BRAF V600-mutant melanoma is a molecular subtype of cutaneous melanoma characterized by activating mutations in the BRAF oncogene, most commonly V600E (substitution of valine for glutamic acid at codon 600), with V600K being the second most common variant. These mutations result in constitutive activation of the BRAF kinase and downstream MAPK/ERK signaling pathway, driving uncontrolled melanocyte proliferation. BRAF V600 mutations occur in approximately 40-50% of cutaneous melanomas and are associated with intermittent sun exposure, younger patient age, and superficial spreading histology. This molecular subtype is paradigmatic for oncogene-targeted therapy, as the combination of BRAF and MEK inhibitors (dabrafenib plus trametinib) has transformed outcomes for patients with advanced disease.
Ask a research question about BRAF V600 Mutant Melanoma. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: BRAF V600 Mutant Melanoma
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-05-06T05:33:39Z'
description: >-
BRAF V600-mutant melanoma is a molecular subtype of cutaneous melanoma characterized
by activating mutations in the BRAF oncogene, most commonly V600E (substitution
of
valine for glutamic acid at codon 600), with V600K being the second most common
variant.
These mutations result in constitutive activation of the BRAF kinase and downstream
MAPK/ERK signaling pathway, driving uncontrolled melanocyte proliferation. BRAF
V600
mutations occur in approximately 40-50% of cutaneous melanomas and are associated
with
intermittent sun exposure, younger patient age, and superficial spreading histology.
This molecular subtype is paradigmatic for oncogene-targeted therapy, as the combination
of BRAF and MEK inhibitors (dabrafenib plus trametinib) has transformed outcomes
for
patients with advanced disease.
categories:
- Skin Cancer
- Molecularly Defined Cancer
- Oncogene-Driven Cancer
parents:
- cutaneous melanoma
has_subtypes:
- name: V600E Melanoma
description: >-
The dominant BRAF V600 melanoma subtype, usually caused by the p.Val600Glu
substitution and accounting for most BRAF V600-mutant cutaneous melanomas.
- name: V600K Melanoma
description: >-
The second most common BRAF V600 melanoma subtype. It is relatively enriched
in older patients and chronically sun-exposed tumors compared with V600E.
- name: Other V600 Melanoma
description: >-
Less common activating BRAF V600 substitutions, including V600R and V600M,
that preserve the same MAPK-activating therapeutic logic.
pathophysiology:
- name: BRAF V600 Oncogenic Mutation
description: >-
BRAF V600 mutations, predominantly V600E and V600K, result in substitution of
the
valine residue in the activation loop of the BRAF kinase. This removes an autoinhibitory
mechanism, causing constitutive kinase activity independent of upstream RAS signaling.
The mutant BRAF signals as a monomer, unlike wild-type BRAF which requires dimerization
for activation.
evidence:
- reference: PMID:40023845
reference_title: "The NF1 tumor suppressor regulates PD-L1 and immune evasion in melanoma."
supports: PARTIAL
snippet: Hotspot BRAF, hotspot NRAS, and NF1 loss-of-function mutations are found in approximately 50%, 25%, and 15% of cutaneous melanomas, respectively.
explanation: This abstract reports frequent hotspot BRAF mutations in cutaneous melanoma, supporting the relevance of BRAF-driven melanoma.
cell_types:
- preferred_term: melanocyte
term:
id: CL:0000148
label: melanocyte
biological_processes:
- preferred_term: MAPK cascade
modifier: INCREASED
term:
id: GO:0000165
label: MAPK cascade
downstream:
- target: Constitutive MAPK Pathway Activation
description: V600E BRAF has 500-fold increased kinase activity compared to wild-type
- name: Constitutive MAPK Pathway Activation
description: >-
Mutant BRAF continuously phosphorylates and activates MEK1/2, which in turn activates
ERK1/2. This constitutive MAPK signaling drives expression of genes promoting
cell
cycle progression, survival, and proliferation. The pathway operates independently
of growth factor stimulation.
biological_processes:
- preferred_term: signal transduction
modifier: INCREASED
term:
id: GO:0007165
label: signal transduction
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
downstream:
- target: Uncontrolled Melanocyte Proliferation
description: ERK drives cyclin D1 expression and G1/S progression
- target: Apoptosis Resistance
description: MAPK signaling promotes survival through multiple mechanisms
- name: Uncontrolled Melanocyte Proliferation
description: >-
Constitutive MAPK signaling drives melanocyte proliferation through ERK-mediated
phosphorylation and stabilization of transcription factors controlling cell cycle
progression, including upregulation of cyclin D1 and suppression of cell cycle
inhibitors such as p27.
cell_types:
- preferred_term: melanocyte
term:
id: CL:0000148
label: melanocyte
locations:
- preferred_term: skin of body
term:
id: UBERON:0002097
label: skin of body
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
- name: Apoptosis Resistance
description: >-
BRAF V600 signaling promotes melanoma cell survival through multiple anti-apoptotic
mechanisms, including upregulation of BCL2 family members and suppression of
pro-apoptotic BIM. This contributes to tumor persistence and therapy resistance.
biological_processes:
- preferred_term: apoptotic process
modifier: DECREASED
term:
id: GO:0006915
label: apoptotic process
- name: Acquired MAPK Reactivation and Bypass Resistance
description: >-
Most advanced BRAF V600-mutant melanomas initially respond to combined BRAF/MEK
inhibition, but acquired resistance commonly develops through renewed MAPK
signaling or parallel survival pathways. Reported mechanisms include secondary
NRAS mutations, MEK/MAP2K1 mutations, BRAF amplification or splice variants,
PI3K-AKT activation, and metabolic adaptation toward oxidative phosphorylation.
biological_processes:
- preferred_term: MAPK cascade
modifier: INCREASED
term:
id: GO:0000165
label: MAPK cascade
- preferred_term: response to xenobiotic stimulus
modifier: ABNORMAL
term:
id: GO:0009410
label: response to xenobiotic stimulus
- name: Immune Evasion via PD-L1 Upregulation
conforms_to: "immune_checkpoint_blockade#Adaptive Immune Resistance"
description: >-
BRAF V600-mutant melanoma is among the most immunogenic solid tumors due to high
UV-induced tumor mutational burden generating abundant neoantigens. Tumor-infiltrating
CD8+ T cells mount anti-tumor responses, but melanoma cells adaptively upregulate
PD-L1
in response to interferon-gamma, suppressing T cell cytotoxicity. BRAF-MAPK signaling
itself also contributes to immune evasion through intrinsic PD-L1 upregulation
via
MEK/ERK-dependent mechanisms.
cell_types:
- preferred_term: CD8-positive, alpha-beta T cell
term:
id: CL:0000625
label: CD8-positive, alpha-beta T cell
biological_processes:
- preferred_term: Negative Regulation of T Cell Mediated Immunity
term:
id: GO:0002710
label: negative regulation of T cell mediated immunity
modifier: INCREASED
evidence:
- reference: PMID:33256089
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Cancer cells including melanoma cells, upregulate PD-L1 expression
on the cell surface. T-lymphocytes with surface expression of PD-1,
interacts with PD-L1 on the tumor, leading to T-cell exhaustion,
thereby, causing dysfunction of the immune system in detecting and
eliminating the tumor cells
explanation: >-
Review directly describes melanoma cells upregulating PD-L1 to
engage PD-1 on T lymphocytes, leading to T cell exhaustion and
immune evasion - supporting the adaptive immune resistance
mechanism in BRAF-mutant melanoma.
histopathology:
- name: Melanocytic Neoplasm
finding_term:
preferred_term: Melanocytic Neoplasm
term:
id: NCIT:C7058
label: Melanocytic Neoplasm
frequency: VERY_FREQUENT
description: Malignant melanoma represents a neoplasm stemming from melanocytes.
evidence:
- reference: PMID:27268913
reference_title: "Malignant melanoma: diagnosis, treatment and cancer stem cells."
supports: SUPPORT
snippet: "Malignant melanoma represents a neoplasm stemming from melanocytes"
explanation: Abstract defines melanoma as a neoplasm stemming from melanocytes.
phenotypes:
- category: Dermatologic
name: Cutaneous Melanoma
frequency: OBLIGATE
diagnostic: true
description: >-
Melanoma arising from cutaneous melanocytes. BRAF V600-mutant melanomas are
typically associated with intermittent UV exposure sites and often display
superficial spreading or nodular histologic patterns.
phenotype_term:
preferred_term: Cutaneous melanoma
term:
id: HP:0012056
label: Cutaneous melanoma
- category: Dermatologic
name: Pigmented Skin Lesion
frequency: VERY_FREQUENT
description: >-
The primary tumor typically presents as an asymmetric, irregularly bordered
pigmented lesion with color variegation, often arising from a pre-existing nevus
or de novo on sun-exposed skin.
phenotype_term:
preferred_term: Neoplasm of the skin
term:
id: HP:0008069
label: Neoplasm of the skin
genetic:
- name: BRAF V600E
gene_term:
preferred_term: BRAF
term:
id: hgnc:1097
label: BRAF
association: Somatic Oncogenic Mutation
notes: >-
The most common BRAF mutation (80-90% of BRAF-mutant melanomas), involving
substitution of valine with glutamic acid at codon 600. Results in constitutive
kinase activation and is the primary therapeutic target for BRAF inhibitors.
- name: BRAF V600K
gene_term:
preferred_term: BRAF
term:
id: hgnc:1097
label: BRAF
association: Somatic Oncogenic Mutation
notes: >-
Second most common BRAF mutation (10-20% of BRAF-mutant melanomas), substituting
valine with lysine at codon 600. Also responsive to BRAF/MEK inhibitor therapy
though possibly with different kinetics.
- name: BRAF V600R
gene_term:
preferred_term: BRAF
term:
id: hgnc:1097
label: BRAF
association: Somatic Oncogenic Mutation
notes: >-
Less common BRAF V600 substitution that still activates BRAF kinase and is
grouped with other actionable V600 alterations when considering BRAF/MEK-targeted
therapy.
