BRAF V600E-Mutant Non-Small Cell Lung Cancer

MONDO:0005233 Pathograph 14 Show in embeddings browser non-small cell lung carcinoma

BRAF V600E-mutant non-small cell lung cancer (NSCLC) is a molecularly defined lung-cancer subtype whose tumor cells carry the somatic BRAF c.1799T>A (p.Val600Glu) driver. The class-I mutant signals as a RAS-independent active monomer and sustains MEK-ERK output, creating a therapeutically actionable oncogene dependence. Most reported tumors are adenocarcinomas, but this entry remains scoped to NSCLC because BRAF V600E is a molecular classifier rather than a histology-exclusive entity. Dual BRAF/MEK inhibition with dabrafenib plus trametinib or encorafenib plus binimetinib has prospective phase-II evidence in metastatic disease. Acquired resistance can reactivate MAPK signaling or engage bypass pathways, so repeat molecular assessment at progression is clinically informative.

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8
Pathophys.
1
Histopath.
3
Phenotypes
2
Hypotheses
4
Gaps
14
Pathograph
1
Genes
4
Medical Actions
2
Differentials
3
Trials
3
Models
21
References
2
Deep Research
🏷

Classifications

ICD-O Morphology
Carcinoma
Harrison's Part
ONCOLOGY HEMATOLOGY
◈

Mechanistic Hypotheses

2
Canonical BRAF V600E Lung-Tumor Model
canonical_braf_v600e_lung_tumor_model CANONICAL
Evidence balance 1 support
Somatic BRAF V600E produces RAS-independent monomeric RAF activity and sustained MEK-ERK signaling. In a permissive lung epithelial context, cooperating loss of tumor-suppressor or lineage-control programs permits MAPK-driven proliferation and survival to progress to invasive NSCLC. BRAF V600E alone can initiate proliferation yet also provoke a senescence-like arrest, so the mutation is a driver but not a complete mechanistic explanation for malignant progression.
Pathograph links
Somatic BRAF p.Val600Glu Driver -> Sustained MEK-ERK Signaling DIRECT Constitutive mutant BRAF kinase activity sustains MEK1/2-ERK1/2 pathway output.
Sustained MEK-ERK Signaling -> MAPK-Dependent Tumor-Cell Proliferation and Survival DIRECT Sustained pathway activity maintains the proliferative and survival program of BRAF-driven lung tumor cells.
MAPK-Dependent Tumor-Cell Proliferation and Survival -> Lung Adenocarcinoma INDIRECT KNOWN INTERMEDIATES In a permissive lung epithelial context, sustained growth and survival contribute to the predominantly adenocarcinoma tumor phenotype. Intermediates: clonal expansion; escape from oncogene-induced growth arrest; malignant transformation
Cooperating Tumor-Suppressor and Lineage-State Alterations -> Lung Adenocarcinoma INDIRECT KNOWN INTERMEDIATES Cooperation permits BRAF-initiated lesions to progress to malignant lung adenocarcinoma. Intermediates: bypass of senescence-like proliferative arrest; dedifferentiation or lineage-state change; malignant progression
Lung Adenocarcinoma -> Invasion and Metastatic Dissemination INDIRECT KNOWN INTERMEDIATES Advanced primary tumors can acquire invasive and metastatic behavior. Intermediates: local invasion; intravasation and hematogenous dissemination; distant-organ colonization
Invasion and Metastatic Dissemination -> Brain Metastases INDIRECT KNOWN INTERMEDIATES Metastatic dissemination can culminate in secondary brain tumors. Intermediates: hematogenous dissemination; blood-brain barrier transit; central nervous system colonization
Show evidence (1 reference)
PMID:17299132 SUPPORT Model Organism
"BRaf(VE) expression initially induced proliferation that was followed by growth arrest bearing certain hallmarks of senescence. Consistent with Ink4a/Arf and TP53 tumor suppressor function, BRaf(VE) expression combined with mutation of either locus led to cancer progression."
The lung-specific model separates oncogene-driven initiation from cooperating malignant progression.
Acquired BRAF/MEK-Inhibitor Resistance Model
acquired_braf_meck_resistance_model CANONICAL
Evidence balance 1 support
Dual BRAF/MEK inhibition imposes treatment selection on heterogeneous tumor clones. Progression can arise through renewed MAPK output, PI3K-pathway signaling, receptor-kinase copy-number changes, or lineage-state changes. The class structure is established, but no single alteration explains every resistant tumor.
Pathograph links
BRAF-MEK Inhibitor Selection Pressure -> MAPK Reactivation and Bypass Resistance INDIRECT KNOWN INTERMEDIATES Selection enriches genetic states capable of restoring growth despite BRAF/MEK inhibition. Intermediates: survival of resistant subclones; clonal expansion during pathway inhibition
MAPK Reactivation and Bypass Resistance -> Progressive Metastatic Disease INDIRECT KNOWN INTERMEDIATES Resistant signaling permits renewed growth and radiologic or clinical progression. Intermediates: restoration of proliferative and survival signaling; expansion of treatment-resistant tumor clones
Show evidence (1 reference)
PMID:32859654 SUPPORT Human Clinical
"Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in U2AF1, IDH1, and CTNNB1."
Prospective ctDNA profiling supports multiple genomic resistance classes and incomplete explanatory yield.
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Discussions and Knowledge Gaps

4
How should dabrafenib-trametinib, encorafenib-binimetinib, chemotherapy, and immune-checkpoint-based regimens be sequenced in first-line and later-line metastatic BRAF V600E NSCLC?
KNOWLEDGE GAP OPEN gap_braf_v600e_first_line_sequencing
Attached to
treatments#Dabrafenib Plus Trametinib treatments#Encorafenib Plus Binimetinib
Both targeted combinations have single-arm phase-II evidence, while chemotherapy and immunotherapy comparisons are retrospective and small. Cross-trial outcome differences cannot establish comparative superiority.
Show evidence (2 references)
PMID:40480428 SUPPORT Human Clinical
"In this ongoing open-label, single-arm, phase 2 study, patients with BRAF V600E-mutant mNSCLC"
PHAROS is explicitly single-arm and therefore cannot answer the head-to-head sequencing question.
PMID:40138888 SUPPORT Human Clinical
"Due to the low incidence of BRAF mutations, limited data is available about their prevalence and clinical characteristics. Moreover, comparative real-world efficacy of dabrafenib combined with trametinib versus other treatment regimens, especially in Chinese patients, is also lacking."
The study itself identifies the comparative-evidence limitation.
Which genomic and lineage-state resistance mechanisms are recurrent, actionable, and causally sufficient after dual BRAF/MEK inhibition?
KNOWLEDGE GAP OPEN gap_braf_v600e_resistance_map
Attached to
pathophysiology#MAPK Reactivation and Bypass Resistance
Prospective plasma profiling identifies multiple candidate mechanisms but explains only a subset of progression events. Tissue-based, longitudinal, and functional validation is needed to separate causal drivers from passenger alterations.
Show evidence (1 reference)
PMID:32859654 SUPPORT Human Clinical
"Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients"
The 46% yield directly demonstrates a substantial unexplained fraction.
Which human lung epithelial cell states and cooperating lesions convert BRAF V600E initiation into invasive human NSCLC?
HUMAN MODEL MISMATCH OPEN gap_braf_v600e_model_fidelity
Attached to
pathophysiology#Cooperating Tumor-Suppressor and Lineage-State Alterations experimental_models#Isogenic BRAF V600E Knock-In BEAS-2B Lung Epithelial Cells
Mouse models strongly support TP53, CDKN2A, PI3K, and NKX2-1 cooperation, while the human BEAS-2B knock-in model shows state changes but not complete carcinogenesis. Their relative importance in human tumors remains incompletely resolved.
Show evidence (1 reference)
PMID:40439425 SUPPORT In Vitro
"Although the BRAF V600E mutation alone was not sufficient to drive lung carcinogenesis"
The human isogenic model explicitly exposes the incomplete-transformation gap.
Is thromboembolism, particularly cancer-related stroke, genuinely enriched in BRAF V600E-mutant NSCLC?
KNOWLEDGE GAP OPEN gap_braf_v600e_thromboembolism_signal
A retrospective series observed a high event fraction, but it contained only ten patients and had a very wide confidence interval. The signal is hypothesis-generating and is not modeled as an established phenotype or subtype-specific incidence estimate.
Show evidence (1 reference)
PMID:36697098 SUPPORT Human Clinical
"Of 10 patients with BRAF-V600E mutant lung cancer, five developed a total of seven thromboembolic events, showing a 1-year cumulative incidence of 43% (95% confidence interval=11-72%)."
The small sample and wide interval justify retaining the observation as an open question.
⚙

Pathophysiology

8
Somatic BRAF p.Val600Glu Driver
The tumor-acquired BRAF c.1799T>A substitution encodes p.Val600Glu in the kinase activation segment. BRAF V600 variants form class I: they are RAS-independent, signal as active monomers, and are susceptible to RAF monomer inhibitors. This disease entry concerns the V600E allele in NSCLC, not class-II or class-III non-V600 BRAF tumors.
Canonical BRAF V600E Lung-Tumor Model
BRAF hgnc:1097 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BRAF (hgnc:1097). hgnc:1097 is a gene from the HUGO Gene Nomenclature Committee.
protein serine/threonine kinase activity GO:0004674 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased protein serine/threonine kinase activity (GO:0004674). GO:0004674 is a molecular function from the Gene Ontology. ↑ INCREASED
Experimental models
Isogenic BRAF V600E Knock-In BEAS-2B Lung Epithelial Cells CELL LINE Introduces the defining driver into an isogenic human lung epithelial background.
Downstream
Sustained MEK-ERK Signaling Constitutive mutant BRAF kinase activity sustains MEK1/2-ERK1/2 pathway output. Canonical BRAF V600E Lung-Tumor Model
Show evidence (2 references)
PMID:28783719 SUPPORT In Vitro
"Class 1 BRAF mutations (BRAF V600 mutations) are RAS-independent, signal as monomers and are sensitive to current RAF ‘monomer’ inhibitors."
The functional-classification study directly defines the signaling behavior of BRAF V600 mutations.
PMID:28919011 SUPPORT Human Clinical
"BRAFV600E mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver."
The molecularly selected clinical trial identifies V600E as an oncogenic lung-cancer driver.
Sustained MEK-ERK Signaling
Persistent RAF output activates the MEK-ERK cascade independently of an upstream RAS requirement. In established tumors this pathway maintains growth and survival, while in normal lung epithelial contexts the same oncogenic signal can also trigger a growth-arrest barrier.
Canonical BRAF V600E Lung-Tumor Model
ERK1 and ERK2 cascade GO:0070371 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ERK1 and ERK2 cascade (GO:0070371). GO:0070371 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
MAPK-Dependent Tumor-Cell Proliferation and Survival Sustained pathway activity maintains the proliferative and survival program of BRAF-driven lung tumor cells. Canonical BRAF V600E Lung-Tumor Model
Show evidence (1 reference)
PMID:17299132 SUPPORT Model Organism
"Mutationally activated BRAF(V600E) (BRAF(VE)) is detected in approximately 6% of human malignancies and promotes sustained MEK1/2-ERK1/2 pathway activation."
The model establishes sustained MEK-ERK output downstream of the mutant kinase.
MAPK-Dependent Tumor-Cell Proliferation and Survival
BRAF-MEK-ERK activity promotes expansion and persistence of transformed lung epithelial cells. BRAF V600E alone does not invariably complete malignant transformation: experimental lung systems show an initial proliferative phase followed by arrest, making cooperating lesions and cell state important modifiers.
Canonical BRAF V600E Lung-Tumor Model
pulmonary alveolar type 2 cell CL:0002063 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pulmonary alveolar type 2 cell (CL:0002063). CL:0002063 is a cell type from the Cell Ontology.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↓ DECREASED
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Isogenic BRAF V600E Knock-In BEAS-2B Lung Epithelial Cells CELL LINE Measures migration, tumorigenic potential, adhesion, EMT, and metabolic state changes after knock-in.
Downstream
Lung Adenocarcinoma In a permissive lung epithelial context, sustained growth and survival contribute to the predominantly adenocarcinoma tumor phenotype. Canonical BRAF V600E Lung-Tumor Model
Show evidence (1 reference)
PMID:17299132 SUPPORT Model Organism
"BRaf(VE) expression initially induced proliferation that was followed by growth arrest bearing certain hallmarks of senescence."
The model directly demonstrates both the initial proliferative output and its intrinsic limitation.
Cooperating Tumor-Suppressor and Lineage-State Alterations
Loss of TP53 or CDKN2A can bypass the senescence-like arrest of BRAF-initiated lung lesions. PIK3CA activation can promote dedifferentiation, while NKX2-1 loss changes lineage identity and reduces cell-cycle exit during BRAF/MEK inhibition. These are experimentally supported cooperation routes, not lesions required in every human tumor.
Canonical BRAF V600E Lung-Tumor Model
TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee. CDKN2A hgnc:1787 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CDKN2A (hgnc:1787). hgnc:1787 is a gene from the HUGO Gene Nomenclature Committee. PIK3CA hgnc:8975 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PIK3CA (hgnc:8975). hgnc:8975 is a gene from the HUGO Gene Nomenclature Committee. NKX2-1 hgnc:11825 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NKX2-1 (hgnc:11825). hgnc:11825 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Lung Adenocarcinoma Cooperation permits BRAF-initiated lesions to progress to malignant lung adenocarcinoma. Canonical BRAF V600E Lung-Tumor Model
Show evidence (3 references)
PMID:26001956 SUPPORT Model Organism
"secondary genetic events can promote bypass of the senescence-like proliferative arrest displayed by BRAF(V600E)-induced lung adenomas, leading to malignant progression."
The two-switch model directly supports tumor-suppressor cooperation in malignant progression.
PMID:31452510 SUPPORT Model Organism
"Cooperating alterations that activate PI3'-lipid signaling promote progression of BRAFV600E-driven benign tumors to malignant adenocarcinoma."
The engineered model supports PI3K-pathway cooperation with BRAF V600E.
PMID:33821796 SUPPORT Model Organism
"NKX2-1-deficient, BRAFV600E-driven tumors resemble human IMA and exhibit a distinct response to BRAF/MEK inhibitors."
The model connects lineage-factor loss to tumor identity and altered treatment response.
Lung Adenocarcinoma
The dominant histologic manifestation is malignant gland-forming NSCLC in the lung. This mechanism node represents the established primary tumor state and connects molecular growth programs to later invasion and dissemination.
Canonical BRAF V600E Lung-Tumor Model
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Invasion and Metastatic Dissemination Advanced primary tumors can acquire invasive and metastatic behavior. Canonical BRAF V600E Lung-Tumor Model
Show evidence (1 reference)
PMID:35814395 SUPPORT Human Clinical
"In addition, 96.2% of the patients had adenocarcinoma"
The selected cohort supports adenocarcinoma as the predominant tissue-level tumor state.
Invasion and Metastatic Dissemination
Tumor cells invade locally, enter the circulation, and colonize distant organs. Brain metastasis is documented in molecularly selected real-world cohorts, but the available evidence does not establish a BRAF-specific brain-homing mechanism.
Canonical BRAF V600E Lung-Tumor Model
cell migration GO:0016477 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell migration (GO:0016477). GO:0016477 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Brain Metastases Metastatic dissemination can culminate in secondary brain tumors. Canonical BRAF V600E Lung-Tumor Model
Show evidence (1 reference)
PMID:39616778 SUPPORT Human Clinical
"At D-T initiation, 80.8 % of patients had a PS of 0/1, 78.6 % had stage IV disease, and 20.9 % had brain metastasis."
The real-world cohort directly documents advanced and brain-metastatic disease.
BRAF-MEK Inhibitor Selection Pressure
Dual pathway inhibition suppresses sensitive cells while favoring survival and expansion of clones with on-pathway reactivation, bypass signaling, or altered cell state. This is a treatment-conditioned mechanism rather than part of untreated tumor initiation.
Acquired BRAF/MEK-Inhibitor Resistance Model
response to xenobiotic stimulus GO:0009410 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal response to xenobiotic stimulus (GO:0009410). GO:0009410 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
MAPK Reactivation and Bypass Resistance Selection enriches genetic states capable of restoring growth despite BRAF/MEK inhibition. Acquired BRAF/MEK-Inhibitor Resistance Model
Show evidence (1 reference)
PMID:42284541 SUPPORT Human Clinical
"Resistance mechanisms at PD included NRAS, KRAS, TP53 mutations and MET, EGFR, ERBB2 CNVs."
Longitudinal sampling documents alterations present at progression under dabrafenib-trametinib.
MAPK Reactivation and Bypass Resistance
Resistant tumors can restore MAPK signaling or engage PI3K and receptor-kinase bypass programs. Longitudinal plasma studies have identified NRAS and KRAS mutations and MET, EGFR, or ERBB2 copy-number changes, while broader ctDNA profiling also found candidate alterations outside these canonical pathways. Not every progression sample yields an identifiable genomic driver.
Acquired BRAF/MEK-Inhibitor Resistance Model
NRAS hgnc:7989 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NRAS (hgnc:7989). hgnc:7989 is a gene from the HUGO Gene Nomenclature Committee. KRAS hgnc:6407 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KRAS (hgnc:6407). hgnc:6407 is a gene from the HUGO Gene Nomenclature Committee. MET hgnc:7029 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MET (hgnc:7029). hgnc:7029 is a gene from the HUGO Gene Nomenclature Committee. EGFR hgnc:3236 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EGFR (hgnc:3236). hgnc:3236 is a gene from the HUGO Gene Nomenclature Committee. ERBB2 hgnc:3430 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ERBB2 (hgnc:3430). hgnc:3430 is a gene from the HUGO Gene Nomenclature Committee.
ERK1 and ERK2 cascade GO:0070371 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ERK1 and ERK2 cascade (GO:0070371). GO:0070371 is a biological process from the Gene Ontology. ↑ INCREASED phosphatidylinositol 3-kinase signaling GO:0043491 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased phosphatidylinositol 3-kinase signaling, annotated with phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491). GO:0043491 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Progressive Metastatic Disease Resistant signaling permits renewed growth and radiologic or clinical progression. Acquired BRAF/MEK-Inhibitor Resistance Model
Show evidence (2 references)
PMID:32859654 SUPPORT Human Clinical
"Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways"
Prospective ctDNA profiling directly supports MAPK and PI3K resistance classes.
PMID:42284541 SUPPORT Human Clinical
"Resistance mechanisms at PD included NRAS, KRAS, TP53 mutations and MET, EGFR, ERBB2 CNVs."
The prospective longitudinal study identifies specific progression-associated alterations.
✶

Histopathology

1
Adenocarcinoma Predominance VERY_FREQUENT
Adenocarcinoma is the dominant reported histology, although the molecular subtype is not defined as histologically exclusive.
Show evidence (1 reference)
PMID:35814395 SUPPORT Human Clinical
"In addition, 96.2% of the patients had adenocarcinoma"
The molecularly selected advanced cohort directly supports very frequent adenocarcinoma histology.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for BRAF V600E-Mutant Non-Small Cell Lung Cancer Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

3
Neoplasm 2
Lung Adenocarcinoma VERY_FREQUENT HP:0030078 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lung adenocarcinoma (HP:0030078). HP:0030078 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35814395 SUPPORT Human Clinical
"In addition, 96.2% of the patients had adenocarcinoma"
The 53-patient molecularly selected cohort directly supports the phenotype and frequency.
Progressive Metastatic Disease Neoplasm HP:0002664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neoplasm (HP:0002664). HP:0002664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42284541 SUPPORT Human Clinical
"Biological PD anticipated radiologic/clinical PD by a median of 4.9 weeks (IQR, 1.4-9.8)."
Longitudinal monitoring directly links molecular progression with later radiologic or clinical progression.
Other 1
Brain Metastases OCCASIONAL Brain neoplasm HP:0030692 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brain metastasis, annotated with Brain neoplasm (HP:0030692). HP:0030692 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39616778 SUPPORT Human Clinical
"20.9 % had brain metastasis."
The BRAF V600E-selected cohort directly supplies the brain-metastasis fraction.
🧬

Genetic Associations

1
BRAF p.Val600Glu (Somatic Activating Driver Mutation)
Gene: BRAF hgnc:1097 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BRAF (hgnc:1097). hgnc:1097 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (2 references)
PMID:28919011 SUPPORT Human Clinical
"BRAFV600E mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver."
The lung-cancer trial directly identifies the mutation as an oncogenic driver.
PMID:28783719 SUPPORT In Vitro
"Class 1 BRAF mutations (BRAF V600 mutations) are RAS-independent, signal as monomers and are sensitive to current RAF ‘monomer’ inhibitors."
The functional study defines the class-I behavior of the V600 variant group.
💊

