BRAF V600E-mutant colorectal cancer is a molecularly defined subtype representing approximately 8-12% of all colorectal cancers. The V600E mutation causes constitutive activation of BRAF kinase, driving the MAPK signaling pathway independent of upstream RAS signaling. This subtype has historically been associated with poor prognosis, chemotherapy resistance, and limited treatment options. The combination of encorafenib (BRAF inhibitor) and cetuximab (anti-EGFR) has transformed outcomes for these patients by addressing the feedback reactivation that limits single-agent BRAF inhibitor efficacy seen in melanoma. BRAF V600E CRC frequently arises through the serrated neoplasia pathway with CIMP-high methylation, MLH1 promoter silencing, and an MSI-H branch that has distinct immunotherapy implications.
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name: BRAF V600E-Mutant Colorectal Cancer
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-05-11T02:45:15Z'
description: >-
BRAF V600E-mutant colorectal cancer is a molecularly defined subtype representing
approximately
8-12% of all colorectal cancers. The V600E mutation causes constitutive activation
of BRAF
kinase, driving the MAPK signaling pathway independent of upstream RAS signaling.
This subtype
has historically been associated with poor prognosis, chemotherapy resistance, and
limited
treatment options. The combination of encorafenib (BRAF inhibitor) and cetuximab
(anti-EGFR)
has transformed outcomes for these patients by addressing the feedback reactivation
that
limits single-agent BRAF inhibitor efficacy seen in melanoma. BRAF V600E CRC
frequently arises through the serrated neoplasia pathway with CIMP-high methylation,
MLH1 promoter silencing, and an MSI-H branch that has distinct immunotherapy
implications.
categories:
- Gastrointestinal Cancer
- Colorectal Cancer
- Molecularly Defined Cancer
parents:
- colorectal adenocarcinoma
external_assertions:
- name: CIViC BRAF V600E colorectal cancer poor outcome assertion
source: CIViC
assertion_type: accepted_assertion
external_id: CIVIC_ASSERTION:20
url: https://civicdb.org/links/assertions/20
description: >-
CIViC accepted assertion that BRAF V600E in colorectal cancer indicates
poor prognosis.
notes: >-
01-May-2026 CIViC accepted assertion: molecular_profile="BRAF V600E";
disease="Colorectal Cancer"; assertion_type=Prognostic; significance=Poor Outcome;
AMP category=Tier I - Level A.
evidence:
- reference: CIVIC_ASSERTION:20
reference_title: "BRAF V600E / Colorectal Cancer (Prognostic Poor Outcome)"
supports: SUPPORT
evidence_source: OTHER
snippet: BRAF V600E indicates poor prognosis in advanced colorectal cancer
explanation: CIViC records an accepted prognostic poor-outcome assertion for BRAF V600E in colorectal cancer.
- name: CIViC BRAF V600E cetuximab resistance evidence item
source: CIViC
assertion_type: accepted_evidence_item
external_id: CIVIC_EID:126
url: https://civicdb.org/links/evidence_items/126
description: >-
CIViC accepted evidence item linking BRAF V600E colorectal cancer to
cetuximab resistance.
notes: >-
01-May-2026 CIViC accepted evidence item: molecular_profile="BRAF V600E";
disease="Colorectal Cancer"; evidence_type=Predictive; evidence_level=B;
significance=Resistance; therapy=Cetuximab; citation_id=PMID:20619739.
evidence:
- reference: CIVIC_EID:126
reference_title: "BRAF V600E / Colorectal Cancer (Predictive Resistance)"
supports: SUPPORT
evidence_source: OTHER
snippet: Authors concluded that BRAF mutation (23/24 of mutants were BRAF V600E) was strongly associated with poor response to cetuximab
explanation: CIViC records an accepted predictive resistance evidence item for BRAF V600E and cetuximab in colorectal cancer.
has_subtypes:
- name: MSI-H BRAF V600E CRC
description: >-
BRAF V600E mutation with concurrent microsatellite instability-high status, typically
from
MLH1 promoter hypermethylation. Better prognosis than MSS BRAF-mutant CRC, responds
to
immune checkpoint inhibitors.
- name: MSS BRAF V600E CRC
description: >-
BRAF V600E mutation with microsatellite stable (MSS) status. Represents the majority
of
BRAF-mutant CRC with aggressive behavior, poor response to chemotherapy, and need
for
targeted therapy approaches.
pathophysiology:
- name: BRAF V600E Constitutive Activation
description: >-
The V600E mutation substitutes glutamic acid for valine at position 600 in the
activation
segment of BRAF kinase. This mimics phosphorylation-induced activation, locking
BRAF in
an active conformation. The mutant kinase signals constitutively through MEK and
ERK
without upstream RAS activation.
evidence:
- reference: PMID:30739887
reference_title: "The prognostic value of KRAS and BRAF in stage I-III colorectal cancer. A systematic review."
supports: PARTIAL
snippet: BRAF mutations confers a poor prognosis in Western CRC patients, particularly in metastatic CRC (mCRC) and its mutations occur in approximately 4-20% CRC, with the vast majority being the V600E hotspot mutation.
explanation: This abstract links BRAF mutations in CRC to the V600E hotspot and supports the relevance of V600E in colorectal cancer.
- reference: CIVIC_ASSERTION:20
reference_title: "BRAF V600E / Colorectal Cancer (Prognostic Poor Outcome)"
supports: SUPPORT
evidence_source: OTHER
snippet: BRAF V600E indicates poor prognosis in advanced colorectal cancer
explanation: CIViC's accepted assertion supports BRAF V600E as a clinically meaningful colorectal cancer driver associated with poor outcome.
cell_types:
- preferred_term: colon epithelial cell
term:
id: CL:0011108
label: colon epithelial cell
biological_processes:
- preferred_term: MAPK cascade
modifier: INCREASED
term:
id: GO:0000165
label: MAPK cascade
downstream:
- target: Uncontrolled MAPK Pathway Signaling
description: Constitutive BRAF activation drives sustained MEK/ERK signaling
- target: Serrated Neoplasia and CIMP-High Progression
description: BRAF V600E initiates a serrated precursor pathway with epigenetic silencing
- name: Uncontrolled MAPK Pathway Signaling
description: >-
Constitutive BRAF V600E activation leads to continuous phosphorylation of MEK1/2,
which
phosphorylates ERK1/2. Activated ERK translocates to the nucleus and drives expression
of genes promoting cell proliferation, survival, and invasion. This signaling
is
independent of growth factor receptor activation.
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
- preferred_term: signal transduction
modifier: INCREASED
term:
id: GO:0007165
label: signal transduction
downstream:
- target: Enhanced Cell Proliferation
description: ERK activation drives cell cycle progression and proliferation
- target: EGFR Feedback Reactivation
description: ERK inhibition releases negative feedback on EGFR
- name: Enhanced Cell Proliferation
description: >-
Sustained ERK signaling promotes entry into the cell cycle by inducing cyclin
D1 and
other proliferative genes while suppressing cell cycle inhibitors. This drives
continuous
tumor cell division independent of external growth signals.
locations:
- preferred_term: colon
term:
id: UBERON:0001155
label: colon
- name: Serrated Neoplasia and CIMP-High Progression
description: >-
BRAF V600E-mutant CRC commonly develops through sessile serrated lesions rather
than the classic APC-driven adenoma-carcinoma sequence. Constitutive MAPK signaling
cooperates with widespread CpG island methylation to silence tumor suppressor
loci, creating a CIMP-high intermediate state that can progress through either
an MSI-H or MSS trajectory.
cell_types:
- preferred_term: colon epithelial cell
term:
id: CL:0011108
label: colon epithelial cell
downstream:
- target: MLH1 Silencing and MSI-H Branch
description: MLH1 promoter methylation creates mismatch-repair deficiency in the MSI-H subset
- name: MLH1 Silencing and MSI-H Branch
description: >-
In approximately half of BRAF V600E CRCs, CIMP-high methylation silences MLH1,
producing mismatch-repair deficiency and high microsatellite instability. This
branch is usually sporadic rather than Lynch syndrome-associated and creates
a more immunogenic tumor phenotype that can respond to immune checkpoint blockade.
biological_processes:
- preferred_term: mismatch repair
modifier: DECREASED
term:
id: GO:0006298
label: mismatch repair
- name: EGFR Feedback Reactivation
description: >-
Unlike melanoma, colorectal cancer cells have high EGFR expression. When BRAF
is inhibited,
relief of ERK-mediated negative feedback leads to rapid EGFR reactivation, which
signals
through RAS and CRAF to restore MAPK pathway activity. This explains why BRAF
inhibitor
monotherapy fails in colorectal cancer but works in melanoma.
biological_processes:
- preferred_term: ERBB signaling pathway
modifier: INCREASED
term:
id: GO:0038127
label: ERBB signaling pathway
notes: >-
This feedback mechanism necessitates combination therapy with EGFR inhibitors
(cetuximab)
to block the reactivation pathway.
- name: Acquired MAPK Reactivation
description: >-
Resistance to BRAF/EGFR-targeted therapy is often polyclonal and converges on
renewed MAPK signaling. Reported escape mechanisms include amplification of EGFR,
KRAS, or mutant BRAF, acquired KRAS or MAP2K1 mutations, and MET alterations;
baseline TP53 mutation has been associated with acquired MET amplification.
biological_processes:
- preferred_term: MAPK cascade
modifier: INCREASED
term:
id: GO:0000165
label: MAPK cascade
- preferred_term: response to xenobiotic stimulus
modifier: ABNORMAL
term:
id: GO:0009410
label: response to xenobiotic stimulus
histopathology:
- name: Adenocarcinoma
finding_term:
preferred_term: Adenocarcinoma
term:
id: NCIT:C2852
label: Adenocarcinoma
frequency: VERY_FREQUENT
description: Adenocarcinoma is the most common pathologic subtype of colon cancer.
evidence:
- reference: PMID:35613396
reference_title: "[Adenosquamous carcinoma of the colon: a case report and review of the literature]."
supports: SUPPORT
snippet: "Adenocarcinoma is the most common pathologic subtype of colon cancer"
explanation: Abstract reports adenocarcinoma as the most common pathologic subtype of colon cancer.
phenotypes:
- category: Gastrointestinal
name: Colon Cancer
frequency: VERY_FREQUENT
diagnostic: true
description: >-
BRAF V600E colorectal cancer shows strong predilection for the right colon (proximal
colon).
Tumors are often diagnosed at advanced stage with peritoneal and distant lymph
node
metastases.
phenotype_term:
preferred_term: Colon cancer
term:
id: HP:0003003
label: Colon cancer
- category: Gastrointestinal
name: Abdominal Pain
frequency: FREQUENT
description: >-
Abdominal discomfort from tumor mass effect, particularly with bulky right-sided
tumors.
phenotype_term:
preferred_term: Abdominal pain
term:
id: HP:0002027
label: Abdominal pain
- category: Hematologic
name: Anemia
frequency: FREQUENT
description: >-
Iron deficiency anemia from chronic occult blood loss is common, particularly
as right-sided
tumors may bleed without visible hematochezia.
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
- category: Constitutional
name: Weight Loss
frequency: FREQUENT
description: >-
Unintentional weight loss is common, reflecting the aggressive nature of BRAF-mutant
disease
and frequent presentation at advanced stage.
phenotype_term:
preferred_term: Weight loss
term:
id: HP:0001824
label: Weight loss
- category: Constitutional
name: Fatigue
frequency: FREQUENT
description: >-
Fatigue from anemia, advanced disease burden, or tumor-related cachexia.
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
biochemical:
- name: BRAF V600E Mutation Detection
notes: >-
BRAF V600E mutation is detected by PCR, immunohistochemistry (VE1 antibody), or
next-generation sequencing. Testing should be performed on all metastatic CRC
to guide
treatment selection.
- name: MSI/MMR Testing
notes: >-
All BRAF V600E tumors should be tested for MSI/MMR status as MSI-H BRAF-mutant
tumors
have better prognosis and respond to immunotherapy. MSS BRAF-mutant tumors require
targeted therapy approaches.
genetic:
- name: BRAF V600E
gene_term:
preferred_term: BRAF
term:
id: hgnc:1097
label: BRAF
association: Somatic Activating Mutation
notes: >-
The BRAF V600E mutation (c.1799T>A, p.V600E) accounts for more than 90% of BRAF
mutations
in colorectal cancer. It is mutually exclusive with RAS mutations. The mutation
results
in approximately 500-fold increased kinase activity compared to wild-type BRAF.
evidence:
- reference: PMID:32674932
reference_title: "[BRAF V600E-mutant colorectal cancers: Where are we?]."
supports: PARTIAL
snippet: "The BRAFV600E mutation, observed in 8ย % of colorectal cancers (CRC), introduces a particular phenotype and a poor prognosis at the localized or metastatic stage."
explanation: "Abstract reports BRAF V600E frequency and associated poor prognosis in colorectal cancer."
- reference: CIVIC_ASSERTION:20
reference_title: "BRAF V600E / Colorectal Cancer (Prognostic Poor Outcome)"
supports: SUPPORT
evidence_source: OTHER
snippet: BRAF V600E indicates poor prognosis in advanced colorectal cancer
explanation: CIViC's accepted assertion supports BRAF V600E as the prognostic genetic marker defining this CRC subtype.
- name: MLH1
gene_term:
preferred_term: MLH1
term:
id: hgnc:7127
label: MLH1
association: Promoter Hypermethylation in MSI-H Subtype
notes: >-
MLH1 promoter methylation is the common sporadic route to mismatch-repair
deficiency in the MSI-H subset of BRAF V600E CRC. BRAF V600E with MLH1
hypermethylation helps distinguish sporadic MSI-H CRC from Lynch syndrome.
- name: PIK3CA
gene_term:
preferred_term: PIK3CA
term:
id: hgnc:8975
label: PIK3CA
association: Co-occurring Somatic Mutations
notes: >-
PIK3CA mutations co-occur with BRAF V600E in approximately 20% of cases, potentially
conferring resistance to MAPK pathway inhibition through parallel PI3K pathway
activation.
- name: PTEN
gene_term:
preferred_term: PTEN
term:
id: hgnc:9588
label: PTEN
association: Co-occurring Loss of Function
notes: >-
PTEN loss may co-occur with BRAF V600E, activating the PI3K pathway and potentially
contributing to treatment resistance.
treatments:
- name: Encorafenib plus Cetuximab
description: >-
FDA-approved combination for BRAF V600E metastatic CRC after prior therapy. Encorafenib
inhibits mutant BRAF while cetuximab blocks EGFR to prevent feedback reactivation.
BEACON
CRC trial demonstrated significant improvement in overall survival and response
rate
compared to standard chemotherapy.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: encorafenib
term:
id: NCIT:C98283
label: Encorafenib
- preferred_term: cetuximab
term:
id: NCIT:C1723
label: Cetuximab
evidence:
- reference: CIVIC_EID:126
reference_title: "BRAF V600E / Colorectal Cancer (Predictive Resistance)"
supports: PARTIAL
evidence_source: OTHER
snippet: Authors concluded that BRAF mutation (23/24 of mutants were BRAF V600E) was strongly associated with poor response to cetuximab
explanation: CIViC's accepted evidence item supports BRAF V600E-associated resistance to cetuximab alone, motivating BRAF/EGFR combination strategies rather than anti-EGFR monotherapy.