- name: BRAF V600M
gene_term:
preferred_term: BRAF
term:
id: hgnc:1097
label: BRAF
association: Somatic Oncogenic Mutation
notes: >-
Rare BRAF V600 substitution included in the broader BRAF V600-mutant melanoma
spectrum; mechanistically it is treated as an activating MAPK-pathway driver.
treatments:
- name: Dabrafenib plus Trametinib
description: >-
First-line targeted therapy combining BRAF inhibitor dabrafenib with MEK inhibitor
trametinib. Combination therapy achieves higher response rates (approximately
70%)
and longer duration of response compared to BRAF inhibitor monotherapy, while
reducing paradoxical MAPK activation and cutaneous squamous cell carcinomas.
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
- name: Vemurafenib plus Cobimetinib
description: >-
Alternative BRAF plus MEK inhibitor combination. Vemurafenib was the first BRAF
inhibitor approved for melanoma. Combined with the MEK inhibitor cobimetinib
to improve efficacy and reduce paradoxical activation side effects.
pdb_structures:
- pdb_id: 3OG7
description: BRAF V600E kinase domain in complex with vemurafenib (PLX4032), showing selective binding to the mutant active conformation that drives melanoma
resolution_angstrom: 2.45
method: X-ray
ligand: vemurafenib
target_protein: BRAF V600E kinase domain
publication: PMID:20823844
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: vemurafenib
term:
id: CHEBI:63637
label: vemurafenib
- preferred_term: cobimetinib
term:
id: CHEBI:90851
label: cobimetinib
- name: Encorafenib plus Binimetinib
description: >-
Third-generation BRAF plus MEK inhibitor combination offering improved
tolerability profile. Encorafenib has a longer half-life than other BRAF
inhibitors, potentially reducing dosing frequency.
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
- name: Immune Checkpoint Inhibitors
description: >-
Anti-PD-1 antibodies (pembrolizumab, nivolumab) alone or combined with
anti-CTLA-4 (ipilimumab) are also effective in BRAF-mutant melanoma. The
optimal sequencing of targeted therapy versus immunotherapy remains an active
area of investigation.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
therapeutic_agent:
- preferred_term: pembrolizumab
term:
id: NCIT:C106432
label: Pembrolizumab
- preferred_term: nivolumab
term:
id: NCIT:C68814
label: Nivolumab
- preferred_term: ipilimumab
term:
id: CHEBI:231679
label: ipilimumab
target_mechanisms:
- target: Immune Evasion via PD-L1 Upregulation
treatment_effect: INHIBITS
description: >-
Anti-PD-1/anti-CTLA-4 antibodies block checkpoint-mediated immune evasion,
restoring the anti-tumor T cell response against neoantigen-rich melanoma cells.
Melanoma's high mutational burden from UV exposure provides abundant neoantigens,
making it among the most responsive tumor types to checkpoint blockade.
evidence:
- reference: PMID:33256089
supports: SUPPORT
evidence_source: OTHER
snippet: >-
FDA approved the combination therapy of anti-CTLA-4 (ipilimumab) with
anti-PD-1 (nivolumab), for the treatment of unresectable or metastatic
melanoma, and resulted in improved response rates by 50%โ60%, with
enhanced durable survival compared to either agent alone
explanation: >-
Review reports FDA-approved combination of ipilimumab (anti-CTLA-4)
and nivolumab (anti-PD-1) in melanoma with 50-60% response rates
and durable survival, directly supporting checkpoint inhibitor
efficacy against melanoma immune evasion.
disease_term:
preferred_term: cutaneous melanoma
term:
id: MONDO:0005012
label: cutaneous melanoma
notes: >-
BRAF V600 mutations define a therapeutically actionable melanoma subtype. Resistance
to BRAF/MEK inhibitors eventually develops in most patients through reactivation
of
MAPK signaling (MEK mutations, BRAF amplification) or activation of bypass pathways
(PI3K/AKT, RAF1). Combination strategies targeting multiple pathways or sequencing
with immunotherapy are areas of active research.
classifications:
icdo_morphology:
classification_value: Melanoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
references:
- reference: DOI:10.1002/jvc2.544
title: Update on the treatment of <i>BRAF</i>mut metastatic melanoma and future perspectives
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: vโRaf murine sarcoma viral oncogene homolog B (BRAF) mutations were first identified in melanoma in 2002, leading to increased cell division and proliferation, and resultant tumour growth.
supporting_text: vโRaf murine sarcoma viral oncogene homolog B (BRAF) mutations were first identified in melanoma in 2002, leading to increased cell division and proliferation, and resultant tumour growth.
evidence:
- reference: DOI:10.1002/jvc2.544
reference_title: Update on the treatment of <i>BRAF</i>mut metastatic melanoma and future perspectives
supports: SUPPORT
evidence_source: OTHER
snippet: vโRaf murine sarcoma viral oncogene homolog B (BRAF) mutations were first identified in melanoma in 2002, leading to increased cell division and proliferation, and resultant tumour growth.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.1002/jvc2.70108
title: 'Clinical Effectiveness of Interventions to Increase SelfโSurveillance in People at High Risk of Melanoma: A Systematic Review'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: People at high risk of cutaneous melanoma are recommended to undertake regular skin selfโexamination (SSE), but the effectiveness of this is uncertain.
supporting_text: People at high risk of cutaneous melanoma are recommended to undertake regular skin selfโexamination (SSE), but the effectiveness of this is uncertain.
evidence:
- reference: DOI:10.1002/jvc2.70108
reference_title: 'Clinical Effectiveness of Interventions to Increase SelfโSurveillance in People at High Risk of Melanoma: A Systematic Review'
supports: SUPPORT
evidence_source: OTHER
snippet: People at high risk of cutaneous melanoma are recommended to undertake regular skin selfโexamination (SSE), but the effectiveness of this is uncertain.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.1007/s12094-024-03497-2
title: SEOM-GEM clinical guidelines for cutaneous melanoma (2023)
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Early diagnosis and treatment administration are key for increasing the chances of survival.
supporting_text: Early diagnosis and treatment administration are key for increasing the chances of survival.
evidence:
- reference: DOI:10.1007/s12094-024-03497-2
reference_title: SEOM-GEM clinical guidelines for cutaneous melanoma (2023)
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Early diagnosis and treatment administration are key for increasing the chances of survival.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.1007/s12325-024-02883-0
title: 'BRAFV600E Metastatic Melanoma Journey: A Perspective from a Patient and his Oncologist'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: 'BRAFV600E Metastatic Melanoma Journey: A Perspective from a Patient and his Oncologist'
supporting_text: 'BRAFV600E Metastatic Melanoma Journey: A Perspective from a Patient and his Oncologist'
- reference: DOI:10.1016/j.ajpath.2012.06.002
title: Targeting BRAF in an Inducible Murine Model of Melanoma
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Targeting BRAF in an Inducible Murine Model of Melanoma
supporting_text: Targeting BRAF in an Inducible Murine Model of Melanoma
- reference: DOI:10.1016/j.eclinm.2023.102290
title: 'Dabrafenib plus trametinib versus anti-PD-1 monotherapy as adjuvant therapy in BRAF V600-mutant stage III melanoma after definitive surgery: a multicenter, retrospective cohort study'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: 'Dabrafenib plus trametinib versus anti-PD-1 monotherapy as adjuvant therapy in BRAF V600-mutant stage III melanoma after definitive surgery: a multicenter, retrospective cohort study'
supporting_text: 'Dabrafenib plus trametinib versus anti-PD-1 monotherapy as adjuvant therapy in BRAF V600-mutant stage III melanoma after definitive surgery: a multicenter, retrospective cohort study'
- reference: DOI:10.1038/s41467-023-44475-6
title: 'Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: 'Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial'
supporting_text: No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma.
evidence:
- reference: DOI:10.1038/s41467-023-44475-6
reference_title: 'Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.1038/s41591-024-03077-5
title: 'Neoadjuvant pembrolizumab, dabrafenib and trametinib in BRAFV600-mutant resectable melanoma: the randomized phase 2 NeoTrio trial'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma.
supporting_text: Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma.
evidence:
- reference: DOI:10.1038/s41591-024-03077-5
reference_title: 'Neoadjuvant pembrolizumab, dabrafenib and trametinib in BRAFV600-mutant resectable melanoma: the randomized phase 2 NeoTrio trial'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.1056/evidoa2400087
title: Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma
supporting_text: Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma
- reference: DOI:10.1080/03007995.2018.1501351
title: Healthcare resource utilization in patients with metastatic melanoma receiving first-line therapy with dabrafenibโ+โtrametinib versus nivolumab or pembrolizumab monotherapy
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Healthcare resource utilization in patients with metastatic melanoma receiving first-line therapy with dabrafenibโ+โtrametinib versus nivolumab or pembrolizumab monotherapy
supporting_text: Healthcare resource utilization in patients with metastatic melanoma receiving first-line therapy with dabrafenibโ+โtrametinib versus nivolumab or pembrolizumab monotherapy
- reference: DOI:10.1084/jem.20181522
title: Use of extracellular vesicles from lymphatic drainage as surrogate markers of melanoma progression and <i>BRAF</i> <i>V600E</i> mutation
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Liquid biopsies from cancer patients have the potential to improve diagnosis and prognosis.
supporting_text: Liquid biopsies from cancer patients have the potential to improve diagnosis and prognosis.
evidence:
- reference: DOI:10.1084/jem.20181522
reference_title: Use of extracellular vesicles from lymphatic drainage as surrogate markers of melanoma progression and <i>BRAF</i> <i>V600E</i> mutation
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Liquid biopsies from cancer patients have the potential to improve diagnosis and prognosis.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.1158/1078-0432.ccr-25-3262
title: Exploratory Analysis of Biomarkers and Treatment Outcomes from the COLUMBUS Study in BRAF V600E/KโMutant Advanced or Metastatic Melanoma
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: 'Treatment with encorafenib ยฑ binimetinib is associated with improved survival versus vemurafenib in patients with BRAF V600E/Kโmutant advanced melanoma.'
supporting_text: 'Treatment with encorafenib ยฑ binimetinib is associated with improved survival versus vemurafenib in patients with BRAF V600E/Kโmutant advanced melanoma.'