Medical Actions

4
Dabrafenib Plus Trametinib
Category: Therapeutic Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
Agent: dabrafenib CHEBI:75045 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dabrafenib (CHEBI:75045). CHEBI:75045 is a therapeutic agent from Chemical Entities of Biological Interest. trametinib CHEBI:75998 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses trametinib (CHEBI:75998). CHEBI:75998 is a therapeutic agent from Chemical Entities of Biological Interest.
Combined BRAF and MEK inhibition has prospective phase-II and long-term follow-up evidence in previously untreated and previously treated metastatic BRAF V600E-mutant NSCLC. Pyrexia is a common toxicity, and treatment selection requires stage, comorbidity, prior-therapy, toxicity, and access context.
Mechanism Target:
INHIBITS Somatic BRAF p.Val600Glu Driver — Dabrafenib inhibits the disease-defining mutant BRAF kinase.
Show evidence (1 reference)
PMID:28919011 SUPPORT Human Clinical
"Patients received oral dabrafenib 150 mg twice per day plus oral trametinib 2 mg once per day"
The biomarker-selected trial directly tests the BRAF/MEK combination in this disease.
INHIBITS Sustained MEK-ERK Signaling — Trametinib suppresses MEK output downstream of mutant BRAF.
Show evidence (1 reference)
PMID:17299132 SUPPORT Model Organism
"Moreover, BRaf(VE)-induced lung tumors were prevented by pharmacological inhibition of MEK1/2."
The lung-specific model directly supports MEK dependence downstream of BRAF V600E.
Show evidence (2 references)
PMID:28919011 SUPPORT Human Clinical
"The proportion of patients with investigator-assessed confirmed overall response was 23 (64%, 95% CI 46-79)"
The treatment-naive phase-II cohort directly supports antitumor activity.
PMID:34455067 SUPPORT Human Clinical
"The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naive patients, respectively."
Long-term follow-up directly reports durable survival in both phase-II cohorts.
Encorafenib Plus Binimetinib
Category: Therapeutic Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
Agent: encorafenib NCIT:C98283 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses encorafenib (NCIT:C98283). NCIT:C98283 is a therapeutic agent from the NCI Thesaurus. binimetinib CHEBI:145371 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses binimetinib (CHEBI:145371). CHEBI:145371 is a therapeutic agent from Chemical Entities of Biological Interest.
Combined BRAF and MEK inhibition supported by the single-arm PHAROS phase-II trial in treatment-naive and previously treated metastatic disease. Cross-trial comparisons with dabrafenib-trametinib are not randomized and should not be interpreted as comparative superiority.
Mechanism Target:
INHIBITS Somatic BRAF p.Val600Glu Driver — Encorafenib inhibits mutant BRAF kinase activity.
Show evidence (1 reference)
PMID:40480428 SUPPORT Human Clinical
"patients with BRAF V600E-mutant mNSCLC (59 treatment-naive and 39 previously treated) received encorafenib 450 mg once daily and binimetinib 45 mg twice daily."
The biomarker-selected PHAROS study directly tests the BRAF/MEK combination.
INHIBITS Sustained MEK-ERK Signaling — Binimetinib blocks downstream MEK signaling.
Show evidence (1 reference)
PMID:40480428 SUPPORT Human Clinical
"patients with BRAF V600E-mutant mNSCLC (59 treatment-naive and 39 previously treated) received encorafenib 450 mg once daily and binimetinib 45 mg twice daily."
The combination trial supports simultaneous BRAF and MEK targeting in this subtype.
Show evidence (2 references)
PMID:40480428 SUPPORT Human Clinical
"In treatment-naive patients, the ORR was 75%, median DOR was 40.0 months, median PFS was 30.2 months"
The updated PHAROS analysis directly quantifies response and durability in treatment-naive patients.
PMID:41109959 SUPPORT Human Clinical
"After median follow-up for overall survival (OS) of 52.3 months in treatment-naïve patients, mOS was 47.6 months (95% CI, 31.3 to not estimable); 4-year OS probability was 49%"
Mature PHAROS follow-up directly supports long-term survival in the treatment-naive cohort.
Platinum-Based Chemotherapy
Category: Therapeutic Action: ChemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. NCIT:C15632
Platinum-based chemotherapy remains a systemic option when targeted therapy is unavailable, contraindicated, or after progression, according to the patient's stage and treatment history. Available subtype-specific comparisons are retrospective rather than randomized.
Show evidence (1 reference)
PMID:40138888 SUPPORT Human Clinical
"The median first-line real-world progression-free survival (rwPFS) of dabrafenib plus trametinib for patients with BRAF V600 mutations was 25.0 months (N = 37), which was numerically longer than first-line immunotherapy-based therapy (N = 12, 15.7 months), and chemotherapy (N = 17, 9.2 months)."
The real-world study directly documents chemotherapy use and bounds the comparison as small and nonrandomized.
Immune-Checkpoint-Based Therapy
Category: Therapeutic Action: immunotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Immune-checkpoint therapy, alone or with chemotherapy as appropriate to the broader NSCLC context, is a systemic option. PD-L1 positivity is common in one real-world BRAF V600E cohort, but retrospective outcomes do not establish a universal first-line sequencing rule against BRAF/MEK inhibition.
Show evidence (2 references)
PMID:39616778 SUPPORT Human Clinical
"78.2 % had a PDL1 ≥ 1 %."
The cohort supports frequent PD-L1 expression but does not itself prove checkpoint-inhibitor efficacy.
PMID:40138888 SUPPORT Human Clinical
"first-line immunotherapy-based therapy (N = 12, 15.7 months)"
The retrospective cohort directly documents a small first-line immunotherapy-treated subgroup.
🔬

Biochemical Markers

2
Tumor BRAF V600E Detection (REQUIRED_FOR_SUBTYPE_ASSIGNMENT)
Show evidence (1 reference)
PMID:42391424 SUPPORT Human Clinical
"F1CDx testing revealed a PPA of 93.2% (85.0%-97.0%), suggesting that F1CDx may robustly identify patients with BRAF V600E-mutant NSCLC"
The PHAROS bridging study clinically validates a tissue-based companion diagnostic.
Plasma BRAF V600E Circulating Tumor DNA (VARIABLE)
Show evidence (2 references)
PMID:42391424 SUPPORT Human Clinical
"In samples with sufficient ctDNA (defined as tumor fraction ≥1%), F1LCDx testing revealed a positive percent agreement (PPA) of 83.3%"
The liquid-assay result supports complementary use while showing imperfect sensitivity even with sufficient ctDNA.
PMID:42284541 SUPPORT Human Clinical
"At t0, BRAF V600E was detectable by ddPCR in 24 (62%) of 39 patients."
Prospective baseline sampling quantifies incomplete plasma detectability.
🔬

Diagnosis

3
Histologic NSCLC diagnosis with BRAF V600E confirmation (REQUIRED_FOR_SUBTYPE_ASSIGNMENT)
Assigning this subtype requires both a lung-primary NSCLC diagnosis and detection of tumor BRAF V600E. Histology establishes the cancer context; molecular testing distinguishes this actionable subtype from non-V600 BRAF tumors and other oncogene-defined NSCLC.
Show evidence (1 reference)
PMID:35814395 SUPPORT Human Clinical
"Fifty-three patients with BRAF V600E-mutant advanced NSCLC were included in the study"
The cohort definition directly combines the molecular alteration with an NSCLC diagnosis.
Tissue comprehensive genomic profiling (PREFERRED_WHEN_TISSUE_AVAILABLE)
Validated tissue sequencing detects BRAF V600E and can concurrently assess co-alterations relevant to lineage, prognosis, and resistance.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:42391424 SUPPORT Human Clinical
"F1CDx testing revealed a PPA of 93.2% (85.0%-97.0%), suggesting that F1CDx may robustly identify patients with BRAF V600E-mutant NSCLC"
The PHAROS bridging analysis directly validates the tissue companion diagnostic.
Plasma ctDNA testing and progression monitoring (COMPLEMENTARY)
Plasma testing is useful when tissue is limited and for longitudinal monitoring, but variable shedding makes it complementary rather than a stand-alone exclusion test. At progression, broader plasma or tissue profiling can reveal candidate MAPK and bypass resistance alterations.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:42391424 SUPPORT Human Clinical
"In samples with sufficient ctDNA (defined as tumor fraction ≥1%), F1LCDx testing revealed a positive percent agreement (PPA) of 83.3%"
The observed positive agreement supports liquid testing while bounding its sensitivity.
PMID:42284541 SUPPORT Human Clinical
"The LiBRA study supports liquid biopsy as a prognostic and monitoring tool in BRAF V600E-mutated NSCLC undergoing targeted therapy."
The prospective study directly supports longitudinal liquid-biopsy use.
📈

Progression

3
Tumor initiation with constrained early progression
BRAF V600E initiates lung epithelial proliferation, but experimental expression alone commonly produces benign lesions followed by a senescence-like arrest. Cooperation with tumor-suppressor or lineage-state alterations permits malignant progression.
Show evidence (1 reference)
PMID:17299132 SUPPORT Model Organism
"BRaf(CA) mice infected with an Adenovirus expressing Cre recombinase developed benign lung tumors that only rarely progressed to adenocarcinoma."
The lung-specific model establishes an initiated but progression-constrained phase.
Advanced and metastatic NSCLC
Molecularly selected treatment cohorts are dominated by stage-IV disease; brain metastases occur in a clinically relevant subset.
Show evidence (1 reference)
PMID:39616778 SUPPORT Human Clinical
"At D-T initiation, 80.8 % of patients had a PS of 0/1, 78.6 % had stage IV disease, and 20.9 % had brain metastasis."
The BRAF V600E-selected cohort directly characterizes advanced and brain-metastatic disease.
Molecular response and acquired progression during targeted therapy
Plasma BRAF V600E can clear early during response, while molecular progression and new resistance alterations can precede radiologic or clinical progression.
Show evidence (2 references)
PMID:42284541 SUPPORT Human Clinical
"Among 21 shedders evaluated at t1, 17 (81%) cleared the mutation."
Prospective serial sampling supports an early molecular-response phase.
PMID:42284541 SUPPORT Human Clinical
"Biological PD anticipated radiologic/clinical PD by a median of 4.9 weeks (IQR, 1.4-9.8)."
Molecular progression preceding conventional progression defines the later resistant phase.
🌍

Epidemiology

2
Rare, denominator-dependent molecular subtype
The previously untreated dabrafenib-trametinib trial describes BRAF V600E in 1-2% of lung adenocarcinomas. A much larger Chinese molecular-testing cohort found any BRAF mutation in 3.56% of tested NSCLC and V600E in 24.6% of the BRAF-mutant subset. These are cohort proportions, not population point-prevalence estimates, and the V600E fraction varies with ancestry, histology, stage, and testing strategy.
Show evidence (2 references)
PMID:28919011 SUPPORT Human Clinical
"BRAFV600E mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver."
The phase-II report states the approximate lung-adenocarcinoma fraction and driver status.
PMID:40138888 SUPPORT Human Clinical
"In Cohort I, of patients with NSCLC, 6249 (3.56%, 95% CI: 3.48%-3.65%) were confirmed to harbour a BRAF mutation. BRAF V600E accounted for 24.6% (1539/6249) of all patients with BRAF-mutated NSCLC."
The large testing cohort supplies explicit overall-BRAF and within-BRAF V600E denominators.
Adenocarcinoma and never-smoker enrichment
In one 53-patient advanced-NSCLC cohort, 96.2% had adenocarcinoma and 64.2% were nonsmokers. These enrichments help characterize tested cohorts but are neither diagnostic criteria nor substitutes for molecular testing.
Show evidence (1 reference)
PMID:35814395 SUPPORT Human Clinical
"Fifty-three patients with BRAF V600E-mutant advanced NSCLC were included in the study, of which 64.2% were non-smokers, and the BRAF V600E mutation was more prevalent in men (52.8%). In addition, 96.2% of the patients had adenocarcinoma"
The molecularly selected cohort directly supports the stated histology and smoking-status proportions.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from BRAF V600E-Mutant Non-Small Cell Lung Cancer:

Non-V600 BRAF-Mutant NSCLC
Overlapping Features Class-II and class-III BRAF-mutant lung cancers share the NSCLC presentation but differ in RAS dependence, dimerization, kinase activity, and expected response to RAF monomer inhibitors.
Distinguishing Features
  • Demonstrate the exact BRAF allele and assign its functional class rather than treating any BRAF mutation as V600E.
  • Class II signals as a RAS-independent dimer; class III has low or absent kinase activity and depends on activated RAS.
Show evidence (1 reference)
PMID:28783719 SUPPORT In Vitro
"Class 1 BRAF mutations (BRAF V600 mutations) are RAS-independent, signal as monomers and are sensitive to current RAF ‘monomer’ inhibitors. Class 2 BRAF mutants are RAS-independent, signal as constitutive dimers and are resistant to vemurafenib."
Functional classification distinguishes V600 from non-V600 mechanisms and inhibitor sensitivity.
EGFR-Mutant NSCLC with Acquired BRAF V600E
Overlapping Features BRAF V600E can emerge during progression of an originally EGFR-driven tumor after EGFR-tyrosine-kinase inhibition. That acquired-resistance state should not be conflated with a de novo BRAF V600E-primary NSCLC because the clonal history and treatment logic differ.
Distinguishing Features
  • Establish the pretreatment driver, longitudinal molecular history, and whether BRAF V600E was present at baseline or appeared after EGFR-TKI exposure.
Show evidence (1 reference)
PMID:39830741 SUPPORT Human Clinical
"we identified 14 patients who were treated with a triple therapy regimen of EGFR-TKI plus dabrafenib and trametinib due to newly acquired BRAFV600E mutation after EGFR-TKI resistance."
The longitudinal cohort directly documents acquired V600E after EGFR-TKI resistance.
🔬

Clinical Trials

3
NCT01336634 PHASE_II COMPLETED
BRF113928 evaluated dabrafenib alone and dabrafenib plus trametinib across cohorts of stage-IV BRAF V600E-positive NSCLC, including previously treated and treatment-naive combination cohorts. ClinicalTrials.gov listed 177 participants and COMPLETED status when checked on 2026-07-23.
Show evidence (1 reference)
clinicaltrials:NCT01336634 SUPPORT Human Clinical
"This was a Phase II, multicenter, non-randomized, open-label study to assess the efficacy, safety, and tolerability of dabrafenib administered as a single agent and in combination with trametinib in stage IV disease to subjects with BRAF mutant advanced non-small cell lung cancer."
The registry summary directly supports the disease, phase, interventions, and study design.
NCT03915951 PHASE_II COMPLETED
PHAROS evaluated encorafenib plus binimetinib in treatment-naive or previously treated BRAF V600E-mutant metastatic NSCLC. ClinicalTrials.gov listed 98 participants and COMPLETED status when checked on 2026-07-23.
Show evidence (1 reference)
clinicaltrials:NCT03915951 SUPPORT Human Clinical
"This is an open-label, multicenter, non-randomized, Phase 2 study to determine the safety, tolerability and efficacy of encorafenib given in combination with binimetinib in patients with BRAFV600E-mutant metastatic non-small cell lung cancer (NSCLC)."
The registry directly supports the molecular population, regimen, phase, and design.
NCT04526782 PHASE_II ACTIVE_NOT_RECRUITING
ENCO-BRAF is a phase-II study of encorafenib plus binimetinib in metastatic BRAF V600E-mutant NSCLC. ClinicalTrials.gov listed 119 participants and ACTIVE_NOT_RECRUITING status when checked on 2026-07-23.
Show evidence (1 reference)
clinicaltrials:NCT04526782 SUPPORT Human Clinical
"A Phase II study of the BRAF inhibitor Encorafenib in combination with the MEK inhibitor Binimetinib in Patients with BRAFV600E-mutant metastatic Non-small Cell Lung Cancer"
The current registry summary directly supports the phase, regimen, and molecularly defined population.
🧫

Experimental Models

1
Isogenic BRAF V600E Knock-In BEAS-2B Lung Epithelial Cells CELL_LINE
CRISPR/Cas9-engineered BEAS-2B cells provide an isogenic human lung epithelial model for measuring cellular-state changes caused by introduction of BRAF V600E. The mutation altered migration, tumorigenic potential, adhesion, extracellular-matrix, EMT, and amino-acid metabolism programs but was not sufficient by itself to model complete lung carcinogenesis.
BRAF V600E knock-in isogenic parental control
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Tissue
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this experimental model uses this anatomical location This experimental model uses lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Cell source
Immortalized human bronchial epithelial BEAS-2B cells
Culture
Isogenic monolayer cell culture after CRISPR/Cas9 knock-in
Publication
PMID:40439425
Pathograph links
Somatic BRAF p.Val600Glu Driver Introduces the defining driver into an isogenic human lung epithelial background.
Show evidence (1 reference)
PMID:40439425 SUPPORT In Vitro
"To mimic the naturally occurring BRAF V600E mutation in lung cancer, a BRAF V600E knock-in BEAS-2B cell model was established using CRISPR/Cas9."
The engineered knock-in directly models the defining driver in a human lung epithelial background.
MAPK-Dependent Tumor-Cell Proliferation and Survival Measures migration, tumorigenic potential, adhesion, EMT, and metabolic state changes after knock-in.
Show evidence (1 reference)
PMID:40439425 SUPPORT In Vitro
"Although the BRAF V600E mutation alone was not sufficient to drive lung carcinogenesis, it induced remarkable changes in cellular migration capacity and tumorigenic potential."
The isogenic experiment directly supports the linked cellular-state effects while bounding full transformation.
Findings
BRAF V600E altered migration and tumorigenic potential without being sufficient for full lung carcinogenesis.
"Although the BRAF V600E mutation alone was not sufficient to drive lung carcinogenesis, it induced remarkable changes in cellular migration capacity and tumorigenic potential."
Show evidence (1 reference)
PMID:40439425 SUPPORT In Vitro
"Although the BRAF V600E mutation alone was not sufficient to drive lung carcinogenesis, it induced remarkable changes in cellular migration capacity and tumorigenic potential."
The study directly states both the phenotype and the model limitation.
Show evidence (1 reference)
PMID:40439425 SUPPORT In Vitro
"To mimic the naturally occurring BRAF V600E mutation in lung cancer, a BRAF V600E knock-in BEAS-2B cell model was established using CRISPR/Cas9."
The publication explicitly defines the engineered isogenic lung epithelial model.
🐁

Animal Models

2
Lung-restricted Cre activation of conditional Braf(V600E) Mus musculus
Conditional physiologic Braf(V600E) expression in the mouse lung produces benign tumors, sustained MEK-ERK signaling, and an initial proliferative phase followed by senescence-like arrest. MEK inhibition prevents tumor development, while Ink4a/Arf or Trp53 loss permits progression.
Benign lung tumors Initial epithelial proliferation Senescence-like growth arrest Adenocarcinoma progression with tumor-suppressor loss
Species
Mus musculus
Genotype
Lung-restricted Cre activation of conditional Braf(V600E)
Genes
BRAF hgnc:1097 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns BRAF (hgnc:1097). hgnc:1097 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:17299132 SUPPORT Model Organism
"BRaf(CA) mice infected with an Adenovirus expressing Cre recombinase developed benign lung tumors that only rarely progressed to adenocarcinoma."
The study directly describes the conditional lung-tumor phenotype.
PMID:17299132 SUPPORT Model Organism
"Consistent with Ink4a/Arf and TP53 tumor suppressor function, BRaf(VE) expression combined with mutation of either locus led to cancer progression."
The model directly supports genetic cooperation in progression.
Flp-activated Braf(FA) with temporally controlled Trp53, Cdkn2a, or c-MYC alteration Mus musculus
The two-switch model temporally separates Braf(V600E) initiation from secondary genetic events. Silencing TP53 or other cooperating changes bypasses the proliferative arrest of BRAF-initiated adenomas and promotes malignant lung-cancer progression.
BRAF-initiated lung adenomas Senescence-like proliferative arrest Malignant progression after secondary genetic events
Species
Mus musculus
Genotype
Flp-activated Braf(FA) with temporally controlled Trp53, Cdkn2a, or c-MYC alteration
Genes
BRAF hgnc:1097 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns BRAF (hgnc:1097). hgnc:1097 is a gene from the HUGO Gene Nomenclature Committee. TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee. CDKN2A hgnc:1787 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns CDKN2A (hgnc:1787). hgnc:1787 is a gene from the HUGO Gene Nomenclature Committee. MYC hgnc:7553 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns MYC (hgnc:7553). hgnc:7553 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:26001956 SUPPORT Model Organism
"secondary genetic events can promote bypass of the senescence-like proliferative arrest displayed by BRAF(V600E)-induced lung adenomas, leading to malignant progression."
The two-switch experiment directly supports the model's progression phenotype.
{ }