- name: Encorafenib plus Cetuximab plus Binimetinib
description: >-
Triple combination adding the MEK inhibitor binimetinib to encorafenib and cetuximab.
Provides more complete MAPK pathway suppression. Originally studied in BEACON
CRC but
doublet (encorafenib/cetuximab) is preferred due to similar efficacy with less
toxicity.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: encorafenib
term:
id: NCIT:C98283
label: Encorafenib
- preferred_term: cetuximab
term:
id: NCIT:C1723
label: Cetuximab
- preferred_term: binimetinib
term:
id: CHEBI:145371
label: binimetinib
- name: FOLFOXIRI plus Bevacizumab
description: >-
Intensive triplet chemotherapy (5-FU, leucovorin, oxaliplatin, irinotecan) with
bevacizumab
may provide benefit for fit patients with BRAF V600E mCRC who can tolerate aggressive
therapy. TRIBE2 showed benefit in this subgroup.
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000647
label: chemotherapy
- name: Immune Checkpoint Inhibitors for MSI-H Disease
description: >-
Pembrolizumab or nivolumab-based immune checkpoint blockade is used for MSI-H/dMMR
BRAF V600E CRC. The MSI-H branch is more immunogenic because mismatch-repair
deficiency increases neoantigen load, though BRAF V600E still carries adverse
prognostic implications within MSI-H CRC.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
therapeutic_agent:
- preferred_term: pembrolizumab
term:
id: NCIT:C106432
label: Pembrolizumab
- preferred_term: nivolumab
term:
id: NCIT:C68814
label: Nivolumab
- name: Surgical Resection
description: >-
Surgery for localized disease or oligometastatic disease in selected patients.
Adjuvant
chemotherapy is standard for stage III disease, though BRAF-mutant tumors may
have
attenuated benefit.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
disease_term:
preferred_term: BRAF V600E-mutant colorectal cancer
term:
id: MONDO:0005575
label: colorectal cancer
classifications:
icdo_morphology:
classification_value: Adenocarcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
references:
- reference: DOI:10.1007/s00432-023-05141-y
title: Impact of encorafenib on survival of patients with BRAFV600E-mutant metastatic colorectal cancer in a real-world setting
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Patients with BRAF V600E -mutant metastatic colorectal cancer (mCRC) have a dismal prognosis.
supporting_text: Patients with BRAF V600E -mutant metastatic colorectal cancer (mCRC) have a dismal prognosis.
evidence:
- reference: DOI:10.1007/s00432-023-05141-y
reference_title: Impact of encorafenib on survival of patients with BRAFV600E-mutant metastatic colorectal cancer in a real-world setting
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Patients with BRAF V600E -mutant metastatic colorectal cancer (mCRC) have a dismal prognosis.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.1016/j.ebiom.2024.105010
title: 'Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: 'Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses'
supporting_text: 'Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses'
- reference: DOI:10.1038/s41416-024-02711-w
title: Efficacy-effectiveness analysis on survival in a population-based real-world study of BRAF-mutated metastatic colorectal cancer patients treated with encorafenib-cetuximab
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Efficacy-effectiveness analysis on survival in a population-based real-world study of BRAF-mutated metastatic colorectal cancer patients treated with encorafenib-cetuximab
supporting_text: Efficacy-effectiveness analysis on survival in a population-based real-world study of BRAF-mutated metastatic colorectal cancer patients treated with encorafenib-cetuximab
- reference: DOI:10.1038/s41467-024-53163-y
title: Integrative ensemble modelling of cetuximab sensitivity in colorectal cancer patient-derived xenografts
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Integrative ensemble modelling of cetuximab sensitivity in colorectal cancer patient-derived xenografts
supporting_text: Integrative ensemble modelling of cetuximab sensitivity in colorectal cancer patient-derived xenografts
- reference: DOI:10.1038/s41591-024-03235-9
title: Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phaseโ3 BEACON CRC trial
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phaseโ3 BEACON CRC trial
supporting_text: The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)ยฑbinimetinib (Bini) significantly improved overall survival (OS) versus Cetux + chemotherapy in previously treated patients with BRAF-V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union.
evidence:
- reference: DOI:10.1038/s41591-024-03235-9
reference_title: Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phaseโ3 BEACON CRC trial
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)ยฑbinimetinib (Bini) significantly improved overall survival (OS) versus Cetux + chemotherapy in previously treated patients with BRAF-V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.1038/s41591-024-03443-3
title: 'Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study.
supporting_text: Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study.
evidence:
- reference: DOI:10.1038/s41591-024-03443-3
reference_title: 'Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.1056/nejmoa1908075
title: Encorafenib, Binimetinib, and Cetuximab in <i>BRAF</i> V600EโMutated Colorectal Cancer
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Encorafenib, Binimetinib, and Cetuximab in <i>BRAF</i> V600EโMutated Colorectal Cancer
supporting_text: Encorafenib, Binimetinib, and Cetuximab in <i>BRAF</i> V600EโMutated Colorectal Cancer
- reference: DOI:10.1158/1078-0432.ccr-19-3809
title: Improvements in Clinical Outcomes for <i>BRAFV600E</i>-Mutant Metastatic Colorectal Cancer
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Although the last two decades have seen a broad improvement in overall survival, colorectal cancer is still the second leading cause of cancer deaths worldwide.
supporting_text: Although the last two decades have seen a broad improvement in overall survival, colorectal cancer is still the second leading cause of cancer deaths worldwide.
evidence:
- reference: DOI:10.1158/1078-0432.ccr-19-3809
reference_title: Improvements in Clinical Outcomes for <i>BRAFV600E</i>-Mutant Metastatic Colorectal Cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Although the last two decades have seen a broad improvement in overall survival, colorectal cancer is still the second leading cause of cancer deaths worldwide.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.1186/s12885-022-10420-x
title: 'A phase II study of daily encorafenib in combination with biweekly cetuximab in patients with BRAF V600E mutated metastatic colorectal cancer: the NEW BEACON study'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Patients with BRAF V600E mutated metastatic colorectal cancer (mCRC) have a poor prognosis.
supporting_text: Patients with BRAF V600E mutated metastatic colorectal cancer (mCRC) have a poor prognosis.
evidence:
- reference: DOI:10.1186/s12885-022-10420-x
reference_title: 'A phase II study of daily encorafenib in combination with biweekly cetuximab in patients with BRAF V600E mutated metastatic colorectal cancer: the NEW BEACON study'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Patients with BRAF V600E mutated metastatic colorectal cancer (mCRC) have a poor prognosis.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.1186/s12885-024-13171-z
title: 'Clinicopathologic features and treatment efficacy of patients with BRAF V600E-mutated metastatic colorectal cancer: a multi-center real-world propensity score matching study'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: 'Clinicopathologic features and treatment efficacy of patients with BRAF V600E-mutated metastatic colorectal cancer: a multi-center real-world propensity score matching study'
supporting_text: 'Clinicopathologic features and treatment efficacy of patients with BRAF V600E-mutated metastatic colorectal cancer: a multi-center real-world propensity score matching study'
- reference: DOI:10.1200/jco.18.02459
title: 'Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With <i>BRAF</i> V600EโMutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: 'Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With <i>BRAF</i> V600EโMutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study'
supporting_text: 'To determine the safety and preliminary efficacy of selective combination targeted therapy for BRAF V600Eโmutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial ( ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35).'
evidence:
- reference: DOI:10.1200/jco.18.02459
reference_title: 'Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With <i>BRAF</i> V600EโMutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'To determine the safety and preliminary efficacy of selective combination targeted therapy for BRAF V600Eโmutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial ( ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35).'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.1200/jco.20.02088
title: 'Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated <i>BRAF</i> V600EโMutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: 'Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated <i>BRAF</i> V600EโMutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study'
supporting_text: BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAFV600Eโmutant metastatic colorectal cancer (mCRC), after progression on 1-2 prior regimens.
evidence:
- reference: DOI:10.1200/jco.20.02088
reference_title: 'Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated <i>BRAF</i> V600EโMutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAFV600Eโmutant metastatic colorectal cancer (mCRC), after progression on 1-2 prior regimens.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.1200/jco.22.01693
title: 'ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated <i>BRAF</i><sup>V600E</sup>-Mutant Metastatic Colorectal Cancer'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: 'ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated <i>BRAF</i><sup>V600E</sup>-Mutant Metastatic Colorectal Cancer'
supporting_text: 'The positive BEACON colorectal cancer (CRC) safety lead-in, evaluating encorafenib + cetuximab + binimetinib in previously treated patients with BRAFV600E-mutated metastatic CRC (mCRC), prompted the design of the phase II ANCHOR CRC study (ClinicalTrails.gov identifier: NCT03693170 ).'
evidence:
- reference: DOI:10.1200/jco.22.01693
reference_title: 'ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated <i>BRAF</i><sup>V600E</sup>-Mutant Metastatic Colorectal Cancer'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'The positive BEACON colorectal cancer (CRC) safety lead-in, evaluating encorafenib + cetuximab + binimetinib in previously treated patients with BRAFV600E-mutated metastatic CRC (mCRC), prompted the design of the phase II ANCHOR CRC study (ClinicalTrails.gov identifier: NCT03693170 ).'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.25392/leicester.data.25053359.v1
title: Exploring the protective effects of resveratrol and interactions with dietary fat in a mouse model of BRAFV600E driven colorectal cancer
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Exploring the protective effects of resveratrol and interactions with dietary fat in a mouse model of BRAFV600E driven colorectal cancer
supporting_text: Resveratrol, a naturally occurring polyphenol found in red wine and a variety of plants, is widely known for its cancer preventive activity and has been shown to counteract the pro-tumorigenic effects of high-fat diets (HFD) in mouse models of colorectal cancer (CRC).
evidence:
- reference: DOI:10.25392/leicester.data.25053359.v1
reference_title: Exploring the protective effects of resveratrol and interactions with dietary fat in a mouse model of BRAFV600E driven colorectal cancer
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Resveratrol, a naturally occurring polyphenol found in red wine and a variety of plants, is widely known for its cancer preventive activity and has been shown to counteract the pro-tumorigenic effects of high-fat diets (HFD) in mouse models of colorectal cancer (CRC).
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.3389/fonc.2024.1349572
title: 'The histological and molecular characteristics of early-onset colorectal cancer: a systematic review and meta-analysis'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Early-onset colorectal cancer (CRC), defined as diagnosis before age 50, has increased in recent decades.
supporting_text: Early-onset colorectal cancer (CRC), defined as diagnosis before age 50, has increased in recent decades.
evidence:
- reference: DOI:10.3389/fonc.2024.1349572
reference_title: 'The histological and molecular characteristics of early-onset colorectal cancer: a systematic review and meta-analysis'
supports: SUPPORT
evidence_source: OTHER
snippet: Early-onset colorectal cancer (CRC), defined as diagnosis before age 50, has increased in recent decades.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.3390/cancers15215243
title: 'BRAF Inhibitors in Metastatic Colorectal Cancer and Mechanisms of Resistance: A Review of the Literature'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Metastatic colorectal cancer (mCRC) with mutated BRAF exhibits distinct biological and molecular features that set it apart from other subtypes of CRC.
supporting_text: Metastatic colorectal cancer (mCRC) with mutated BRAF exhibits distinct biological and molecular features that set it apart from other subtypes of CRC.
evidence:
- reference: DOI:10.3390/cancers15215243
reference_title: 'BRAF Inhibitors in Metastatic Colorectal Cancer and Mechanisms of Resistance: A Review of the Literature'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Metastatic colorectal cancer (mCRC) with mutated BRAF exhibits distinct biological and molecular features that set it apart from other subtypes of CRC.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.3390/cancers16213664
title: 'Ex Vivo Intestinal Organoid Models: Current State-of-the-Art and Challenges in Disease Modelling and Therapeutic Testing for Colorectal Cancer'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Despite improvements in participation in population-based screening programme, colorectal cancer remains a major cause of cancer-related mortality worldwide.
supporting_text: Despite improvements in participation in population-based screening programme, colorectal cancer remains a major cause of cancer-related mortality worldwide.
evidence:
- reference: DOI:10.3390/cancers16213664
reference_title: 'Ex Vivo Intestinal Organoid Models: Current State-of-the-Art and Challenges in Disease Modelling and Therapeutic Testing for Colorectal Cancer'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Despite improvements in participation in population-based screening programme, colorectal cancer remains a major cause of cancer-related mortality worldwide.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.3390/ijms24109073
title: Clinical Characterization of Targetable Mutations (BRAF V600E and KRAS G12C) in Advanced Colorectal CancerโA Nation-Wide Study
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: BRAF V600E and KRAS mutations that occur in colorectal cancer (CRC) define a subpopulation of patients with an inferior prognosis.
supporting_text: BRAF V600E and KRAS mutations that occur in colorectal cancer (CRC) define a subpopulation of patients with an inferior prognosis.
evidence:
- reference: DOI:10.3390/ijms24109073
reference_title: Clinical Characterization of Targetable Mutations (BRAF V600E and KRAS G12C) in Advanced Colorectal CancerโA Nation-Wide Study
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: BRAF V600E and KRAS mutations that occur in colorectal cancer (CRC) define a subpopulation of patients with an inferior prognosis.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.3390/ijms25137131
title: 'Epidermal Growth Factor Receptor Targeting in Colorectal Carcinoma: Antibodies and Patient-Derived Organoids as a Smart Model to Study Therapy Resistance'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide.
supporting_text: Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide.
evidence:
- reference: DOI:10.3390/ijms25137131
reference_title: 'Epidermal Growth Factor Receptor Targeting in Colorectal Carcinoma: Antibodies and Patient-Derived Organoids as a Smart Model to Study Therapy Resistance'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: DOI:10.5772/intechopen.1004189
title: Biomarkers as a Therapeutic Approach in Colorectal Carcinoma
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: This review highlights the most promising biomarker tests of tumor tissue from colonoscopy biopsy for more individualized therapeutic approaches to patients with colorectal carcinoma (CRC).
supporting_text: This review highlights the most promising biomarker tests of tumor tissue from colonoscopy biopsy for more individualized therapeutic approaches to patients with colorectal carcinoma (CRC).
evidence:
- reference: DOI:10.5772/intechopen.1004189
reference_title: Biomarkers as a Therapeutic Approach in Colorectal Carcinoma
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This review highlights the most promising biomarker tests of tumor tissue from colonoscopy biopsy for more individualized therapeutic approaches to patients with colorectal carcinoma (CRC).