evidence:
- reference: DOI:10.1158/1078-0432.ccr-25-3262
reference_title: Exploratory Analysis of Biomarkers and Treatment Outcomes from the COLUMBUS Study in BRAF V600E/KโMutant Advanced or Metastatic Melanoma
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Treatment with encorafenib ยฑ binimetinib is associated with improved survival versus vemurafenib in patients with BRAF V600E/Kโmutant advanced melanoma.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.1177/10732748241274978
title: 'Cutaneous Oncology: Strategies for Melanoma Prevention, Diagnosis, and Therapy'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Skin cancer comprises one-third of all diagnosed cancer cases and remains a major health concern.
supporting_text: Skin cancer comprises one-third of all diagnosed cancer cases and remains a major health concern.
evidence:
- reference: DOI:10.1177/10732748241274978
reference_title: 'Cutaneous Oncology: Strategies for Melanoma Prevention, Diagnosis, and Therapy'
supports: SUPPORT
evidence_source: OTHER
snippet: Skin cancer comprises one-third of all diagnosed cancer cases and remains a major health concern.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.1186/s43556-026-00425-4
title: 'BRAF inhibitor resistance in melanoma: from resistance mechanisms to therapeutic innovations'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: BRAF inhibitors (BRAFi) have transformed the treatment of BRAF mutant melanoma, but inherent and acquired resistance remains a major barrier to curative outcomes.
supporting_text: BRAF inhibitors (BRAFi) have transformed the treatment of BRAF mutant melanoma, but inherent and acquired resistance remains a major barrier to curative outcomes.
evidence:
- reference: DOI:10.1186/s43556-026-00425-4
reference_title: 'BRAF inhibitor resistance in melanoma: from resistance mechanisms to therapeutic innovations'
supports: SUPPORT
evidence_source: OTHER
snippet: BRAF inhibitors (BRAFi) have transformed the treatment of BRAF mutant melanoma, but inherent and acquired resistance remains a major barrier to curative outcomes.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.3109/0284186x.2015.1114677
title: Trends in melanoma in the elderly in Denmark, 1980โ2012
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Trends in melanoma in the elderly in Denmark, 1980โ2012
supporting_text: Trends in melanoma in the elderly in Denmark, 1980โ2012
- reference: DOI:10.3389/fonc.2024.1504142
title: 'The evolution of BRAF-targeted therapies in melanoma: overcoming hurdles and unleashing novel strategies'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Melanoma, a highly aggressive form of skin cancer, poses a significant global health burden, with 331,647 new cases and 58,645 deaths reported in 2022.
supporting_text: Melanoma, a highly aggressive form of skin cancer, poses a significant global health burden, with 331,647 new cases and 58,645 deaths reported in 2022.
evidence:
- reference: DOI:10.3389/fonc.2024.1504142
reference_title: 'The evolution of BRAF-targeted therapies in melanoma: overcoming hurdles and unleashing novel strategies'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Melanoma, a highly aggressive form of skin cancer, poses a significant global health burden, with 331,647 new cases and 58,645 deaths reported in 2022.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.3390/cancers15092607
title: 'BRAF V600-Mutated Metastatic Melanoma and Targeted Therapy Resistance: An Update of the Current Knowledge'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Melanoma is the most common cause of death in skin cancer due to its high metastatic potential.
supporting_text: Melanoma is the most common cause of death in skin cancer due to its high metastatic potential.
evidence:
- reference: DOI:10.3390/cancers15092607
reference_title: 'BRAF V600-Mutated Metastatic Melanoma and Targeted Therapy Resistance: An Update of the Current Knowledge'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Melanoma is the most common cause of death in skin cancer due to its high metastatic potential.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.3390/cancers15164026
title: 'BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Melanoma is an aggressive form of skin cancer resulting from the malignant transformation of melanocytes.
supporting_text: Melanoma is an aggressive form of skin cancer resulting from the malignant transformation of melanocytes.
evidence:
- reference: DOI:10.3390/cancers15164026
reference_title: 'BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Melanoma is an aggressive form of skin cancer resulting from the malignant transformation of melanocytes.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.3390/cancers16244186
title: New Screening Methods in Melanoma
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: The World Health Organisation reports that melanoma had an incidence of 331,722 cases worldwide in 2022, ranking it 17th on the list of the most prevalent malignancies.
supporting_text: The World Health Organisation reports that melanoma had an incidence of 331,722 cases worldwide in 2022, ranking it 17th on the list of the most prevalent malignancies.
evidence:
- reference: DOI:10.3390/cancers16244186
reference_title: New Screening Methods in Melanoma
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: The World Health Organisation reports that melanoma had an incidence of 331,722 cases worldwide in 2022, ranking it 17th on the list of the most prevalent malignancies.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.3390/cancers17111784
title: 'Skin Photodamage and Melanomagenesis: A Comprehensive Review'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Melanoma, the most aggressive form of skin cancer, still represents a significant and growing public health concern.
supporting_text: Melanoma, the most aggressive form of skin cancer, still represents a significant and growing public health concern.
evidence:
- reference: DOI:10.3390/cancers17111784
reference_title: 'Skin Photodamage and Melanomagenesis: A Comprehensive Review'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Melanoma, the most aggressive form of skin cancer, still represents a significant and growing public health concern.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.3390/cancers17193152
title: 'Treatment-Related Adverse Events in Individuals with BRAF-Mutant Cutaneous Melanoma Treated with BRAF and MEK Inhibitors: A Systematic Review and Meta-Analysis'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: 'Treatment-Related Adverse Events in Individuals with BRAF-Mutant Cutaneous Melanoma Treated with BRAF and MEK Inhibitors: A Systematic Review and Meta-Analysis'
supporting_text: We conducted a systematic review of clinical trials and case reports analyzing the safety of the currently approved BRAF and MEK inhibitors in adults with cutaneous melanoma (CM), and a meta-analysis to estimate the pooled prevalence of treatment-related adverse events (TRAEs).
evidence:
- reference: DOI:10.3390/cancers17193152
reference_title: 'Treatment-Related Adverse Events in Individuals with BRAF-Mutant Cutaneous Melanoma Treated with BRAF and MEK Inhibitors: A Systematic Review and Meta-Analysis'
supports: SUPPORT
evidence_source: OTHER
snippet: We conducted a systematic review of clinical trials and case reports analyzing the safety of the currently approved BRAF and MEK inhibitors in adults with cutaneous melanoma (CM), and a meta-analysis to estimate the pooled prevalence of treatment-related adverse events (TRAEs).
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.3390/cells9051289
title: 'From Tank to Treatment: Modeling Melanoma in Zebrafish'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Melanoma is the deadliest form of skin cancer and one of few cancers with a growing incidence.
supporting_text: Melanoma is the deadliest form of skin cancer and one of few cancers with a growing incidence.
evidence:
- reference: DOI:10.3390/cells9051289
reference_title: 'From Tank to Treatment: Modeling Melanoma in Zebrafish'
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Melanoma is the deadliest form of skin cancer and one of few cancers with a growing incidence.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.3390/curroncol31120568
title: 'Braf-Mutant Melanomas: Biology and Therapy'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: The incidence of melanoma, the most lethal form of skin cancer, has increased mainly due to ultraviolet exposure.
supporting_text: The incidence of melanoma, the most lethal form of skin cancer, has increased mainly due to ultraviolet exposure.
evidence:
- reference: DOI:10.3390/curroncol31120568
reference_title: 'Braf-Mutant Melanomas: Biology and Therapy'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The incidence of melanoma, the most lethal form of skin cancer, has increased mainly due to ultraviolet exposure.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.3390/jcm13061607
title: Primary Cutaneous MelanomaโManagement in 2024
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Maximizing survival for patients with primary cutaneous melanomas (melanomas) depends on an early diagnosis and appropriate management.
supporting_text: Maximizing survival for patients with primary cutaneous melanomas (melanomas) depends on an early diagnosis and appropriate management.
evidence:
- reference: DOI:10.3390/jcm13061607
reference_title: Primary Cutaneous MelanomaโManagement in 2024
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Maximizing survival for patients with primary cutaneous melanomas (melanomas) depends on an early diagnosis and appropriate management.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: DOI:10.3390/ph18081235
title: 'Molecular Basis of BRAF Inhibitor Resistance in Melanoma: A Systematic Review'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-falcon.md
findings:
- statement: Melanoma, the deadliest human skin cancer, frequently harbors activating BRAF mutations, with V600E being the most prevalent.
supporting_text: Melanoma, the deadliest human skin cancer, frequently harbors activating BRAF mutations, with V600E being the most prevalent.
evidence:
- reference: DOI:10.3390/ph18081235
reference_title: 'Molecular Basis of BRAF Inhibitor Resistance in Melanoma: A Systematic Review'
supports: SUPPORT
evidence_source: OTHER
snippet: Melanoma, the deadliest human skin cancer, frequently harbors activating BRAF mutations, with V600E being the most prevalent.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:20806172
title: '[Early diagnosis of skin cancer].'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: Survival from melanoma is strongly related to tumour thickness.
supporting_text: Survival from melanoma is strongly related to tumour thickness.
evidence:
- reference: PMID:20806172
reference_title: '[Early diagnosis of skin cancer].'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Survival from melanoma is strongly related to tumour thickness.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:21253789
title: 'Thinking about the role (largely ignored) of heavy metals in cancer prevention: hexavalent chromium and melanoma as a case in point.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2011;188:65-74. doi: 10.1007/978-3-642-10858-7_5.'
supporting_text: '2011;188:65-74. doi: 10.1007/978-3-642-10858-7_5.'
evidence:
- reference: PMID:21253789
reference_title: 'Thinking about the role (largely ignored) of heavy metals in cancer prevention: hexavalent chromium and melanoma as a case in point.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2011;188:65-74. doi: 10.1007/978-3-642-10858-7_5.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:22536370
title: Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2012;7(4):e35309. doi: 10.1371/journal.pone.0035309.'
supporting_text: '2012;7(4):e35309. doi: 10.1371/journal.pone.0035309.'
evidence:
- reference: PMID:22536370
reference_title: Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials.
supports: SUPPORT
evidence_source: OTHER
snippet: '2012;7(4):e35309. doi: 10.1371/journal.pone.0035309.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:22865452
title: Inactivation of the HIF-1ฮฑ/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2012 Oct 1;72(19):5035-47. doi: 10.1158/0008-5472.CAN-12-0979.'