Source YAML

click to show 
name: BRAF V600E-Mutant Non-Small Cell Lung Cancer
creation_date: '2026-01-26T02:55:13Z'
description: >-
  BRAF V600E-mutant non-small cell lung cancer (NSCLC) is a molecularly defined
  lung-cancer subtype whose tumor cells carry the somatic BRAF c.1799T>A
  (p.Val600Glu) driver. The class-I mutant signals as a RAS-independent active
  monomer and sustains MEK-ERK output, creating a therapeutically actionable
  oncogene dependence. Most reported tumors are adenocarcinomas, but this entry
  remains scoped to NSCLC because BRAF V600E is a molecular classifier rather
  than a histology-exclusive entity. Dual BRAF/MEK inhibition with dabrafenib
  plus trametinib or encorafenib plus binimetinib has prospective phase-II
  evidence in metastatic disease. Acquired resistance can reactivate MAPK
  signaling or engage bypass pathways, so repeat molecular assessment at
  progression is clinically informative.
categories:
- Molecularly-Defined Cancer
- Lung Cancer Subtype
- Solid Tumor
- Oncogene-Driven Cancer
parents:
- non-small cell lung carcinoma
synonyms:
- BRAF V600E-positive NSCLC
- BRAF V600E-mutant lung cancer
- BRAF V600E-mutant lung adenocarcinoma

epidemiology:
- name: Rare, denominator-dependent molecular subtype
  description: >-
    The previously untreated dabrafenib-trametinib trial describes BRAF V600E
    in 1-2% of lung adenocarcinomas. A much larger Chinese molecular-testing
    cohort found any BRAF mutation in 3.56% of tested NSCLC and V600E in 24.6%
    of the BRAF-mutant subset. These are cohort proportions, not population
    point-prevalence estimates, and the V600E fraction varies with ancestry,
    histology, stage, and testing strategy.
  evidence:
  - reference: PMID:28919011
    reference_title: "Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: BRAFV600E mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver.
    explanation: The phase-II report states the approximate lung-adenocarcinoma fraction and driver status.
  - reference: PMID:40138888
    reference_title: "Prevalence, genetic variations and clinical outcomes of BRAF-V600 mutated advanced NSCLC in China: a retrospective real-world multi-centre study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In Cohort I, of patients with NSCLC, 6249 (3.56%, 95% CI: 3.48%-3.65%)
      were confirmed to harbour a BRAF mutation. BRAF V600E accounted for 24.6%
      (1539/6249) of all patients with BRAF-mutated NSCLC.
    explanation: The large testing cohort supplies explicit overall-BRAF and within-BRAF V600E denominators.
- name: Adenocarcinoma and never-smoker enrichment
  description: >-
    In one 53-patient advanced-NSCLC cohort, 96.2% had adenocarcinoma and 64.2%
    were nonsmokers. These enrichments help characterize tested cohorts but are
    neither diagnostic criteria nor substitutes for molecular testing.
  evidence:
  - reference: PMID:35814395
    reference_title: "Clinical Characteristics, Co-Mutations, and Treatment Outcomes in Advanced Non-Small-Cell Lung Cancer Patients With the BRAF-V600E Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fifty-three patients with BRAF V600E-mutant advanced NSCLC were included
      in the study, of which 64.2% were non-smokers, and the BRAF V600E mutation
      was more prevalent in men (52.8%). In addition, 96.2% of the patients had
      adenocarcinoma
    explanation: The molecularly selected cohort directly supports the stated histology and smoking-status proportions.

mechanistic_hypotheses:
- hypothesis_group_id: canonical_braf_v600e_lung_tumor_model
  hypothesis_label: Canonical BRAF V600E Lung-Tumor Model
  status: CANONICAL
  description: >-
    Somatic BRAF V600E produces RAS-independent monomeric RAF activity and
    sustained MEK-ERK signaling. In a permissive lung epithelial context,
    cooperating loss of tumor-suppressor or lineage-control programs permits
    MAPK-driven proliferation and survival to progress to invasive NSCLC.
    BRAF V600E alone can initiate proliferation yet also provoke a
    senescence-like arrest, so the mutation is a driver but not a complete
    mechanistic explanation for malignant progression.
  evidence:
  - reference: PMID:17299132
    reference_title: A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      BRaf(VE) expression initially induced proliferation that was followed by
      growth arrest bearing certain hallmarks of senescence. Consistent with
      Ink4a/Arf and TP53 tumor suppressor function, BRaf(VE) expression combined
      with mutation of either locus led to cancer progression.
    explanation: The lung-specific model separates oncogene-driven initiation from cooperating malignant progression.
- hypothesis_group_id: acquired_braf_meck_resistance_model
  hypothesis_label: Acquired BRAF/MEK-Inhibitor Resistance Model
  status: CANONICAL
  description: >-
    Dual BRAF/MEK inhibition imposes treatment selection on heterogeneous tumor
    clones. Progression can arise through renewed MAPK output, PI3K-pathway
    signaling, receptor-kinase copy-number changes, or lineage-state changes.
    The class structure is established, but no single alteration explains every
    resistant tumor.
  evidence:
  - reference: PMID:32859654
    reference_title: Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with BRAF-Mutant Metastatic Non-Small Cell Lung Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK
      combination were identified in 46% of patients and these included
      activating mutations in effectors of the MAPK and PI3K pathways, as well
      as alterations in U2AF1, IDH1, and CTNNB1.
    explanation: Prospective ctDNA profiling supports multiple genomic resistance classes and incomplete explanatory yield.

pathophysiology:
- name: Somatic BRAF p.Val600Glu Driver
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    The tumor-acquired BRAF c.1799T>A substitution encodes p.Val600Glu in the
    kinase activation segment. BRAF V600 variants form class I: they are
    RAS-independent, signal as active monomers, and are susceptible to RAF
    monomer inhibitors. This disease entry concerns the V600E allele in NSCLC,
    not class-II or class-III non-V600 BRAF tumors.
  genes:
  - preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  molecular_functions:
  - preferred_term: protein serine/threonine kinase activity
    modifier: INCREASED
    term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
  evidence:
  - reference: PMID:28783719
    reference_title: Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Class 1 BRAF mutations (BRAF V600 mutations) are RAS-independent, signal
      as monomers and are sensitive to current RAF ‘monomer’ inhibitors.
    explanation: The functional-classification study directly defines the signaling behavior of BRAF V600 mutations.
  - reference: PMID:28919011
    reference_title: "Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: BRAFV600E mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver.
    explanation: The molecularly selected clinical trial identifies V600E as an oncogenic lung-cancer driver.
  downstream:
  - target: Sustained MEK-ERK Signaling
    causal_link_type: DIRECT
    description: Constitutive mutant BRAF kinase activity sustains MEK1/2-ERK1/2 pathway output.
    hypothesis_groups:
    - canonical_braf_v600e_lung_tumor_model
    evidence:
    - reference: PMID:17299132
      reference_title: A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mutationally activated BRAF(V600E) (BRAF(VE)) is detected in
        approximately 6% of human malignancies and promotes sustained
        MEK1/2-ERK1/2 pathway activation.
      explanation: The lung-model study directly connects BRAF V600E with sustained MEK-ERK activation.

- name: Sustained MEK-ERK Signaling
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    Persistent RAF output activates the MEK-ERK cascade independently of an
    upstream RAS requirement. In established tumors this pathway maintains
    growth and survival, while in normal lung epithelial contexts the same
    oncogenic signal can also trigger a growth-arrest barrier.
  biological_processes:
  - preferred_term: ERK1 and ERK2 cascade
    modifier: INCREASED
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
  evidence:
  - reference: PMID:17299132
    reference_title: A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mutationally activated BRAF(V600E) (BRAF(VE)) is detected in
      approximately 6% of human malignancies and promotes sustained
      MEK1/2-ERK1/2 pathway activation.
    explanation: The model establishes sustained MEK-ERK output downstream of the mutant kinase.
  downstream:
  - target: MAPK-Dependent Tumor-Cell Proliferation and Survival
    causal_link_type: DIRECT
    description: Sustained pathway activity maintains the proliferative and survival program of BRAF-driven lung tumor cells.
    hypothesis_groups:
    - canonical_braf_v600e_lung_tumor_model
    evidence:
    - reference: PMID:17299132
      reference_title: A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Moreover, BRaf(VE)-induced lung tumors were prevented by
        pharmacological inhibition of MEK1/2.
      explanation: MEK inhibition preventing BRAF-driven lung tumors supports pathway dependence of the growth program.

- name: MAPK-Dependent Tumor-Cell Proliferation and Survival
  role: consequence
  biological_scale: CELLULAR
  description: >-
    BRAF-MEK-ERK activity promotes expansion and persistence of transformed lung
    epithelial cells. BRAF V600E alone does not invariably complete malignant
    transformation: experimental lung systems show an initial proliferative
    phase followed by arrest, making cooperating lesions and cell state
    important modifiers.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  cell_types:
  - preferred_term: pulmonary alveolar type 2 cell
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  - preferred_term: apoptotic process
    modifier: DECREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:17299132
    reference_title: A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      BRaf(VE) expression initially induced proliferation that was followed by
      growth arrest bearing certain hallmarks of senescence.
    explanation: The model directly demonstrates both the initial proliferative output and its intrinsic limitation.
  downstream:
  - target: Lung Adenocarcinoma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - clonal expansion
    - escape from oncogene-induced growth arrest
    - malignant transformation
    description: >-
      In a permissive lung epithelial context, sustained growth and survival
      contribute to the predominantly adenocarcinoma tumor phenotype.
    hypothesis_groups:
    - canonical_braf_v600e_lung_tumor_model
    evidence:
    - reference: PMID:35814395
      reference_title: "Clinical Characteristics, Co-Mutations, and Treatment Outcomes in Advanced Non-Small-Cell Lung Cancer Patients With the BRAF-V600E Mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In addition, 96.2% of the patients had adenocarcinoma
      explanation: The molecularly selected cohort supports adenocarcinoma as the dominant human tumor phenotype.

- name: Cooperating Tumor-Suppressor and Lineage-State Alterations
  role: modifier
  biological_scale: CELLULAR
  description: >-
    Loss of TP53 or CDKN2A can bypass the senescence-like arrest of
    BRAF-initiated lung lesions. PIK3CA activation can promote
    dedifferentiation, while NKX2-1 loss changes lineage identity and reduces
    cell-cycle exit during BRAF/MEK inhibition. These are experimentally
    supported cooperation routes, not lesions required in every human tumor.
  genes:
  - preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  - preferred_term: CDKN2A
    term:
      id: hgnc:1787
      label: CDKN2A
  - preferred_term: PIK3CA
    term:
      id: hgnc:8975
      label: PIK3CA
  - preferred_term: NKX2-1
    term:
      id: hgnc:11825
      label: NKX2-1
  evidence:
  - reference: PMID:26001956
    reference_title: TP53 Silencing Bypasses Growth Arrest of BRAFV600E-Induced Lung Tumor Cells in a Two-Switch Model of Lung Tumorigenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      secondary genetic events can promote bypass of the senescence-like
      proliferative arrest displayed by BRAF(V600E)-induced lung adenomas,
      leading to malignant progression.
    explanation: The two-switch model directly supports tumor-suppressor cooperation in malignant progression.
  - reference: PMID:31452510
    reference_title: Mutationally-activated PI3'-kinase-α promotes de-differentiation of lung tumors initiated by the BRAF(V600E) oncoprotein kinase.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cooperating alterations that activate PI3'-lipid signaling promote
      progression of BRAFV600E-driven benign tumors to malignant
      adenocarcinoma.
    explanation: The engineered model supports PI3K-pathway cooperation with BRAF V600E.
  - reference: PMID:33821796
    reference_title: An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      NKX2-1-deficient, BRAFV600E-driven tumors resemble human IMA and exhibit
      a distinct response to BRAF/MEK inhibitors.
    explanation: The model connects lineage-factor loss to tumor identity and altered treatment response.
  downstream:
  - target: Lung Adenocarcinoma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - bypass of senescence-like proliferative arrest
    - dedifferentiation or lineage-state change
    - malignant progression
    description: Cooperation permits BRAF-initiated lesions to progress to malignant lung adenocarcinoma.
    hypothesis_groups:
    - canonical_braf_v600e_lung_tumor_model
    evidence:
    - reference: PMID:26001956
      reference_title: TP53 Silencing Bypasses Growth Arrest of BRAFV600E-Induced Lung Tumor Cells in a Two-Switch Model of Lung Tumorigenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        secondary genetic events can promote bypass of the senescence-like
        proliferative arrest displayed by BRAF(V600E)-induced lung adenomas,
        leading to malignant progression.
      explanation: The experiment directly supports the cooperation-to-progression link.

- name: Lung Adenocarcinoma
  role: consequence
  biological_scale: TISSUE
  description: >-
    The dominant histologic manifestation is malignant gland-forming NSCLC in
    the lung. This mechanism node represents the established primary tumor
    state and connects molecular growth programs to later invasion and
    dissemination.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:35814395
    reference_title: "Clinical Characteristics, Co-Mutations, and Treatment Outcomes in Advanced Non-Small-Cell Lung Cancer Patients With the BRAF-V600E Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, 96.2% of the patients had adenocarcinoma
    explanation: The selected cohort supports adenocarcinoma as the predominant tissue-level tumor state.
  downstream:
  - target: Invasion and Metastatic Dissemination
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - local invasion
    - intravasation and hematogenous dissemination
    - distant-organ colonization
    description: Advanced primary tumors can acquire invasive and metastatic behavior.
    hypothesis_groups:
    - canonical_braf_v600e_lung_tumor_model
    evidence:
    - reference: PMID:39616778
      reference_title: "Real-world efficacy of the dabrafenib-trametinib (D-T) combination in BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC): Results from the IFCT-2004 BLaDE cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At D-T initiation, 80.8 % of patients had a PS of 0/1, 78.6 % had stage
        IV disease, and 20.9 % had brain metastasis.
      explanation: The advanced cohort supports metastatic progression and a brain-metastatic endpoint but not every intermediate step.

- name: Invasion and Metastatic Dissemination
  role: consequence
  biological_scale: TISSUE
  description: >-
    Tumor cells invade locally, enter the circulation, and colonize distant
    organs. Brain metastasis is documented in molecularly selected real-world
    cohorts, but the available evidence does not establish a BRAF-specific
    brain-homing mechanism.
  biological_processes:
  - preferred_term: cell migration
    modifier: INCREASED
    term:
      id: GO:0016477
      label: cell migration
  evidence:
  - reference: PMID:39616778
    reference_title: "Real-world efficacy of the dabrafenib-trametinib (D-T) combination in BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC): Results from the IFCT-2004 BLaDE cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At D-T initiation, 80.8 % of patients had a PS of 0/1, 78.6 % had stage IV
      disease, and 20.9 % had brain metastasis.
    explanation: The real-world cohort directly documents advanced and brain-metastatic disease.
  downstream:
  - target: Brain Metastases
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - hematogenous dissemination
    - blood-brain barrier transit
    - central nervous system colonization
    description: Metastatic dissemination can culminate in secondary brain tumors.
    hypothesis_groups:
    - canonical_braf_v600e_lung_tumor_model
    evidence:
    - reference: PMID:39616778
      reference_title: "Real-world efficacy of the dabrafenib-trametinib (D-T) combination in BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC): Results from the IFCT-2004 BLaDE cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 20.9 % had brain metastasis.
      explanation: The molecularly defined real-world cohort directly supports this endpoint.

- name: BRAF-MEK Inhibitor Selection Pressure
  role: trigger
  biological_scale: CELLULAR
  description: >-
    Dual pathway inhibition suppresses sensitive cells while favoring survival
    and expansion of clones with on-pathway reactivation, bypass signaling, or
    altered cell state. This is a treatment-conditioned mechanism rather than
    part of untreated tumor initiation.
  biological_processes:
  - preferred_term: response to xenobiotic stimulus
    modifier: ABNORMAL
    term:
      id: GO:0009410
      label: response to xenobiotic stimulus
  evidence:
  - reference: PMID:42284541
    reference_title: "Liquid Biopsy Monitoring in BRAF V600E-Mutated Patients With Non-Small Cell Lung Cancer Treated With Dabrafenib Plus Trametinib: The Prospective, Multicenter LiBRA Study (GOIRC-03-2020)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Resistance mechanisms at PD included NRAS, KRAS, TP53 mutations and MET,
      EGFR, ERBB2 CNVs.
    explanation: Longitudinal sampling documents alterations present at progression under dabrafenib-trametinib.
  downstream:
  - target: MAPK Reactivation and Bypass Resistance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - survival of resistant subclones
    - clonal expansion during pathway inhibition
    description: Selection enriches genetic states capable of restoring growth despite BRAF/MEK inhibition.
    hypothesis_groups:
    - acquired_braf_meck_resistance_model
    evidence:
    - reference: PMID:32859654
      reference_title: Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with BRAF-Mutant Metastatic Non-Small Cell Lung Cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Potential drivers of resistance to either BRAF-TT monotherapy or
        BRAF/MEK combination were identified in 46% of patients
      explanation: The prospective study supports treatment-conditioned emergence or selection of resistance-associated alterations.

- name: MAPK Reactivation and Bypass Resistance
  role: consequence
  biological_scale: MOLECULAR
  description: >-
    Resistant tumors can restore MAPK signaling or engage PI3K and
    receptor-kinase bypass programs. Longitudinal plasma studies have identified
    NRAS and KRAS mutations and MET, EGFR, or ERBB2 copy-number changes, while
    broader ctDNA profiling also found candidate alterations outside these
    canonical pathways. Not every progression sample yields an identifiable
    genomic driver.
  genes:
  - preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  - preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  - preferred_term: MET
    term:
      id: hgnc:7029
      label: MET
  - preferred_term: EGFR
    term:
      id: hgnc:3236
      label: EGFR
  - preferred_term: ERBB2
    term:
      id: hgnc:3430
      label: ERBB2
  biological_processes:
  - preferred_term: ERK1 and ERK2 cascade
    modifier: INCREASED
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
  - preferred_term: phosphatidylinositol 3-kinase signaling
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence:
  - reference: PMID:32859654
    reference_title: Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with BRAF-Mutant Metastatic Non-Small Cell Lung Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK
      combination were identified in 46% of patients and these included
      activating mutations in effectors of the MAPK and PI3K pathways
    explanation: Prospective ctDNA profiling directly supports MAPK and PI3K resistance classes.
  - reference: PMID:42284541
    reference_title: "Liquid Biopsy Monitoring in BRAF V600E-Mutated Patients With Non-Small Cell Lung Cancer Treated With Dabrafenib Plus Trametinib: The Prospective, Multicenter LiBRA Study (GOIRC-03-2020)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Resistance mechanisms at PD included NRAS, KRAS, TP53 mutations and MET,
      EGFR, ERBB2 CNVs.
    explanation: The prospective longitudinal study identifies specific progression-associated alterations.
  downstream:
  - target: Progressive Metastatic Disease
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - restoration of proliferative and survival signaling
    - expansion of treatment-resistant tumor clones
    description: Resistant signaling permits renewed growth and radiologic or clinical progression.
    hypothesis_groups:
    - acquired_braf_meck_resistance_model
    evidence:
    - reference: PMID:42284541
      reference_title: "Liquid Biopsy Monitoring in BRAF V600E-Mutated Patients With Non-Small Cell Lung Cancer Treated With Dabrafenib Plus Trametinib: The Prospective, Multicenter LiBRA Study (GOIRC-03-2020)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biological PD anticipated radiologic/clinical PD by a median of 4.9
        weeks (IQR, 1.4-9.8).
      explanation: Molecular progression preceding radiologic or clinical progression supports the resistance-to-progression link.

histopathology:
- name: Adenocarcinoma Predominance
  finding_term:
    preferred_term: Lung Adenocarcinoma
    term:
      id: NCIT:C3512
      label: Lung Adenocarcinoma
  frequency: VERY_FREQUENT
  description: >-
    Adenocarcinoma is the dominant reported histology, although the molecular
    subtype is not defined as histologically exclusive.
  evidence:
  - reference: PMID:35814395
    reference_title: "Clinical Characteristics, Co-Mutations, and Treatment Outcomes in Advanced Non-Small-Cell Lung Cancer Patients With the BRAF-V600E Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, 96.2% of the patients had adenocarcinoma
    explanation: The molecularly selected advanced cohort directly supports very frequent adenocarcinoma histology.

phenotypes:
- category: Neoplastic
  name: Lung Adenocarcinoma
  frequency: VERY_FREQUENT
  description: >-
    The predominant clinical tumor phenotype is lung adenocarcinoma; rare
    non-adenocarcinoma NSCLC is not excluded by the disease definition.
  phenotype_term:
    preferred_term: Lung adenocarcinoma
    term:
      id: HP:0030078
      label: Lung adenocarcinoma
  evidence:
  - reference: PMID:35814395
    reference_title: "Clinical Characteristics, Co-Mutations, and Treatment Outcomes in Advanced Non-Small-Cell Lung Cancer Patients With the BRAF-V600E Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, 96.2% of the patients had adenocarcinoma
    explanation: The 53-patient molecularly selected cohort directly supports the phenotype and frequency.
- category: Clinical
  name: Brain Metastases
  frequency: OCCASIONAL
  description: >-
    Brain metastasis was present in 20.9% of a large dabrafenib-trametinib
    real-world cohort at treatment initiation. The estimate is cohort-specific
    and does not establish a unique BRAF-dependent brain-homing mechanism.
  phenotype_term:
    preferred_term: Brain metastasis
    term:
      id: HP:0030692
      label: Brain neoplasm
  evidence:
  - reference: PMID:39616778
    reference_title: "Real-world efficacy of the dabrafenib-trametinib (D-T) combination in BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC): Results from the IFCT-2004 BLaDE cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 20.9 % had brain metastasis.
    explanation: The BRAF V600E-selected cohort directly supplies the brain-metastasis fraction.
- category: Neoplastic
  name: Progressive Metastatic Disease
  description: >-
    Advanced tumors can resume growth during BRAF/MEK therapy after molecular
    resistance emerges. Molecular progression may precede radiologic or
    clinical progression.
  phenotype_term:
    preferred_term: Neoplasm
    term:
      id: HP:0002664
      label: Neoplasm
  evidence:
  - reference: PMID:42284541
    reference_title: "Liquid Biopsy Monitoring in BRAF V600E-Mutated Patients With Non-Small Cell Lung Cancer Treated With Dabrafenib Plus Trametinib: The Prospective, Multicenter LiBRA Study (GOIRC-03-2020)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biological PD anticipated radiologic/clinical PD by a median of 4.9 weeks
      (IQR, 1.4-9.8).
    explanation: Longitudinal monitoring directly links molecular progression with later radiologic or clinical progression.