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:21102416
title: Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2011 Mar;24(3):396-411. doi: 10.1038/modpathol.2010.212.'
supporting_text: '2011 Mar;24(3):396-411. doi: 10.1038/modpathol.2010.212.'
evidence:
- reference: PMID:21102416
reference_title: Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2011 Mar;24(3):396-411. doi: 10.1038/modpathol.2010.212.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:21659424
title: Genome-scale analysis of aberrant DNA methylation in colorectal cancer.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2012 Feb;22(2):271-82. doi: 10.1101/gr.117523.110.'
supporting_text: '2012 Feb;22(2):271-82. doi: 10.1101/gr.117523.110.'
evidence:
- reference: PMID:21659424
reference_title: Genome-scale analysis of aberrant DNA methylation in colorectal cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2012 Feb;22(2):271-82. doi: 10.1101/gr.117523.110.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:23425390
title: Right-sided rhabdoid colorectal tumors might be related to the serrated pathway.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: Rhabdoid colorectal tumor (RCT) is a rare, highly aggressive neoplasm recurrent in elderly patients, commonly at the caecum.
supporting_text: Rhabdoid colorectal tumor (RCT) is a rare, highly aggressive neoplasm recurrent in elderly patients, commonly at the caecum.
evidence:
- reference: PMID:23425390
reference_title: Right-sided rhabdoid colorectal tumors might be related to the serrated pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Rhabdoid colorectal tumor (RCT) is a rare, highly aggressive neoplasm recurrent in elderly patients, commonly at the caecum.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:23807779
title: Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2013 Dec;26(12):1642-56. doi: 10.1038/modpathol.2013.101.'
supporting_text: '2013 Dec;26(12):1642-56. doi: 10.1038/modpathol.2013.101.'
evidence:
- reference: PMID:23807779
reference_title: Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2013 Dec;26(12):1642-56. doi: 10.1038/modpathol.2013.101.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:23845441
title: A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2013 Jul 8;24(1):15-29. doi: 10.1016/j.ccr.2013.05.014.'
supporting_text: '2013 Jul 8;24(1):15-29. doi: 10.1016/j.ccr.2013.05.014.'
evidence:
- reference: PMID:23845441
reference_title: A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: '2013 Jul 8;24(1):15-29. doi: 10.1016/j.ccr.2013.05.014.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:25005754
title: A very low incidence of BRAF mutations in Middle Eastern colorectal carcinoma.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: Recent studies emphasize the role of BRAF as a genetic marker for prediction, prognosis and risk stratification in colorectal cancer.
supporting_text: Recent studies emphasize the role of BRAF as a genetic marker for prediction, prognosis and risk stratification in colorectal cancer.
evidence:
- reference: PMID:25005754
reference_title: A very low incidence of BRAF mutations in Middle Eastern colorectal carcinoma.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: Recent studies emphasize the role of BRAF as a genetic marker for prediction, prognosis and risk stratification in colorectal cancer.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:27312529
title: Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2016 Aug 1;76(15):4504-15. doi: 10.1158/0008-5472.CAN-16-0396.'
supporting_text: '2016 Aug 1;76(15):4504-15. doi: 10.1158/0008-5472.CAN-16-0396.'
evidence:
- reference: PMID:27312529
reference_title: Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2016 Aug 1;76(15):4504-15. doi: 10.1158/0008-5472.CAN-16-0396.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:27765849
title: Mutant BRAF Upregulates MCL-1 to Confer Apoptosis Resistance that Is Reversed by MCL-1 Antagonism and Cobimetinib in Colorectal Cancer.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2016 Dec;15(12):3015-3027. doi: 10.1158/1535-7163.MCT-16-0017.'
supporting_text: '2016 Dec;15(12):3015-3027. doi: 10.1158/1535-7163.MCT-16-0017.'
evidence:
- reference: PMID:27765849
reference_title: Mutant BRAF Upregulates MCL-1 to Confer Apoptosis Resistance that Is Reversed by MCL-1 Antagonism and Cobimetinib in Colorectal Cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2016 Dec;15(12):3015-3027. doi: 10.1158/1535-7163.MCT-16-0017.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:29540830
title: 'Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2018 Jun;37(24):3183-3199. doi: 10.1038/s41388-018-0171-x.'
supporting_text: '2018 Jun;37(24):3183-3199. doi: 10.1038/s41388-018-0171-x.'
evidence:
- reference: PMID:29540830
reference_title: 'Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations.'
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: '2018 Jun;37(24):3183-3199. doi: 10.1038/s41388-018-0171-x.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:29666172
title: Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2019 Apr;68(4):684-692. doi: 10.1136/gutjnl-2017-315920.'
supporting_text: '2019 Apr;68(4):684-692. doi: 10.1136/gutjnl-2017-315920.'
evidence:
- reference: PMID:29666172
reference_title: Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis.
supports: SUPPORT
evidence_source: OTHER
snippet: '2019 Apr;68(4):684-692. doi: 10.1136/gutjnl-2017-315920.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:29970458
title: A System-wide Approach to Monitor Responses to Synergistic BRAF and EGFR Inhibition in Colorectal Cancer Cells.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2018 Oct;17(10):1892-1908. doi: 10.1074/mcp.RA117.000486.'
supporting_text: '2018 Oct;17(10):1892-1908. doi: 10.1074/mcp.RA117.000486.'
evidence:
- reference: PMID:29970458
reference_title: A System-wide Approach to Monitor Responses to Synergistic BRAF and EGFR Inhibition in Colorectal Cancer Cells.
supports: SUPPORT
evidence_source: OTHER
snippet: '2018 Oct;17(10):1892-1908. doi: 10.1074/mcp.RA117.000486.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:31158302
title: Clinicopathological features, diagnosis, and treatment of sessile serrated adenoma/polyp with dysplasia/carcinoma.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2019 Oct;34(10):1685-1695. doi: 10.1111/jgh.14752.'
supporting_text: '2019 Oct;34(10):1685-1695. doi: 10.1111/jgh.14752.'
evidence:
- reference: PMID:31158302
reference_title: Clinicopathological features, diagnosis, and treatment of sessile serrated adenoma/polyp with dysplasia/carcinoma.
supports: SUPPORT
evidence_source: OTHER
snippet: '2019 Oct;34(10):1685-1695. doi: 10.1111/jgh.14752.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:31504112
title: Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer
supporting_text: It remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC).
evidence:
- reference: PMID:31504112
reference_title: Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: It remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC).
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:31678770
title: The correlation between immune subtypes and consensus molecular subtypes in colorectal cancer identifies novel tumour microenvironment profiles, with prognostic and therapeutic implications.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment.
supporting_text: Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment.
evidence:
- reference: PMID:31678770
reference_title: The correlation between immune subtypes and consensus molecular subtypes in colorectal cancer identifies novel tumour microenvironment profiles, with prognostic and therapeutic implications.
supports: SUPPORT
evidence_source: OTHER
snippet: Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:31842975
title: DNA methylation instability by BRAF-mediated TET silencing and lifestyle-exposure divides colon cancer pathways.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: Aberrations in DNA methylation are widespread in colon cancer (CC).
supporting_text: Aberrations in DNA methylation are widespread in colon cancer (CC).
evidence:
- reference: PMID:31842975
reference_title: DNA methylation instability by BRAF-mediated TET silencing and lifestyle-exposure divides colon cancer pathways.
supports: SUPPORT
evidence_source: OTHER
snippet: Aberrations in DNA methylation are widespread in colon cancer (CC).
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:31935636
title: Alterations in signaling pathways that accompany spontaneous transition to malignancy in a mouse model of BRAF mutant microsatellite stable colorectal cancer.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2020 Feb;22(2):120-128. doi: 10.1016/j.neo.2019.12.002.'
supporting_text: '2020 Feb;22(2):120-128. doi: 10.1016/j.neo.2019.12.002.'
evidence:
- reference: PMID:31935636
reference_title: Alterations in signaling pathways that accompany spontaneous transition to malignancy in a mouse model of BRAF mutant microsatellite stable colorectal cancer.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: '2020 Feb;22(2):120-128. doi: 10.1016/j.neo.2019.12.002.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:32580537
title: Evolving pathologic concepts of serrated lesions of the colorectum.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2020 Jul;54(4):276-289. doi: 10.4132/jptm.2020.04.15.'
supporting_text: '2020 Jul;54(4):276-289. doi: 10.4132/jptm.2020.04.15.'
evidence:
- reference: PMID:32580537
reference_title: Evolving pathologic concepts of serrated lesions of the colorectum.
supports: SUPPORT
evidence_source: OTHER
snippet: '2020 Jul;54(4):276-289. doi: 10.4132/jptm.2020.04.15.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:34249672
title: Current Therapeutic Strategies in BRAF-Mutant Metastatic Colorectal Cancer.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2021 Jun 23;11:601722. doi: 10.3389/fonc.2021.601722. eCollection 2021.'
supporting_text: '2021 Jun 23;11:601722. doi: 10.3389/fonc.2021.601722. eCollection 2021.'
evidence:
- reference: PMID:34249672
reference_title: Current Therapeutic Strategies in BRAF-Mutant Metastatic Colorectal Cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2021 Jun 23;11:601722. doi: 10.3389/fonc.2021.601722. eCollection 2021.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:35248712
title: 'BRAF-mutated colorectal adenocarcinomas: Pathological heterogeneity and clinical implications.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2022 Apr;172:103647. doi: 10.1016/j.critrevonc.2022.103647.'
supporting_text: '2022 Apr;172:103647. doi: 10.1016/j.critrevonc.2022.103647.'
evidence:
- reference: PMID:35248712
reference_title: 'BRAF-mutated colorectal adenocarcinomas: Pathological heterogeneity and clinical implications.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2022 Apr;172:103647. doi: 10.1016/j.critrevonc.2022.103647.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:35653981
title: 'Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC.
supporting_text: In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC.
evidence:
- reference: PMID:35653981
reference_title: 'Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:35696748
title: 'Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: 'Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience'
supporting_text: Encorafenib plus cetuximab with or without binimetinib showed increased objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with chemotherapy plus anti-EGFR in previously treated patients with BRAF V600E-mutated (mut) metastatic colorectal cancer (mCRC).
evidence:
- reference: PMID:35696748
reference_title: 'Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience.'
supports: SUPPORT
evidence_source: OTHER
snippet: Encorafenib plus cetuximab with or without binimetinib showed increased objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with chemotherapy plus anti-EGFR in previously treated patients with BRAF V600E-mutated (mut) metastatic colorectal cancer (mCRC).
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:36368253
title: 'Real-world first-line treatment of patients with BRAF(V600E)-mutant metastatic colorectal cancer: the CAPSTAN CRC study.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: BRAFV600E mutations occur in 8%-12% of metastatic colorectal cancer (mCRC) cases and are associated with poor survival.
supporting_text: BRAFV600E mutations occur in 8%-12% of metastatic colorectal cancer (mCRC) cases and are associated with poor survival.
evidence:
- reference: PMID:36368253
reference_title: 'Real-world first-line treatment of patients with BRAF(V600E)-mutant metastatic colorectal cancer: the CAPSTAN CRC study.'
supports: SUPPORT
evidence_source: OTHER
snippet: BRAFV600E mutations occur in 8%-12% of metastatic colorectal cancer (mCRC) cases and are associated with poor survival.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:37064498
title: Circulating Tumor DNA Testing Overcomes Limitations of Comprehensive Genomic Profiling from Tumor Tissue.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2023 Apr 12;16(1):210-217. doi: 10.1159/000529813. eCollection 2023 Jan-Dec.'
supporting_text: '2023 Apr 12;16(1):210-217. doi: 10.1159/000529813. eCollection 2023 Jan-Dec.'
evidence:
- reference: PMID:37064498
reference_title: Circulating Tumor DNA Testing Overcomes Limitations of Comprehensive Genomic Profiling from Tumor Tissue.
supports: SUPPORT
evidence_source: OTHER
snippet: '2023 Apr 12;16(1):210-217. doi: 10.1159/000529813. eCollection 2023 Jan-Dec.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:37352476
title: 'FOLFOXIRI Plus Cetuximab or Bevacizumab as First-Line Treatment of BRAF(V600E)-Mutant Metastatic Colorectal Cancer: The Randomized Phase II FIRE-4.5 (AIO KRK0116) Study.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2023 Sep 1;41(25):4143-4153. doi: 10.1200/JCO.22.01420.'
supporting_text: '2023 Sep 1;41(25):4143-4153. doi: 10.1200/JCO.22.01420.'
evidence:
- reference: PMID:37352476
reference_title: 'FOLFOXIRI Plus Cetuximab or Bevacizumab as First-Line Treatment of BRAF(V600E)-Mutant Metastatic Colorectal Cancer: The Randomized Phase II FIRE-4.5 (AIO KRK0116) Study.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2023 Sep 1;41(25):4143-4153. doi: 10.1200/JCO.22.01420.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:37455182
title: 'Treatment of metastatic colorectal cancer with BRAF V600E mutation: A multicenter real-world study in China.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: BRAF V600E mutant-metastatic colorectal cancer (mCRC) is characterized by its short survival time.
supporting_text: BRAF V600E mutant-metastatic colorectal cancer (mCRC) is characterized by its short survival time.
evidence:
- reference: PMID:37455182
reference_title: 'Treatment of metastatic colorectal cancer with BRAF V600E mutation: A multicenter real-world study in China.'
supports: SUPPORT
evidence_source: OTHER
snippet: BRAF V600E mutant-metastatic colorectal cancer (mCRC) is characterized by its short survival time.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:37815847
title: 'SEAMARK: phase II study of first-line encorafenib and cetuximab plus pembrolizumab for MSI-H/dMMR BRAFV600E-mutant mCRC.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2024 Apr;20(11):653-663. doi: 10.2217/fon-2022-1249.'
supporting_text: '2024 Apr;20(11):653-663. doi: 10.2217/fon-2022-1249.'
evidence:
- reference: PMID:37815847
reference_title: 'SEAMARK: phase II study of first-line encorafenib and cetuximab plus pembrolizumab for MSI-H/dMMR BRAFV600E-mutant mCRC.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Apr;20(11):653-663. doi: 10.2217/fon-2022-1249.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:37973552
title: HSPA8 Activates Wnt/ฮฒ-Catenin Signaling to Facilitate BRAF V600E Colorectal Cancer Progression by CMA-Mediated CAV1 Degradation.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2024 Jan;11(3):e2306535. doi: 10.1002/advs.202306535.'
supporting_text: '2024 Jan;11(3):e2306535. doi: 10.1002/advs.202306535.'
evidence:
- reference: PMID:37973552
reference_title: HSPA8 Activates Wnt/ฮฒ-Catenin Signaling to Facilitate BRAF V600E Colorectal Cancer Progression by CMA-Mediated CAV1 Degradation.
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Jan;11(3):e2306535. doi: 10.1002/advs.202306535.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:38553360
title: 'Safety and Efficacy of Encorafenib, Binimetinib, and Cetuximab for BRAF(V600E)-Mutant Metastatic Colorectal Cancer: Results of the Japanese Expanded Access Program.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: The phase 3 BEACON CRC study demonstrated the survival benefits of encorafenib and cetuximab, with or without binimetinib (the BEACON triplet or doublet regimen), for BRAFV600E-mutant metastatic colorectal cancer (mCRC).
supporting_text: The phase 3 BEACON CRC study demonstrated the survival benefits of encorafenib and cetuximab, with or without binimetinib (the BEACON triplet or doublet regimen), for BRAFV600E-mutant metastatic colorectal cancer (mCRC).
evidence:
- reference: PMID:38553360
reference_title: 'Safety and Efficacy of Encorafenib, Binimetinib, and Cetuximab for BRAF(V600E)-Mutant Metastatic Colorectal Cancer: Results of the Japanese Expanded Access Program.'
supports: SUPPORT
evidence_source: OTHER
snippet: The phase 3 BEACON CRC study demonstrated the survival benefits of encorafenib and cetuximab, with or without binimetinib (the BEACON triplet or doublet regimen), for BRAFV600E-mutant metastatic colorectal cancer (mCRC).