supporting_text: '2012 Oct 1;72(19):5035-47. doi: 10.1158/0008-5472.CAN-12-0979.'
evidence:
- reference: PMID:22865452
reference_title: Inactivation of the HIF-1ฮฑ/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2012 Oct 1;72(19):5035-47. doi: 10.1158/0008-5472.CAN-12-0979.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:23569304
title: Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2013 May 10;31(14):1767-74. doi: 10.1200/JCO.2012.44.7888.'
supporting_text: '2013 May 10;31(14):1767-74. doi: 10.1200/JCO.2012.44.7888.'
evidence:
- reference: PMID:23569304
reference_title: Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2013 May 10;31(14):1767-74. doi: 10.1200/JCO.2012.44.7888.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:24119386
title: Improvement of the quality of BRAF testing in melanomas with nationwide external quality assessment, for the BRAF EQA group.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: Knowledge about tumour gene mutation status is essential for the treatment of increasing numbers of cancer patients, and testing quality has a major impact on treatment response and cost.
supporting_text: Knowledge about tumour gene mutation status is essential for the treatment of increasing numbers of cancer patients, and testing quality has a major impact on treatment response and cost.
evidence:
- reference: PMID:24119386
reference_title: Improvement of the quality of BRAF testing in melanomas with nationwide external quality assessment, for the BRAF EQA group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Knowledge about tumour gene mutation status is essential for the treatment of increasing numbers of cancer patients, and testing quality has a major impact on treatment response and cost.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:24148783
title: The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: Melanoma is the most deadly form of skin cancer.
supporting_text: Melanoma is the most deadly form of skin cancer.
evidence:
- reference: PMID:24148783
reference_title: The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Melanoma is the most deadly form of skin cancer.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:24154489
title: Characterization of vemurafenib phototoxicity in a mouse model.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2014 Jan;137(1):259-67. doi: 10.1093/toxsci/kft237.'
supporting_text: '2014 Jan;137(1):259-67. doi: 10.1093/toxsci/kft237.'
evidence:
- reference: PMID:24154489
reference_title: Characterization of vemurafenib phototoxicity in a mouse model.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: '2014 Jan;137(1):259-67. doi: 10.1093/toxsci/kft237.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:24424406
title: Analysis of the B-RafV600E mutation in cutaneous melanoma patients with occupational sun exposure.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2014 Mar;31(3):1079-82. doi: 10.3892/or.2014.2977.'
supporting_text: '2014 Mar;31(3):1079-82. doi: 10.3892/or.2014.2977.'
evidence:
- reference: PMID:24424406
reference_title: Analysis of the B-RafV600E mutation in cutaneous melanoma patients with occupational sun exposure.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2014 Mar;31(3):1079-82. doi: 10.3892/or.2014.2977.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:24610826
title: 'Molecular pathways: BRAF induces bioenergetic adaptation by attenuating oxidative phosphorylation.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2014 May 1;20(9):2257-63. doi: 10.1158/1078-0432.CCR-13-0898.'
supporting_text: '2014 May 1;20(9):2257-63. doi: 10.1158/1078-0432.CCR-13-0898.'
evidence:
- reference: PMID:24610826
reference_title: 'Molecular pathways: BRAF induces bioenergetic adaptation by attenuating oxidative phosphorylation.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2014 May 1;20(9):2257-63. doi: 10.1158/1078-0432.CCR-13-0898.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:24713734
title: BRAF pyrosequencing analysis aided by a lookup table.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2014 May;141(5):639-47. doi: 10.1309/AJCPVWH1K2ZIHHTV.'
supporting_text: '2014 May;141(5):639-47. doi: 10.1309/AJCPVWH1K2ZIHHTV.'
evidence:
- reference: PMID:24713734
reference_title: BRAF pyrosequencing analysis aided by a lookup table.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: '2014 May;141(5):639-47. doi: 10.1309/AJCPVWH1K2ZIHHTV.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:24903021
title: Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2014 Jul;2(7):643-54. doi: 10.1158/2326-6066.CIR-13-0215.'
supporting_text: '2014 Jul;2(7):643-54. doi: 10.1158/2326-6066.CIR-13-0215.'
evidence:
- reference: PMID:24903021
reference_title: Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.
supports: SUPPORT
evidence_source: OTHER
snippet: '2014 Jul;2(7):643-54. doi: 10.1158/2326-6066.CIR-13-0215.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:25048604
title: Association between BRAFV600E and NRASQ61R mutations and clinicopathologic characteristics, risk factors and clinical outcome of primary invasive cutaneous melanoma.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2014 Oct;25(10):1379-86. doi: 10.1007/s10552-014-0443-x.'
supporting_text: '2014 Oct;25(10):1379-86. doi: 10.1007/s10552-014-0443-x.'
evidence:
- reference: PMID:25048604
reference_title: Association between BRAFV600E and NRASQ61R mutations and clinicopathologic characteristics, risk factors and clinical outcome of primary invasive cutaneous melanoma.
supports: SUPPORT
evidence_source: OTHER
snippet: '2014 Oct;25(10):1379-86. doi: 10.1007/s10552-014-0443-x.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:25069660
title: Skin cancer prevention campaign aimed at beachgoers on the Costa del Sol (southern Spain).
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: Sunbathing on the beach is one of the main risks for skin cancer.
supporting_text: Sunbathing on the beach is one of the main risks for skin cancer.
evidence:
- reference: PMID:25069660
reference_title: Skin cancer prevention campaign aimed at beachgoers on the Costa del Sol (southern Spain).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Sunbathing on the beach is one of the main risks for skin cancer.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:25357015
title: Clinicopathological characteristics and mutation profiling in primary cutaneous melanoma.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: The incidence of mutations in malignant melanoma varies remarkably according to the subtype of melanoma, and this in itself is affected by racial and geographical factors.
supporting_text: The incidence of mutations in malignant melanoma varies remarkably according to the subtype of melanoma, and this in itself is affected by racial and geographical factors.
evidence:
- reference: PMID:25357015
reference_title: Clinicopathological characteristics and mutation profiling in primary cutaneous melanoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The incidence of mutations in malignant melanoma varies remarkably according to the subtype of melanoma, and this in itself is affected by racial and geographical factors.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:25456393
title: 'Lymph node metastases of melanoma: challenges for BRAF mutation detection.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2015 Jan;46(1):113-9. doi: 10.1016/j.humpath.2014.09.014.'
supporting_text: '2015 Jan;46(1):113-9. doi: 10.1016/j.humpath.2014.09.014.'
evidence:
- reference: PMID:25456393
reference_title: 'Lymph node metastases of melanoma: challenges for BRAF mutation detection.'
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: '2015 Jan;46(1):113-9. doi: 10.1016/j.humpath.2014.09.014.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:25724524
title: Contribution of Beta-HPV Infection and UV Damage to Rapid-Onset Cutaneous Squamous Cell Carcinoma during BRAF-Inhibition Therapy.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2015 Jun 1;21(11):2624-34. doi: 10.1158/1078-0432.CCR-14-2667.'
supporting_text: '2015 Jun 1;21(11):2624-34. doi: 10.1158/1078-0432.CCR-14-2667.'
evidence:
- reference: PMID:25724524
reference_title: Contribution of Beta-HPV Infection and UV Damage to Rapid-Onset Cutaneous Squamous Cell Carcinoma during BRAF-Inhibition Therapy.
supports: SUPPORT
evidence_source: OTHER
snippet: '2015 Jun 1;21(11):2624-34. doi: 10.1158/1078-0432.CCR-14-2667.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:26182194
title: Nephrotoxicity of the BRAF Inhibitors Vemurafenib and Dabrafenib.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2015 Nov;1(8):1133-4. doi: 10.1001/jamaoncol.2015.1713.'
supporting_text: '2015 Nov;1(8):1133-4. doi: 10.1001/jamaoncol.2015.1713.'
evidence:
- reference: PMID:26182194
reference_title: Nephrotoxicity of the BRAF Inhibitors Vemurafenib and Dabrafenib.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2015 Nov;1(8):1133-4. doi: 10.1001/jamaoncol.2015.1713.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:26921540
title: Multicenter Evaluation of a Novel Automated Rapid Detection System of BRAF Status in Formalin-Fixed, Paraffin-Embedded Tissues.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2016 May;18(3):370-377. doi: 10.1016/j.jmoldx.2015.12.005.'
supporting_text: '2016 May;18(3):370-377. doi: 10.1016/j.jmoldx.2015.12.005.'
evidence:
- reference: PMID:26921540
reference_title: Multicenter Evaluation of a Novel Automated Rapid Detection System of BRAF Status in Formalin-Fixed, Paraffin-Embedded Tissues.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2016 May;18(3):370-377. doi: 10.1016/j.jmoldx.2015.12.005.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:27221301
title: '[The effect of solar ultraviolet radiation (UVR) on induction of skin cancers].'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: BRAF gene mutations were observed in ~50% of CMM cases.
supporting_text: BRAF gene mutations were observed in ~50% of CMM cases.
evidence:
- reference: PMID:27221301
reference_title: '[The effect of solar ultraviolet radiation (UVR) on induction of skin cancers].'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: BRAF gene mutations were observed in ~50% of CMM cases.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:28424234
title: 'BRAF V600 mutation detection in melanoma: a comparison of two laboratory testing methods.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2017 Nov;70(11):935-940. doi: 10.1136/jclinpath-2017-204367.'
supporting_text: '2017 Nov;70(11):935-940. doi: 10.1136/jclinpath-2017-204367.'
evidence:
- reference: PMID:28424234
reference_title: 'BRAF V600 mutation detection in melanoma: a comparison of two laboratory testing methods.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2017 Nov;70(11):935-940. doi: 10.1136/jclinpath-2017-204367.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:28475671
title: 'Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma.
supporting_text: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma.
evidence:
- reference: PMID:28475671
reference_title: 'Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study.'
supports: SUPPORT
evidence_source: OTHER
snippet: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:28501764
title: "Open-label, multicentre safety study of vemurafenib inย 3219 patients with BRAF(V600) mutation-positive metastatic melanoma: 2-year follow-up data and long-term responders' analysis."