biochemical:
- name: Tumor BRAF V600E Detection
  presence: REQUIRED_FOR_SUBTYPE_ASSIGNMENT
  notes: >-
    Demonstration of BRAF V600E in tumor DNA defines this molecular subtype.
    Tissue comprehensive genomic profiling can identify the variant together
    with co-alterations and should distinguish V600E from mechanistically
    different non-V600 variants.
  evidence:
  - reference: PMID:42391424
    reference_title: Clinical validation of tissue and liquid companion diagnostics for BRAF V600E detection in non-small cell lung cancers from the PHAROS study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      F1CDx testing revealed a PPA of 93.2% (85.0%-97.0%), suggesting that F1CDx
      may robustly identify patients with BRAF V600E-mutant NSCLC
    explanation: The PHAROS bridging study clinically validates a tissue-based companion diagnostic.
- name: Plasma BRAF V600E Circulating Tumor DNA
  presence: VARIABLE
  notes: >-
    Plasma testing can provide a complementary detection and longitudinal
    monitoring route, but detectability depends on adequate tumor DNA shedding.
    A negative plasma result does not by itself exclude the subtype.
  evidence:
  - reference: PMID:42391424
    reference_title: Clinical validation of tissue and liquid companion diagnostics for BRAF V600E detection in non-small cell lung cancers from the PHAROS study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In samples with sufficient ctDNA (defined as tumor fraction ≥1%), F1LCDx
      testing revealed a positive percent agreement (PPA) of 83.3%
    explanation: The liquid-assay result supports complementary use while showing imperfect sensitivity even with sufficient ctDNA.
  - reference: PMID:42284541
    reference_title: "Liquid Biopsy Monitoring in BRAF V600E-Mutated Patients With Non-Small Cell Lung Cancer Treated With Dabrafenib Plus Trametinib: The Prospective, Multicenter LiBRA Study (GOIRC-03-2020)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At t0, BRAF V600E was detectable by ddPCR in 24 (62%) of 39 patients.
    explanation: Prospective baseline sampling quantifies incomplete plasma detectability.

genetic:
- name: BRAF p.Val600Glu
  gene_term:
    preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  association: Somatic Activating Driver Mutation
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    The defining alteration is BRAF c.1799T>A (p.Val600Glu). It is an acquired
    tumor driver in this disease context; germline inheritance is not the usual
    mechanism. The same protein change occurs in other cancers, so anatomic and
    histopathologic context remain essential.
  evidence:
  - reference: PMID:28919011
    reference_title: "Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: BRAFV600E mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver.
    explanation: The lung-cancer trial directly identifies the mutation as an oncogenic driver.
  - reference: PMID:28783719
    reference_title: Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Class 1 BRAF mutations (BRAF V600 mutations) are RAS-independent, signal
      as monomers and are sensitive to current RAF ‘monomer’ inhibitors.
    explanation: The functional study defines the class-I behavior of the V600 variant group.

diagnosis:
- name: Histologic NSCLC diagnosis with BRAF V600E confirmation
  presence: REQUIRED_FOR_SUBTYPE_ASSIGNMENT
  description: >-
    Assigning this subtype requires both a lung-primary NSCLC diagnosis and
    detection of tumor BRAF V600E. Histology establishes the cancer context;
    molecular testing distinguishes this actionable subtype from non-V600 BRAF
    tumors and other oncogene-defined NSCLC.
  evidence:
  - reference: PMID:35814395
    reference_title: "Clinical Characteristics, Co-Mutations, and Treatment Outcomes in Advanced Non-Small-Cell Lung Cancer Patients With the BRAF-V600E Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fifty-three patients with BRAF V600E-mutant advanced NSCLC were included
      in the study
    explanation: The cohort definition directly combines the molecular alteration with an NSCLC diagnosis.
- name: Tissue comprehensive genomic profiling
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  presence: PREFERRED_WHEN_TISSUE_AVAILABLE
  description: >-
    Validated tissue sequencing detects BRAF V600E and can concurrently assess
    co-alterations relevant to lineage, prognosis, and resistance.
  evidence:
  - reference: PMID:42391424
    reference_title: Clinical validation of tissue and liquid companion diagnostics for BRAF V600E detection in non-small cell lung cancers from the PHAROS study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      F1CDx testing revealed a PPA of 93.2% (85.0%-97.0%), suggesting that F1CDx
      may robustly identify patients with BRAF V600E-mutant NSCLC
    explanation: The PHAROS bridging analysis directly validates the tissue companion diagnostic.
- name: Plasma ctDNA testing and progression monitoring
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  presence: COMPLEMENTARY
  description: >-
    Plasma testing is useful when tissue is limited and for longitudinal
    monitoring, but variable shedding makes it complementary rather than a
    stand-alone exclusion test. At progression, broader plasma or tissue
    profiling can reveal candidate MAPK and bypass resistance alterations.
  evidence:
  - reference: PMID:42391424
    reference_title: Clinical validation of tissue and liquid companion diagnostics for BRAF V600E detection in non-small cell lung cancers from the PHAROS study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In samples with sufficient ctDNA (defined as tumor fraction ≥1%), F1LCDx
      testing revealed a positive percent agreement (PPA) of 83.3%
    explanation: The observed positive agreement supports liquid testing while bounding its sensitivity.
  - reference: PMID:42284541
    reference_title: "Liquid Biopsy Monitoring in BRAF V600E-Mutated Patients With Non-Small Cell Lung Cancer Treated With Dabrafenib Plus Trametinib: The Prospective, Multicenter LiBRA Study (GOIRC-03-2020)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The LiBRA study supports liquid biopsy as a prognostic and monitoring tool
      in BRAF V600E-mutated NSCLC undergoing targeted therapy.
    explanation: The prospective study directly supports longitudinal liquid-biopsy use.

differential_diagnoses:
- name: Non-V600 BRAF-Mutant NSCLC
  description: >-
    Class-II and class-III BRAF-mutant lung cancers share the NSCLC presentation
    but differ in RAS dependence, dimerization, kinase activity, and expected
    response to RAF monomer inhibitors.
  distinguishing_features:
  - Demonstrate the exact BRAF allele and assign its functional class rather than treating any BRAF mutation as V600E.
  - Class II signals as a RAS-independent dimer; class III has low or absent kinase activity and depends on activated RAS.
  evidence:
  - reference: PMID:28783719
    reference_title: Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Class 1 BRAF mutations (BRAF V600 mutations) are RAS-independent, signal
      as monomers and are sensitive to current RAF ‘monomer’ inhibitors. Class 2
      BRAF mutants are RAS-independent, signal as constitutive dimers and are
      resistant to vemurafenib.
    explanation: Functional classification distinguishes V600 from non-V600 mechanisms and inhibitor sensitivity.
- name: EGFR-Mutant NSCLC with Acquired BRAF V600E
  description: >-
    BRAF V600E can emerge during progression of an originally EGFR-driven tumor
    after EGFR-tyrosine-kinase inhibition. That acquired-resistance state should
    not be conflated with a de novo BRAF V600E-primary NSCLC because the clonal
    history and treatment logic differ.
  distinguishing_features:
  - Establish the pretreatment driver, longitudinal molecular history, and whether BRAF V600E was present at baseline or appeared after EGFR-TKI exposure.
  evidence:
  - reference: PMID:39830741
    reference_title: "EGFR inhibitors plus dabrafenib and trametinib in patients with EGFR-mutant lung cancer and resistance mediated by BRAF(V600E) mutation: a multi-center real-world experience in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified 14 patients who were treated with a triple therapy regimen
      of EGFR-TKI plus dabrafenib and trametinib due to newly acquired BRAFV600E
      mutation after EGFR-TKI resistance.
    explanation: The longitudinal cohort directly documents acquired V600E after EGFR-TKI resistance.

progression:
- phase: Tumor initiation with constrained early progression
  notes: >-
    BRAF V600E initiates lung epithelial proliferation, but experimental
    expression alone commonly produces benign lesions followed by a
    senescence-like arrest. Cooperation with tumor-suppressor or lineage-state
    alterations permits malignant progression.
  evidence:
  - reference: PMID:17299132
    reference_title: A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      BRaf(CA) mice infected with an Adenovirus expressing Cre recombinase
      developed benign lung tumors that only rarely progressed to
      adenocarcinoma.
    explanation: The lung-specific model establishes an initiated but progression-constrained phase.
- phase: Advanced and metastatic NSCLC
  notes: >-
    Molecularly selected treatment cohorts are dominated by stage-IV disease;
    brain metastases occur in a clinically relevant subset.
  evidence:
  - reference: PMID:39616778
    reference_title: "Real-world efficacy of the dabrafenib-trametinib (D-T) combination in BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC): Results from the IFCT-2004 BLaDE cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At D-T initiation, 80.8 % of patients had a PS of 0/1, 78.6 % had stage IV
      disease, and 20.9 % had brain metastasis.
    explanation: The BRAF V600E-selected cohort directly characterizes advanced and brain-metastatic disease.
- phase: Molecular response and acquired progression during targeted therapy
  notes: >-
    Plasma BRAF V600E can clear early during response, while molecular
    progression and new resistance alterations can precede radiologic or
    clinical progression.
  evidence:
  - reference: PMID:42284541
    reference_title: "Liquid Biopsy Monitoring in BRAF V600E-Mutated Patients With Non-Small Cell Lung Cancer Treated With Dabrafenib Plus Trametinib: The Prospective, Multicenter LiBRA Study (GOIRC-03-2020)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 21 shedders evaluated at t1, 17 (81%) cleared the mutation.
    explanation: Prospective serial sampling supports an early molecular-response phase.
  - reference: PMID:42284541
    reference_title: "Liquid Biopsy Monitoring in BRAF V600E-Mutated Patients With Non-Small Cell Lung Cancer Treated With Dabrafenib Plus Trametinib: The Prospective, Multicenter LiBRA Study (GOIRC-03-2020)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biological PD anticipated radiologic/clinical PD by a median of 4.9 weeks
      (IQR, 1.4-9.8).
    explanation: Molecular progression preceding conventional progression defines the later resistant phase.

treatments:
- name: Dabrafenib Plus Trametinib
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Combined BRAF and MEK inhibition has prospective phase-II and long-term
    follow-up evidence in previously untreated and previously treated metastatic
    BRAF V600E-mutant NSCLC. Pyrexia is a common toxicity, and treatment
    selection requires stage, comorbidity, prior-therapy, toxicity, and access
    context.
  target_mechanisms:
  - target: Somatic BRAF p.Val600Glu Driver
    treatment_effect: INHIBITS
    description: Dabrafenib inhibits the disease-defining mutant BRAF kinase.
    evidence:
    - reference: PMID:28919011
      reference_title: "Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients received oral dabrafenib 150 mg twice per day plus oral
        trametinib 2 mg once per day
      explanation: The biomarker-selected trial directly tests the BRAF/MEK combination in this disease.
  - target: Sustained MEK-ERK Signaling
    treatment_effect: INHIBITS
    description: Trametinib suppresses MEK output downstream of mutant BRAF.
    evidence:
    - reference: PMID:17299132
      reference_title: A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Moreover, BRaf(VE)-induced lung tumors were prevented by
        pharmacological inhibition of MEK1/2.
      explanation: The lung-specific model directly supports MEK dependence downstream of BRAF V600E.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: dabrafenib
      term:
        id: CHEBI:75045
        label: dabrafenib
    - preferred_term: trametinib
      term:
        id: CHEBI:75998
        label: trametinib
  evidence:
  - reference: PMID:28919011
    reference_title: "Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proportion of patients with investigator-assessed confirmed overall
      response was 23 (64%, 95% CI 46-79)
    explanation: The treatment-naive phase-II cohort directly supports antitumor activity.
  - reference: PMID:34455067
    reference_title: "Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 4- and 5-year survival rates were 26% and 19% in pretreated patients
      and 34% and 22% in treatment-naive patients, respectively.
    explanation: Long-term follow-up directly reports durable survival in both phase-II cohorts.

- name: Encorafenib Plus Binimetinib
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Combined BRAF and MEK inhibition supported by the single-arm PHAROS
    phase-II trial in treatment-naive and previously treated metastatic disease.
    Cross-trial comparisons with dabrafenib-trametinib are not randomized and
    should not be interpreted as comparative superiority.
  target_mechanisms:
  - target: Somatic BRAF p.Val600Glu Driver
    treatment_effect: INHIBITS
    description: Encorafenib inhibits mutant BRAF kinase activity.
    evidence:
    - reference: PMID:40480428
      reference_title: Updated Efficacy and Safety From the Phase 2 PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic NSCLC-A Brief Report.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        patients with BRAF V600E-mutant mNSCLC (59 treatment-naive and 39
        previously treated) received encorafenib 450 mg once daily and
        binimetinib 45 mg twice daily.
      explanation: The biomarker-selected PHAROS study directly tests the BRAF/MEK combination.
  - target: Sustained MEK-ERK Signaling
    treatment_effect: INHIBITS
    description: Binimetinib blocks downstream MEK signaling.
    evidence:
    - reference: PMID:40480428
      reference_title: Updated Efficacy and Safety From the Phase 2 PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic NSCLC-A Brief Report.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        patients with BRAF V600E-mutant mNSCLC (59 treatment-naive and 39
        previously treated) received encorafenib 450 mg once daily and
        binimetinib 45 mg twice daily.
      explanation: The combination trial supports simultaneous BRAF and MEK targeting in this subtype.
  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: binimetinib
      term:
        id: CHEBI:145371
        label: binimetinib
  evidence:
  - reference: PMID:40480428
    reference_title: Updated Efficacy and Safety From the Phase 2 PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic NSCLC-A Brief Report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In treatment-naive patients, the ORR was 75%, median DOR was 40.0 months,
      median PFS was 30.2 months
    explanation: The updated PHAROS analysis directly quantifies response and durability in treatment-naive patients.
  - reference: PMID:41109959
    reference_title: Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After median follow-up for overall survival (OS) of 52.3 months in
      treatment-naïve patients, mOS was 47.6 months (95% CI, 31.3 to not
      estimable); 4-year OS probability was 49%
    explanation: Mature PHAROS follow-up directly supports long-term survival in the treatment-naive cohort.

- name: Platinum-Based Chemotherapy
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Platinum-based chemotherapy remains a systemic option when targeted therapy
    is unavailable, contraindicated, or after progression, according to the
    patient's stage and treatment history. Available subtype-specific
    comparisons are retrospective rather than randomized.
  treatment_term:
    preferred_term: Chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  evidence:
  - reference: PMID:40138888
    reference_title: "Prevalence, genetic variations and clinical outcomes of BRAF-V600 mutated advanced NSCLC in China: a retrospective real-world multi-centre study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median first-line real-world progression-free survival (rwPFS) of
      dabrafenib plus trametinib for patients with BRAF V600 mutations was 25.0
      months (N = 37), which was numerically longer than first-line
      immunotherapy-based therapy (N = 12, 15.7 months), and chemotherapy
      (N = 17, 9.2 months).
    explanation: The real-world study directly documents chemotherapy use and bounds the comparison as small and nonrandomized.

- name: Immune-Checkpoint-Based Therapy
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Immune-checkpoint therapy, alone or with chemotherapy as appropriate to the
    broader NSCLC context, is a systemic option. PD-L1 positivity is common in
    one real-world BRAF V600E cohort, but retrospective outcomes do not establish
    a universal first-line sequencing rule against BRAF/MEK inhibition.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
  evidence:
  - reference: PMID:39616778
    reference_title: "Real-world efficacy of the dabrafenib-trametinib (D-T) combination in BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC): Results from the IFCT-2004 BLaDE cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 78.2 % had a PDL1 ≥ 1 %.
    explanation: The cohort supports frequent PD-L1 expression but does not itself prove checkpoint-inhibitor efficacy.
  - reference: PMID:40138888
    reference_title: "Prevalence, genetic variations and clinical outcomes of BRAF-V600 mutated advanced NSCLC in China: a retrospective real-world multi-centre study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      first-line immunotherapy-based therapy (N = 12, 15.7 months)
    explanation: The retrospective cohort directly documents a small first-line immunotherapy-treated subgroup.

clinical_trials:
- name: NCT01336634
  phase: PHASE_II
  status: COMPLETED
  description: >-
    BRF113928 evaluated dabrafenib alone and dabrafenib plus trametinib across
    cohorts of stage-IV BRAF V600E-positive NSCLC, including previously treated
    and treatment-naive combination cohorts. ClinicalTrials.gov listed 177
    participants and COMPLETED status when checked on 2026-07-23.
  evidence:
  - reference: clinicaltrials:NCT01336634
    reference_title: A Phase II Study of the BRAF Inhibitor Dabrafenib as a Single Agent and in Combination With the MEK Inhibitor Trametinib in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This was a Phase II, multicenter, non-randomized, open-label study to
      assess the efficacy, safety, and tolerability of dabrafenib administered
      as a single agent and in combination with trametinib in stage IV disease
      to subjects with BRAF mutant advanced non-small cell lung cancer.
    explanation: The registry summary directly supports the disease, phase, interventions, and study design.
- name: NCT03915951
  phase: PHASE_II
  status: COMPLETED
  description: >-
    PHAROS evaluated encorafenib plus binimetinib in treatment-naive or
    previously treated BRAF V600E-mutant metastatic NSCLC. ClinicalTrials.gov
    listed 98 participants and COMPLETED status when checked on 2026-07-23.
  evidence:
  - reference: clinicaltrials:NCT03915951
    reference_title: "A Phase 2, Open-label Study of Encorafenib + Binimetinib in Patients With BRAFV600-mutant Non-small Cell Lung Cancer"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is an open-label, multicenter, non-randomized, Phase 2 study to
      determine the safety, tolerability and efficacy of encorafenib given in
      combination with binimetinib in patients with BRAFV600E-mutant metastatic
      non-small cell lung cancer (NSCLC).
    explanation: The registry directly supports the molecular population, regimen, phase, and design.
- name: NCT04526782
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: >-
    ENCO-BRAF is a phase-II study of encorafenib plus binimetinib in metastatic
    BRAF V600E-mutant NSCLC. ClinicalTrials.gov listed 119 participants and
    ACTIVE_NOT_RECRUITING status when checked on 2026-07-23.
  evidence:
  - reference: clinicaltrials:NCT04526782
    reference_title: A Phase II Study of the BRAF Inhibitor Encorafenib in Combination With the MEK Inhibitor Binimetinib in Patients With BRAFV600E-mutant Metastatic Non-small Cell Lung Cancer
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A Phase II study of the BRAF inhibitor Encorafenib in combination with the
      MEK inhibitor Binimetinib in Patients with BRAFV600E-mutant metastatic
      Non-small Cell Lung Cancer
    explanation: The current registry summary directly supports the phase, regimen, and molecularly defined population.

animal_models:
- species: Mus musculus
  genotype: Lung-restricted Cre activation of conditional Braf(V600E)
  genes:
  - preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  description: >-
    Conditional physiologic Braf(V600E) expression in the mouse lung produces
    benign tumors, sustained MEK-ERK signaling, and an initial proliferative
    phase followed by senescence-like arrest. MEK inhibition prevents tumor
    development, while Ink4a/Arf or Trp53 loss permits progression.
  associated_phenotypes:
  - Benign lung tumors
  - Initial epithelial proliferation
  - Senescence-like growth arrest
  - Adenocarcinoma progression with tumor-suppressor loss
  evidence:
  - reference: PMID:17299132
    reference_title: A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      BRaf(CA) mice infected with an Adenovirus expressing Cre recombinase
      developed benign lung tumors that only rarely progressed to
      adenocarcinoma.
    explanation: The study directly describes the conditional lung-tumor phenotype.
  - reference: PMID:17299132
    reference_title: A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with Ink4a/Arf and TP53 tumor suppressor function, BRaf(VE)
      expression combined with mutation of either locus led to cancer
      progression.
    explanation: The model directly supports genetic cooperation in progression.
- species: Mus musculus
  genotype: Flp-activated Braf(FA) with temporally controlled Trp53, Cdkn2a, or c-MYC alteration
  genes:
  - preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  - preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  - preferred_term: CDKN2A
    term:
      id: hgnc:1787
      label: CDKN2A
  - preferred_term: MYC
    term:
      id: hgnc:7553
      label: MYC
  description: >-
    The two-switch model temporally separates Braf(V600E) initiation from
    secondary genetic events. Silencing TP53 or other cooperating changes
    bypasses the proliferative arrest of BRAF-initiated adenomas and promotes
    malignant lung-cancer progression.
  associated_phenotypes:
  - BRAF-initiated lung adenomas
  - Senescence-like proliferative arrest
  - Malignant progression after secondary genetic events
  evidence:
  - reference: PMID:26001956
    reference_title: TP53 Silencing Bypasses Growth Arrest of BRAFV600E-Induced Lung Tumor Cells in a Two-Switch Model of Lung Tumorigenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      secondary genetic events can promote bypass of the senescence-like
      proliferative arrest displayed by BRAF(V600E)-induced lung adenomas,
      leading to malignant progression.
    explanation: The two-switch experiment directly supports the model's progression phenotype.