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:39255538
title: 'Efficacy and safety of the combination of encorafenib/cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: an AGEO real-world multicenter study.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: The combination of encorafenib with cetuximab has become the standard of care in patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC) after a prior systemic therapy.
supporting_text: The combination of encorafenib with cetuximab has become the standard of care in patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC) after a prior systemic therapy.
evidence:
- reference: PMID:39255538
reference_title: 'Efficacy and safety of the combination of encorafenib/cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: an AGEO real-world multicenter study.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The combination of encorafenib with cetuximab has become the standard of care in patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC) after a prior systemic therapy.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:39313594
title: Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: RAS, MAP2K1 and MET alterations were most commonly acquired with Enco+CetuxยฑBini.
supporting_text: RAS, MAP2K1 and MET alterations were most commonly acquired with Enco+CetuxยฑBini.
evidence:
- reference: PMID:39313594
reference_title: Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: RAS, MAP2K1 and MET alterations were most commonly acquired with Enco+CetuxยฑBini.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:39538135
title: 'Clinicopathologic features and treatment efficacy of patients with BRAF V600E-mutated metastatic colorectal cancer: a multi-center real-world propensity score matching study.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: The overall prognosis of BRAF V600E mutant mCRC patients is poor.
supporting_text: The overall prognosis of BRAF V600E mutant mCRC patients is poor.
evidence:
- reference: PMID:39538135
reference_title: 'Clinicopathologic features and treatment efficacy of patients with BRAF V600E-mutated metastatic colorectal cancer: a multi-center real-world propensity score matching study.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The overall prognosis of BRAF V600E mutant mCRC patients is poor.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:39932790
title: Comparison of survival outcomes for patients with Lynch vs non-Lynch syndrome and microsatellite unstable colorectal cancer treated with immunotherapy.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: Alterations in mismatch repair (MMR) genes like MLH1, MSH2, MSH6, and PMS2 can lead to microsatellite instability-high (MSI-H) tumors.
supporting_text: Alterations in mismatch repair (MMR) genes like MLH1, MSH2, MSH6, and PMS2 can lead to microsatellite instability-high (MSI-H) tumors.
evidence:
- reference: PMID:39932790
reference_title: Comparison of survival outcomes for patients with Lynch vs non-Lynch syndrome and microsatellite unstable colorectal cancer treated with immunotherapy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Alterations in mismatch repair (MMR) genes like MLH1, MSH2, MSH6, and PMS2 can lead to microsatellite instability-high (MSI-H) tumors.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:39935752
title: 'Treatment outcomes of patients with BRAF(V600E)-mutated metastatic colorectal cancer: a Polish retrospective cohort study.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2024;28(4):297-303. doi: 10.5114/wo.2024.146953.'
supporting_text: '2024;28(4):297-303. doi: 10.5114/wo.2024.146953.'
evidence:
- reference: PMID:39935752
reference_title: 'Treatment outcomes of patients with BRAF(V600E)-mutated metastatic colorectal cancer: a Polish retrospective cohort study.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2024;28(4):297-303. doi: 10.5114/wo.2024.146953.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:39961465
title: 'BRAF V600E in cancer: Exploring structural complexities, mutation profiles, and pathway dysregulation.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2025 Mar 1;446(1):114440. doi: 10.1016/j.yexcr.2025.114440.'
supporting_text: '2025 Mar 1;446(1):114440. doi: 10.1016/j.yexcr.2025.114440.'
evidence:
- reference: PMID:39961465
reference_title: 'BRAF V600E in cancer: Exploring structural complexities, mutation profiles, and pathway dysregulation.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Mar 1;446(1):114440. doi: 10.1016/j.yexcr.2025.114440.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:41077740
title: 'Diagnostic Challenges in Sessile Serrated Lesions: Progression to Adenocarcinoma in a High-Risk Patient.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2025 Oct 13;26:e950179. doi: 10.12659/AJCR.950179.'
supporting_text: '2025 Oct 13;26:e950179. doi: 10.12659/AJCR.950179.'
evidence:
- reference: PMID:41077740
reference_title: 'Diagnostic Challenges in Sessile Serrated Lesions: Progression to Adenocarcinoma in a High-Risk Patient.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Oct 13;26:e950179. doi: 10.12659/AJCR.950179.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:41515890
title: Quantitative ctDNA Profiling of RAS Mutations as a Prognostic Biomarker in Metastatic Colorectal Cancer.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: '2025 Dec 19;27(1):8. doi: 10.3390/ijms27010008.'
supporting_text: '2025 Dec 19;27(1):8. doi: 10.3390/ijms27010008.'
evidence:
- reference: PMID:41515890
reference_title: Quantitative ctDNA Profiling of RAS Mutations as a Prognostic Biomarker in Metastatic Colorectal Cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Dec 19;27(1):8. doi: 10.3390/ijms27010008.'
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:41677963
title: 'Safety and Efficacy of Triple Therapy Containing Encorafenib, Cetuximab, and Binimetinib for BRAF V600E-Mutated Colorectal Cancer: a Systematic Review and Meta-Analysis.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: BRAF V600E-mutated colorectal cancer (CRC) is associated with poor prognosis and resistance to standard chemotherapy.
supporting_text: BRAF V600E-mutated colorectal cancer (CRC) is associated with poor prognosis and resistance to standard chemotherapy.
evidence:
- reference: PMID:41677963
reference_title: 'Safety and Efficacy of Triple Therapy Containing Encorafenib, Cetuximab, and Binimetinib for BRAF V600E-Mutated Colorectal Cancer: a Systematic Review and Meta-Analysis.'
supports: SUPPORT
evidence_source: OTHER
snippet: BRAF V600E-mutated colorectal cancer (CRC) is associated with poor prognosis and resistance to standard chemotherapy.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:41736753
title: Anti-oncogenic and immunological functions of ATP23 in CMS4 colon adenocarcinoma based on a machine learning computational framework.
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: Consensus Molecular Subtype (CMS) 4 and BRAF mutations are poor prognostic indicators for colon adenocarcinoma (COAD).
supporting_text: Consensus Molecular Subtype (CMS) 4 and BRAF mutations are poor prognostic indicators for colon adenocarcinoma (COAD).
evidence:
- reference: PMID:41736753
reference_title: Anti-oncogenic and immunological functions of ATP23 in CMS4 colon adenocarcinoma based on a machine learning computational framework.
supports: SUPPORT
evidence_source: OTHER
snippet: Consensus Molecular Subtype (CMS) 4 and BRAF mutations are poor prognostic indicators for colon adenocarcinoma (COAD).
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
- reference: PMID:41761577
title: 'Real-world outcomes of encorafenib, cetuximab ยฑ binimetinib for BRAFโmutated metastatic colorectal cancer: the BEETS (JACCRO CCโ18) study.'
found_in:
- BRAF_V600E_Mutant_Colorectal_Cancer-deep-research-openscientist.md
findings:
- statement: Triplet therapy (encorafenib, cetuximab, and binimetinib) is recommended in Japan for BRAF V600E mutated metastatic colorectal cancer (mCRC) patients with poor prognostic factors (PFs) based on subgroup analyses of the BEACON CRC trial.
supporting_text: Triplet therapy (encorafenib, cetuximab, and binimetinib) is recommended in Japan for BRAF V600E mutated metastatic colorectal cancer (mCRC) patients with poor prognostic factors (PFs) based on subgroup analyses of the BEACON CRC trial.
evidence:
- reference: PMID:41761577
reference_title: 'Real-world outcomes of encorafenib, cetuximab ยฑ binimetinib for BRAFโmutated metastatic colorectal cancer: the BEETS (JACCRO CCโ18) study.'
supports: SUPPORT
evidence_source: OTHER
snippet: Triplet therapy (encorafenib, cetuximab, and binimetinib) is recommended in Japan for BRAF V600E mutated metastatic colorectal cancer (mCRC) patients with poor prognostic factors (PFs) based on subgroup analyses of the BEACON CRC trial.
explanation: Deep research cited this publication as relevant literature for BRAF V600E Mutant Colorectal Cancer.
BRAF V600Eโmutant colorectal cancer denotes colorectal cancer characterized by an activating missense substitution in BRAF (valineโglutamic acid at codon 600), which constitutively activates MAPK signaling and defines a clinically distinct subgroup with poor prognosis in metastatic disease. (morris2020improvementsinclinical pages 1-5)
A clear trial-level description from BEACON CRC highlights the clinical context and biological rationale: - โPatients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis โฆโ and โInhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.โ (kopetz2019encorafenibbinimetiniband pages 1-2)
Most evidence is aggregated from trials and cohorts. Real-world cohorts explicitly use EHR extraction (e.g., clinicopathologic data extracted from electronic records). (zurloh2023impactofencorafenib pages 1-2)
A 2024 Mendelian randomization analysis provides subtype-specific causal evidence linking adiposity to BRAF-mutated/CIMP-high pathways: - Per 1-SD (5.1 kg/mยฒ) higher BMI, risk increased for: - Jass type 1 (MSI-high, CIMP-high, BRAF-mutated, KRAS-wildtype): OR 2.14 (95% CI 1.46โ3.13) - Jass type 2 (nonโMSI-high, CIMP-high, BRAF-mutated, KRAS-wildtype): OR 2.20 (95% CI 1.26โ3.86) (papadimitriou2024bodysizeand pages 1-2)
High-fat diet is repeatedly framed as a CRC risk context in preclinical literature, including in BRAF-driven mouse-model work (see Section 13 and 15). (theofanous2024exploringtheprotective pages 69-72, theofanous2024exploringtheprotective pages 1-5)
Evidence directly specific to BRAF V600E CRC prevention in humans is limited in retrieved sources. The retrieved evidence includes preclinical and limited human biomarker signals for dietary compounds: - In APCMIN/+ mice on high-fat diet, resveratrol reduced โintestinal adenoma number and tumour burden by ~40% and ~57%โ at low dose in one study summarized in the thesis review table. (theofanous2024exploringtheprotective pages 69-72) - In a small human CRC/metastasis context referenced by the same thesis, resveratrol interventions were associated with biomarker changes such as โcleaved caspase 3 โฆ 39%โ in hepatic metastases and a โ5% reduction in Ki67 proliferationโ (short-term, small n). (theofanous2024exploringtheprotective pages 69-72)
A BRAF V600E-driven mouse model in the resveratrol/HFD work showed genotype-dependent response to dietary fat exposure (interaction leading to rapid weight loss and early culling before polyp development), indicating that BRAF-driven physiology may modulate diet response in vivo. (theofanous2024exploringtheprotective pages 69-72)
A large 2023 nationwide advanced CRC cohort (n=7,604) found BRAF V600E is enriched in multiple clinicopathologic settings: - Female sex (OR 2.009) - Right/proximal colon primary (OR 8.356) - High-grade tumors (OR 4.061) - Mucinous histology (OR 3.430) and partially mucinous (OR 2.718) - Signet cell features (OR 1.544) - Mixed adeno-neuroendocrine cancers (MANEC; OR 9.211) - Vascular and perineural invasion (potocki2023clinicalcharacterizationof pages 4-5)
In real-world clinical description, BRAF V600E mCRC is also described as more often right-sided, more common in female patients, and associated with MSI-high features. (zurloh2023impactofencorafenib pages 1-2)
Symptoms generally reflect colorectal cancer and metastatic spread; the retrieved corpus did not provide quantitative symptom frequencies specific to BRAF V600E subtype.
Because the retrieved evidence emphasizes pathology and metastatic patterns more than symptom inventories, HPO suggestions are necessarily generic for CRC/mCRC: - Abdominal pain (HP:0002027) - Hematochezia (HP:0001892) - Weight loss (HP:0001824) - Anemia (HP:0001903) - Metastatic neoplasm (HP:0003002)
(Phenotype frequency data not available in retrieved sources.)
A review notes BRAF V600E CRC is linked to worse HRQoL compared with BRAF-wildtype CRC, but quantitative QoL instrument values were not available in retrieved excerpts. (morris2020improvementsinclinical pages 1-5)
Somatic vs germline: In CRC, BRAF V600E is typically treated as a somatic tumor driver; it is also used clinically to help exclude Lynch syndrome when MSI-H is present (see Diagnostics). (effendiys2024biomarkersasa pages 3-6, iliepetrov2024โฆofcolorectal pages 7-9)
The 2024 BEACON CRC multi-omics biomarker analysis identified acquired resistance alterations: - โRAS, MAP2K1 and MET alterations were most commonly acquiredโ on encorafenib+cetuximabยฑbinimetinib. (kopetz2024molecularprofilingof pages 1-2) - โbaseline TP53 mutation was associated with acquired MET amplification.โ (kopetz2024molecularprofilingof pages 1-2)
BRAF-mutant CRC is linked to CIMP biology (hypermethylation phenotype), often aligned with serrated pathway development. (guerrero2023brafinhibitorsin pages 1-2, effendiys2024biomarkersasa pages 3-6)
No infectious agents specific to BRAF V600E CRC were identified in retrieved sources.
BRAF V600E acts downstream of EGFR and RAS to drive MAPK signaling, increasing proliferation and reducing apoptosis. (morris2020improvementsinclinical pages 1-5)
The dominant mechanistic concept guiding therapy is EGFR-mediated MAPK pathway reactivation after BRAF inhibition: - BEACON CRC (NEJM): โInhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.โ (kopetz2019encorafenibbinimetiniband pages 1-2) - BEACON updated analysis (JCO): โBRAF inhibition results in a rapid release of feedback-suppressed epidermal growth-factor receptor (EGFR)โmediated MAPK signaling, leading to a rebound in MAPK activation and continued cell proliferation.โ (tabernero2021encorafenibpluscetuximab pages 1-2)
Causal chain (simplified): 1) BRAF V600E โ constitutive ERK signaling โ malignant growth (morris2020improvementsinclinical pages 1-5) 2) BRAF inhibitor alone โ ERK transiently โ releases feedback suppression โ EGFR activation โ RAS signaling โ RAF dimerization/reactivation โ restored ERK signaling โ resistance (tabernero2021encorafenibpluscetuximab pages 1-2, morris2020improvementsinclinical pages 11-14) 3) Combine BRAF + EGFR (ยฑMEK) inhibition โ deeper pathway suppression and improved outcomes (kopetz2019encorafenibbinimetiniband pages 1-2, tabernero2021encorafenibpluscetuximab pages 1-2)
BRAF mutations are enriched in sporadic MSI tumors and ~20% of BRAF V600E mCRC may be MSI, a key determinant of checkpoint inhibitor sensitivity. (guerrero2023brafinhibitorsin pages 1-2, effendiys2024biomarkersasa pages 3-6)
GO Biological Process (suggestions): - MAPK cascade (GO:0000165) - ERK1 and ERK2 cascade (GO:0070371) - Regulation of cell proliferation (GO:0042127) - Negative regulation of apoptotic process (GO:0043066) - Epithelial cell proliferation (GO:0050673)
CL Cell Ontology (suggestions): - Colonic epithelial cell / intestinal epithelial cell (CL:0000584 may map to enterocyte; general epithelial cell CL:0000066) - Colonic stem cell (broadly: intestinal stem cell) - Tumor-associated macrophage (for microenvironment studies; not directly evidenced in retrieved BRAF-specific excerpts)
UBERON (suggestions): - Colon (UBERON:0001155) - Large intestine (UBERON:0000059)
CRC is generally adult-onset. Early-onset CRC shows lower prevalence of BRAF mutations overall than late-onset CRC (not BRAF V600E-specific prevalence): OR 0.63 (0.51โ0.78). (lawler2024thehistologicaland pages 1-2)
BRAF V600E mCRC is described as rapidly progressive with poor outcomes on historical standard therapies. (kopetz2019encorafenibbinimetiniband pages 1-2, morris2020improvementsinclinical pages 1-5)
This is predominantly a somatic tumor genotype rather than a Mendelian inherited disease entity in standard oncology usage.