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: The orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAFV600 mutations.
supporting_text: The orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAFV600 mutations.
evidence:
- reference: PMID:28501764
reference_title: "Open-label, multicentre safety study of vemurafenib inย 3219 patients with BRAF(V600) mutation-positive metastatic melanoma: 2-year follow-up data and long-term responders' analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAFV600 mutations.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:28593303
title: Factors in Early Adolescence Associated With a Mole-Prone Phenotype in Late Adolescence.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2017 Oct 1;153(10):990-998. doi: 10.1001/jamadermatol.2017.1547.'
supporting_text: '2017 Oct 1;153(10):990-998. doi: 10.1001/jamadermatol.2017.1547.'
evidence:
- reference: PMID:28593303
reference_title: Factors in Early Adolescence Associated With a Mole-Prone Phenotype in Late Adolescence.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2017 Oct 1;153(10):990-998. doi: 10.1001/jamadermatol.2017.1547.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:30096703
title: Possible immune adverse events as predictors of durable response to BRAF inhibitors in patients with BRAF V600-mutant metastatic melanoma.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2018 Sep;101:229-235. doi: 10.1016/j.ejca.2018.06.030.'
supporting_text: '2018 Sep;101:229-235. doi: 10.1016/j.ejca.2018.06.030.'
evidence:
- reference: PMID:30096703
reference_title: Possible immune adverse events as predictors of durable response to BRAF inhibitors in patients with BRAF V600-mutant metastatic melanoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2018 Sep;101:229-235. doi: 10.1016/j.ejca.2018.06.030.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:30150674
title: Metabolic reprogramming of stromal fibroblasts by melanoma exosome microRNA favours a pre-metastatic microenvironment.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2018 Aug 27;8(1):12905. doi: 10.1038/s41598-018-31323-7.'
supporting_text: '2018 Aug 27;8(1):12905. doi: 10.1038/s41598-018-31323-7.'
evidence:
- reference: PMID:30150674
reference_title: Metabolic reprogramming of stromal fibroblasts by melanoma exosome microRNA favours a pre-metastatic microenvironment.
supports: SUPPORT
evidence_source: OTHER
snippet: '2018 Aug 27;8(1):12905. doi: 10.1038/s41598-018-31323-7.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:30238891
title: Melanoma.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2018 Sep 15;392(10151):971-984. doi: 10.1016/S0140-6736(18)31559-9.'
supporting_text: '2018 Sep 15;392(10151):971-984. doi: 10.1016/S0140-6736(18)31559-9.'
evidence:
- reference: PMID:30238891
reference_title: Melanoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2018 Sep 15;392(10151):971-984. doi: 10.1016/S0140-6736(18)31559-9.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:30481565
title: Metabolic targeting synergizes with MAPK inhibition and delays drug resistance in melanoma.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2019 Feb 1;442:453-463. doi: 10.1016/j.canlet.2018.11.018.'
supporting_text: '2019 Feb 1;442:453-463. doi: 10.1016/j.canlet.2018.11.018.'
evidence:
- reference: PMID:30481565
reference_title: Metabolic targeting synergizes with MAPK inhibition and delays drug resistance in melanoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2019 Feb 1;442:453-463. doi: 10.1016/j.canlet.2018.11.018.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:30739835
title: Impact of radiation, systemic therapy and treatment sequencing on survival of patients with melanoma brain metastases.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: Combining stereotactic radiosurgery (SRS) and active systemic therapies (STs) achieved favourable survival outcomes in patients with melanoma brain metastases (MBMs) in retrospective analyses.
supporting_text: Combining stereotactic radiosurgery (SRS) and active systemic therapies (STs) achieved favourable survival outcomes in patients with melanoma brain metastases (MBMs) in retrospective analyses.
evidence:
- reference: PMID:30739835
reference_title: Impact of radiation, systemic therapy and treatment sequencing on survival of patients with melanoma brain metastases.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Combining stereotactic radiosurgery (SRS) and active systemic therapies (STs) achieved favourable survival outcomes in patients with melanoma brain metastases (MBMs) in retrospective analyses.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:30923800
title: Association of Indoor Tanning Exposure With Age at Melanoma Diagnosis and BRAF V600E Mutations.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2019 Nov 1;111(11):1228-1231. doi: 10.1093/jnci/djz048.'
supporting_text: '2019 Nov 1;111(11):1228-1231. doi: 10.1093/jnci/djz048.'
evidence:
- reference: PMID:30923800
reference_title: Association of Indoor Tanning Exposure With Age at Melanoma Diagnosis and BRAF V600E Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2019 Nov 1;111(11):1228-1231. doi: 10.1093/jnci/djz048.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:30939167
title: 'Panniculitis and vitiligo occurring during BRAF and MEK inhibitors combination in advanced melanoma patients: Potential predictive role of treatment efficacy.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2019 Apr 2;14(4):e0214884. doi: 10.1371/journal.pone.0214884. eCollection 2019.'
supporting_text: '2019 Apr 2;14(4):e0214884. doi: 10.1371/journal.pone.0214884. eCollection 2019.'
evidence:
- reference: PMID:30939167
reference_title: 'Panniculitis and vitiligo occurring during BRAF and MEK inhibitors combination in advanced melanoma patients: Potential predictive role of treatment efficacy.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2019 Apr 2;14(4):e0214884. doi: 10.1371/journal.pone.0214884. eCollection 2019.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:31744817
title: A Versatile ES Cell-Based Melanoma Mouse Modeling Platform.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2020 Feb 15;80(4):912-921. doi: 10.1158/0008-5472.CAN-19-2924.'
supporting_text: '2020 Feb 15;80(4):912-921. doi: 10.1158/0008-5472.CAN-19-2924.'
evidence:
- reference: PMID:31744817
reference_title: A Versatile ES Cell-Based Melanoma Mouse Modeling Platform.
supports: SUPPORT
evidence_source: OTHER
snippet: '2020 Feb 15;80(4):912-921. doi: 10.1158/0008-5472.CAN-19-2924.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:32445930
title: Impact of Sun Exposure and Tanning Patterns onย Next-Generation Sequencing Mutations in Melanoma.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: For the past 30 y, the incidence rate of malignant melanoma has risen steadily.
supporting_text: For the past 30 y, the incidence rate of malignant melanoma has risen steadily.
evidence:
- reference: PMID:32445930
reference_title: Impact of Sun Exposure and Tanning Patterns onย Next-Generation Sequencing Mutations in Melanoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: For the past 30 y, the incidence rate of malignant melanoma has risen steadily.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:33587894
title: 'Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: Melanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy.
supporting_text: Melanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy.
evidence:
- reference: PMID:33587894
reference_title: 'Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study.'
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: Melanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:33801689
title: 'BRAF Gene and Melanoma: Back to the Future.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2021 Mar 27;22(7):3474. doi: 10.3390/ijms22073474.'
supporting_text: '2021 Mar 27;22(7):3474. doi: 10.3390/ijms22073474.'
evidence:
- reference: PMID:33801689
reference_title: 'BRAF Gene and Melanoma: Back to the Future.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2021 Mar 27;22(7):3474. doi: 10.3390/ijms22073474.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:34064013
title: 'Real-World Experience with Targeted Therapy in BRAF Mutant Advanced Melanoma Patients: Results from a Multicenter Retrospective Observational Study Advanced Melanoma in Russia (Experience) (ADMIRE).'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2021 May 21;13(11):2529. doi: 10.3390/cancers13112529.'
supporting_text: '2021 May 21;13(11):2529. doi: 10.3390/cancers13112529.'
evidence:
- reference: PMID:34064013
reference_title: 'Real-World Experience with Targeted Therapy in BRAF Mutant Advanced Melanoma Patients: Results from a Multicenter Retrospective Observational Study Advanced Melanoma in Russia (Experience) (ADMIRE).'
supports: SUPPORT
evidence_source: OTHER
snippet: '2021 May 21;13(11):2529. doi: 10.3390/cancers13112529.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:34108180
title: Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2021 Aug 15;27(16):4500-4510. doi: 10.1158/1078-0432.CCR-20-3586.'
supporting_text: '2021 Aug 15;27(16):4500-4510. doi: 10.1158/1078-0432.CCR-20-3586.'
evidence:
- reference: PMID:34108180
reference_title: Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: '2021 Aug 15;27(16):4500-4510. doi: 10.1158/1078-0432.CCR-20-3586.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:34243078
title: 'Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM).
supporting_text: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM).
evidence:
- reference: PMID:34243078
reference_title: 'Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM).
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:34246984
title: Plasma proteome alterations by MAPK inhibitors in BRAF(V600)-mutated metastatic cutaneous melanoma.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2021 Aug;23(8):783-791. doi: 10.1016/j.neo.2021.06.002.'
supporting_text: '2021 Aug;23(8):783-791. doi: 10.1016/j.neo.2021.06.002.'
evidence:
- reference: PMID:34246984
reference_title: Plasma proteome alterations by MAPK inhibitors in BRAF(V600)-mutated metastatic cutaneous melanoma.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: '2021 Aug;23(8):783-791. doi: 10.1016/j.neo.2021.06.002.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:35353115
title: Global Burden of Cutaneous Melanoma in 2020 and Projections to 2040.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2022 May 1;158(5):495-503. doi: 10.1001/jamadermatol.2022.0160.'
supporting_text: '2022 May 1;158(5):495-503. doi: 10.1001/jamadermatol.2022.0160.'
evidence:
- reference: PMID:35353115
reference_title: Global Burden of Cutaneous Melanoma in 2020 and Projections to 2040.
supports: SUPPORT
evidence_source: OTHER
snippet: '2022 May 1;158(5):495-503. doi: 10.1001/jamadermatol.2022.0160.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:35530323
title: 'Acceptability of Drugs in the Treatment of Unresectable/Metastatic BRAF V600-Mutant Melanoma: A Systematic Review and Network Meta-Analysis.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: Although many novel regimens have entered the treatment paradigm for unresectable/metastatic BRAF V600-mutant melanoma, there is still a lack of head-to-head comparison in terms of security.
supporting_text: Although many novel regimens have entered the treatment paradigm for unresectable/metastatic BRAF V600-mutant melanoma, there is still a lack of head-to-head comparison in terms of security.