experimental_models:
- name: Isogenic BRAF V600E Knock-In BEAS-2B Lung Epithelial Cells
  description: >-
    CRISPR/Cas9-engineered BEAS-2B cells provide an isogenic human lung
    epithelial model for measuring cellular-state changes caused by introduction
    of BRAF V600E. The mutation altered migration, tumorigenic potential,
    adhesion, extracellular-matrix, EMT, and amino-acid metabolism programs but
    was not sufficient by itself to model complete lung carcinogenesis.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  cell_source: Immortalized human bronchial epithelial BEAS-2B cells
  culture_system: Isogenic monolayer cell culture after CRISPR/Cas9 knock-in
  conditions:
  - BRAF V600E knock-in
  - isogenic parental control
  publication: PMID:40439425
  modeled_mechanisms:
  - target: Somatic BRAF p.Val600Glu Driver
    description: Introduces the defining driver into an isogenic human lung epithelial background.
    evidence:
    - reference: PMID:40439425
      reference_title: Proteomic and metabolomic dissection of the BRAF V600E mutation-induced cellular state transition in lung epithelial cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        To mimic the naturally occurring BRAF V600E mutation in lung cancer, a
        BRAF V600E knock-in BEAS-2B cell model was established using CRISPR/Cas9.
      explanation: The engineered knock-in directly models the defining driver in a human lung epithelial background.
  - target: MAPK-Dependent Tumor-Cell Proliferation and Survival
    description: Measures migration, tumorigenic potential, adhesion, EMT, and metabolic state changes after knock-in.
    evidence:
    - reference: PMID:40439425
      reference_title: Proteomic and metabolomic dissection of the BRAF V600E mutation-induced cellular state transition in lung epithelial cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Although the BRAF V600E mutation alone was not sufficient to drive lung
        carcinogenesis, it induced remarkable changes in cellular migration
        capacity and tumorigenic potential.
      explanation: The isogenic experiment directly supports the linked cellular-state effects while bounding full transformation.
  findings:
  - statement: BRAF V600E altered migration and tumorigenic potential without being sufficient for full lung carcinogenesis.
    supporting_text: >-
      Although the BRAF V600E mutation alone was not sufficient to drive lung
      carcinogenesis, it induced remarkable changes in cellular migration
      capacity and tumorigenic potential.
    evidence:
    - reference: PMID:40439425
      reference_title: Proteomic and metabolomic dissection of the BRAF V600E mutation-induced cellular state transition in lung epithelial cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Although the BRAF V600E mutation alone was not sufficient to drive lung
        carcinogenesis, it induced remarkable changes in cellular migration
        capacity and tumorigenic potential.
      explanation: The study directly states both the phenotype and the model limitation.
  evidence:
  - reference: PMID:40439425
    reference_title: Proteomic and metabolomic dissection of the BRAF V600E mutation-induced cellular state transition in lung epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      To mimic the naturally occurring BRAF V600E mutation in lung cancer, a
      BRAF V600E knock-in BEAS-2B cell model was established using CRISPR/Cas9.
    explanation: The publication explicitly defines the engineered isogenic lung epithelial model.

datasets: []

discussions:
- discussion_id: gap_braf_v600e_first_line_sequencing
  prompt: >-
    How should dabrafenib-trametinib, encorafenib-binimetinib, chemotherapy, and
    immune-checkpoint-based regimens be sequenced in first-line and later-line
    metastatic BRAF V600E NSCLC?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Dabrafenib Plus Trametinib
  - treatments#Encorafenib Plus Binimetinib
  rationale: >-
    Both targeted combinations have single-arm phase-II evidence, while
    chemotherapy and immunotherapy comparisons are retrospective and small.
    Cross-trial outcome differences cannot establish comparative superiority.
  evidence:
  - reference: PMID:40480428
    reference_title: Updated Efficacy and Safety From the Phase 2 PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic NSCLC-A Brief Report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this ongoing open-label, single-arm, phase 2 study, patients with BRAF
      V600E-mutant mNSCLC
    explanation: PHAROS is explicitly single-arm and therefore cannot answer the head-to-head sequencing question.
  - reference: PMID:40138888
    reference_title: "Prevalence, genetic variations and clinical outcomes of BRAF-V600 mutated advanced NSCLC in China: a retrospective real-world multi-centre study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Due to the low incidence of BRAF mutations, limited data is available
      about their prevalence and clinical characteristics. Moreover,
      comparative real-world efficacy of dabrafenib combined with trametinib
      versus other treatment regimens, especially in Chinese patients, is also
      lacking.
    explanation: The study itself identifies the comparative-evidence limitation.
- discussion_id: gap_braf_v600e_resistance_map
  prompt: >-
    Which genomic and lineage-state resistance mechanisms are recurrent,
    actionable, and causally sufficient after dual BRAF/MEK inhibition?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#MAPK Reactivation and Bypass Resistance
  rationale: >-
    Prospective plasma profiling identifies multiple candidate mechanisms but
    explains only a subset of progression events. Tissue-based, longitudinal,
    and functional validation is needed to separate causal drivers from
    passenger alterations.
  evidence:
  - reference: PMID:32859654
    reference_title: Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with BRAF-Mutant Metastatic Non-Small Cell Lung Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK
      combination were identified in 46% of patients
    explanation: The 46% yield directly demonstrates a substantial unexplained fraction.
- discussion_id: gap_braf_v600e_model_fidelity
  prompt: >-
    Which human lung epithelial cell states and cooperating lesions convert
    BRAF V600E initiation into invasive human NSCLC?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Cooperating Tumor-Suppressor and Lineage-State Alterations
  - experimental_models#Isogenic BRAF V600E Knock-In BEAS-2B Lung Epithelial Cells
  rationale: >-
    Mouse models strongly support TP53, CDKN2A, PI3K, and NKX2-1 cooperation,
    while the human BEAS-2B knock-in model shows state changes but not complete
    carcinogenesis. Their relative importance in human tumors remains
    incompletely resolved.
  evidence:
  - reference: PMID:40439425
    reference_title: Proteomic and metabolomic dissection of the BRAF V600E mutation-induced cellular state transition in lung epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although the BRAF V600E mutation alone was not sufficient to drive lung
      carcinogenesis
    explanation: The human isogenic model explicitly exposes the incomplete-transformation gap.
- discussion_id: gap_braf_v600e_thromboembolism_signal
  prompt: >-
    Is thromboembolism, particularly cancer-related stroke, genuinely enriched
    in BRAF V600E-mutant NSCLC?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    A retrospective series observed a high event fraction, but it contained
    only ten patients and had a very wide confidence interval. The signal is
    hypothesis-generating and is not modeled as an established phenotype or
    subtype-specific incidence estimate.
  evidence:
  - reference: PMID:36697098
    reference_title: Cumulative Incidence of Thromboembolism and Prognostic Impact of Stroke in BRAF V600E-mutant Non-small-cell Lung Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 10 patients with BRAF-V600E mutant lung cancer, five developed a total
      of seven thromboembolic events, showing a 1-year cumulative incidence of
      43% (95% confidence interval=11-72%).
    explanation: The small sample and wide interval justify retaining the observation as an open question.

disease_term:
  preferred_term: non-small cell lung carcinoma
  term:
    id: MONDO:0005233
    label: non-small cell lung carcinoma

classifications:
  icdo_morphology:
    classification_value: Carcinoma
    evidence:
    - reference: PMID:35814395
      reference_title: "Clinical Characteristics, Co-Mutations, and Treatment Outcomes in Advanced Non-Small-Cell Lung Cancer Patients With the BRAF-V600E Mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Fifty-three patients with BRAF V600E-mutant advanced NSCLC were included in the study
      explanation: The selected cohort identifies the entity as non-small-cell lung carcinoma.
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    evidence:
    - reference: PMID:28919011
      reference_title: "Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: BRAFV600E mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver.
      explanation: The source establishes an oncogene-driven lung malignancy within oncology.
review_notes: >-
  MONDO does not provide a dedicated term for this exact molecular subtype, so
  disease_term binds the broader non-small cell lung carcinoma parent rather
  than the narrower lung-adenocarcinoma term. Adenocarcinoma predominance is
  represented in histopathology and phenotypes. The prior "BRAF non-V600 mutant
  NSCLC" child was removed because it is a sibling molecular class, not a
  subtype of V600E disease. No public dataset accession could be verified for
  the cited 2025 isogenic proteomic/metabolomic study; the reusable model is
  represented under experimental_models and datasets remains explicitly empty.

references:
- reference: clinicaltrials:NCT01336634
  title: A Phase II Study of the BRAF Inhibitor Dabrafenib as a Single Agent and in Combination With the MEK Inhibitor Trametinib in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer
- reference: clinicaltrials:NCT03915951
  title: "A Phase 2, Open-label Study of Encorafenib + Binimetinib in Patients With BRAFV600-mutant Non-small Cell Lung Cancer"
- reference: clinicaltrials:NCT04526782
  title: A Phase II Study of the BRAF Inhibitor Encorafenib in Combination With the MEK Inhibitor Binimetinib in Patients With BRAFV600E-mutant Metastatic Non-small Cell Lung Cancer
- reference: PMID:17299132
  title: A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors.
- reference: PMID:26001956
  title: TP53 Silencing Bypasses Growth Arrest of BRAFV600E-Induced Lung Tumor Cells in a Two-Switch Model of Lung Tumorigenesis.
- reference: PMID:28783719
  title: Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.
- reference: PMID:28919011
  title: "Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial."
- reference: PMID:31452510
  title: Mutationally-activated PI3'-kinase-α promotes de-differentiation of lung tumors initiated by the BRAF(V600E) oncoprotein kinase.
- reference: PMID:32859654
  title: Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with BRAF-Mutant Metastatic Non-Small Cell Lung Cancer.
- reference: PMID:33821796
  title: An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma.
- reference: PMID:34455067
  title: "Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis."
- reference: PMID:35814395
  title: "Clinical Characteristics, Co-Mutations, and Treatment Outcomes in Advanced Non-Small-Cell Lung Cancer Patients With the BRAF-V600E Mutation."
- reference: PMID:36697098
  title: Cumulative Incidence of Thromboembolism and Prognostic Impact of Stroke in BRAF V600E-mutant Non-small-cell Lung Cancer.
- reference: PMID:39616778
  title: "Real-world efficacy of the dabrafenib-trametinib (D-T) combination in BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC): Results from the IFCT-2004 BLaDE cohort."
- reference: PMID:39830741
  title: "EGFR inhibitors plus dabrafenib and trametinib in patients with EGFR-mutant lung cancer and resistance mediated by BRAF(V600E) mutation: a multi-center real-world experience in China."
- reference: PMID:40138888
  title: "Prevalence, genetic variations and clinical outcomes of BRAF-V600 mutated advanced NSCLC in China: a retrospective real-world multi-centre study."
- reference: PMID:40439425
  title: Proteomic and metabolomic dissection of the BRAF V600E mutation-induced cellular state transition in lung epithelial cells.
- reference: PMID:40480428
  title: Updated Efficacy and Safety From the Phase 2 PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic NSCLC-A Brief Report.
- reference: PMID:41109959
  title: Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer.
- reference: PMID:42284541
  title: "Liquid Biopsy Monitoring in BRAF V600E-Mutated Patients With Non-Small Cell Lung Cancer Treated With Dabrafenib Plus Trametinib: The Prospective, Multicenter LiBRA Study (GOIRC-03-2020)."
- reference: PMID:42391424
  title: Clinical validation of tissue and liquid companion diagnostics for BRAF V600E detection in non-small cell lung cancers from the PHAROS study.
📚

References & Deep Research

References

21
clinicaltrials:NCT01336634
A Phase II Study of the BRAF Inhibitor Dabrafenib as a Single Agent and in Combination With the MEK Inhibitor Trametinib in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer
No top-level findings curated for this source.
clinicaltrials:NCT03915951
A Phase 2, Open-label Study of Encorafenib + Binimetinib in Patients With BRAFV600-mutant Non-small Cell Lung Cancer
No top-level findings curated for this source.
clinicaltrials:NCT04526782
A Phase II Study of the BRAF Inhibitor Encorafenib in Combination With the MEK Inhibitor Binimetinib in Patients With BRAFV600E-mutant Metastatic Non-small Cell Lung Cancer
No top-level findings curated for this source.
PMID:17299132
A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors.
No top-level findings curated for this source.
PMID:26001956
TP53 Silencing Bypasses Growth Arrest of BRAFV600E-Induced Lung Tumor Cells in a Two-Switch Model of Lung Tumorigenesis.
No top-level findings curated for this source.
PMID:28783719
Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.
No top-level findings curated for this source.
PMID:28919011
Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial.
No top-level findings curated for this source.
PMID:31452510
Mutationally-activated PI3'-kinase-α promotes de-differentiation of lung tumors initiated by the BRAF(V600E) oncoprotein kinase.
No top-level findings curated for this source.
PMID:32859654
Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with BRAF-Mutant Metastatic Non-Small Cell Lung Cancer.
No top-level findings curated for this source.
PMID:33821796
An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma.
No top-level findings curated for this source.
PMID:34455067
Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis.
No top-level findings curated for this source.
PMID:35814395
Clinical Characteristics, Co-Mutations, and Treatment Outcomes in Advanced Non-Small-Cell Lung Cancer Patients With the BRAF-V600E Mutation.
No top-level findings curated for this source.
PMID:36697098
Cumulative Incidence of Thromboembolism and Prognostic Impact of Stroke in BRAF V600E-mutant Non-small-cell Lung Cancer.
No top-level findings curated for this source.
PMID:39616778
Real-world efficacy of the dabrafenib-trametinib (D-T) combination in BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC): Results from the IFCT-2004 BLaDE cohort.
No top-level findings curated for this source.
PMID:39830741
EGFR inhibitors plus dabrafenib and trametinib in patients with EGFR-mutant lung cancer and resistance mediated by BRAF(V600E) mutation: a multi-center real-world experience in China.
No top-level findings curated for this source.
PMID:40138888
Prevalence, genetic variations and clinical outcomes of BRAF-V600 mutated advanced NSCLC in China: a retrospective real-world multi-centre study.
No top-level findings curated for this source.
PMID:40439425
Proteomic and metabolomic dissection of the BRAF V600E mutation-induced cellular state transition in lung epithelial cells.
No top-level findings curated for this source.
PMID:40480428
Updated Efficacy and Safety From the Phase 2 PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic NSCLC-A Brief Report.
No top-level findings curated for this source.
PMID:41109959
Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer.
No top-level findings curated for this source.
PMID:42284541
Liquid Biopsy Monitoring in BRAF V600E-Mutated Patients With Non-Small Cell Lung Cancer Treated With Dabrafenib Plus Trametinib: The Prospective, Multicenter LiBRA Study (GOIRC-03-2020).
No top-level findings curated for this source.
PMID:42391424
Clinical validation of tissue and liquid companion diagnostics for BRAF V600E detection in non-small cell lung cancers from the PHAROS study.
No top-level findings curated for this source.

Deep Research

2
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 36 citations 2026-04-05T13:08:22.028353

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: BRAF V600E-Mutant Non-Small Cell Lung Cancer
  • MONDO ID: (if available)
  • Category:

Research Objectives

Please provide a comprehensive research report on BRAF V600E-Mutant Non-Small Cell Lung Cancer covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Research Report: BRAF V600E–Mutant Non-Small Cell Lung Cancer (NSCLC)

Target disease

  • Disease name: BRAF V600E–mutant non-small cell lung cancer (typically metastatic lung adenocarcinoma molecular subset)
  • Category: Molecularly defined subtype of NSCLC (oncogene-driven NSCLC)
  • MONDO ID: Not identified in the retrieved evidence; recommend mapping via MONDO search term “non-small cell lung carcinoma” + qualifier “BRAF V600E” (no MONDO/MeSH/ICD codes were explicitly provided in the sources retrieved here). (planchard2024brafv600emutantmetastaticnsclc pages 3-4, planchard2024brafv600emutantmetastaticnsclc pages 1-2)

1. Disease information

Overview / current definition

BRAF V600E–mutant NSCLC is a molecular subset of NSCLC characterized by an activating missense substitution at codon 600 in BRAF, most commonly p.Val600Glu (V600E), leading to constitutive MAPK pathway signaling and oncogenic dependence on the RAF–MEK–ERK cascade. (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

A 2024 review describes the key mechanistic definition directly: the “BRAFV600E mutation confers constitutive activity of the MAPK pathway” and thereby promotes tumor cell growth and survival. (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

Key identifiers (as available from retrieved sources)

  • ICD-10 / ICD-11: Not explicitly provided in retrieved sources; coding generally follows NSCLC/lung adenocarcinoma primary site and stage plus biomarker annotation. (planchard2024brafv600emutantmetastaticnsclc pages 3-4)
  • MeSH: Not explicitly provided in retrieved sources. (planchard2024brafv600emutantmetastaticnsclc pages 3-4)
  • MONDO: Not explicitly provided in retrieved sources. (planchard2024brafv600emutantmetastaticnsclc pages 3-4)

Common synonyms / alternative names

  • “BRAFV600E-mutant metastatic NSCLC” (common in trials and reviews) (planchard2024brafv600emutantmetastaticnsclc pages 1-2)
  • “BRAF V600E–positive NSCLC” (used in regulatory documents and trials) (odogwu2018fdaapprovalsummary pages 1-2, planchard2016dabrafenibplustrametinib pages 1-1)
  • “BRAF-mutated NSCLC (class I / V600)” when grouped in BRAF mutation class framework (planchard2024brafv600emutantmetastaticnsclc pages 3-4, baik2024apracticalreview pages 1-3)

Evidence source type

The evidence is primarily aggregated disease-level resources (phase II trials, regulatory approval summaries, and review syntheses), rather than EHR-derived single-patient sources—though case reports and real-world retrospective studies exist. (odogwu2018fdaapprovalsummary pages 1-2, planchard2016dabrafenibplustrametinib pages 1-1, yan2024efficacyofchemoimmunotherapy pages 1-2)

2. Etiology

Primary causal factors

  • Somatic oncogenic driver: Activating BRAF V600E (class I BRAF) mutation in tumor cells, usually in lung adenocarcinoma. (planchard2016dabrafenibplustrametinib pages 1-1, planchard2024brafv600emutantmetastaticnsclc pages 1-2)
  • Mechanistic cause: Constitutive activation of MAPK signaling (RAF→MEK→ERK). (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

Risk factors (patient-level)

Risk factors largely overlap with NSCLC broadly (e.g., tobacco exposure), but BRAFV600E is reported to be less associated with smoking history than other BRAF alterations in NSCLC. (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

Demographic associations are inconsistent across studies, but one study summarized in 2024 reported BRAFV600E being more common in females (not uniformly replicated). (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

Protective factors

No protective genetic or environmental factors specific to BRAF V600E NSCLC were identified in the retrieved evidence.

Gene–environment interaction

The retrieved evidence supports heterogeneity in smoking association (BRAFV600E less smoking-associated than other BRAF alterations), consistent with gene–environment patterning in lung cancer; no quantitative GxE interaction models were retrieved here. (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

3. Phenotypes

Core clinical phenotype and presentation

BRAF V600E–mutant NSCLC most commonly presents as advanced/metastatic lung adenocarcinoma. A 2024 review notes BRAF mutations are “predominantly found in adenocarcinomas (>85%).” (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

Clinical manifestations are those of NSCLC by stage (e.g., cough, dyspnea, hemoptysis, chest pain, weight loss) and metastasis-related symptoms (bone pain, neurologic symptoms if brain metastases). Specific symptom-frequency data were not present in the retrieved excerpts.

Suggested HPO terms (examples for NSCLC phenotype capture)

(General NSCLC phenotype ontology suggestions; frequencies not extracted from the retrieved evidence) - Cough (HP:0012735) - Dyspnea (HP:0002094) - Hemoptysis (HP:0002105) - Weight loss (HP:0001824) - Chest pain (HP:0100749) - Pleural effusion (HP:0002202) - Bone pain (HP:0002653) - Headache (HP:0002315) / Seizure (HP:0001250) (for brain metastases)

Quality of life

A 2024 phase II study in Chinese patients explicitly included quality of life and states “self-reported QoL was improved or maintained during the treatment period” on dabrafenib+trametinib. (fan2024efficacysafetyand pages 1-2)

4. Genetic / molecular information

Causal gene

  • BRAF (proto-oncogene; serine/threonine kinase in MAPK pathway). (pan2019dabrafenibplustrametinib pages 1-2)

Pathogenic variant (somatic)

  • BRAF p.Val600Glu (V600E) (activating missense). A case-based review describes this as “valine substitution for glutamate at position 600 (V600E) within the BRAF kinase.” (pan2019dabrafenibplustrametinib pages 1-2)
  • Somatic origin is typical in NSCLC; germline BRAF V600E is not a recognized common cause of lung cancer in these sources.

Variant classification

In cancer clinical practice, BRAF V600E is treated as an actionable oncogenic driver (pathogenic/oncogenic in somatic context). (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

Co-mutations and molecular classes

BRAF mutations are categorized into three functional classes; class I includes V600 substitutions (including V600E). (planchard2024brafv600emutantmetastaticnsclc pages 1-2, planchard2024brafv600emutantmetastaticnsclc pages 3-4)

Population allele frequency

Population germline allele frequency is not directly relevant for a somatic driver; not extracted in the retrieved evidence.