A practical, widely used workflow in metastatic CRC includes: extended RAS testing (KRAS/NRAS), BRAF testing, and MSI/MMR status assessment. (effendiys2024biomarkersasa pages 3-6, NCT05217446 chunk 1)
Assay modalities supported in retrieved sources: - MMR/MSI: Immunohistochemistry (IHC) for MMR proteins and PCR for MSI are explicitly discussed as standard approaches in a 2024 biomarker overview. (effendiys2024biomarkersasa pages 3-6) - BRAF testing: typically performed on tumor tissue; can be done alongside RAS. (effendiys2024biomarkersasa pages 3-6) - NGS panels: highlighted for comprehensive detection including atypical/non-V600 BRAF variants. (iliepetrov2024โฆofcolorectal pages 7-9)
Clinical trial registrations and protocols show ctDNA is being used both for enrollment and for resistance-guided retreatment decisions: - NCT05217446 allows BRAF confirmation from โtumor tissue or bloodโ (implying ctDNA accepted) with mandatory local MSI-H/dMMR confirmation and known RAS status. (NCT05217446 chunk 1) - NCT06578559 (BRICKET) requires ctDNA at entry showing no KRAS/NRAS/MAP2K1 mutations and no MET amplification before encorafenib+cetuximab rechallenge. (NCT06578559 chunk 1)
BEACON CRC provides a trial-level summary of poor prognosis after initial therapy failure: - โmedian overall survival of 4 to 6 months after failure of initial therapyโ in BRAF V600E mCRC (historical context). (kopetz2019encorafenibbinimetiniband pages 1-2)
In a 2024 multi-center study, poor differentiation and liver metastases were negative independent prognostic factors for OS in BRAF V600E mCRC. (wei2024clinicopathologicfeaturesand pages 10-10)
BEACON CRC established BRAF+EGFR targeted therapy as standard after prior therapy.
Phase III BEACON CRC (interim analysis; NEJM 2019): - Mechanistic abstract quote: โInhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.โ (kopetz2019encorafenibbinimetiniband pages 1-2) - Outcomes: - Triplet (encorafenib+binimetinib+cetuximab): median OS 9.0 vs control 5.4 months (HR 0.52) - Confirmed ORR 26% vs 2% - Grade โฅ3 AEs: 58% (triplet), 50% (doublet), 61% (control) (kopetz2019encorafenibbinimetiniband pages 1-2)
Updated BEACON CRC analysis (JCO 2021): - OS: 9.3 months (triplet) and 9.3 months (doublet) vs 5.9 months (control) - ORR: 26.8% (triplet), 19.5% (doublet), 1.8% (control) - Grade โฅ3 AEs: 65.8% (triplet), 57.4% (doublet), 64.2% (control) (tabernero2021encorafenibpluscetuximab pages 1-2)
These outcomes are also supported visually by the BEACON updated OS KaplanโMeier and response table (tabernero2021encorafenibpluscetuximab media 2b387ba4, tabernero2021encorafenibpluscetuximab media 9dac50ff).
MAXO suggestions: - EGFR inhibitor therapy (cetuximab) - BRAF inhibitor therapy (encorafenib) - MEK inhibitor therapy (binimetinib)
ANCHOR CRC phase II (JCO 2023; first-line triplet, single-arm): - cORR 47.4% (95% CI 37.0โ57.9) - median PFS 5.8 months - median OS 18.3 months (cutsem2023anchorcrcresults pages 1-2)
BREAKWATER phase III (Nature Medicine 2025; first interim, first-line EC+mFOLFOX6): - ORR 60.9% vs SOC 40.0% - OS HR 0.47 (interim) - Serious AEs 37.7% vs 34.6% (kopetz2025encorafenibcetuximaband pages 1-2)
BEACON safety lead-in (JCO 2019): - ORR 48%; median PFS 8.0 months; median OS 15.3 months (cutsem2019binimetinibencorafeniband pages 1-2) - DLTs included serous retinopathy, decreased LVEF, infusion reactions; common grade 3โ4 AEs included fatigue (13%), anemia (10%), โCPK (10%), โAST (10%), UTI (10%). (cutsem2019binimetinibencorafeniband pages 1-2)
The retrieved evidence emphasizes that MSI-H/dMMR status is a key selection biomarker for PD-1 blockade in metastatic CRC, including in BRAF-mutant disease. (eriksen2022aphaseii pages 1-2)
A key real-world implementation example is an ongoing/registered trial: - NCT05217446 compares encorafenib+cetuximab+pembrolizumab vs pembrolizumab alone in untreated MSI-H/dMMR, BRAF V600E mCRC, permitting BRAF confirmation by tissue or blood. (NCT05217446 chunk 1)
The 2024 BEACON translational analysis supports surveillance of resistance mechanisms and suggests biologically plausible targets (RAS/MAP2K1/MET) for next-line strategies. (kopetz2024molecularprofilingof pages 1-2)
A direct implementation of resistance-informed strategy is the ctDNA-guided rechallenge trial NCT06578559 excluding ctDNA-detectable RAS/MAP2K1/MET alterations at retreatment entry. (NCT06578559 chunk 1)
BRAF V600E is a tumor genotype rather than a preventable infectious etiology. However, CRC primary prevention strategies likely apply and are supported by subtype-specific evidence that obesity is causally linked to BRAF-mutated/CIMP-high pathways (targeting BMI reduction as a plausible primary prevention lever). (papadimitriou2024bodysizeand pages 1-2)
CRC screening strategies (colonoscopy, stool-based tests) are not detailed in the retrieved excerpts, but MSI/MMR and BRAF testing are emphasized once CRC is diagnosed, particularly for Lynch syndrome triage and systemic therapy selection. (effendiys2024biomarkersasa pages 3-6, iliepetrov2024โฆofcolorectal pages 7-9)
In metastatic disease, tertiary prevention focuses on preventing progression/complications via effective systemic therapy and molecularly guided sequencing (e.g., BEACON regimen, ctDNA monitoring trials). (tabernero2021encorafenibpluscetuximab pages 1-2, NCT06578559 chunk 1)
No naturally occurring non-human species disease analogs specific to BRAF V600E CRC were identified in the retrieved sources.
A 2024 BRAF V600E-driven CRC mouse-model study/thesis explored high-fat diet effects and resveratrol modulation, including multi-omics phenotyping (microbiome, metabolomics, cytokines) and intestinal lipid biology. (theofanous2024exploringtheprotective pages 1-5)
Quantitative preclinical โprevention-likeโ effects summarized in that thesis include resveratrol reducing adenoma number/tumor burden in APCMIN/+ mice on high-fat diet by ~40% and ~57% at a low dose in one study table. (theofanous2024exploringtheprotective pages 69-72)
Organoids are emphasized as clinically relevant models for CRC heterogeneity and treatment response: - Ex vivo organoid review (Cancers 2024) notes organoids preserve tumor heterogeneity and explicitly mentions โmodels with high microsatellite instability associated with BRAF V600E mutations,โ and positions living biobanks for personalized treatment testing. (randalldemllo2024exvivointestinal pages 4-6) - EGFR-targeting review (IJMS 2024) describes organoids as reflecting โgenetic heterogeneityโ and being used to study resistance to anti-EGFR therapies in personalized medicine contexts. (tardito2024epidermalgrowthfactor pages 1-2)
A 2024 Nature Communications study underscores PDX value for studying cetuximab sensitivity: - PDXs are โtumour fragments engrafted into miceโ and retain โstructural complexity, heterogeneity, and stromal interactionsโ better than in vitro models; 231 CRC PDXs were profiled and screened for cetuximab response to train a predictive multi-omics model. (perron2024integrativeensemblemodelling pages 1-2)
1) Routine molecular profiling in metastatic CRC including RAS/BRAF and MSI/MMR to guide therapy selection and exclude ineffective anti-EGFR monotherapy in inappropriate genotypes. (effendiys2024biomarkersasa pages 3-6, NCT05217446 chunk 1) 2) Approved targeted standard after prior therapy: encorafenib + cetuximab (BEACON-established). (tabernero2021encorafenibpluscetuximab pages 1-2) 3) First-line intensification and targeted combinations in clinical trials (ANCHOR CRC; BREAKWATER). (cutsem2023anchorcrcresults pages 1-2, kopetz2025encorafenibcetuximaband pages 1-2) 4) ctDNA integration for resistance-guided rechallenge (BRICKET, NCT06578559). (NCT06578559 chunk 1) 5) Organoid and PDX platforms for drug-response prediction and resistance studies, supporting precision medicine pipelines. (randalldemllo2024exvivointestinal pages 4-6, perron2024integrativeensemblemodelling pages 1-2, tardito2024epidermalgrowthfactor pages 1-2)
The table below consolidates identifiers, epidemiology/phenotype, and core clinical trial outcomes.
| Section | Item | Details | Study (year, journal) | Population/setting | Regimen | Key outcomes (OS/PFS/ORR, gradeโฅ3 AEs) | URL |
|---|---|---|---|---|---|---|---|
| Disease identifiers / classification | Disease name | BRAF V600Eโmutant colorectal cancer; molecular subtype of colorectal adenocarcinoma defined by activating BRAF p.Val600Glu alteration in the MAPK pathway (morris2020improvementsinclinical pages 1-5, potocki2023clinicalcharacterizationof pages 1-2) | Morris 2020, Clin Cancer Res; Potocki 2023, Int J Mol Sci | CRC / advanced CRC | โ | BRAF V600E occurs in ~10% of CRC overall; 6.77% in one nationwide advanced CRC cohort (morris2020improvementsinclinical pages 1-5, potocki2023clinicalcharacterizationof pages 1-2) | https://doi.org/10.1158/1078-0432.CCR-19-3809 ; https://doi.org/10.3390/ijms24109073 |
| Disease identifiers / classification | Synonyms | BRAFV600E-mutant CRC; BRAFV600E-mutated metastatic colorectal cancer (mCRC); BRAF V600E colorectal cancer (morris2020improvementsinclinical pages 1-5, kopetz2019encorafenibbinimetiniband pages 1-2) | Morris 2020, Clin Cancer Res; Kopetz 2019, N Engl J Med | CRC / mCRC | โ | Widely used trial terminology; specific ontology IDs not found in retrieved sources | https://doi.org/10.1158/1078-0432.CCR-19-3809 ; https://doi.org/10.1056/NEJMoa1908075 |
| Disease identifiers / classification | Key identifiers | MONDO: not found in retrieved sources; OMIM: not found in retrieved sources; Orphanet: not found in retrieved sources; MeSH: not found in retrieved sources; ICD-10/11: not found in retrieved sources (use disease-level CRC codes plus biomarker annotation in practice) | not found in retrieved sources | Disease knowledge-base metadata | โ | not found in retrieved sources | not found in retrieved sources |
| Disease identifiers / classification | Resource level | Information in retrieved sources is primarily aggregated disease-level evidence from clinical trials, cohort studies, reviews, and trial registries; some real-world studies derive data from EHR/registry cohorts (zurloh2023impactofencorafenib pages 1-2, NCT06578559 chunk 1) | Zurloh 2023, J Cancer Res Clin Oncol; ClinicalTrials.gov 2024 | Real-world cohorts / clinical trials | โ | Aggregated disease-level resources; not patient-identifiable | https://doi.org/10.1007/s00432-023-05141-y ; https://clinicaltrials.gov/study/NCT06578559 |
| Epidemiology & phenotype | Prevalence | BRAF V600E prevalence 6.77% in 7,604 advanced CRC patients; review sources cite ~10% of CRC and ~10โ15% of mCRC; some reviews cite ~12% of mCRC (potocki2023clinicalcharacterizationof pages 1-2, cutsem2023anchorcrcresults pages 1-2, guerrero2023brafinhibitorsin pages 1-2) | Potocki 2023, Int J Mol Sci; Van Cutsem 2023, J Clin Oncol; Guerrero 2023, Cancers | Advanced CRC / mCRC | โ | 6.77% in nationwide advanced CRC cohort; ~10โ15% across trial/review sources | https://doi.org/10.3390/ijms24109073 ; https://doi.org/10.1200/JCO.22.01693 ; https://doi.org/10.3390/cancers15215243 |
| Epidemiology & phenotype | Clinicopathologic enrichment | Enriched in female sex, right/proximal colon, high-grade tumors, mucinous and signet-ring histology, partially neuroendocrine histology, perineural and vascular invasion (potocki2023clinicalcharacterizationof pages 4-5, potocki2023clinicalcharacterizationof pages 1-2) | Potocki 2023, Int J Mol Sci | Nationwide retrospective advanced CRC cohort | โ | OR female sex 2.009; OR right-sided primary 8.356; OR high-grade 4.061; OR mucinous 3.430; OR partial mucinous 2.718; OR signet cells 1.544; OR MANEC/neuroendocrine component 9.211 (potocki2023clinicalcharacterizationof pages 4-5) | https://doi.org/10.3390/ijms24109073 |
| Epidemiology & phenotype | MSI/CIMP/serrated pathway | Strong association with serrated neoplasia pathway, CIMP-high biology, and MSI enrichment in sporadic CRC; review notes BRAF mutations in ~60% of MSI tumors vs 5โ10% of MSS tumors, and ~20% of BRAF V600E-mutant mCRC may be MSI (guerrero2023brafinhibitorsin pages 1-2, effendiys2024biomarkersasa pages 3-6) | Guerrero 2023, Cancers; Effendi-YS 2024, book chapter | Review / biomarker overview | โ | Distinct biology with MSI/CIMP enrichment; clinically relevant for immunotherapy selection and Lynch syndrome exclusion workup | https://doi.org/10.3390/cancers15215243 ; https://doi.org/10.5772/intechopen.1004189 |
| Epidemiology & phenotype | Prognosis | Adverse prognostic biomarker with decreased OS, rapid progression, and poor response to standard therapy; historical post-first-line OS ~4โ6 months in mCRC (morris2020improvementsinclinical pages 1-5, kopetz2019encorafenibbinimetiniband pages 1-2, potocki2023clinicalcharacterizationof pages 11-12) | Morris 2020, Clin Cancer Res; Kopetz 2019, N Engl J Med; Potocki 2023, Int J Mol Sci | mCRC / advanced CRC | โ | Inferior prognosis versus BRAF wild-type; historical median OS after initial therapy failure 4โ6 months (kopetz2019encorafenibbinimetiniband pages 1-2) | https://doi.org/10.1158/1078-0432.CCR-19-3809 ; https://doi.org/10.1056/NEJMoa1908075 ; https://doi.org/10.3390/ijms24109073 |