evidence:
- reference: PMID:35530323
reference_title: 'Acceptability of Drugs in the Treatment of Unresectable/Metastatic BRAF V600-Mutant Melanoma: A Systematic Review and Network Meta-Analysis.'
supports: SUPPORT
evidence_source: OTHER
snippet: Although many novel regimens have entered the treatment paradigm for unresectable/metastatic BRAF V600-mutant melanoma, there is still a lack of head-to-head comparison in terms of security.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:35623961
title: 'European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment - Update 2022.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2022 Jul;170:256-284. doi: 10.1016/j.ejca.2022.04.018.'
supporting_text: '2022 Jul;170:256-284. doi: 10.1016/j.ejca.2022.04.018.'
evidence:
- reference: PMID:35623961
reference_title: 'European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment - Update 2022.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2022 Jul;170:256-284. doi: 10.1016/j.ejca.2022.04.018.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:37016119
title: 'Comparative analysis of adjuvant therapy for stage III BRAF-mut melanoma: A real-world retrospective study from single center in China.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: BRAF V600 mutation is the most common oncogenic alternation in melanoma and is visible in around 50% of cutaneous and 10%-15% of acral or mucosal subtypes.
supporting_text: BRAF V600 mutation is the most common oncogenic alternation in melanoma and is visible in around 50% of cutaneous and 10%-15% of acral or mucosal subtypes.
evidence:
- reference: PMID:37016119
reference_title: 'Comparative analysis of adjuvant therapy for stage III BRAF-mut melanoma: A real-world retrospective study from single center in China.'
supports: SUPPORT
evidence_source: OTHER
snippet: BRAF V600 mutation is the most common oncogenic alternation in melanoma and is visible in around 50% of cutaneous and 10%-15% of acral or mucosal subtypes.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:37256936
title: Gene-edited and -engineered stem cell platform drives immunotherapy for brain metastatic melanomas.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2023 May 31;15(698):eade8732. doi: 10.1126/scitranslmed.ade8732.'
supporting_text: '2023 May 31;15(698):eade8732. doi: 10.1126/scitranslmed.ade8732.'
evidence:
- reference: PMID:37256936
reference_title: Gene-edited and -engineered stem cell platform drives immunotherapy for brain metastatic melanomas.
supports: SUPPORT
evidence_source: OTHER
snippet: '2023 May 31;15(698):eade8732. doi: 10.1126/scitranslmed.ade8732.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:37920169
title: Successes and challenges in modeling heterogeneous BRAF(V600E) mutated central nervous system neoplasms.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2023 Oct 18;13:1223199. doi: 10.3389/fonc.2023.1223199. eCollection 2023.'
supporting_text: '2023 Oct 18;13:1223199. doi: 10.3389/fonc.2023.1223199. eCollection 2023.'
evidence:
- reference: PMID:37920169
reference_title: Successes and challenges in modeling heterogeneous BRAF(V600E) mutated central nervous system neoplasms.
supports: SUPPORT
evidence_source: OTHER
snippet: '2023 Oct 18;13:1223199. doi: 10.3389/fonc.2023.1223199. eCollection 2023.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:38327091
title: Global pannexin 1 deletion increases tumor-infiltrating lymphocytes in the BRAF/Pten mouse melanoma model.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2024 Apr;18(4):969-987. doi: 10.1002/1878-0261.13596.'
supporting_text: '2024 Apr;18(4):969-987. doi: 10.1002/1878-0261.13596.'
evidence:
- reference: PMID:38327091
reference_title: Global pannexin 1 deletion increases tumor-infiltrating lymphocytes in the BRAF/Pten mouse melanoma model.
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Apr;18(4):969-987. doi: 10.1002/1878-0261.13596.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:38972133
title: Therapeutic implications of the metabolic changes associated with BRAF inhibition in melanoma.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2024 Sep;129:102795. doi: 10.1016/j.ctrv.2024.102795.'
supporting_text: '2024 Sep;129:102795. doi: 10.1016/j.ctrv.2024.102795.'
evidence:
- reference: PMID:38972133
reference_title: Therapeutic implications of the metabolic changes associated with BRAF inhibition in melanoma.
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Sep;129:102795. doi: 10.1016/j.ctrv.2024.102795.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:39354418
title: 'Weekly carboplatin plus paclitaxel chemotherapy in advanced melanoma patients resistant to anti-PD-1 inhibitors: a retrospective, monocentric experience.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2024 Oct 1;24(1):1220. doi: 10.1186/s12885-024-12961-9.'
supporting_text: '2024 Oct 1;24(1):1220. doi: 10.1186/s12885-024-12961-9.'
evidence:
- reference: PMID:39354418
reference_title: 'Weekly carboplatin plus paclitaxel chemotherapy in advanced melanoma patients resistant to anti-PD-1 inhibitors: a retrospective, monocentric experience.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Oct 1;24(1):1220. doi: 10.1186/s12885-024-12961-9.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:39418569
title: 'Melanoma: Diagnosis and Treatment.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: Lauters R(1), Brown AD(2), Harrington KA(3).
supporting_text: Lauters R(1), Brown AD(2), Harrington KA(3).
evidence:
- reference: PMID:39418569
reference_title: 'Melanoma: Diagnosis and Treatment.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Lauters R(1), Brown AD(2), Harrington KA(3).
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:39508497
title: High BRAF V600 Mutation Level Associated with Worse Outcome in Metastatic Melanoma Patients Receiving BRAF and MEK Inhibitors.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2024 Nov 7;104:adv40913. doi: 10.2340/actadv.v104.40913.'
supporting_text: '2024 Nov 7;104:adv40913. doi: 10.2340/actadv.v104.40913.'
evidence:
- reference: PMID:39508497
reference_title: High BRAF V600 Mutation Level Associated with Worse Outcome in Metastatic Melanoma Patients Receiving BRAF and MEK Inhibitors.
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Nov 7;104:adv40913. doi: 10.2340/actadv.v104.40913.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:39700658
title: 'European consensus-based interdisciplinary guideline for melanoma. Part 1: Diagnostics - Update 2024.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2025 Jan 17;215:115152. doi: 10.1016/j.ejca.2024.115152.'
supporting_text: '2025 Jan 17;215:115152. doi: 10.1016/j.ejca.2024.115152.'
evidence:
- reference: PMID:39700658
reference_title: 'European consensus-based interdisciplinary guideline for melanoma. Part 1: Diagnostics - Update 2024.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Jan 17;215:115152. doi: 10.1016/j.ejca.2024.115152.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:39961465
title: 'BRAF V600E in cancer: Exploring structural complexities, mutation profiles, and pathway dysregulation.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2025 Mar 1;446(1):114440. doi: 10.1016/j.yexcr.2025.114440.'
supporting_text: '2025 Mar 1;446(1):114440. doi: 10.1016/j.yexcr.2025.114440.'
evidence:
- reference: PMID:39961465
reference_title: 'BRAF V600E in cancer: Exploring structural complexities, mutation profiles, and pathway dysregulation.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Mar 1;446(1):114440. doi: 10.1016/j.yexcr.2025.114440.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:40020669
title: FAK inhibition combined with the RAF-MEK clamp avutometinib overcomes resistance to targeted and immune therapies in BRAF V600E melanoma.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2025 Mar 10;43(3):428-445.e6. doi: 10.1016/j.ccell.2025.02.001.'
supporting_text: '2025 Mar 10;43(3):428-445.e6. doi: 10.1016/j.ccell.2025.02.001.'
evidence:
- reference: PMID:40020669
reference_title: FAK inhibition combined with the RAF-MEK clamp avutometinib overcomes resistance to targeted and immune therapies in BRAF V600E melanoma.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Mar 10;43(3):428-445.e6. doi: 10.1016/j.ccell.2025.02.001.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:40250457
title: 'Clinical validation of droplet digital PCR assays in detecting BRAF(V600)-mutant circulating tumour DNA as a prognostic biomarker in patients with resected stage III melanoma receiving adjuvant therapy (COMBI-AD): a biomarker analysis from a double-blind, randomised phase 3 trial.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: Cell-free, circulating tumour DNA (ctDNA) is an established measure of minimal residual disease; however, it is not utilised in melanoma management.
supporting_text: Cell-free, circulating tumour DNA (ctDNA) is an established measure of minimal residual disease; however, it is not utilised in melanoma management.
evidence:
- reference: PMID:40250457
reference_title: 'Clinical validation of droplet digital PCR assays in detecting BRAF(V600)-mutant circulating tumour DNA as a prognostic biomarker in patients with resected stage III melanoma receiving adjuvant therapy (COMBI-AD): a biomarker analysis from a double-blind, randomised phase 3 trial.'
supports: SUPPORT
evidence_source: OTHER
snippet: Cell-free, circulating tumour DNA (ctDNA) is an established measure of minimal residual disease; however, it is not utilised in melanoma management.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:40411977
title: 'Efficacy of encorafenib plus binimetinib in patients with BRAF-mutated melanoma brain metastases: Results from the Dutch Melanoma Treatment Registry.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2025 Jun 18;223:115514. doi: 10.1016/j.ejca.2025.115514.'
supporting_text: '2025 Jun 18;223:115514. doi: 10.1016/j.ejca.2025.115514.'
evidence:
- reference: PMID:40411977
reference_title: 'Efficacy of encorafenib plus binimetinib in patients with BRAF-mutated melanoma brain metastases: Results from the Dutch Melanoma Treatment Registry.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Jun 18;223:115514. doi: 10.1016/j.ejca.2025.115514.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:40503961
title: 'POLARIS: encorafenib plus binimetinib for people with BRAF V600-mutant melanoma with brain metastasis.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2025 Jul;21(16):1961-1963. doi: 10.1080/14796694.2025.2514426.'
supporting_text: '2025 Jul;21(16):1961-1963. doi: 10.1080/14796694.2025.2514426.'
evidence:
- reference: PMID:40503961
reference_title: 'POLARIS: encorafenib plus binimetinib for people with BRAF V600-mutant melanoma with brain metastasis.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Jul;21(16):1961-1963. doi: 10.1080/14796694.2025.2514426.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:40643496
title: COP1 Deficiency in BRAF(V600E) Melanomas Confers Resistance to Inhibitors of the MAPK Pathway.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2025 Jun 25;14(13):975. doi: 10.3390/cells14130975.'
supporting_text: '2025 Jun 25;14(13):975. doi: 10.3390/cells14130975.'
evidence:
- reference: PMID:40643496
reference_title: COP1 Deficiency in BRAF(V600E) Melanomas Confers Resistance to Inhibitors of the MAPK Pathway.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Jun 25;14(13):975. doi: 10.3390/cells14130975.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:40850313
title: 'Targeted therapy for rare BRAF-mutated melanoma: Updated multicenter analysis and launch of a publicly accessible online outcome database.'