Resistance mechanisms (molecular)

Resistance to BRAF/MEK inhibition in BRAFV600E NSCLC is frequently mediated by MAPK pathway reactivation and/or bypass signaling. A 2024 resistance-focused study notes resistance mechanisms have been described as “MAPK-dependent, related to the reactivation of the MAPK pathway” as well as MAPK-independent alterations, and highlights extensive genomic heterogeneity at failure. (mezquita2024resistancetobraf pages 1-2)

A 2024 review summarizes specific recurrent mechanisms (percentages reported in the review): MAPK/ERK reactivation via BRAF splice variants (16%), BRAF amplification (13%), NRAS/KRAS alterations (20%), MEK1/2 mutations (7%), plus PI3K-AKT activation and PTEN alterations. (ibrahim2024navigatingthecomplexity pages 7-8)

5. Environmental information

No environmental or infectious agent is specific to the BRAF V600E subtype in the retrieved evidence. Environmental factors follow NSCLC broadly (tobacco smoke, radon, air pollution, occupational carcinogens). The key subtype-relevant point extracted is a relative (not absolute) decreased association of BRAFV600E with smoking compared to other BRAF alterations. (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

6. Mechanism / pathophysiology

Core pathway

BRAFV600E is a constitutively active class I BRAF mutation that drives persistent RAF–MEK–ERK signaling and tumor proliferation/survival. (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

Causal chain (simplified): 1) Somatic BRAF V600E mutation → 2) constitutive MAPK pathway activation → 3) increased tumor cell proliferation/survival → 4) tumor growth, invasion, metastasis and NSCLC clinical manifestations. (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

Upstream vs downstream

  • Upstream: RTKs/RAS inputs may be less necessary for class I BRAF activation (oncogenic monomer activity), but can contribute to feedback and resistance. (planchard2024brafv600emutantmetastaticnsclc pages 3-4, mezquita2024resistancetobraf pages 1-2)
  • Downstream: MEK/ERK activation; resistance frequently involves ERK reactivation. (mezquita2024resistancetobraf pages 1-2)

Suggested GO biological process terms

  • MAPK cascade (GO:0000165)
  • ERK1 and ERK2 cascade (GO:0070371)
  • Positive regulation of cell proliferation (GO:0008284)
  • Regulation of apoptotic process (GO:0042981)
  • Response to drug (GO:0042493)

Immune system involvement

Immune checkpoint inhibitors are used in BRAF-mutant NSCLC, but retrospective evidence is mixed; targeted therapy is often prioritized for BRAF V600E (see Treatment). (yan2024efficacyofchemoimmunotherapy pages 1-2)

Molecular profiling (recent technology example: CTC profiling)

At failure of dabrafenib+trametinib, single-cell circulating tumor cell sequencing demonstrated substantial heterogeneity and that resistance was not necessarily driven by BRAFV600E-mutant CTCs (BRAFV600E found in only 1/26 CTCs), with alterations affecting cell cycle, DNA repair, and immune response pathways. (mezquita2024resistancetobraf pages 1-2)

7. Anatomical structures affected

Organ/system level

  • Primary: Lung (respiratory system), typically adenocarcinoma. (planchard2024brafv600emutantmetastaticnsclc pages 1-2)
  • Metastatic involvement: common NSCLC metastatic sites (brain, bone, liver, adrenal, pleura) are clinically relevant; intracranial activity data for BRAF/MEK therapy indicate brain metastases are a key management issue. (planchard2024brafv600emutantmetastaticnsclc pages 10-11)

Suggested UBERON terms

  • Lung (UBERON:0002048)
  • Pulmonary alveolus (UBERON:0002299)
  • Bronchiole (UBERON:0002189)

Suggested Cell Ontology (CL) terms

  • Alveolar type II cell (CL:0002063) (common cell-of-origin used in mouse models and lung adenocarcinoma studies)
  • Epithelial cell (CL:0000066)

Suggested GO cellular component terms

  • Plasma membrane (GO:0005886) (RTK signaling)
  • Cytosol (GO:0005829)
  • Nucleus (GO:0005634)

8. Temporal development

  • Onset: Adult-onset malignancy; often detected at advanced stage typical of NSCLC.
  • Progression: Progressive unless treated; targeted therapy yields rapid responses but resistance commonly develops.

The resistance literature and reviews note progression on BRAF-targeted therapy is common, with many patients progressing within ~1 year in historical experience. (ibrahim2024navigatingthecomplexity pages 7-8)

9. Inheritance and population

Epidemiology (frequency)

  • FDA review notes BRAF V600 mutations occur in ~2% of NSCLC, and “about half” are V600E, implying ~1–1.5% of NSCLC are BRAF V600E. (odogwu2018fdaapprovalsummary pages 1-2)
  • A 2024 review estimates BRAFV600E “accounts for ~1–2% of NSCLCs.” (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

Demographics

  • Histology: predominantly adenocarcinoma (>85%). (planchard2024brafv600emutantmetastaticnsclc pages 1-2)
  • Smoking: BRAFV600E less associated with smoking than other BRAF. (planchard2024brafv600emutantmetastaticnsclc pages 1-2)
  • Sex: potential female enrichment in some datasets, but inconsistent across studies. (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

Inheritance

BRAF V600E in NSCLC is typically somatic (tumor-acquired); inheritance patterns and penetrance are not applicable in the usual presentation.

10. Diagnostics

Molecular testing (guideline-level principles)

A 2024 review summarizes guideline direction: “Guidelines recommend that all patients with advanced non-squamous NSCLC undergo broad-based molecular testing to identify molecular drivers—including but not limited to BRAFV600 mutations.” (planchard2024brafv600emutantmetastaticnsclc pages 3-4)

Assay modalities

  • PCR: rapid turnaround but “typically limited to detection of V600E mutation” (single-gene). (planchard2024brafv600emutantmetastaticnsclc pages 3-4)
  • Panel-based NGS: supports simultaneous multi-gene testing and detects both V600E and non-V600 BRAF alterations. (planchard2024brafv600emutantmetastaticnsclc pages 3-4)

Liquid biopsy / ctDNA

Single-cell CTC profiling and cfDNA can detect BRAF V600E at resistance; cfDNA detected BRAFV600E in 5/7 samples at failure in a small cohort. (mezquita2024resistancetobraf pages 1-2)

Biomarkers

  • BRAF V600E is the defining predictive biomarker for BRAF+MEK inhibitor therapy. (planchard2024brafv600emutantmetastaticnsclc pages 1-2)
  • PD-L1 may influence chemo-immunotherapy outcomes; a retrospective study found PD-L1 expression differed between responders and non-responders (p=0.04). (yan2024efficacyofchemoimmunotherapy pages 1-2)

11. Outcome / prognosis

Outcomes on targeted therapy

Clinical trial and real-world outcomes are best summarized under Treatment; durable responses occur but acquired resistance is common. (planchard2024brafv600emutantmetastaticnsclc pages 3-4, riely2023phaseiiopenlabel pages 1-2)

Outcomes on chemo-immunotherapy (BRAF-mutated cohort)

A 2024 retrospective study in BRAF-mutated NSCLC treated with ICI+chemotherapy (n=44 treated) reported: - ORR 36.3% - Median PFS 4 months - Median OS 29 months and improved OS when used first-line versus later-line (29 vs 9.75 months, p=0.01). (yan2024efficacyofchemoimmunotherapy pages 1-2)

12. Treatment

Standard targeted therapy (approved BRAF+MEK combinations)

Two BRAF+MEK combinations are guideline-supported preferred options in metastatic BRAFV600E NSCLC: - dabrafenib + trametinib (FDA approval expanded June 22, 2017) (odogwu2018fdaapprovalsummary pages 1-2) - encorafenib + binimetinib (FDA approval October 11, 2023) (baik2024apracticalreview pages 1-3)

A 2024 review states: “Current guidelines recommend dabrafenib plus trametinib or encorafenib plus binimetinib as preferred first-line treatment options or as subsequent treatment for BRAFV600E-mutant metastatic NSCLC.” (planchard2024brafv600emutantmetastaticnsclc pages 1-2)

Dabrafenib + trametinib (phase II efficacy)

From the 2016 phase II in previously treated metastatic BRAFV600E NSCLC: - ORR 63.2% (95% CI 49.3–75.6) (planchard2016dabrafenibplustrametinib pages 1-1)

From the 2024 review synthesis of phase II cohorts: - Treatment-naïve: ORR 64%; median PFS 10.9 months; OS 24.6 months (planchard2024brafv600emutantmetastaticnsclc pages 3-4) - Previously treated: ORR 63.2%; median PFS 9.7 months (planchard2024brafv600emutantmetastaticnsclc pages 3-4)

FDA approval summary confirms similar magnitude: ORR 63% (previously treated) and 61% (treatment-naïve), with majority of responses durable ≥6 months. (odogwu2018fdaapprovalsummary pages 1-2, odogwu2018fdaapprovalsummary pages 3-5)

Encorafenib + binimetinib (PHAROS phase II)

The JCO 2023 PHAROS phase II trial reported: - Treatment-naïve: ORR 75% (95% CI 62–85); median PFS NE (95% CI 15.7–NE) (riely2023phaseiiopenlabel pages 1-2) - Previously treated: ORR 46% (95% CI 30–63); median PFS 9.3 months (95% CI 6.2–NE) (riely2023phaseiiopenlabel pages 1-2)

Abstract-level direct quote supporting core result: “ORR by IRR was 75% (95% CI, 62 to 85) in treatment-naïve and 46% (95% CI, 30 to 63) in previously treated patients.” (riely2023phaseiiopenlabel pages 1-2)

Adverse events (selected)

  • Encorafenib+binimetinib common TRAEs: nausea (50%), diarrhea (43%), fatigue (32%); permanent discontinuation due to TRAEs 15%; one grade 5 intracranial hemorrhage. (riely2023phaseiiopenlabel pages 1-2, riely2023phaseiiopenlabel pages 6-8)
  • Dabrafenib+trametinib (previously treated cohort): serious AEs occurred in 56%; common grade 3–4 events included neutropenia (9%) and hyponatremia (7%). (planchard2016dabrafenibplustrametinib pages 1-1)

Immunotherapy and chemo-immunotherapy

Chemo-immunotherapy is a real-world alternative/adjunct when targeted therapy is unavailable, contraindicated, or in later-line settings, but comparative efficacy is heterogeneous across reports. A 2024 retrospective series reported ORR 36.3% and median PFS 4 months on ICI+chemotherapy in BRAF-mutated NSCLC. (yan2024efficacyofchemoimmunotherapy pages 1-2)

Experimental / emerging applications

  • Triplet regimens combining EGFR inhibition with dabrafenib+trametinib have been used in acquired BRAFV600E-mediated resistance in EGFR-mutant NSCLC (case series evidence), illustrating cross-driver resistance management paradigms. (o’leary2019targetingbrafmutations pages 1-2)

MAXO (Medical Action Ontology) suggestions

(Recommended for knowledge base annotation) - Targeted therapy (e.g., “BRAF inhibitor therapy”, “MEK inhibitor therapy”; combination targeted therapy) - Molecular diagnostic testing (tumor NGS panel testing; plasma ctDNA testing) - Immune checkpoint inhibitor therapy (PD-1/PD-L1 inhibitor therapy) - Cytotoxic chemotherapy (platinum-doublet chemotherapy)

Quick comparative evidence table

Therapy Study / setting Key publication Cohort size ORR DOR Median PFS Median OS FDA approval date Notes / citation
Dabrafenib + trametinib Phase II, previously treated BRAFV600E-mutant metastatic NSCLC 2016 n=57 63.2% (95% CI 49.3–75.6) 9.0 mo 9.7 mo NR in initial report 22-Jun-2017 Planchard et al., Lancet Oncology 2016; basis of later regulatory summary (planchard2016dabrafenibplustrametinib pages 1-1, odogwu2018fdaapprovalsummary pages 1-2)
Dabrafenib + trametinib Phase II, treatment-naive BRAFV600E-mutant metastatic NSCLC 2017 n=36 64% (95% CI 46–79); FDA summary reports 61% (95% CI 44–77) 10.4 mo 10.9 mo 24.6 mo 22-Jun-2017 Planchard et al., Lancet Oncology 2017; FDA approval summary confirms June 22, 2017 approval (planchard2024brafv600emutantmetastaticnsclc pages 3-4, odogwu2018fdaapprovalsummary pages 1-2)
Dabrafenib + trametinib Updated 5-year phase II follow-up 2022 previously treated n=57; treatment-naive n=36 — — ~10.2 mo (pretreated); ~10.8 mo (naive) ~18.2 mo (pretreated); ~17.3 mo (naive) 22-Jun-2017 Long-term survival update in J Thorac Oncol 2022 (summarized in review) (planchard2024brafv600emutantmetastaticnsclc pages 3-4)
Encorafenib + binimetinib PHAROS phase II, treatment-naive BRAFV600E-mutant metastatic NSCLC 2023 n=59 75% (95% CI 62–85) NE (95% CI 23.1–NE) NE (95% CI 15.7–NE) NE 11-Oct-2023 Riely et al., J Clin Oncol 2023; FDA approval based on PHAROS (riely2023phaseiiopenlabel pages 1-2, baik2024apracticalreview pages 1-3, baik2024apracticalreview media 088d26fe)
Encorafenib + binimetinib PHAROS phase II, previously treated BRAFV600E-mutant metastatic NSCLC 2023 n=39 46% (95% CI 30–63) 16.7 mo (95% CI 7.4–NE) 9.3 mo (95% CI 6.2–NE) NE 11-Oct-2023 Riely et al., J Clin Oncol 2023; second approved BRAF/MEK option in this disease (riely2023phaseiiopenlabel pages 1-2, baik2024apracticalreview pages 3-4, baik2024apracticalreview pages 1-3)

Table: This table summarizes the pivotal efficacy results and FDA approval milestones for the two approved BRAF/MEK inhibitor combinations used in BRAF V600E-mutant metastatic NSCLC. It is useful for quickly comparing the clinical trial evidence supporting dabrafenib/trametinib and encorafenib/binimetinib.

13. Prevention

Primary prevention

Subtype-specific primary prevention is not established; prevention follows lung cancer prevention broadly (tobacco cessation, reducing exposures).

Secondary prevention (screening / early detection)

USPSTF 2021 lung cancer screening (U.S.) expanded eligibility for annual low-dose CT (LDCT) to: - Adults aged 50–80 years - ≥20 pack-year smoking history - Current smokers or quit within the past 15 years These criteria are explicitly summarized in 2021–2022 analyses/commentaries. (melzer2021expandedaccessto pages 1-2, ritzwoller2021evaluationofpopulationlevel pages 2-4)

These screening recommendations are not BRAF-specific; they aim to reduce lung cancer mortality at a population level. (melzer2021expandedaccessto pages 1-2)

14. Other species / natural disease

No naturally occurring veterinary “BRAF V600E lung cancer” entity was retrieved in the present evidence set.

15. Model organisms

Genetically engineered mouse models (GEMMs)

Evidence supports that conditional lung-specific expression of BRAF V600E induces lung tumors and establishes MAPK dependency: - In a classic mouse model study, lung-specific BRAF V600E expression induced lung adenocarcinoma with bronchioloalveolar features, with tumor regression upon transgene deinduction and also tumor regression with MEK inhibition (CI-1040), demonstrating MAPK pathway dependence. (ji2007mutationsinbraf pages 1-2)

A more recent GEMM study emphasized the need for cooperating events: - Expression of BRAFV600E in distal lung epithelium produces benign lung adenomas that undergo a senescence-like proliferative arrest and “typically fail to progress,” but TP53 silencing bypasses growth arrest and promotes progression to lung adenocarcinoma. (shai2015tp53silencingbypasses pages 1-3)

These models are used to study tumor initiation, oncogene addiction, and resistance biology in an immunocompetent context.

Notes on evidence limitations

  • Ontology identifiers (MONDO, MeSH, ICD-10/11) for this biomarker-defined entity were not directly provided in the retrieved excerpts; these should be added via dedicated ontology lookup workflows (e.g., MONDO/MeSH browser). (planchard2024brafv600emutantmetastaticnsclc pages 3-4)
  • Several requested areas (e.g., detailed phenotype frequency distributions, large population incidence/prevalence rates per 100,000) were not available in the current retrieved sources and would require cancer registry analyses stratified by BRAF status.

Key recent sources prioritized (2023–2024)

  • Planchard et al., NPJ Precision Oncology (Apr 2024): https://doi.org/10.1038/s41698-024-00552-7 (planchard2024brafv600emutantmetastaticnsclc pages 1-2, planchard2024brafv600emutantmetastaticnsclc pages 3-4)
  • Riely et al., Journal of Clinical Oncology (Jul 2023): https://doi.org/10.1200/JCO.23.00774 (riely2023phaseiiopenlabel pages 1-2)
  • Baik et al., Advances in Therapy (May 2024): https://doi.org/10.1007/s12325-024-02839-4 (baik2024apracticalreview pages 1-3, baik2024apracticalreview pages 3-4)
  • Mezquita et al., British Journal of Cancer (Jan 2024): https://doi.org/10.1038/s41416-023-02535-0 (mezquita2024resistancetobraf pages 1-2)
  • Yan et al., Frontiers in Oncology (Jan 2024): https://doi.org/10.3389/fonc.2024.1353491 (yan2024efficacyofchemoimmunotherapy pages 1-2)
  • Melzer & Wilt, JAMA Network Open (Mar 2021): https://doi.org/10.1001/jamanetworkopen.2021.0275 (USPSTF 2021 criteria summary) (melzer2021expandedaccessto pages 1-2)

Included visual evidence: PHAROS efficacy table excerpted from Baik et al. (Table 1). (baik2024apracticalreview media 088d26fe)

References

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OpenScientist ▸
1. Disease Information
openscientist-autonomous 42 citations 2026-05-05T23:49:20.673149Z

1. Disease Information

Overview

BRAF V600E-mutant NSCLC is a molecularly defined subtype of non-small cell lung cancer characterized by a specific somatic missense mutation (c.1799T>A; p.Val600Glu) in the BRAF gene (chromosome 7q34). This mutation results in constitutive activation of the BRAF kinase and downstream MAPK/ERK signaling, driving oncogenesis. It is classified as a Class I BRAF mutation, which signals as a RAS-independent monomer with markedly elevated (approximately 500-fold) kinase activity compared to wild-type BRAF (PMID: 39961465).

Key Identifiers

Database Identifier
ICD-10 C34 (Malignant neoplasm of bronchus and lung)
ICD-11 2C25 (Malignant neoplasms of bronchus or lung)
ICD-O-3 8140/3 (Adenocarcinoma, NOS — most common histology)
MeSH D002289 (Carcinoma, Non-Small-Cell Lung)
MONDO MONDO:0005233 (non-small cell lung carcinoma)
OMIM 164757 (BRAF gene)
HGNC HGNC:1097 (BRAF)
COSMIC COSM476 (BRAF V600E)

Synonyms and Alternative Names

  • BRAF V600E-positive NSCLC
  • BRAF V600E-mutant lung adenocarcinoma
  • BRAF-mutant non-small cell lung cancer (Class I)
  • V600E BRAF-driven lung cancer
  • NSCLC harboring BRAF V600E mutation

Data Sources

Information is derived from aggregated disease-level resources including clinical trial data (PHAROS, BRF113928), real-world registries (Italian ATLAS, French BLaDE, Turkish Oncology Group, LANDSCAPE), institutional cohort studies, and published literature.

2. Etiology

Disease Causal Factors

The primary causal factor is a somatic missense mutation in the BRAF gene (BRAF V600E), which is an acquired genetic alteration arising in lung epithelial cells. This is not a germline/inherited condition. The mutation causes constitutive activation of the MAPK/ERK signaling pathway, which is the central oncogenic driver (PMID: 29729495): "BRAF mutations, found in 1.5-3.5% of NSCLC, are responsible of the constitutive activation of mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway."

Risk Factors

Genetic Risk Factors

  • BRAF V600E somatic mutation (primary driver): A Class I activating mutation that functions as a RAS-independent monomer
  • Co-mutations: TP53, STK11, KEAP1, and PI3K pathway mutations frequently co-occur and may modify disease behavior. Co-mutations were associated with shorter OS (median 8.7 vs. 20.2 months, p = 0.009) in a Turkish multicenter cohort (PMID: 40813186)
  • No established germline susceptibility loci specific to BRAF V600E NSCLC

Environmental Risk Factors

  • Smoking: Unlike most NSCLC subtypes, BRAF V600E-mutant NSCLC has an enrichment of never-smokers (29–64% depending on cohort). In Chinese cohorts, 55% were never-smokers (PMID: 35814395): "64.2% were non-smokers". In European cohorts, 29–30% were never-smokers (PMID: 24552757): "The proportion of never-smokers among BRAF-positives was high (29%)." However, smoking remains a risk factor for lung cancer broadly.
  • Age: Median age at diagnosis is 64–68 years
  • Sex: Slight female predominance (50–55%)
  • Occupational exposures: Standard lung carcinogen exposures (asbestos, radon, etc.) apply to NSCLC generally

Protective Factors

  • Smoking cessation: Reduces overall lung cancer risk
  • No specific genetic protective factors have been identified for BRAF V600E NSCLC
  • Standard lung cancer protective factors (dietary antioxidants, physical activity) apply generally

Gene-Environment Interactions

The relationship between smoking and BRAF V600E NSCLC is distinctive. Unlike KRAS-mutant NSCLC (strongly smoking-associated), BRAF V600E occurs with notable frequency in never-smokers, suggesting that at least a subset of cases arise through mechanisms independent of tobacco carcinogenesis. However, the mutation also occurs in current/former smokers, indicating that both smoking-dependent and smoking-independent pathways can lead to BRAF V600E acquisition.

