tumor Type: Thyroid
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:22241789
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Vemurafenib (BRAF inhibitor)
Evidence Level: Early trials
Gene: BRAF
Primary Tumor Type: Thyroid carcinoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:22608338;PMID:20818844;PMID:23489023
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Vemurafenib (BRAF inhibitor)
Evidence Level: Early trials
Gene: BRAF
Primary Tumor Type: Malignant astrocytoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:22586120
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Resistant
Cdna: c.1799T>A
Drug: Panitumumab (EGFR mAb inhibitor)
Evidence Level: Late trials
Gene: BRAF
Primary Tumor Type: Colorectal adenocarcinoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:20619739;PMID:21163703;PMID:23325582
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Dabrafenib (BRAF inhibitor)
Evidence Level: Case report
Gene: BRAF
Primary Tumor Type: Gastrointestinal stromal
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:23470635;PMID:22608338
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Vemurafenib (BRAF inhibitor)
Evidence Level: NCCN guidelines
Gene: BRAF
Primary Tumor Type:
Non-small cell lung;Lagerhans cell histiocytosis;Erdheim-Chester
histiocytosis
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:26287849
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Dabrafenib + Trametinib (BRAF inhibitor + MEK inhibitor)
Evidence Level: FDA guidelines
Gene: BRAF
Primary Tumor Type: Cutaneous melanoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: FDA
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: ERK inhibitors
Evidence Level: Early trials
Gene: BRAF
Primary Tumor Type: Lung adenocarcinoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: ASCO 2017 (abstr 2508)
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Dabrafenib (BRAF inhibitor)
Evidence Level: Early trials
Gene: BRAF
Primary Tumor Type: Lung adenocarcinoma;Thyroid
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source:
PMID:23524406;PMID:22608338;ASCO 2013 (abstr 8009);ESMO 2014 (abstr
LBA38_PR);PMID:20818844;PMID:23489023;PMID:27080216
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: BRAF inhibitor + CDK2/4 inhibitors
Evidence Level: Pre-clinical
Gene: BRAF
Primary Tumor Type: Cutaneous melanoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:22997239
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Vemurafenib (BRAF inhibitor)
Evidence Level: FDA guidelines
Gene: BRAF
Primary Tumor Type: Cutaneous melanoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: FDA
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Dabrafenib (BRAF inhibitor)
Evidence Level: NCCN guidelines
Gene: BRAF
Primary Tumor Type: Non-small cell lung
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: NCCN
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Dabrafenib + Trametinib (BRAF inhibitor + MEK inhibitor)
Evidence Level: Early trials
Gene: BRAF
Primary Tumor Type: Colorectal adenocarcinoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:26392102;ASCO 2015 (abstr 8006)
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Selumetinib (MEK inhibitor)
Evidence Level: Early trials
Gene: BRAF
Primary Tumor Type: Pediatric glioma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: NCT01089101
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Dabrafenib + Trametinib (BRAF inhibitor + MEK inhibitor)
Evidence Level: Case report
Gene: BRAF
Primary Tumor Type: Neuroendocrine
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:27048246
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Dabrafenib + Trametinib (BRAF inhibitor + MEK inhibitor)
Evidence Level: FDA guidelines
Gene: BRAF
Primary Tumor Type: Lung adenocarcinoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:27283860
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: MEK inhibitors
Evidence Level: Pre-clinical
Gene: BRAF
Primary Tumor Type: Ovary
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:19018267
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: BRAF inhibitor + HSP90 inhibitors
Evidence Level: Pre-clinical
Gene: BRAF
Primary Tumor Type: Cutaneous melanoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:22351686
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Dabrafenib (BRAF inhibitor)
Evidence Level: FDA guidelines
Gene: BRAF
Primary Tumor Type: Cutaneous melanoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: FDA
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug:
Panitumumab + Dabrafenib + Trametinib (EGFR mAb inhibitor + BRAF
inhibitor + MEK inhibitor)
Evidence Level: Early trials
Gene: BRAF
Primary Tumor Type: Colorectal adenocarcinoma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: ASCO 2014 (abstr 3515);ASCO 2015 (abstr 103)
Transcript: ENST00000288602
## Cgi
License: http://bit.ly/2FqS871
Association: Responsive
Cdna: c.1799T>A
Drug: Vemurafenib (BRAF inhibitor)
Evidence Level: Case report
Gene: BRAF
Primary Tumor Type: Lung adenocarcinoma;Hairy-Cell leukemia;Myeloma
Protein Change: BRAF:V600E
Region: inside_[cds_in_exon_15]
Source: PMID:22743296;PMID:22621641;PMID:23612012
Transcript: ENST00000288602
```