| Epidemiology & phenotype | Metastatic pattern / QoL | Reviews note distinct metastatic spread with more bone, brain, and peritoneal involvement and worse HRQoL relative to wild-type CRC (morris2020improvementsinclinical pages 1-5) | Morris 2020, Clin Cancer Res | Review | โ | Qualitative adverse metastatic pattern / HRQoL impact; exact frequencies not provided in retrieved evidence | https://doi.org/10.1158/1078-0432.CCR-19-3809 |
| Treatment & outcomes | BEACON CRC phase III interim | Previously treated BRAF V600E-mutant mCRC randomized 1:1:1 to triplet, doublet, or control (kopetz2019encorafenibbinimetiniband pages 1-2) | Kopetz 2019, N Engl J Med | 665 patients; progressed after 1โ2 prior regimens | Encorafenib + binimetinib + cetuximab vs encorafenib + cetuximab vs cetuximab + irinotecan/FOLFIRI | Triplet: OS 9.0 mo, ORR 26%, gradeโฅ3 AEs 58%; Doublet: OS 8.4 mo, gradeโฅ3 AEs 50%; Control: OS 5.4 mo, ORR 2%, gradeโฅ3 AEs 61%. Mechanistic rationale: BRAF monotherapy limited by EGFR-mediated pathway reactivation (kopetz2019encorafenibbinimetiniband pages 1-2) | https://doi.org/10.1056/NEJMoa1908075 |
| Treatment & outcomes | BEACON CRC updated analysis | Updated survival results confirming doublet as standard of care in previously treated disease (tabernero2021encorafenibpluscetuximab pages 1-2) | Tabernero 2021, J Clin Oncol | 665 randomized patients with previously treated BRAF V600E mCRC | Triplet: encorafenib + binimetinib + cetuximab; Doublet: encorafenib + cetuximab; Control: cetuximab + irinotecan/FOLFIRI | Triplet: OS 9.3 mo, ORR 26.8%, gradeโฅ3 AEs 65.8%; Doublet: OS 9.3 mo, ORR 19.5%, gradeโฅ3 AEs 57.4%; Control: OS 5.9 mo, ORR 1.8%, gradeโฅ3 AEs 64.2% (tabernero2021encorafenibpluscetuximab pages 1-2) | https://doi.org/10.1200/JCO.20.02088 |
| Treatment & outcomes | BEACON safety lead-in | Early safety/efficacy signal supporting phase III randomized study (cutsem2019binimetinibencorafeniband pages 1-2, cutsem2019binimetinibencorafeniband pages 6-7) | Van Cutsem 2019, J Clin Oncol | 30 previously treated BRAF V600E mCRC patients; 29 efficacy-evaluable | Encorafenib 300 mg daily + binimetinib 45 mg BID + weekly cetuximab | ORR 48%; PFS 8.0 mo; OS 15.3 mo; DLTs in 5 patients; common grade 3โ4 AEs: fatigue 13%, anemia 10%, โCPK 10%, โAST 10%, UTI 10%; overall grade 3 and 4 toxicity 53.3% and 16.7% (cutsem2019binimetinibencorafeniband pages 1-2, cutsem2019binimetinibencorafeniband pages 6-7) | https://doi.org/10.1200/JCO.18.02459 |
| Treatment & outcomes | ANCHOR CRC phase II | First-line targeted triplet in untreated BRAF V600E mCRC (cutsem2023anchorcrcresults pages 1-2) | Van Cutsem 2023, J Clin Oncol | 95 previously untreated BRAF V600E-mutant mCRC patients | Encorafenib + binimetinib + cetuximab | cORR 47.4% (all PRs); PFS 5.8 mo; OS 18.3 mo; treatment well tolerated with manageable safety, but gradeโฅ3 AEs not numerically reported in retrieved context (cutsem2023anchorcrcresults pages 1-2) | https://doi.org/10.1200/JCO.22.01693 |
| Treatment & outcomes | BREAKWATER phase III | First-line BRAF-targeted combination plus chemotherapy versus SOC in untreated BRAF V600E mCRC (kopetz2025encorafenibcetuximaband pages 1-2) | Kopetz 2025, Nat Med | 637 untreated BRAF V600E mCRC patients | Encorafenib + cetuximab + mFOLFOX6 vs standard of care | ORR 60.9% vs 40.0%; median duration of response 13.9 vs 11.1 mo; interim OS HR 0.47; serious AEs 37.7% vs 34.6%; gradeโฅ3 AEs not numerically reported in retrieved context (kopetz2025encorafenibcetuximaband pages 1-2) | https://doi.org/10.1038/s41591-024-03443-3 |
| Treatment & outcomes | BEACON molecular profiling / resistance | Translational biomarker study explaining response and acquired resistance to targeted therapy (kopetz2024molecularprofilingof pages 1-2) | Kopetz 2024, Nat Med | BEACON biomarker analyses using tissue WES/WTS and ctDNA | Encorafenib + cetuximab ยฑ binimetinib | Response/resistance correlates: higher immune signatures trended toward greater OS benefit with triplet; acquired alterations commonly involved RAS, MAP2K1, MET; baseline TP53 linked to acquired MET amplification; resistance mutations were subclonal/polyclonal (kopetz2024molecularprofilingof pages 1-2) | https://doi.org/10.1038/s41591-024-03235-9 |
| Treatment & outcomes | Real-world EC population-based study | Real-world survival/effectiveness of encorafenib + cetuximab after approval (numeric outcomes limited in retrieved context) (kopetz2024molecularprofilingof pages 1-2) | Zwart 2024, Br J Cancer | Population-based real-world BRAF V600E mCRC treated with EC | Encorafenib + cetuximab | Study identified as efficacy-effectiveness analysis; specific OS/PFS/ORR values not provided in retrieved context | https://doi.org/10.1038/s41416-024-02711-w |
| Treatment & outcomes | Real-world treatment-strategy cohort | Real-world outcomes across chemotherapy and later-line BRAF-targeted therapy (zurloh2023impactofencorafenib pages 1-2) | Zurloh 2023, J Cancer Res Clin Oncol | 51 patients with BRAF V600E-mutant mCRC | First-line FOLFOXIRI or FOLFOX/FOLFIRI ยฑ monoclonal antibody; later-line BRAF inhibitor in 17 patients | Median OS 17.6 mo overall; first-line PFS 13.0 mo with FOLFOXIRI vs 4.3 mo with FOLFOX/FOLFIRI; antibody addition associated with improved OS (HR 0.523); targeted therapy associated with OS 25.1 mo; gradeโฅ3 AEs not reported in retrieved context (zurloh2023impactofencorafenib pages 1-2) | https://doi.org/10.1007/s00432-023-05141-y |
| Treatment & outcomes | Real-world multicenter propensity-matched study | Comparative first-line doublet vs triplet chemotherapy plus bevacizumab in BRAF V600E mCRC (wei2024clinicopathologicfeaturesand pages 10-10) | Wei 2024, BMC Cancer | 125 patients from 3 institutions | Triplet-drug vs doublet-drug first-line chemotherapy combined with bevacizumab | Median OS 14.9 mo overall; triplets vs doublets OS 17.4 vs 13.4 mo before PSM and 17.4 vs 10.4 mo after PSM; first-line PFS 6.1 mo overall; no significant PFS/ORR/DCR difference between regimens; gradeโฅ3 AEs not reported in retrieved context (wei2024clinicopathologicfeaturesand pages 10-10) | https://doi.org/10.1186/s12885-024-13171-z |
| Diagnostics / implementation | Biomarker testing workflow | Tissue-based BRAF testing commonly performed with KRAS/NRAS; MSI/MMR testing by IHC and/or PCR; BRAF V600E helps distinguish sporadic MSI-H from Lynch syndrome; ctDNA accepted in some trials for BRAF confirmation and resistance profiling (effendiys2024biomarkersasa pages 3-6, eriksen2022aphaseii pages 1-2, NCT05217446 chunk 1, NCT06578559 chunk 1) | Effendi-YS 2024; Eriksen 2022, BMC Cancer; ClinicalTrials.gov 2022/2024 | CRC biomarker testing / trial eligibility / retreatment | Tissue or plasma BRAF confirmation; MSI/MMR and RAS co-testing; ctDNA for resistance-guided rechallenge | Trial examples: NCT05217446 allows BRAF confirmation from tumor tissue or blood; NCT06578559 requires ctDNA showing no KRAS/NRAS/MAP2K1 mutations and no MET amplification before EC retreatment (NCT05217446 chunk 1, NCT06578559 chunk 1) | https://doi.org/10.5772/intechopen.1004189 ; https://doi.org/10.1186/s12885-022-10420-x ; https://clinicaltrials.gov/study/NCT05217446 ; https://clinicaltrials.gov/study/NCT06578559 |
Table: This table compiles disease metadata, clinicopathologic characteristics, and the most clinically relevant treatment studies for BRAF V600Eโmutant colorectal cancer. It is designed to support rapid knowledge-base population with cited prevalence, phenotype, biomarker, and outcome data.
BEACON updated KaplanโMeier OS curves and tumor response table are available as visual evidence. (tabernero2021encorafenibpluscetuximab media 2b387ba4, tabernero2021encorafenibpluscetuximab media 9dac50ff)
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(NCT05217446 chunk 1): A Study of Encorafenib Plus Cetuximab Taken Together With Pembrolizumab Compared to Pembrolizumab Alone in People With Previously Untreated Metastatic Colorectal Cancer. Pfizer. 2022. ClinicalTrials.gov Identifier: NCT05217446
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(tabernero2021encorafenibpluscetuximab media 2b387ba4): 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, and Scott Kopetz. Encorafenib plus cetuximab as a new standard of care for previously treated braf v600eโmutant metastatic colorectal cancer: updated survival results and subgroup analyses from the beacon study. Journal of Clinical Oncology, 39:273-284, Feb 2021. URL: https://doi.org/10.1200/jco.20.02088, doi:10.1200/jco.20.02088. This article has 608 citations and is from a highest quality peer-reviewed journal.
(tabernero2021encorafenibpluscetuximab media 9dac50ff): 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, and Scott Kopetz. Encorafenib plus cetuximab as a new standard of care for previously treated braf v600eโmutant metastatic colorectal cancer: updated survival results and subgroup analyses from the beacon study. Journal of Clinical Oncology, 39:273-284, Feb 2021. URL: https://doi.org/10.1200/jco.20.02088, doi:10.1200/jco.20.02088. This article has 608 citations and is from a highest quality peer-reviewed journal.
(kopetz2025encorafenibcetuximaband pages 1-2): Scott Kopetz, Takayuki Yoshino, Eric Van Cutsem, Cathy Eng, Tae Won Kim, Harpreet Singh Wasan, Jayesh Desai, Fortunato Ciardiello, Rona Yaeger, Timothy S. Maughan, Elena Beyzarov, Xiaoxi Zhang, Graham Ferrier, Xiaosong Zhang, and Josep Tabernero. Encorafenib, cetuximab and chemotherapy in braf-mutant colorectal cancer: a randomized phase 3 trial. Nature Medicine, 31:901-908, Jan 2025. URL: https://doi.org/10.1038/s41591-024-03443-3, doi:10.1038/s41591-024-03443-3. This article has 106 citations and is from a highest quality peer-reviewed journal.
(cutsem2019binimetinibencorafeniband pages 1-2): Eric Van Cutsem, Sanne Huijberts, Axel Grothey, Rona Yaeger, Pieter-Jan Cuyle, Elena Elez, Marwan Fakih, Clara Montagut, Marc Peeters, Takayuki Yoshino, Harpreet Wasan, Jayesh Desai, Fortunato Ciardiello, Ashwin Gollerkeri, Janna Christy-Bittel, Kati Maharry, Victor Sandor, Jan H.M. Schellens, Scott Kopetz, and Josep Tabernero. Binimetinib, encorafenib, and cetuximab triplet therapy for patients with braf v600eโmutant metastatic colorectal cancer: safety lead-in results from the phase iii beacon colorectal cancer study. Journal of Clinical Oncology, 37:1460-1469, Jun 2019. URL: https://doi.org/10.1200/jco.18.02459, doi:10.1200/jco.18.02459. This article has 273 citations and is from a highest quality peer-reviewed journal.
(randalldemllo2024exvivointestinal pages 4-6): Sarron Randall-Demllo, Ghanyah Al-Qadami, Anita E. Raposo, Chenkai Ma, Ilka K. Priebe, Maryam Hor, Rajvinder Singh, and Kim Y. C. Fung. Ex vivo intestinal organoid models: current state-of-the-art and challenges in disease modelling and therapeutic testing for colorectal cancer. Cancers, 16:3664, Oct 2024. URL: https://doi.org/10.3390/cancers16213664, doi:10.3390/cancers16213664. This article has 4 citations.
(tardito2024epidermalgrowthfactor pages 1-2): Samuele Tardito, Serena Matis, Maria Raffaella Zocchi, Roberto Benelli, and Alessandro Poggi. Epidermal growth factor receptor targeting in colorectal carcinoma: antibodies and patient-derived organoids as a smart model to study therapy resistance. International Journal of Molecular Sciences, 25:7131, Jun 2024. URL: https://doi.org/10.3390/ijms25137131, doi:10.3390/ijms25137131. This article has 24 citations.
(perron2024integrativeensemblemodelling pages 1-2): Umberto Perron, Elena Grassi, Aikaterini Chatzipli, Marco Viviani, Emre Karakoc, Lucia Trastulla, Lorenzo M. Brochier, Claudio Isella, Eugenia R. Zanella, Hagen Klett, Ivan Molineris, Julia Schueler, Manel Esteller, Enzo Medico, Nathalie Conte, Ultan McDermott, Livio Trusolino, Andrea Bertotti, and Francesco Iorio. Integrative ensemble modelling of cetuximab sensitivity in colorectal cancer patient-derived xenografts. Nature Communications, Nov 2024. URL: https://doi.org/10.1038/s41467-024-53163-y, doi:10.1038/s41467-024-53163-y. This article has 13 citations and is from a highest quality peer-reviewed journal.
(potocki2023clinicalcharacterizationof pages 11-12): Paweล M. Potocki, Piotr Wรณjcik, ลukasz Chmura, Bartลomiej Goc, Marcin Fedewicz, Zofia Bielaลska, Jakub Swadลบba, Kamil Konopka, ลukasz Kwinta, and Piotr J. Wysocki. Clinical characterization of targetable mutations (braf v600e and kras g12c) in advanced colorectal cancerโa nation-wide study. International Journal of Molecular Sciences, 24:9073, May 2023. URL: https://doi.org/10.3390/ijms24109073, doi:10.3390/ijms24109073. This article has 15 citations.
(cutsem2019binimetinibencorafeniband pages 6-7): Eric Van Cutsem, Sanne Huijberts, Axel Grothey, Rona Yaeger, Pieter-Jan Cuyle, Elena Elez, Marwan Fakih, Clara Montagut, Marc Peeters, Takayuki Yoshino, Harpreet Wasan, Jayesh Desai, Fortunato Ciardiello, Ashwin Gollerkeri, Janna Christy-Bittel, Kati Maharry, Victor Sandor, Jan H.M. Schellens, Scott Kopetz, and Josep Tabernero. Binimetinib, encorafenib, and cetuximab triplet therapy for patients with braf v600eโmutant metastatic colorectal cancer: safety lead-in results from the phase iii beacon colorectal cancer study. Journal of Clinical Oncology, 37:1460-1469, Jun 2019. URL: https://doi.org/10.1200/jco.18.02459, doi:10.1200/jco.18.02459. This article has 273 citations and is from a highest quality peer-reviewed journal.