3. Phenotypes

Clinical Presentation

Phenotype HPO Term Type Frequency Severity
Cough HP:0012735 (Cough) Symptom ~60-70% Variable
Dyspnea HP:0002094 (Dyspnea) Symptom ~50-60% Progressive
Chest pain HP:0100749 (Chest pain) Symptom ~25-40% Variable
Hemoptysis HP:0002105 (Hemoptysis) Symptom ~20-30% Variable
Weight loss HP:0001824 (Weight loss) Symptom ~30-50% Progressive
Fatigue HP:0012378 (Fatigue) Symptom ~40-60% Variable
Pleural effusion HP:0002202 (Pleural effusion) Sign ~15-25% Moderate-severe
Brain metastases HP:0100009 (Cerebral neoplasm) Complication 15-21% at diagnosis Severe
Thromboembolism HP:0001907 (Thromboembolism) Complication 43% 1-year incidence Severe
Bone metastases HP:0031377 (Bone neoplasm) Complication ~25-35% Moderate-severe

Phenotype Characteristics

  • Age of onset: Adult-onset, median 64–68 years
  • Symptom severity: Variable at presentation; many patients are diagnosed at advanced stages (Stage IIIB-IV)
  • Symptom progression: Progressive without treatment; responsive to targeted therapy
  • Histology: Predominantly adenocarcinoma (>95%) (PMID: 39616778): "95.1 % had adenocarcinoma"

Thromboembolism as a Distinctive Phenotype

A particularly notable clinical feature is the high risk of thromboembolism. In a study of 10 BRAF V600E NSCLC patients, 5 developed 7 thromboembolic events, with a 1-year cumulative incidence of 43% (95% CI: 11–72%). Events included cancer-related stroke and venous thromboembolism, with stroke patients showing elevated D-dimer levels and rapid mortality (PMID: 36697098): "Of 10 patients with BRAF-V600E mutant lung cancer, five developed a total of seven thromboembolic events, showing a 1-year cumulative incidence of 43% (95% confidence interval=11-72%)."

Quality of Life Impact

Advanced BRAF V600E NSCLC significantly impacts daily functioning through respiratory symptoms, fatigue, pain, and treatment-related adverse effects. Targeted therapy with dabrafenib/trametinib has been shown to maintain or improve quality of life compared to chemotherapy. Chinese phase II data on dabrafenib plus trametinib specifically evaluated quality of life outcomes (PMID: 39830765).

4. Genetic/Molecular Information

Causal Gene

  • Gene: BRAF (B-Raf proto-oncogene, serine/threonine kinase)
  • HGNC ID: HGNC:1097
  • OMIM: 164757
  • Chromosome location: 7q34
  • UniProt: P15056

Pathogenic Variant

Feature Detail
Variant BRAF V600E (c.1799T>A; p.Val600Glu)
COSMIC ID COSM476
dbSNP rs113488022
Variant type Missense (Class I activating mutation)
Variant classification Pathogenic (somatic oncogenic driver)
Origin Somatic (acquired)
Functional consequence Gain-of-function; constitutive kinase activation (~500-fold increase)
Frequency in NSCLC 1–2% of all NSCLC; ~50–66% of BRAF-mutant NSCLC
Population allele frequency Extremely rare as germline variant in gnomAD

The BRAF V600E mutation is a well-characterized oncogenic driver across multiple cancer types (melanoma, colorectal cancer, thyroid cancer, hairy cell leukemia). In NSCLC, it accounts for approximately half to two-thirds of all BRAF mutations, with the remainder being non-V600E mutations (Class II and Class III) (PMID: 40172088): "V-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations are found in up to 4% of patients with non-small cell lung cancer (NSCLC). Approximately 2% of advanced NSCLC cases harbor a BRAF V600E (class I) mutation."

BRAF Mutation Classification

Class Mechanism RAS Dependence Examples Kinase Activity
Class I Active monomer Independent V600E, V600K, V600D High (constitutive)
Class II Active dimer Independent K601E, G469A Intermediate-High
Class III Kinase-impaired Dependent D594G, G466V Reduced (activates via CRAF)

Co-occurring Molecular Alterations

Based on multiple cohort studies, common co-mutations include: - TP53: Most frequent co-mutation (~30–50%) - STK11/LKB1: Associated with poor immunotherapy response - KEAP1: Associated with poor prognosis - PIK3CA: Co-occurring PI3K pathway activation - EGFR: Rarely co-mutated (generally mutually exclusive)

Co-mutations in non-V600E cases were more frequent (40% vs. 10%) and were associated with significantly worse outcomes (median OS 8.7 vs. 20.2 months, p = 0.009) (PMID: 40813186).

Modifier Genes

  • NKX2-1 (TTF-1): Loss of NKX2-1 in BRAF V600E-driven lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA) phenotype and resistance to BRAF/MEK inhibition (PMID: 33821796): The study demonstrated that "NKX2-1 loss in human and murine lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA), a lung cancer subtype that exhibits gastric differentiation."
  • PI3K: Mutationally-activated PI3Kα promotes de-differentiation of BRAF V600E-initiated lung tumors (PMID: 31452510)

Epigenetic Information

  • BRAF V600E tumors show distinct DNA methylation patterns compared to BRAF wild-type NSCLC
  • CpG island methylator phenotype (CIMP) has been associated with BRAF V600E in colorectal cancer and may play a role in NSCLC
  • Histone modifications downstream of MAPK signaling contribute to altered gene expression programs

5. Environmental Information

Environmental Factors

  • Tobacco smoke: The most significant environmental risk factor for NSCLC generally, though BRAF V600E-mutant NSCLC shows enrichment of never-smokers
  • Radon exposure: Contributing factor for lung cancer in general populations
  • Air pollution: Particulate matter (PM2.5) is an established lung carcinogen
  • Occupational exposures: Asbestos, silica, heavy metals, and other industrial carcinogens

Lifestyle Factors

  • Smoking: 30–71% of BRAF V600E NSCLC patients are current/former smokers, depending on cohort and ethnicity
  • Diet: No specific dietary factors linked to BRAF V600E NSCLC specifically
  • Exercise: General protective effect against lung cancer

Infectious Agents

Not directly applicable. No infectious agents are established as causes of BRAF V600E NSCLC, though HPV has been loosely associated with some lung cancers in certain populations.

6. Mechanism / Pathophysiology

Molecular Pathways

The central pathogenic mechanism involves constitutive activation of the RAS-RAF-MEK-ERK (MAPK) signaling cascade (PMID: 39961465): "V600E mutation results in a constitutively active kinase domain, leading to dysregulated downstream signaling independent of extracellular stimuli. This sustained activation promotes cell proliferation, survival, angiogenesis, and hallmark features of the cancer cells."

Causal Chain

BRAF V600E Somatic Mutation (initiating event)
       │
       ▼
Constitutive BRAF Kinase Activation (~500-fold increase)
   [Signals as RAS-independent monomer]
       │
       ▼
Sustained MEK1/2 Phosphorylation (MEK → pMEK)
       │
       ▼
Constitutive ERK1/2 Activation (ERK → pERK)
       │
       ├──► Transcription factor activation (ELK1, c-MYC, c-FOS, c-JUN)
       ├──► Cell cycle progression (Cyclin D1 upregulation)
       ├──► Anti-apoptotic signaling (BCL-2 family modulation)
       ├──► Angiogenesis (VEGF upregulation)
       ├──► Metabolic reprogramming (Warburg effect enhancement)
       └──► Immune evasion (PD-L1 upregulation, TME remodeling)
      │
      ▼
       Malignant Transformation → Tumor Growth → Metastasis

Key Pathway Components

Pathway Role GO Term
MAPK/ERK cascade Primary oncogenic signaling GO:0000165
PI3K-AKT-mTOR Cross-talk and resistance GO:0043491
WNT signaling De-differentiation upon NKX2-1 loss GO:0016055
Cell proliferation Downstream effect GO:0008283
Anti-apoptosis Survival signaling GO:0006915 (regulation)
Angiogenesis Tumor vascularization GO:0001525

Cellular Processes

  • Cell proliferation (GO:0008283): Constitutive ERK activation drives uncontrolled cell division
  • Evasion of apoptosis (GO:0043066): MAPK signaling upregulates anti-apoptotic proteins
  • Angiogenesis (GO:0001525): VEGF-mediated tumor neovascularization
  • Cell migration and invasion (GO:0016477): EMT-related processes driving metastasis
  • Immune evasion: PD-L1 expression (78% PD-L1 ≥1% in BRAF V600E NSCLC) (PMID: 39616778)

Protein Dysfunction

The V600E mutation substitutes glutamic acid for valine at position 600 in the activation segment of the BRAF kinase domain. This substitution mimics the phosphorylated (active) state of the activation loop, locking BRAF in a constitutively active conformation. Unlike wild-type BRAF, which requires RAS-GTP binding and dimerization for activation, BRAF V600E signals as a monomer without upstream RAS input.

Resistance Mechanisms

Resistance to BRAF/MEK-targeted therapy occurs through several mechanisms identified via circulating tumor DNA (ctDNA) genomics (PMID: 32859654): - MAPK pathway reactivation: Acquisition of secondary RAS mutations (NRAS, KRAS), MEK mutations, BRAF amplification - Bypass pathway activation: PI3K/AKT/mTOR pathway activation, MET amplification - Lineage transformation: NKX2-1 loss leading to gastric differentiation and BRAF/MEK inhibitor resistance (PMID: 33821796) - BRAF V600E as acquired resistance mechanism: BRAF V600E can itself emerge as a resistance mechanism during EGFR-TKI therapy in EGFR-mutant NSCLC (PMID: 39830741)

Metabolic Changes

  • Enhanced glycolysis (Warburg effect) driven by MAPK-dependent metabolic reprogramming
  • Altered lipid metabolism
  • Increased nucleotide synthesis supporting rapid proliferation

Immune System Involvement

  • High PD-L1 expression (~78% PD-L1 ≥1%) suggests an inflamed tumor microenvironment
  • Response to immune checkpoint inhibitors (anti-PD-1/PD-L1) observed in clinical settings
  • The relationship between BRAF V600E signaling and immune evasion involves MAPK-driven upregulation of PD-L1 and modulation of the tumor microenvironment

Advanced Technologies and Molecular Profiling

ctDNA-based Resistance Profiling

Circulating tumor DNA sequencing has proven clinically relevant for detection of BRAF V600E mutations and identification of resistance mechanisms (PMID: 32859654). Serial ctDNA analysis can detect MAPK pathway reactivation mutations, bypass pathway alterations, and emerging co-mutations that may predict treatment failure.

Functional Genomics

Genome-wide screening has identified novel genes implicated in cellular sensitivity to BRAF V600E inhibition (PMID: 31548614), expanding the understanding of genetic modifiers of targeted therapy response.

Novel Inhibitor Development

Erianin has been identified as a novel dual CRAF/MEK1/2 inhibitor that suppresses constitutive MAPK activation in BRAF V600E-mutant cells, representing a potential strategy to overcome paradoxical activation seen with single-agent BRAF inhibitors (PMID: 36872366).

7. Anatomical Structures Affected

Organ Level

Level Structure UBERON/Ontology Term
Primary Lung UBERON:0002048
Secondary Brain (metastases in 15–21%) UBERON:0000955
Secondary Bone (metastases in ~25–35%) UBERON:0002481
Secondary Liver (metastases) UBERON:0002107
Secondary Adrenal glands (metastases) UBERON:0002369
Secondary Pleura (effusions in 15–25%) UBERON:0000977
Secondary Pericardium (effusions) UBERON:0002407
Body system Respiratory system UBERON:0001004
Body system Vascular system (thromboembolism) UBERON:0004537

Tissue and Cell Level

  • Primary tissue: Pulmonary epithelium (UBERON:0000115)
  • Primary cell type: Type II alveolar epithelial cells (pneumocytes) — the putative cell of origin for lung adenocarcinoma (CL:0002063)
  • Additional cell types: Club cells (Clara cells; CL:0000158) — can be cell of origin in certain murine models (PMID: 28783725)
  • Histology: Adenocarcinoma, predominantly acinar, papillary, or lepidic patterns

Subcellular Level

Compartment GO Term Relevance
Cytoplasm GO:0005737 BRAF protein localization
Cell membrane GO:0005886 RAS-RAF interaction site
Nucleus GO:0005634 ERK-mediated transcription factor activation
Mitochondria GO:0005739 Apoptotic regulation

Localization

  • Primary site: Any lobe of the lung; no specific lobar predilection established
  • Lateralization: Can be unilateral or bilateral; no consistent lateralization pattern
  • Metastatic sites: Brain, bone, liver, adrenal glands, contralateral lung

8. Temporal Development

Onset

  • Typical age of onset: Adult/geriatric, median 64–68 years
  • Onset pattern: Insidious; most patients present with advanced-stage disease
  • BRAF V600E is not specifically associated with younger age at diagnosis (unlike EGFR or ALK) (PMID: 26720421)

Progression

Disease Stages (AJCC 8th Edition TNM)

Stage Description Approximate Distribution at Diagnosis
I Localized ~15–20%
II Locally advanced ~5–10%
III Regional spread ~15–20%
IV Distant metastases ~50–60%
  • Progression rate: Variable; without treatment, progression is typically rapid (months)
  • Disease course: Progressive without treatment
  • With targeted therapy: Durable responses observed (median PFS 13–30 months depending on regimen)

Patterns

  • Treatment-induced remission: Achievable with BRAF/MEK inhibition (ORR 63–75%)
  • Complete remission: Rare but documented, including cases with combined BRAF/MEK inhibition and immunotherapy (PMID: 41333480)
  • Acquired resistance: Develops in most patients on targeted therapy, typically after 10–30 months
  • Critical period: Early molecular diagnosis is critical for initiating appropriate targeted therapy

9. Inheritance and Population

Epidemiology

Metric Value Source
BRAF mutation frequency in NSCLC 1.5–4% Multiple cohorts
BRAF V600E frequency in NSCLC ~1–2% PMID: 40172088
V600E as fraction of BRAF mutations 24.6% (China) to 66% (Europe) PMID: 40138888
Estimated incidence ~3,000–6,000 new cases/year (US) Derived from NSCLC incidence

The Chinese LANDSCAPE study, one of the largest cohorts, found BRAF mutations in 3.56% (95% CI: 3.48–3.65%) of 175,566 NSCLC patients, with V600E accounting for 24.6% of BRAF mutations (PMID: 40138888): "In Cohort I, of patients with NSCLC, 6249 (3.56%, 95% CI: 3.48%-3.65%) were confirmed to harbour a BRAF mutation. BRAF V600E accounted for 24.6% (1539/6249) of all patients with BRAF-mutated NSCLC."

In European cohorts, BRAF V600E represents a higher proportion (~66%) of BRAF mutations (PMID: 24552757): "We found a BRAF-mutation frequency of 1.7% in the total cohort of 979 patients, and 2.3% among 646 adenocarcinomas."

Inheritance Pattern

  • Somatic mutation: Not inherited; arises as an acquired mutation in lung tissue
  • Inheritance pattern: Not applicable (somatic oncogenic driver)
  • No established germline predisposition specifically to BRAF V600E NSCLC

Population Demographics

Demographic Characteristic
Sex ratio Slight female predominance (50–55% female)
Median age 64–68 years
Smoking status 29–64% never-smokers (varies by ethnicity)
Ethnicity Higher V600E proportion in Western populations (~66%) vs. Asian (~25%)
Histology >95% adenocarcinoma

Clinical characteristics from the French BLaDE cohort (PMID: 39616778): "A total of 163 patients were included: 50.3 % were female, 30.2 % were never smokers, 95.1 % had adenocarcinoma, and 78.2 % had a PDL1 ≥ 1 %. The median age was 68.3 years."

From a Chinese multicenter study (PMID: 35814395): "Fifty-three patients with BRAF V600E-mutant advanced NSCLC were included in the study, of which 64.2% were non-smokers, and the BRAF V600E mutation was more prevalent in men (52.8%). In addition, 96.2% of the patients had adenocarcinoma."

10. Diagnostics

Molecular Testing (Essential)

Comprehensive molecular testing at diagnosis is mandatory for identifying BRAF V600E and guiding treatment. NCCN guidelines recommend broad molecular profiling of all advanced NSCLC (PMID: 31454018): "all patients with metastatic non-small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1" and "Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non-small cell lung cancer."

Testing Modality Utility Notes
NGS (tissue-based) Gold standard Detects BRAF V600E alongside other actionable mutations
Liquid biopsy (ctDNA) Alternative/complementary 82% concordance with tissue NGS (PMID: 40437208)
IHC (VE1 antibody) Screening/confirmation BRAF V600E-specific antibody available (PMID: 30188361)
PCR-based assays Targeted detection Cobas BRAF V600E test, Idylla
FISH Not applicable Not used for BRAF point mutations

Liquid Biopsy

ctDNA-based testing has emerged as a critical diagnostic tool. The BFAST study demonstrated that NGS ctDNA analysis improves actionable mutation identification (PMID: 38190582). Multiple platforms are validated including FoundationOne Liquid CDx, Guardant360, and UltraSEEK Lung Panel.

Real-world experience has demonstrated that ctDNA profiling identifies therapeutically relevant mutations at rates comparable to tissue-based NGS (PMID: 40821453; PMID: 40503459). Exhaled breath condensate (EBC) analysis represents a novel lung-specific liquid biopsy modality under investigation (PMID: 35526313).

Immunohistochemistry

The BRAF V600E-specific VE1 antibody can be used for IHC screening or confirmation. As noted in a review of diagnostic IHC for NSCLC (PMID: 30188361): "IHC using mutant-specific BRAF V600E, RET, pan-TRK, and LKB1 antibodies can be orthogonal tools for screening or confirmation of molecular events."

Clinical Tests

Test Application
CT chest/abdomen/pelvis Staging, response assessment
PET-CT Staging, detecting metastatic disease
Brain MRI Mandatory at baseline (15–21% brain metastases)
PFTs Pre-operative assessment
D-dimer Thromboembolism risk assessment
PD-L1 IHC Immunotherapy eligibility

Pathology/Histology

  • Adenocarcinoma histology in >95% of cases
  • Various growth patterns: acinar, papillary, lepidic, solid, micropapillary
  • TTF-1 (NKX2-1) positive in most cases; loss associated with mucinous/gastric differentiation

Differential Diagnosis

  • Other driver-positive NSCLC (EGFR, ALK, ROS1, RET, MET, KRAS G12C, HER2)
  • BRAF non-V600E mutant NSCLC (Class II and III mutations)
  • Driver-negative NSCLC
  • Metastatic BRAF V600E melanoma to the lung
  • Metastatic BRAF V600E thyroid cancer to the lung

11. Outcome/Prognosis

Survival and Mortality

Treatment Outcomes Summary

Treatment Setting ORR Median PFS Median OS Source
Dabrafenib + Trametinib 1st-line 63.9–75% 10.2–25.0 mo NR–24.6 mo Multiple
Dabrafenib + Trametinib ≥2nd-line 63–68% 8.6–12.6 mo 18.2 mo BRF113928
Encorafenib + Binimetinib 1st-line 75% 30.2 mo 47.6 mo PHAROS
Encorafenib + Binimetinib ≥2nd-line 46% 7.4 mo 23.5 mo PHAROS
Chemotherapy (Pt-pemetrexed) 1st-line 39–77% 6.1–14.7 mo Variable Multiple
Immunotherapy ± chemo 1st-line Variable Variable Variable Limited data

The PHAROS trial updated data showed the longest reported median OS for any targeted therapy in BRAF V600E NSCLC: 47.6 months (95% CI: 31.3–NE) in treatment-naïve patients, with 4-year OS probability of 49% (PMID: 41109959): "After median follow-up for overall survival (OS) of 52.3 months in treatment-naïve patients, mOS was 47.6 months (95% CI, 31.3 to not estimable); 4-year OS probability was 49% (95% CI, 35 to 62)."

A matching-adjusted indirect comparison suggested encorafenib plus binimetinib may be superior to dabrafenib plus trametinib in first-line treatment: PFS HR = 0.47 (95% CI: 0.26–0.85; P = 0.01), OS HR = 0.55 (95% CI: 0.30–1.01; P = 0.06) (PMID: 41604820): "Compared with D + T, E + B was associated with a statistically significant improvement in PFS [hazard ratio (HR) = 0.47; 95% CI 0.26-0.85; P = 0.01]."

Real-world data corroborate clinical trial findings. The Italian ATLAS registry reported first-line D+T mPFS of 19.8 months (95% CI: 10.7–29.0) with a 2-year OS rate of 65.4% (PMID: 41475048). The French BLaDE cohort showed first-line D+T mPFS of 18.2 months and 12-month OS rate of 67.4% (PMID: 39616778): "Among the 44 patients who received D + T as a first-line therapy, the 12-month OS rate was 67.4 %, with an mPFS of 18.2 months."

Prognostic Factors

Factor Impact Evidence
Co-mutations Negative (OS 8.7 vs. 20.2 mo, p=0.009) PMID: 40813186
Brain metastases Negative prognosis Multiple cohorts
PD-L1 status No significant impact on OS PMID: 40813186
Treatment line (D+T) No significant difference 1L vs. later PMID: 40813186
Non-V600E BRAF subtype Higher brain metastasis rate (60% vs. 15%) PMID: 40813186
BRAF mutation status vs. wild-type Not a strong independent prognostic factor for OS PMID: 31181537

The French Cooperative Thoracic Intergroup Biomarkers France study reported (PMID: 31181537): "BRAF mutation was not found to be prognostic of overall survival" when comparing BRAF-mutant to wild-type NSCLC treated with standard chemotherapy.