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: '2025 Oct 1;228:115703. doi: 10.1016/j.ejca.2025.115703.'
supporting_text: '2025 Oct 1;228:115703. doi: 10.1016/j.ejca.2025.115703.'
evidence:
- reference: PMID:40850313
reference_title: 'Targeted therapy for rare BRAF-mutated melanoma: Updated multicenter analysis and launch of a publicly accessible online outcome database.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Oct 1;228:115703. doi: 10.1016/j.ejca.2025.115703.'
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:41537702
title: Exploratory Analysis of Biomarkers and Treatment Outcomes from the COLUMBUS Study in BRAF V600E/K-Mutant Advanced or Metastatic Melanoma.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: The greatest benefits of encorafenib plus binimetinib were observed in patients with evidence of high TMB and/or tumor-immune infiltration.
supporting_text: The greatest benefits of encorafenib plus binimetinib were observed in patients with evidence of high TMB and/or tumor-immune infiltration.
evidence:
- reference: PMID:41537702
reference_title: Exploratory Analysis of Biomarkers and Treatment Outcomes from the COLUMBUS Study in BRAF V600E/K-Mutant Advanced or Metastatic Melanoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The greatest benefits of encorafenib plus binimetinib were observed in patients with evidence of high TMB and/or tumor-immune infiltration.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
- reference: PMID:41935307
title: PHI-501, a dual inhibitor of RAF and DDR1/2, overcomes MAPK drug resistance in Melanoma.
found_in:
- BRAF_V600_Mutant_Melanoma-deep-research-openscientist.md
findings:
- statement: Melanoma, an aggressive skin cancer caused by BRAF or NRAS mutations, is characterized by the hyperactivation of the MAPK pathway.
supporting_text: Melanoma, an aggressive skin cancer caused by BRAF or NRAS mutations, is characterized by the hyperactivation of the MAPK pathway.
evidence:
- reference: PMID:41935307
reference_title: PHI-501, a dual inhibitor of RAF and DDR1/2, overcomes MAPK drug resistance in Melanoma.
supports: SUPPORT
evidence_source: OTHER
snippet: Melanoma, an aggressive skin cancer caused by BRAF or NRAS mutations, is characterized by the hyperactivation of the MAPK pathway.
explanation: Deep research cited this publication as relevant literature for BRAF V600 Mutant Melanoma.
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.
Please provide a comprehensive research report on BRAF V600 Mutant Melanoma 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.
Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed
Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Search first: CTD, PubMed, PheGenI, GxE databases
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
Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser
Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Search first: CDC databases, WHO, PubMed, NHANES
Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON
Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Search first: PubMed, Gene Ontology, Reactome
Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
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
Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Search first: OMIM, Orphanet, HPO, PubMed
Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.
Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Search first: NSGC resources, ACMG guidelines, GeneReviews
Search first: Clinical guidelines, FDA approvals, PubMed
Search first: NCBI Taxonomy
Search first: VBO (Vertebrate Breed Ontology)
Search first: NCBI Gene
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
| Disease label | ICD-10 code | MeSH term / ID | Key molecular synonyms | Staging system referenced | Source (first author, year) | Publication date | URL / DOI |
|---|---|---|---|---|---|---|---|
| BRAF V600โmutant cutaneous melanoma | C43 (malignant melanoma of skin) (hoejberg2016trendsinmelanoma pages 1-3) | Melanoma / D008545 (NCT02036086 chunk 2) | BRAFmut; BRAFV600mut; BRAFV600E/K (marquezrodas2024seomgemclinicalguidelines pages 1-2, ghate2018healthcareresourceutilization pages 1-5) | AJCC 8th edition (marquezrodas2024seomgemclinicalguidelines pages 1-2, dixon2024primarycutaneousmelanomaโmanagement pages 1-2) | Mรกrquez-Rodas, 2024; Hoejberg, 2016; ClinicalTrials.gov NCT02036086 (marquezrodas2024seomgemclinicalguidelines pages 1-2, NCT02036086 chunk 2, hoejberg2016trendsinmelanoma pages 1-3) | May 2024; Jan 2016; trial record 2015 | https://doi.org/10.1007/s12094-024-03497-2 ; https://doi.org/10.3109/0284186x.2015.1114677 ; NCT02036086 |
| BRAF V600โmutant metastatic melanoma | C43 (used for malignant melanoma of skin in registry-based melanoma coding; metastatic subset not separately coded in retrieved texts) (hoejberg2016trendsinmelanoma pages 1-3) | Melanoma / D008545 (NCT02036086 chunk 2) | BRAF-mutant melanoma; BRAFV600-mutant melanoma; BRAFV600E/Kโmutant advanced or metastatic melanoma (dummer2026exploratoryanalysisof pages 20-21) | AJCC 8th edition referenced in melanoma guidelines/management sources (marquezrodas2024seomgemclinicalguidelines pages 1-2, dixon2024primarycutaneousmelanomaโmanagement pages 1-2) | Dummer, 2026; Ghate, 2018; ClinicalTrials.gov NCT02036086 (dummer2026exploratoryanalysisof pages 20-21, ghate2018healthcareresourceutilization pages 1-5, NCT02036086 chunk 2) | Jan 2026; Aug 2018; trial record 2015 | https://doi.org/10.1158/1078-0432.ccr-25-3262 ; https://doi.org/10.1080/03007995.2018.1501351 ; NCT02036086 |
Table: This table summarizes the principal coded disease terms and naming conventions that can anchor a knowledge base entry for BRAF V600โmutant melanoma. It also notes the staging framework used in the retrieved guideline and trial sources.
Definition/overview. Cutaneous melanoma is a malignant neoplasm derived from melanocytes and is the skin-cancer subtype responsible for most skin cancer deaths due to metastatic potential (belloni2025treatmentrelatedadverseevents pages 1-2, frantz2020fromtankto pages 1-3). โBRAF V600โmutant melanomaโ is a molecularly defined subset characterized by an activating missense substitution at BRAF codon 600 (most commonly V600E; also V600K/R/D/M), which constitutively activates MAPK signaling and enables use of BRAF/MEK targeted therapies (castellani2023brafmutationsin pages 1-2, castellani2023brafmutationsin pages 2-4).
Key identifiers and code systems (available in retrieved sources). Melanoma was operationalized as ICD-10 C43 in a Danish registry analysis (hoejberg2016trendsinmelanoma pages 1-3). A ClinicalTrials.gov record lists MeSH โMelanomaโ (MeSH ID D008545) (NCT02036086 chunk 2).
Common synonyms/alternative names used in the literature. โCutaneous melanoma,โ โBRAF-mutant melanoma,โ โBRAF V600E/Kโmutant melanoma,โ and shorthand โBRAFmut/BRAFV600mutโ appear in clinical and review literature and guidelines (mohr2025updateonthe pages 2-3, marquezrodas2024seomgemclinicalguidelines pages 1-2, dummer2026exploratoryanalysisof pages 20-21).
Evidence source type. The evidence synthesized here is primarily aggregated disease-level knowledge (guidelines/reviews), augmented with randomized trials and observational/real-world cohorts (marquezrodas2024seomgemclinicalguidelines pages 1-2, bai2023dabrafenibplustrametinib pages 1-2, ascierto2024sequentialimmunotherapyand pages 1-2).
Causal and mechanistic factors. Ultraviolet (UV) radiation (natural sunlight and artificial tanning) is consistently described as the leading environmental risk factor for melanoma development (florent2023brafv600mutatedmetastatic pages 1-2, mohr2025updateonthe pages 2-2). Molecularly, BRAF V600 mutations are common early driver events (including in nevi), but additional alterations are typically required for progression to melanoma (pelosi2024brafmutantmelanomasbiology pages 4-5, pelosi2024brafmutantmelanomasbiology pages 2-4).
Risk factors (environmental/host/genetic). Reported risks include high UV exposure, personal or family history of melanoma (florent2023brafv600mutatedmetastatic pages 1-2), and host pigmentation phenotypes (e.g., pale skin, freckles, light/red hair) associated with increased melanoma risk (castellani2023brafmutationsin pages 1-2). BRAF-mutant melanomas are reported to be more frequent in younger patients and those with intermittent (occasional) sun exposure compared with chronically sun-exposed individuals (castellani2023brafmutationsin pages 2-4). The V600K subtype is specifically linked to chronic sun damage/exposure (pelosi2024brafmutantmelanomasbiology pages 4-5, pelosi2024brafmutantmelanomasbiology pages 2-4).
Protective factors. Direct protective factors were not quantified in the retrieved melanoma/BRAF V600โspecific sources; however, UV exposure is the leading modifiable driver, implying sun-protective behaviors as primary prevention (mohr2025updateonthe pages 2-2, manganelli2025skinphotodamageand pages 1-2).
Geneโenvironment interaction (current understanding). One mechanistic bridge between UV exposure and melanocyte biology is UV-triggered melanocortin signaling (e.g., ฮฑ-MSH/MC1R โ MITF via cAMPโPKAโCREB), linking environmental exposure to transcriptional programs that intersect with MAPK pathway biology (castellani2023brafmutationsin pages 4-6).