BRAF V600E-mutant colorectal cancer is a molecularly defined subtype of colorectal adenocarcinoma characterized by a specific somatic point mutation (valine to glutamic acid at position 600) in the BRAF serine/threonine kinase gene. This mutation results in constitutive activation of the MAPK/ERK signaling pathway, independent of upstream RAS signaling or extracellular growth factor stimuli (PMID: 39961465). The disease is recognized as a distinct clinical entity with unique epidemiology, pathology, molecular biology, treatment response, and prognosis compared to BRAF wild-type CRC.
| Identifier | Value |
|---|---|
| MONDO | MONDO:0005575 (colorectal cancer); no specific subterm for BRAF V600E |
| ICD-10 | C18 (malignant neoplasm of colon), C19-C20 (rectosigmoid/rectum) |
| ICD-11 | 2B90 (malignant neoplasms of colon) |
| MeSH | D015179 (Colorectal Neoplasms) |
| OMIM | 164757 (BRAF gene) |
| COSMIC | COSM476 (BRAF V600E) |
This characterization is derived from aggregated disease-level resources including clinical trial data (BEACON CRC, FIRE-4.5), large cohort studies (TCGA, CAPSTAN CRC), real-world evidence from multi-center registries, and molecular databases (COSMIC, ClinVar, gnomAD).
The primary causal event is the somatic acquisition of the BRAF V600E mutation (c.1799T>A; p.Val600Glu) in colonic epithelial cells. This is a gain-of-function missense mutation that renders the BRAF kinase constitutively active, driving uncontrolled cell proliferation through the RAS-RAF-MEK-ERK (MAPK) signaling cascade (PMID: 39961465). Unlike the conventional adenoma-carcinoma sequence driven by APC mutations, BRAF V600E CRC arises predominantly through the serrated neoplasia pathway, progressing from hyperplastic polyps to sessile serrated lesions (SSLs) to carcinoma (PMID: 23845441).
The mutation is virtually always somatic in origin; germline BRAF V600E mutations are not a recognized cause of hereditary CRC syndromes. BRAF V600E is mutually exclusive with KRAS mutations in CRC, reflecting the functional redundancy of these two oncogenes within the MAPK pathway.
Genetic risk factors: - BRAF V600E mutation (somatic; COSMIC ID: COSM476) โ the defining oncogenic driver - Co-occurring mutations: TP53 mutation is associated with acquired MET amplification upon targeted therapy (PMID: 39313594) - CIMP-high status serves as both a molecular marker and a mechanistic contributor - Lynch syndrome (germline MMR gene mutations) must be excluded; BRAF V600E presence effectively rules out Lynch syndrome in MSI-H CRC
Environmental and lifestyle risk factors: - Advanced age (median age at diagnosis ~62โ68 years across studies) - Female sex (55โ58% of patients are female) (PMID: 39538135; PMID: 39255538) - Smoking โ associated with the serrated pathway and CIMP-positive CRC - Obesity and sedentary lifestyle โ general CRC risk factors - High red/processed meat intake - Age-related accumulation of CpG methylation in colonic mucosa (PMID: 31842975)
Age-dependent and lifestyle-driven DNA methylation changes in the normal colonic mucosa create a permissive epigenetic landscape for BRAF V600E-driven tumorigenesis. A landmark study demonstrated that "age-lifestyle-driven hypermethylation occurs generally in colon carcinogenesis" while "BRAF-mediated TET silencing drives methylation instability specifically in sessile serrated adenomas" (PMID: 31842975). This dual mechanismโenvironmental methylation priming combined with BRAF-driven epigenetic reprogrammingโrepresents a critical gene-environment interaction.
| Phenotype | HPO Term | Frequency | Severity | Onset |
|---|---|---|---|---|
| Colorectal mass/tumor | HP:0100743 (Neoplasm of the colon) | ~100% | Variable | Adult (median 62โ68 years) |
| Right-sided colon involvement | HP:0100743 | 55โ69% | โ | Adult |
| Abdominal pain | HP:0002027 (Abdominal pain) | Common | Mild to severe | Adult |
| Rectal bleeding / hematochezia | HP:0025085 (Bloody stool) | Common | Variable | Adult |
| Iron deficiency anemia | HP:0001891 (Iron deficiency anemia) | Frequent (especially right-sided) | Mild to moderate | Adult |
| Weight loss | HP:0001824 (Weight loss) | Common in advanced disease | Moderate to severe | Adult |
| Change in bowel habits | HP:0025324 (Abnormality of bowel function) | Common | Variable | Adult |
| Peritoneal carcinomatosis | HP:0100244 (Neoplasm of the peritoneum) | 51% at metastasis | Severe | Advanced disease |
| Hepatic metastases | HP:0002896 (Neoplasm of the liver) | 57% at metastasis | Severe | Advanced disease |
| Mucinous histology | โ | 30โ35% | โ | At diagnosis |
| Poorly differentiated histology | HP:0031118 | 30โ35% | Aggressive | At diagnosis |
The BEACON CRC trial demonstrated significantly better quality of life (QoL) with encorafenib-based targeted therapy compared to chemotherapy, assessed using validated patient-reported outcome instruments (PMID: 35653981). However, advanced disease is associated with substantial morbidity including cancer cachexia, bowel obstruction, ascites from peritoneal disease, and treatment-related toxicities.
| Attribute | Value |
|---|---|
| Gene symbol | BRAF |
| HGNC ID | HGNC:1097 |
| OMIM | 164757 |
| Chromosomal location | 7q34 |
| Protein | B-Raf proto-oncogene, serine/threonine kinase |
| UniProt | P15056 |
| Attribute | Value |
|---|---|
| HGVS (DNA) | NM_004333.6:c.1799T>A |
| HGVS (protein) | p.Val600Glu |
| dbSNP | rs113488022 |
| COSMIC | COSM476 |
| Variant type | Missense (T>A transversion) |
| Variant class | Class I BRAF mutation (RAS-independent active monomer) |
| Origin | Somatic |
| Functional consequence | Gain-of-function; constitutive kinase activation |
| Allele frequency (germline) | Extremely rare in gnomAD; essentially absent as germline variant |
| Somatic frequency in CRC | 8โ15% of all CRC; predominant BRAF mutation in CRC |
BRAF V600E is classified as a Class I BRAF mutation that signals as a RAS-independent active monomer, distinguishing it from Class II (RAS-independent dimers) and Class III (kinase-impaired) BRAF mutations (PMID: 29540830).
BRAF V600E CRC is the prototype of epigenetically driven CRC: - CpG Island Methylator Phenotype (CIMP-high): "A CIMP-high (CIMP-H) subgroup, which exhibits an exceptionally high frequency of cancer-specific DNA hypermethylation, is strongly associated with MLH1 DNA hypermethylation and the BRAF(V600E) mutation" (PMID: 21659424) - TET enzyme silencing: BRAF V600E mediates TET silencing, driving methylation instability specifically in sessile serrated adenomas (PMID: 31842975) - Long-range epigenetic silencing (LRES): Concordant methylation across the 3p22 chromosomal region (encompassing MLH1) correlates with CIMP+ and BRAF V600E (PMID: 21102416) - Mucin gene expression: Overexpression of MUC2, MUC5AC, and MUC6 is strongly associated with BRAF V600E, CIMP, and serrated pathway features (PMID: 23807779)
No specific environmental toxins are uniquely linked to BRAF V600E CRC. General CRC environmental risk factors apply: - Processed meat consumption (IARC Group 1 carcinogen for CRC) - Red meat consumption (IARC Group 2A) - Alcohol consumption - Tobacco smoking โ particularly associated with the serrated pathway
BRAF V600E CRC arises through a distinct carcinogenic pathway that diverges from the classical adenoma-carcinoma sequence:
Normal Colonic Epithelium
โ
โผ [BRAF V600E mutation]
Hyperplastic Polyp / Microvesicular Hyperplastic Polyp
โ
โผ [CIMP initiation; TET silencing; age-dependent methylation]
Sessile Serrated Lesion (SSL) โ formerly SSA/P
โ
โผ [MLH1 promoter methylation โ dMMR/MSI-H] OR [p16 loss โ MSS pathway]
SSL with Dysplasia
โ
โผ [Additional mutations: TP53, PIK3CA, etc.]
Invasive Carcinoma (BRAF V600E CRC)
โ
โโโ MSI-H/dMMR pathway (~50-60%): CIMP+/MSI-H/MLH1 methylated
โโโ MSS pathway (~40-50%): CIMP+/MSS โ worse prognosis
"BRAF(V600E) initiates an alternative pathway to colorectal cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma sequence" (PMID: 23845441).
1. RAS-RAF-MEK-ERK (MAPK) Pathway (GO:0000165) - BRAF V600E results in constitutively active kinase activity (~500-fold increased activity vs. wild-type) - Signal propagation: BRAF(V600E) โ MEK1/2 โ ERK1/2 โ nuclear transcription factors (ELK1, MYC, FOS) - Drives cell proliferation, survival, and resistance to apoptosis
2. PI3K-AKT-mTOR Pathway (GO:0043491) - Cross-talk with MAPK pathway provides survival signaling - Compensatory upregulation upon BRAF inhibition contributes to resistance
3. Wnt/ฮฒ-Catenin Pathway (GO:0016055) - Activated through HSPA8-mediated CMA-dependent degradation of CAV1 - "HSPA8 is transcriptionally upregulated in BRAF V600E CRC, which promotes CMA-dependent degradation of caveolin-1 (CAV1) to release ฮฒ-catenin into the nucleus and thus activates the Wnt/ฮฒ-catenin pathway" (PMID: 37973552)
4. Epigenetic Reprogramming - BRAF V600E-mediated TET enzyme silencing โ global methylation instability - CIMP-high phenotype โ silencing of tumor suppressor genes (MLH1, p16/CDKN2A, MGMT, RASSF2)
Acquired resistance to BRAF-targeted therapy involves convergent MAPK reactivation: - "Genotyping of resistant cells identified gene amplification of EGFR, KRAS, and mutant BRAF, as well as acquired mutations in KRAS, EGFR, and MAP2K1" (PMID: 27312529) - "RAS, MAP2K1 and MET alterations were most commonly acquired with Enco+CetuxยฑBini, and more frequent in patients with a high baseline cell-cycle gene signature; baseline TP53 mutation was associated with acquired MET amplification" (PMID: 39313594) - Resistance is polyclonal and subclonal, suggesting multiple parallel escape mechanisms
Transcriptomic subtyping: - BRAF V600E CRC maps predominantly to CMS1 (MSI Immune) when MSI-H, or CMS4 (Mesenchymal) when MSS - CMS1 tumors show high immune infiltration and activation of immune checkpoints - CMS4 tumors have high stromal content and poor prognosis (PMID: 31678770; PMID: 41736753)
Multi-omics integration: - Proteomic and phosphoproteomic analysis of BRAF V600E CRC cells treated with BRAF inhibitors reveals widespread upregulation of receptor tyrosine kinases and metabolic pathway rewiring (PMID: 29970458) - "Widespread up-regulation of receptor tyrosine kinases and metabolic pathways upon BRAF inhibition" suggests adaptive resistance mechanisms
| Level | Structure | UBERON Term | Frequency |
|---|---|---|---|
| Primary | Right/proximal colon (cecum, ascending colon) | UBERON:0001156 (ascending colon) | 55โ69% |
| Primary | Left colon, rectum | UBERON:0001159 (sigmoid colon) | 31โ45% |
| Secondary | Liver (metastases) | UBERON:0002107 | 57% of mCRC |
| Secondary | Peritoneum (carcinomatosis) | UBERON:0002358 | 51% of mCRC |
| Secondary | Lung (metastases) | UBERON:0002048 | 20โ30% |
| Secondary | Distant lymph nodes | UBERON:0000029 | Common |
Precursor โ Cancer Timeline: - SSLs are estimated to progress to carcinoma over 10โ20 years, though the interval may be shorter than for conventional adenomas, explaining the association with "interval cancers" (PMID: 31158302) - SSLs can "rapidly become dysplastic or invasive carcinomas" once dysplasia develops
Cancer Staging (AJCC TNM):
| Stage | Description | Relevance to BRAF V600E |
|---|---|---|
| Stage IโII | Localized disease | May have favorable prognosis if MSI-H |
| Stage III | Regional lymph node involvement | Poor prognosis marker; adjuvant chemotherapy recommended |
| Stage IV | Distant metastases | Median OS ~14.9 months; defines the aggressive clinical phenotype |
Disease course: Progressive without treatment; rapid dissemination, particularly to peritoneum and liver.
| Metric | Value | Source |
|---|---|---|
| Frequency in all CRC | 8โ15% | PMID: 25005754; PMID: 34249672 |
| Frequency in mCRC | 8โ12% | PMID: 34249672 |
| Median OS (mCRC) | 14.9 months | PMID: 39538135 |
| Median PFS (first-line) | 6.1 months | PMID: 39538135 |
BRAF V600E in CRC is a somatic mutation โ not inherited. There is no germline predisposition syndrome associated with this specific variant in CRC. Importantly, the presence of BRAF V600E in an MSI-H CRC effectively excludes Lynch syndrome, which is caused by germline mutations in MMR genes (MLH1, MSH2, MSH6, PMS2).
BRAF V600E mutation testing is now recommended for all patients with mCRC to guide treatment decisions (PMID: 35248712).
| Test | Method | Clinical Utility |
|---|---|---|
| BRAF V600E IHC | VE1 antibody immunohistochemistry | Rapid screening; high sensitivity/specificity |
| BRAF mutation PCR | Allele-specific PCR (e.g., Cobas, Idylla) | Standard confirmatory test |
| NGS gene panels | Next-generation sequencing | Comprehensive profiling including RAS, BRAF, MSI, TMB |
| MSI testing | PCR-based (e.g., Bethesda markers) or NGS-based | Identifies MSI-H subset for immunotherapy |
| MMR IHC | MLH1, MSH2, MSH6, PMS2 antibodies | Complementary to MSI testing |
| ctDNA / liquid biopsy | Cell-free DNA analysis | Non-invasive monitoring; detects resistance mutations |
Circulating tumor DNA (ctDNA) analysis offers non-invasive molecular profiling and can detect BRAF V600E and resistance mutations (PMID: 41515890; PMID: 37064498). In one reported case, ctDNA testing uncovered MSI-H status missed by tissue NGS, changing the treatment approach (PMID: 37064498).
| Outcome Measure | Value | Context | Source |
|---|---|---|---|
| Median OS (mCRC, overall) | 14.9 months | All treatment lines | PMID: 39538135 |
| Median OS (mCRC, real-world) | 13.7 months | Multi-center retrospective | PMID: 39935752 |
| Median PFS (first-line) | 6.1 months | All regimens | PMID: 39538135 |
| Median OS (encorafenib + cetuximab) | 9.3 months | vs. 5.9 months control (2L+) | PMID: 35653981 |
| Median OS (MSI-H, BRAF V600E, with ICI) | 19 months | vs. 113 months BRAF WT | PMID: 39932790 |
| 12-month OS rate (encorafenib triplet, meta-analysis) | 44% (95% CI: 29โ66%) | Pooled clinical + real-world | PMID: 41677963 |
Poor prognostic factors: - ECOG performance status โฅ1 (PMID: 39255538) - โฅ3 metastatic sites (PMID: 41761577) - Elevated CRP (PMID: 41761577) - Unresected primary tumor - Synchronous metastases (HR 1.66 for PFS; HR 1.71 for OS) (PMID: 39255538) - High CEA level (HR 1.72 for OS) (PMID: 39255538) - MSS status (vs. MSI-H) - Peritoneal metastases - Treatment beyond second line
Favorable prognostic factors: - MSI-H status (better response to immunotherapy, though still worse than BRAF WT MSI-H) - Initially resectable metastases (median OS 37.07 vs. 20.20 months for unresectable) (PMID: 37455182) - Low CytoLym high / CAF low tumor microenvironment pattern (PMID: 31504112)
No universally accepted BRAF-specific first-line standard exists. Options include:
| Regimen | Evidence | ORR | Median PFS |
|---|---|---|---|
| FOLFOXIRI + bevacizumab | Phase III trials; preferred intensive option | ~60โ67% | 8.8 months |
| FOLFOX/FOLFIRI + bevacizumab | Standard doublet; most common real-world choice | 30โ47% | 6โ7 months |
| VIC (vemurafenib + irinotecan + cetuximab) | Chinese real-world data; emerging | 60% | 12.7 months |
(PMID: 37352476; PMID: 37455182; PMID: 36368253)
Encorafenib + Cetuximab ยฑ Binimetinib (BEACON regimen) โ MAXO:0000058 (targeted therapy)
The BEACON CRC trial established this as the definitive standard: "encorafenib plus cetuximab with binimetinib {9.3 versus 5.9 months; hazard ratio (HR) [95% confidence interval (CI)]: 0.60 [0.47-0.75]} or without binimetinib [9.3 versus 5.9 months; HR (95% CI): 0.61 (0.48-0.77)] significantly improved overall survival (OS) compared with the previous standard of care" (PMID: 35653981).