Complications

  • Thromboembolism: 43% 1-year cumulative incidence including cancer-related stroke and VTE (PMID: 36697098)
  • Brain metastases: Present in 15–21% at diagnosis; can develop during disease course
  • Bone metastases: Pain, pathological fractures, hypercalcemia
  • Pleural/pericardial effusions: Respiratory and cardiovascular compromise

12. Treatment

FDA-Approved Targeted Therapies

Dabrafenib (BRAF inhibitor) + Trametinib (MEK inhibitor)

  • MAXO terms: MAXO:0001298 (targeted molecular therapy)
  • Mechanism: Dabrafenib inhibits BRAF V600E kinase; trametinib inhibits MEK1/2 downstream
  • FDA approval: June 2017 for BRAF V600E-mutant metastatic NSCLC
  • Also approved: Tumor-agnostic indication for BRAF V600E solid tumors (June 2022) (PMID: 39529955): "Dabrafenib plus trametinib, as the first tumor-agnostic therapy, has been approved by the US Food and Drug Administration for the treatment of adult and pediatric patients aged 6 years and older harboring a BRAF V600E mutation with unresectable or metastatic solid tumors."
  • Dosing: Dabrafenib 150 mg BID + Trametinib 2 mg QD
  • Key efficacy data:
  • Treatment-naïve: ORR 63.9–75%, median PFS 10.2–25 months
  • Chinese phase II: ORR 75% (95% CI: 50.9–91.3%) (PMID: 39830765): "The ORR by both central and investigator assessment was 75% [95% confidence interval (CI): 50.9-91.3%]."
  • Italian ATLAS real-world: median PFS 19.8 months (95% CI: 10.7–29.0), 2-year OS 65.4%
  • French BLaDE real-world: 1L mPFS 18.2 months, 12-month OS 67.4% (PMID: 39616778)
  • Previously treated: ORR 63%, median PFS 9.7 months (PMID: 27283860): "BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC)."
  • Common adverse events: Pyrexia, fatigue, nausea, peripheral edema, rash, elevated liver enzymes

Encorafenib (BRAF inhibitor) + Binimetinib (MEK inhibitor)

  • FDA approval: October 2023 for BRAF V600E-mutant metastatic NSCLC (based on PHAROS)
  • Dosing: Encorafenib 450 mg QD + Binimetinib 45 mg BID
  • Key efficacy data (PHAROS):
  • Treatment-naïve: ORR 75%, median DOR 40.0 months, median PFS 30.2 months, median OS 47.6 months, 3-year OS 53% (PMID: 40480428; PMID: 41109959)
  • Previously treated: ORR 46%, median PFS 7.4 months, median OS 23.5 months (PMID: 37270692)
  • Adverse events: GI toxicity (including rare colitis (PMID: 34436699)), fatigue, musculoskeletal pain
  • Potentially superior to D+T: PFS HR = 0.47 (p = 0.01) by MAIC (PMID: 41604820)

Immunotherapy

  • Checkpoint inhibitors: Anti-PD-1/PD-L1 agents (pembrolizumab, nivolumab, atezolizumab)
  • High PD-L1 expression (78% ≥1%) supports immunotherapy use
  • Real-world data suggest no detriment from PD-L1 inhibitors compared to driver-negative NSCLC (PMID: 37744307): "Substantial use of anti-PD-(L)1 therapy and associated clinical outcomes are consistent with previous real-world findings and suggest no detriment from PD-(L)1 inhibitors for advanced nonsquamous NSCLC harboring one of these four genomic alterations relative to driver-negative NSCLC."
  • Case reports of durable response with pembrolizumab monotherapy (PMID: 41777654)
  • Combination of BRAF/MEK inhibition with immunotherapy (triplet therapy) is under investigation (PMID: 41333480)

Chemotherapy

  • Platinum-based doublets: Standard options include platinum/pemetrexed
  • Platinum-pemetrexed outperforms platinum-taxane: ORR 77% vs. 33% (p = 0.006), PFS 14.7 vs. 3.2 months (p = 0.002) (PMID: 40813186)
  • BRAF V600E patients may have shorter PFS to platinum-based chemotherapy vs. non-V600E (4.1 vs. 8.9 months, p = 0.297) (PMID: 23833300)
  • BRAF mutation is not a strong prognostic factor when treated with standard chemotherapy (PMID: 31181537)

Single-Agent BRAF Inhibitors

  • Vemurafenib monotherapy: Limited efficacy in NSCLC with 0% complete response rate and increased adverse events compared to melanoma (PMID: 41383110): "A 0% complete response rate was observed in colorectal cancer, non-small cell lung cancer, and papillary thyroid cancer."
  • Single-agent BRAF inhibition is inferior to combination BRAF+MEK inhibition due to paradoxical MAPK reactivation

Treatment for Acquired BRAF V600E (EGFR-Mutant NSCLC)

  • BRAF V600E can emerge as resistance mechanism during EGFR-TKI therapy
  • Triple therapy (EGFR-TKI + dabrafenib + trametinib): ORR 35.7%, DCR 78.6%, median PFS 6.7 months (PMID: 39830741)

Surgical and Interventional

  • Surgical resection: For early-stage disease (Stage I-IIIA); standard lobectomy with lymph node dissection (MAXO:0000004)
  • Radiation therapy: Stereotactic radiosurgery for brain metastases; definitive chemoradiation for locally advanced disease (MAXO:0000014)

Treatment Algorithm

BRAF V600E-Mutant Metastatic NSCLC
      │
      ▼
    ┌─────────────────┐
    │ Molecular Testing│ ← NGS (tissue or liquid biopsy)
    │ confirms V600E   │
    └────────┬────────┘
     │
     ▼
   First-line Therapy:
   ┌────────────────────────┐
   │ Encorafenib+Binimetinib│ ← Preferred (PHAROS data)
   │     OR                  │
   │ Dabrafenib+Trametinib  │ ← Alternative (BRF113928)
   └────────┬───────────────┘
    │ (Progression)
    ▼
   Second-line Options:
   ├─ Immunotherapy ± chemotherapy
   ├─ Alternative BRAF/MEK combination
   ├─ Platinum-based chemotherapy (prefer Pt-pemetrexed)
   └─ Clinical trials

13. Prevention

Primary Prevention

  • Smoking cessation: Most impactful intervention for lung cancer prevention generally; relevant even though BRAF V600E NSCLC has higher never-smoker rates
  • Radon mitigation: Home radon testing and remediation
  • Occupational safety: Limiting exposure to known carcinogens
  • No specific prevention strategies for BRAF V600E NSCLC per se

Secondary Prevention (Screening)

  • Low-dose CT (LDCT) screening: Recommended for high-risk individuals (ages 50–80, ≥20 pack-years smoking history) per USPSTF
  • LDCT screening has potential to detect early-stage disease including BRAF V600E NSCLC
  • Comprehensive molecular testing of screen-detected tumors can identify BRAF V600E at early stages
  • Multiple programs worldwide are implementing integrated lung cancer screening with smoking cessation (PMID: 36204992; PMID: 36522781)
  • Note: Current screening guidelines focus on smoking-related risk and may miss never-smoker BRAF V600E NSCLC patients

Tertiary Prevention

  • Surveillance: Regular imaging and ctDNA monitoring during and after treatment
  • Thromboprophylaxis: Consider given the 43% 1-year thromboembolism risk
  • Brain MRI monitoring: Regular brain imaging given high brain metastasis rate
  • ctDNA monitoring: Emerging role for minimal residual disease detection and early resistance identification

14. Other Species / Natural Disease

Comparative Biology

  • BRAF gene conservation: BRAF is highly conserved across vertebrates
  • Canine BRAF mutations: V595E (homologous to human V600E) found in canine cancers, particularly transitional cell carcinoma of the bladder (NCBI Taxon: 9615)
  • Mouse Braf (NCBI Gene ID: 109880): Orthologous gene used extensively in modeling
  • BRAF V600E is the most commonly studied oncogenic mutation across species due to its high conservation

Natural Disease

  • No naturally occurring BRAF V600E lung cancer has been well-described in other species
  • BRAF V600E occurs naturally in multiple human cancer types (melanoma, colorectal, thyroid, hairy cell leukemia)
  • The mutation is a key driver in canine urinary bladder cancer but does not typically present as lung cancer in companion animals

Transmission

  • Not applicable — BRAF V600E NSCLC is not transmissible or zoonotic

15. Model Organisms

Genetically Engineered Mouse Models (GEMMs)

Model Features Key Findings Reference
BrafV600E;Trp53fl/fl (GEMM) Conditional BRAF V600E expression in lung Develops lung adenocarcinoma; used to study targeted therapy response Multiple
BrafV600E;Nkx2-1fl/fl BRAF V600E with NKX2-1 deletion Invasive mucinous adenocarcinoma; resistance to BRAF/MEK inhibitors PMID: 33821796
BrafV600E;Pik3caH1047R BRAF V600E with PI3K activation De-differentiation of lung tumors PMID: 31452510
BrafD631A (kinase-inactive) Kinase-inactive BRAF allele Demonstrates BRAF-inactivating mutations initiate lung cancer; wild-type Braf sustains Kras/BrafD631A tumors PMID: 28783725

Cell Line and Xenograft Models

  • Human BRAF V600E NSCLC cell lines: Available for in vitro studies of drug sensitivity and resistance
  • Thyroid cancer xenografts: 8505C-Luc2 (BRAF V600E) cells injected intravenously into NOD-SCID mice produced lung metastases in 100% of mice; vemurafenib treatment dramatically reduced tumor growth (PMID: 24262022): "The in vivo treatment of 8505C xenograft lung metastases with vemurafenib dramatically reduced the growth and signal intensity with good correlation with actual tumor burden."

Model Characteristics and Limitations

Phenotype recapitulation: - Mouse GEMMs recapitulate key features of human BRAF V600E NSCLC including adenocarcinoma histology, MAPK pathway activation, and response to BRAF/MEK inhibitors - The NKX2-1 deletion model faithfully reproduces the invasive mucinous adenocarcinoma phenotype seen in a subset of human patients - BRAF kinase-inactive models (PMID: 28783725) revealed that "the signal intensity of the MAPK pathway is a critical determinant not only in tumour development, but also in dictating the nature of the cancer-initiating cell and ultimately the resulting tumour phenotype"

Limitations: - Mouse immune microenvironment differs from human tumors, limiting immunotherapy studies - Response kinetics to targeted therapy may differ between species - Acquired resistance mechanisms may not fully mirror human disease - Metastatic patterns in mouse models may not replicate human patterns - Most GEMMs use Cre-Lox conditional systems that activate the mutation simultaneously across many cells, unlike the single-cell origin of human cancer

Research Applications

  • Drug efficacy testing (BRAF/MEK inhibitors, combination therapies)
  • Resistance mechanism studies (MAPK reactivation, bypass pathways)
  • Lineage plasticity and differentiation state investigations
  • Immune microenvironment characterization
  • Biomarker discovery and validation
  • Novel therapeutic target identification

Key Findings — Detailed Evidence

Finding 1: BRAF V600E Mutation Prevalence

BRAF mutations are found in 1.5–4% of NSCLC overall, with V600E accounting for approximately 50–66% of BRAF mutations in Western cohorts and ~25% in Asian cohorts. This translates to a BRAF V600E frequency of approximately 1–2% of all NSCLC cases. The large Chinese LANDSCAPE cohort (N=175,566) found BRAF mutations in 3.56% of patients, with V600E in 24.6% of those (PMID: 40138888). A European cohort of 979 patients found BRAF mutations in 1.7% overall and 2.3% of adenocarcinomas (PMID: 24552757). The disease almost exclusively presents as adenocarcinoma (>95%).

Finding 2: Dabrafenib + Trametinib Efficacy

Dual BRAF/MEK inhibition with D+T has been validated across clinical trials and real-world cohorts. Phase II data show ORR of 63.9–75% in treatment-naïve patients. Real-world datasets from Italy (ATLAS), France (BLaDE), and Turkey confirm efficacy with median PFS of 13–25 months. The Chinese phase II trial demonstrated ORR of 75% (PMID: 39830765). The tumor-agnostic approval of D+T for BRAF V600E solid tumors further validates this combination across cancer types.

Finding 3: Encorafenib + Binimetinib Superiority

The PHAROS trial established E+B as a highly effective option with potentially the longest PFS and OS of any targeted therapy in this setting. Updated data show median PFS of 30.2 months, median OS of 47.6 months, and 4-year OS probability of 49% in treatment-naïve patients (PMID: 41109959). A matching-adjusted indirect comparison suggested PFS superiority over D+T (HR 0.47, p=0.01), though this requires confirmation in a direct randomized comparison (PMID: 41604820).

Finding 4: MAPK Pathway Constitutive Activation

The V600E mutation results in ~500-fold increased kinase activity compared to wild-type BRAF, functioning as a RAS-independent monomer. This constitutive activation promotes cell proliferation, survival, angiogenesis, and immune evasion through sustained MEK-ERK signaling (PMID: 39961465; PMID: 29729495; PMID: 27283860).

Finding 5: Distinctive Clinical Characteristics

BRAF V600E NSCLC patients show a characteristic clinical profile: predominantly adenocarcinoma (95–96%), median age 64–68 years, slight female predominance (50–55%), and notably high never-smoker proportion (29–64%). Brain metastases are present in 15–21% at diagnosis. PD-L1 expression is high (78% ≥1%), supporting immunotherapy consideration (PMID: 39616778; PMID: 35814395).

Finding 6: Thromboembolism Risk

A strikingly high rate of thromboembolism was documented with a 1-year cumulative incidence of 43% (95% CI: 11–72%) in BRAF V600E NSCLC patients. Events included cancer-related stroke and venous thromboembolism, with stroke patients experiencing high D-dimer levels and short-term mortality (PMID: 36697098). This finding has significant implications for clinical management and thromboprophylaxis.

Evidence Base

Landmark Clinical Trials

Trial Phase Key Result PMID
BRF113928 (previously treated) II D+T: ORR 63%, mPFS 9.7 mo PMID: 27283860
PHAROS (E+B) II 1L: ORR 75%, mPFS 30.2 mo, mOS 47.6 mo PMID: 41109959
Chinese Phase II (D+T) II ORR 75%, manageable safety PMID: 39830765

Key Real-World Studies

Cohort N Key Finding PMID
Italian ATLAS 88+ 1L D+T mPFS 19.8 mo, 2-yr OS 65.4% PMID: 41475048
French BLaDE (IFCT) 163 1L D+T mPFS 18.2 mo, 12-mo OS 67.4% PMID: 39616778
Turkish Oncology Group 88 Co-mutations worsen OS (8.7 vs. 20.2 mo) PMID: 40813186
Chinese LANDSCAPE 175,566 BRAF 3.56%, V600E 24.6% of BRAF PMID: 40138888
IFCT Biomarkers France 17,664 BRAF mutation not prognostic with chemo PMID: 31181537
Dana-Farber 883 BRAF 4%, V600E not associated with younger age PMID: 23833300

Mechanistic and Biological Studies

Topic Key Contribution PMID
BRAF V600E structural biology Constitutive kinase activation mechanism PMID: 39961465
NKX2-1/ERK/WNT feedback NKX2-1 loss → gastric differentiation → therapy resistance PMID: 33821796
PI3K cooperation PI3K activation promotes de-differentiation PMID: 31452510
BRAF kinase-inactive models Inactivating BRAF mutations can initiate lung cancer PMID: 28783725
ctDNA resistance profiling Identifies resistance mechanisms to BRAF-targeted therapy PMID: 32859654
Novel MAPK inhibitors Erianin as dual CRAF/MEK inhibitor PMID: 36872366

Limitations and Knowledge Gaps

  1. Small patient populations: Due to the rarity of BRAF V600E NSCLC (~1–2% of NSCLC), most studies are small phase II trials or retrospective cohorts. No randomized phase III data exist comparing BRAF/MEK combinations head-to-head or against immunotherapy.

  2. Ethnic/geographic variation: The proportion of BRAF V600E among BRAF mutations varies dramatically between Asian (24.6%) and Western (66%) populations. The reasons for this disparity are unknown and may affect treatment generalizability.

  3. Optimal treatment sequencing: The best sequence of targeted therapy, immunotherapy, and chemotherapy remains undefined. Whether immunotherapy should precede, follow, or be combined with BRAF/MEK inhibition is an active area of investigation.

  4. Thromboembolism mechanism: The remarkably high thromboembolism risk (43% 1-year incidence) is inadequately studied. The biological basis linking BRAF V600E to hypercoagulability needs elucidation, and prophylactic anticoagulation strategies need evaluation.

  5. Resistance mechanisms: While some resistance mechanisms have been identified (MAPK reactivation, bypass pathway activation, lineage switching), comprehensive profiling in NSCLC-specific cohorts is limited compared to melanoma.

  6. Biomarkers of response/resistance: Beyond PD-L1 status and co-mutations, predictive biomarkers to guide treatment selection are lacking.

  7. Encorafenib + Binimetinib vs. Dabrafenib + Trametinib: The MAIC suggesting E+B superiority is based on indirect comparison methodology, which has inherent limitations. A direct randomized comparison is needed.

  8. Early-stage disease: The role of adjuvant targeted therapy for resected BRAF V600E NSCLC is unknown. Data are extrapolated from the tumor-agnostic dabrafenib/trametinib approval but dedicated studies are needed.

  9. Brain metastases: Intracranial activity of BRAF/MEK combinations in NSCLC is less well characterized compared to melanoma.

  10. Long-term survivorship: With improving outcomes (median OS approaching 4 years), long-term toxicity, quality of life, and survivorship data are needed.

Proposed Follow-up Experiments/Actions

Clinical Studies

  1. Randomized phase III trial: Direct comparison of encorafenib/binimetinib vs. dabrafenib/trametinib in treatment-naïve BRAF V600E NSCLC
  2. Triplet combination trial: BRAF/MEK inhibition + anti-PD-1 immunotherapy (building on case report evidence of complete responses)
  3. Adjuvant targeted therapy trial: Dabrafenib/trametinib or encorafenib/binimetinib for resected early-stage BRAF V600E NSCLC
  4. Thromboprophylaxis trial: Evaluating prophylactic anticoagulation in BRAF V600E NSCLC patients
  5. ctDNA-guided treatment adaptation: Using serial ctDNA monitoring to guide treatment switching at molecular progression

Translational Research

  1. Comprehensive resistance profiling: Multi-omic analysis (genomic, transcriptomic, proteomic) of paired pre/post-resistance samples from BRAF V600E NSCLC patients
  2. Immune microenvironment characterization: Single-cell RNA-seq and spatial transcriptomics of BRAF V600E NSCLC to understand immune contexture and optimal immunotherapy combinations
  3. Thromboembolism biology: Mechanistic studies investigating BRAF V600E signaling in coagulation cascade activation, platelet function, and tissue factor expression
  4. NKX2-1 loss biology: Deeper investigation of lineage switching as resistance mechanism, with potential therapeutic strategies to prevent or reverse gastric differentiation
  5. Population-specific studies: Investigating why BRAF V600E represents a lower proportion of BRAF mutations in Asian vs. Western populations — potential differences in mutagenic processes

Diagnostic Innovation

  1. Exhaled breath condensate (EBC): Further validation of EBC-based liquid biopsy for BRAF mutation detection as a non-invasive lung-specific approach (PMID: 35526313)
  2. MRD monitoring: Developing and validating ctDNA-based minimal residual disease detection protocols for post-operative surveillance

Ontology Term Summary

Category Terms
MONDO MONDO:0005233 (non-small cell lung carcinoma)
HPO HP:0012735 (Cough), HP:0002094 (Dyspnea), HP:0002105 (Hemoptysis), HP:0001824 (Weight loss), HP:0001907 (Thromboembolism), HP:0002202 (Pleural effusion), HP:0100009 (Cerebral neoplasm), HP:0012378 (Fatigue)
GO (Biological Process) GO:0000165 (MAPK cascade), GO:0008283 (Cell proliferation), GO:0006915 (Apoptotic process), GO:0001525 (Angiogenesis), GO:0016477 (Cell migration), GO:0043066 (Negative regulation of apoptotic process)
GO (Cellular Component) GO:0005737 (Cytoplasm), GO:0005886 (Plasma membrane), GO:0005634 (Nucleus), GO:0005739 (Mitochondrion)
GO (Molecular Function) GO:0004674 (Protein serine/threonine kinase activity), GO:0005524 (ATP binding)
CL (Cell Type) CL:0002063 (Type II pneumocyte), CL:0000158 (Club cell), CL:0001064 (Malignant cell)
UBERON (Anatomy) UBERON:0002048 (Lung), UBERON:0000955 (Brain), UBERON:0002481 (Bone tissue), UBERON:0002107 (Liver), UBERON:0002369 (Adrenal gland)
CHEBI CHEBI:75047 (Dabrafenib), CHEBI:75998 (Trametinib), CHEBI:90227 (Encorafenib), CHEBI:90876 (Binimetinib), CHEBI:63637 (Vemurafenib)
MAXO MAXO:0001298 (Targeted molecular therapy), MAXO:0000004 (Surgical procedure), MAXO:0000014 (Radiation therapy), MAXO:0000127 (Genetic testing)

Report generated from systematic analysis of 64 publications encompassing clinical trials, real-world cohort studies, mechanistic investigations, and diagnostic innovation research. All citations verified against original abstracts where available.