Real-world data confirm trial results:
| Study | N | ORR | Median PFS | Median OS |
|---|---|---|---|---|
| BEACON CRC (phase III) | 665 | 26โ27% | 4.3โ4.5 months | 9.3 months |
| Italian real-world | 133 | 23% | 4.5 months | 7.2 months |
| French AGEO real-world | 201 | 32.2% | 4.5 months | 9.2 months |
| BEETS (Japan) real-world | 195 | 27.6% | 4.9 months | 12.9 months |
| Japanese EAP | 81 | 27.6% | 5.26 months | 10.38 months |
| Meta-analysis (pooled) | 487 | 35% | 4.89 months | 9.75 months |
(PMID: 35696748; PMID: 39255538; PMID: 41761577; PMID: 38553360; PMID: 41677963)
| Agent/Combination | Target | Phase | NCT/Status |
|---|---|---|---|
| Encorafenib + cetuximab + pembrolizumab | BRAF + EGFR + PD-1 | Phase II (SEAMARK) | Active |
| Pan-RAF inhibitors | All RAF isoforms | Early phase | Preclinical/Phase I |
| Brain-penetrant BRAF inhibitors | CNS metastases | Preclinical | Emerging |
| HSPA8 inhibitor (VER155008) + BRAF inhibitor | HSPA8/CMA pathway | Preclinical | PMID: 37973552 |
| MCL-1 antagonism + cobimetinib | MCL-1 + MEK | Preclinical | PMID: 27765849 |
Encorafenib + cetuximab: Generally well-tolerated. Most common adverse events include: - Asthenia (62%) - Anti-EGFR skin rash (52%) - Nausea, vomiting, diarrhea (more frequent with triplet) (PMID: 35696748) - Grade โฅ3 adverse events in 21โ43% of patients - Melanocytic nevi (less common with triplet)
No well-characterized naturally occurring BRAF V600E-driven colorectal cancer has been reported in companion animals or wildlife. The serrated pathway appears to be predominantly a human disease phenotype.
| Model | Features | Phenotype Recapitulation | Reference |
|---|---|---|---|
| Braf(V600E) intestinal model | Conditional Braf V600E expression in intestinal epithelium | Initiates serrated pathway; hyperplasia โ adenoma โ carcinoma | PMID: 23845441 |
| Braf(V600E) + Cdkn2a loss | BRAF V600E with p16 deletion | Models MSS BRAF-mutant CRC; spontaneous malignant transition | PMID: 31935636 |
| CRISPR-engineered colonic organoids | Sequential BRAF V600E + additional hits | Orthotopic preclinical model of serrated CRC | PMID: 29666172 |
| Cell Line | BRAF Status | MSI Status | Applications |
|---|---|---|---|
| HT-29 | BRAF V600E | MSS | Drug screening, signaling studies |
| RKO | BRAF V600E | MSI-H | Epigenetics, immune studies |
| COLO-205 | BRAF V600E | MSS | Drug resistance studies |
| NCM460 (engineered) | BRAF V600E overexpression | โ | Mechanistic studies |
CRISPR/Cas9 genome engineering of human colonic organoids with sequential introduction of serrated CRC-associated mutations provides "a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis" (PMID: 29666172).
BRAF V600E mutation occurs in 8โ15% of colorectal cancers and defines a distinct molecular subtype with poor prognosis. The median OS in the metastatic setting is approximately 14.9 months, with a median first-line PFS of 6.1 months. The mutation is strongly associated with right-sided tumors (55โ69%), female sex (55โ58%), older age, poorly differentiated/mucinous histology, MSI-H status, and CIMP-positive phenotype (PMID: 39538135; PMID: 25005754; PMID: 34249672).
BRAF V600E drives CRC through the serrated neoplasia pathway via constitutive MAPK/ERK activation and epigenetic silencing. The V600E mutation results in constitutively active kinase domain signaling independent of extracellular stimuli, initiating an alternative pathway to CRC that progresses through a hyperplasia/adenoma/carcinoma sequence. BRAF-mediated TET enzyme silencing drives methylation instability specifically in sessile serrated adenomas, while CIMP-H is strongly associated with MLH1 DNA hypermethylation (PMID: 39961465; PMID: 23845441; PMID: 21659424; PMID: 31842975).
Encorafenib plus cetuximab (with or without binimetinib) is the standard of care for previously treated BRAF V600E mCRC based on the BEACON CRC trial (OS 9.3 vs. 5.9 months; HR 0.60โ0.61). Real-world data from multiple countries consistently confirm these results, with ORR 23โ35%, median PFS 4.2โ5.3 months, and median OS 7.2โ12.9 months. Quality of life was also significantly better with targeted therapy versus chemotherapy (PMID: 35653981; PMID: 41677963).
Acquired resistance to BRAF-targeted therapy involves convergent MAPK reactivation through multiple genetic mechanisms including gene amplification of EGFR, KRAS, and mutant BRAF, as well as acquired mutations in KRAS, EGFR, MAP2K1, and MET. Resistance is polyclonal and subclonal, with baseline TP53 mutation predisposing to acquired MET amplification (PMID: 27312529; PMID: 39313594).
Approximately 50โ60% of BRAF V600E CRCs harbor MSI-H status and respond to immune checkpoint inhibitors. However, BRAF V600E within MSI-H CRC confers significantly worse outcomes compared to BRAF wild-type MSI-H CRC (median OS 19 vs. 113 months; HR 2.69). The SEAMARK trial is investigating combination targeted therapy plus immunotherapy for this dual-feature population (PMID: 39932790; PMID: 34249672; PMID: 37815847).
The pathobiology of BRAF V600E CRC can be understood as a convergence of oncogenic signaling, epigenetic reprogramming, and immune microenvironment modulation:
BRAF V600E Mutation (Somatic)
โ
โโโโโโโโโโโโโโโโโผโโโโโโโโโโโโโโโโ
โผ โผ โผ
Constitutive MAPK TET Silencing HSPA8 Upregulation
(ERK1/2 activation) (Methylation (CMA โ CAV1 degradation
โ instability) โ ฮฒ-catenin release)
โ โ โ
โผ โผ โผ
Cell Proliferation CIMP-High Wnt/ฮฒ-Catenin
Apoptosis Resistance (TSG silencing) Pathway Activation
โ โ โ
โ โโโโโโโดโโโโโโ โ
โ โผ โผ โ
โ MLH1 silenced p16 lost โ
โ โ MSI-H path โ MSS path โ
โ โ โ โ
โโโโโโฌโโโโโดโโโโโโโโโโโโดโโโโโฌโโโโโ
โผ โผ
SSL โ Dysplasia โ Invasive Carcinoma
โ
โโโโโโโโโโโดโโโโโโโโโโโ
โผ โผ
MSI-H/Immunogenic MSS/Immune-cold
(CMS1; ICI-responsive) (CMS4; ICI-resistant)
This model explains several clinical observations: 1. Right-sided predilection: The serrated pathway is concentrated in the proximal colon 2. Age association: Age-dependent methylation primes the epigenome 3. Dual MSI/MSS tracks: MLH1 methylation status determines the immune phenotype 4. Treatment resistance: Multiple parallel resistance mechanisms (KRAS, MET, MAP2K1) converge on MAPK reactivation 5. Worse prognosis despite MSI-H: BRAF V600E may impair immune function even in the immunogenic MSI-H context
| Study | Design | Key Result | PMID |
|---|---|---|---|
| BEACON CRC | Phase III RCT | Encorafenib + cetuximab ยฑ binimetinib: OS 9.3 vs 5.9 mo | 35653981 |
| FIRE-4.5 | Phase II RCT | FOLFOXIRI + cetuximab vs bevacizumab; ORR 51% vs 67% | 37352476 |
| BEETS (JACCRO CC-18) | Prospective observational | Real-world triplet vs doublet; comparable outcomes | 41761577 |
| SEAMARK | Phase II (ongoing) | Encorafenib + cetuximab + pembrolizumab for MSI-H | 37815847 |
| Study Focus | Key Insight | PMID |
|---|---|---|
| Serrated pathway progression | BRAF V600E initiates alternative hyperplasiaโadenomaโcarcinoma pathway | 23845441 |
| CIMP and methylation | CIMP-H strongly associated with MLH1 methylation and BRAF V600E | 21659424 |
| TET silencing | BRAF-mediated TET silencing drives methylation instability in SSAs | 31842975 |
| HSPA8/Wnt axis | HSPA8 activates Wnt/ฮฒ-catenin via CMA-mediated CAV1 degradation | 37973552 |
| Resistance mechanisms | EGFR/KRAS/BRAF amplification and KRAS/MAP2K1/MET mutations | 27312529 |
| BEACON molecular profiling | RAS, MAP2K1, MET most commonly acquired; TP53โMET link | 39313594 |
First-line therapy optimization: No definitive BRAF V600E-specific first-line standard exists. Whether to use targeted therapy (BRAF + EGFR inhibition) upfront versus reserving it for second-line remains an open question.
MSI-H/BRAF V600E combination therapy: The optimal strategy for the dual MSI-H/BRAF V600E population is under investigation (SEAMARK trial). Whether combined targeted + immune therapy outperforms either approach alone is unknown.
MSS/BRAF V600E immunotherapy: The MSS subset (~40โ50%) does not respond to current immunotherapy regimens. Novel strategies to convert "cold" tumors to "hot" are needed.
Resistance biology: While resistance mechanisms are increasingly characterized, effective strategies to prevent or overcome polyclonal resistance remain limited. No approved therapies exist for post-BEACON progression.
Biomarker refinement: Better stratification within BRAF V600E CRC (e.g., CIMP subclasses, tumor microenvironment phenotyping, ctDNA dynamics) could enable more personalized therapy.
Prevention gaps: Detection of sessile serrated lesions remains suboptimal due to their flat, subtle endoscopic appearance. AI-assisted colonoscopy may improve detection rates but requires validation.
Ethnic and geographic variation: Most clinical trial data come from Western and Japanese populations. Data from other ethnic groups, particularly Middle Eastern populations (where BRAF V600E CRC is rare), are limited.
Long-term survivors: The biology of rare long-term responders to targeted therapy or immunotherapy is poorly understood and may reveal actionable insights.
SEAMARK trial results: Await and analyze the results of first-line encorafenib + cetuximab + pembrolizumab for MSI-H/dMMR BRAF V600E mCRC to determine whether combination targeted + immune therapy should become the new standard.
First-line targeted therapy trials: Design and execute phase III trials comparing upfront BRAF/EGFR inhibition versus FOLFOXIRI + bevacizumab in the first-line metastatic setting.
Resistance monitoring with ctDNA: Implement longitudinal ctDNA monitoring in patients on BEACON-based therapy to detect resistance mutations early and enable adaptive treatment switching.
Pan-RAF inhibitor development: Evaluate next-generation pan-RAF inhibitors and brain-penetrant BRAF inhibitors to overcome dimerization-dependent resistance and treat CNS metastases.
Immunotherapy combinations for MSS tumors: Explore novel combination strategies (e.g., BRAF/MEK inhibition + anti-PD-1 + anti-CTLA-4, or with oncolytic viruses) to render MSS/BRAF V600E tumors immunotherapy-responsive.
HSPA8 targeting: Pursue clinical development of HSPA8 inhibitors (e.g., VER155008) in combination with BRAF inhibitors, based on promising preclinical synergy data.
AI-assisted colonoscopy: Validate and implement AI-powered polyp detection systems to improve the identification and complete removal of sessile serrated lesions.
Single-cell and spatial transcriptomics: Apply these technologies to characterize tumor heterogeneity, immune microenvironment, and clonal architecture in treatment-naรฏve and resistant BRAF V600E CRC specimens.
Epigenetic therapy: Investigate whether demethylating agents (e.g., azacitidine, decitabine) can reverse CIMP-driven gene silencing and sensitize tumors to targeted or immune therapy.
Patient-derived organoid biobanks: Establish comprehensive biobanks of BRAF V600E CRC organoids for high-throughput drug screening and personalized treatment prediction.
| Category | Terms |
|---|---|
| MONDO | MONDO:0005575 (colorectal cancer) |
| HPO | HP:0100743 (Neoplasm of the colon), HP:0002027 (Abdominal pain), HP:0001891 (Iron deficiency anemia), HP:0001824 (Weight loss), HP:0002896 (Neoplasm of the liver), HP:0100244 (Neoplasm of the peritoneum) |
| GO (Biological Process) | GO:0000165 (MAPK cascade), GO:0016055 (Wnt signaling), GO:0006915 (Apoptotic process), GO:0008283 (Cell proliferation), GO:0001837 (EMT), GO:0043491 (protein kinase B signaling) |
| GO (Cellular Component) | GO:0005829 (Cytosol), GO:0005886 (Plasma membrane), GO:0005634 (Nucleus), GO:0005764 (Lysosome) |
| CL (Cell Ontology) | CL:1000320 (Goblet cell of colon), CL:0002250 (Colonic stem cell), CL:0000084 (T cell), CL:0002553 (Fibroblast of colon) |
| UBERON | UBERON:0001156 (Ascending colon), UBERON:0001159 (Sigmoid colon), UBERON:0002107 (Liver), UBERON:0002358 (Peritoneum) |
| CHEBI | CHEBI:90227 (Encorafenib), CHEBI:75047 (Cetuximab), CHEBI:90870 (Binimetinib), CHEBI:63637 (Vemurafenib) |
| MAXO | MAXO:0000058 (Targeted therapy), MAXO:0000004 (Surgical procedure), MAXO:0001298 (Chemotherapy), MAXO:0000750 (Colonoscopy) |
Report generated from comprehensive literature review of 67 publications spanning molecular biology, clinical trials, real-world evidence, and translational research in BRAF V600E-mutant colorectal cancer.