Suggested HPO terms (examples). - Cutaneous neoplasm/skin lesion: HP:0008069 (abnormality of skin morphology) / HP:0008064 (skin neoplasm; if using disease-phenotype mapping) - Ulceration: HP:0001052 - Increased Breslow thickness / deep invasion: not a single canonical HPO term; can map via โinvasive melanomaโ phenotype ontology in cancer-specific vocabularies (not retrieved here)
Suggested HPO terms (examples). - Metastatic neoplasm: HP:0003002 - Lymph node metastasis: HP:0012735 - Brain metastasis: not a standard HPO term in all releases; often represented via โmetastatic neoplasm of the brainโ in oncology ontologies (mapping may require NCIt)
A meta-analysis reported pooled toxicity prevalences for commonly used BRAF/MEK inhibitor regimens: - Vemurafenib: arthralgia 44% (95% CI 29โ59%); rash 39% (95% CI 22โ56%) (belloni2025treatmentrelatedadverseevents pages 1-2). - Dabrafenib + trametinib: fatigue 47% (95% CI 38โ56%); pyrexia 40% (95% CI 26โ54%) (belloni2025treatmentrelatedadverseevents pages 1-2).
Suggested HPO terms (examples). - Arthralgia: HP:0002829 - Rash: HP:0000988 - Pyrexia: HP:0001945 - Fatigue: HP:0012378
Quality of life (QoL). In the retrieved set, QoL evidence is largely indirect (treatment discontinuation/toxicity; patient narrative). A patient+oncologist perspective emphasizes long-term adverse effects and individualized decision-making over a decade-long course (finke2024brafv600emetastaticmelanoma pages 1-2).
Suggested GO Biological Process terms (examples). - MAPK cascade: GO:0000165 - ERK1 and ERK2 cascade: GO:0070371 - Positive regulation of cell population proliferation: GO:0008284 - Epithelial to mesenchymal transition (phenotype switching analogue): GO:0001837
Suggested Cell Ontology (CL) terms (examples). - Melanocyte: CL:0000148 - Regulatory T cell (immune evasion context): CL:0000815 (supported by BRAF-driven Treg recruitment models in the broader literature base retrieved) (shang2026brafinhibitorresistance pages 2-3)
Co-altered pathways/genes frequently implicated include NRAS, NF1, PTEN, TP53, CDKN2A, TERT promoter, and regulators of melanoma state such as MITF (pelosi2024brafmutantmelanomasbiology pages 1-2, castellani2023brafmutationsin pages 11-12).
Mechanisms of resistance to BRAF-targeted therapy include: - Primary resistance in ~50% of treatment-naรฏve patients (reported) (castellani2023brafmutationsin pages 11-12). - Acquired resistance frequently via MAPK reactivation (~80% of BRAFi-resistant tumors) and/or PI3K/AKT/mTOR pathway activation (castellani2023brafmutationsin pages 11-12). - Adaptive resistance via loss of ERK negative feedback leading to RTK upregulation (e.g., PDGFRฮฒ, EGFR) (castellani2023brafmutationsin pages 11-12). - Phenotype switching involving MITF-high melanocyte-like vs MITF-low mesenchymal invasive states (AXL/EGFR/TEAD programs; WNT5A/ROR2 axis) (castellani2023brafmutationsin pages 11-12).
Primary environmental driver is UV radiation exposure (sunlight; indoor tanning), with UVA/UVB causing DNA damage, oxidative stress, inflammation, and immunosuppression (castellani2023brafmutationsin pages 1-2, manganelli2025skinphotodamageand pages 1-2). No infectious etiology is indicated in the retrieved sources.
Causal chain (simplified): UV-induced DNA damage and mutagenesis in melanocytes + acquisition of activating BRAFV600 mutation โ constitutive MAPK/ERK signaling โ melanocyte proliferation/survival and tumor initiation (often as nevi) โ additional cooperating alterations (e.g., PTEN loss, TERT promoter) enable escape from senescence and progression โ invasion/metastasis and microenvironmental remodeling โ therapy response followed by adaptive/acquired resistance (MAPK reactivation, phenotype switching, RTK/PI3K bypass, autophagy) (castellani2023brafmutationsin pages 4-6, pelosi2024brafmutantmelanomasbiology pages 2-4, castellani2023brafmutationsin pages 11-12).
Immune involvement. The tumor microenvironment contributes to resistance via stromal and immune components; CAF and immune remodeling are emphasized in resistance reviews (florent2023brafv600mutatedmetastatic pages 1-2). The early immune-modulating effects of oncogenic BRAF (e.g., Treg recruitment) are also supported by retrieved experimental literature (shang2026brafinhibitorresistance pages 2-3).
Suggested UBERON terms (examples). - Skin: UBERON:0002097 - Lymph node: UBERON:0000029 - Brain: UBERON:0000955
BRAF V600โmutant melanoma is predominantly somatic. Hereditary melanoma (~10% of cases) is reported to lack BRAF mutations, implying BRAF V600 melanomas are primarily sporadic (castellani2023brafmutationsin pages 2-4).
Burden statistics. Global Cancer Observatory (GCO) 2022: 331,647 new melanoma cases and 58,645 deaths (imani2024theevolutionof pages 1-2). A 2025 meta-analysis summary cites similar 2022 global estimates and projects ~510,000 new cases and ~96,000 deaths by 2040 (belloni2025treatmentrelatedadverseevents pages 1-2).
Survival statistics (general melanoma). Europe-wide 5-year survival is cited at ~85% (mohr2025updateonthe pages 2-2). A melanoma screening review reports 5-year survival in most European countries is 80โ90% with country-level variation (czerw2024newscreeningmethods pages 2-3).
Histopathology/biopsy. The SEOM-GEM guideline states suspicious lesions should be confirmed by excisional biopsy and staged per AJCC (marquezrodas2024seomgemclinicalguidelines pages 1-2).
IHC markers for melanoma. Recommended markers include S-100, SOX10, HMB-45, PRAME, MART-1 (marquezrodas2024seomgemclinicalguidelines pages 1-2).
Molecular testing for BRAF. SEOM-GEM: โDetermination of BRAF V600 status is mandatory in patients with stage IV melanomaโ (marquezrodas2024seomgemclinicalguidelines pages 1-2). In clinical trials and safety literature, BRAF V600 mutation detection has been performed using PCR-based assays, NGS, and Sanger sequencing (belloni2025treatmentrelatedadverseevents pages 7-8).
Liquid biopsy / circulating biomarkers. ctDNA (BRAF V600E) is described as prognostic and dynamic with treatment, and can detect emergent resistance mutations (NRAS, MAP2K1, AKT1, PIK3CA) (castellani2023brafmutationsin pages 17-18). Extracellular vesicle DNA from lymphatic drainage (exudative seroma) can detect BRAFV600E and was reported to correlate with relapse risk in stage III disease (garciasilva2019useofextracellular pages 1-2).
Metastatic sequencing outcomes (SECOMBIT). 4-year OS differed by first-line sequencing: 46% (targetedโimmunotherapy), 64% (immunotherapyโtargeted), 59% (sandwich) (ascierto2024sequentialimmunotherapyand pages 1-2). Total PFS to second progression at 4 years was 29%, 55%, and 54% in Arms A/B/C, respectively (ascierto2024sequentialimmunotherapyand pages 1-2).
Brain-metastasis outcomes (SECOMBIT analysis). 60-month brain-metastases-free survival was 56% (targeted-first), 80% (immunotherapy-first; HR vs A 0.40), and 85% (sandwich; HR vs A 0.35) (ascierto2024sequencingofcheckpoint pages 1-2).
Approved combinations are widely used in advanced disease; guideline notes include vemurafenib+cobimetinib, dabrafenib+trametinib, and encorafenib+binimetinib (marquezrodas2024seomgemclinicalguidelines pages 4-5).
Adjuvant (stage III). SEOM-GEM notes COMBI-AD supports 1 year dabrafenib+trametinib as a standard adjuvant option for completely resected stage III BRAF-mutated melanoma (marquezrodas2024seomgemclinicalguidelines pages 4-5). In a large multicenter retrospective cohort (n=598), adjuvant dabrafenib+trametinib had longer RFS than adjuvant antiโPD-1 monotherapy: median RFS 51.0 vs 44.8 months; multivariable HR 0.58 (P=0.007); OS similar (multivariable HR 0.90) (bai2023dabrafenibplustrametinib pages 1-2).
MAXO suggestions (examples). - BRAF inhibitor therapy; MEK inhibitor therapy; combination targeted therapy (MAXO mapping not directly retrieved; recommended as action ontology entries).
SECOMBIT provides prospective evidence supporting immunotherapy-first (ipilimumab+nivolumab) as preferred first-line sequencing for many patients with BRAF V600โmutant metastatic melanoma (ascierto2024sequentialimmunotherapyand pages 1-2). The NEJM Evidence analysis further supports immunotherapy-first or sandwich sequences for reducing brain metastasis risk (ascierto2024sequencingofcheckpoint pages 1-2).
NeoTrio tested pembrolizumab alone vs addition of dabrafenib+trametinib sequentially or concurrently. - Abstract quote: โThe pathological response rate was 55% (11/20; including six pathological complete responses (pCRs)) with pembrolizumab, 50% (10/20; three pCRs) with sequential therapy and 80% (16/20; ten pCRs) with concurrent therapyโฆโ (long2024neoadjuvantpembrolizumabdabrafenib pages 1-2). - 2-year outcomes: event-free survival 60%, 80%, 71% (pembro, sequential, concurrent) (long2024neoadjuvantpembrolizumabdabrafenib pages 1-2). - Safety quote: โTreatment-related adverse events affected 75โ100% of patients during neoadjuvant treatment, with seven early discontinuations (all in the concurrent arm).โ (long2024neoadjuvantpembrolizumabdabrafenib pages 1-2).
Visual evidence (NeoTrio survival curves). KaplanโMeier curves and 12-/24-month landmark rates for EFS/RFS/OS are shown in Figure 2 (long2024neoadjuvantpembrolizumabdabrafenib media 7989da9e).
Pooled prevalence estimates: vemurafenib-associated arthralgia 44% and rash 39%; dabrafenib+trametinib-associated fatigue 47% and pyrexia 40% (belloni2025treatmentrelatedadverseevents pages 1-2).
Primary prevention. UVR is the principal modifiable driver; a recent comprehensive photodamage review states UVR is the leading environmental factor and accounts for an estimated 60โ70% of cutaneous melanoma cases (manganelli2025skinphotodamageand pages 1-2).
Secondary prevention/high-risk surveillance. A systematic review of interventions to increase skin self-examination (SSE) in high-risk individuals found low-certainty evidence that interventions improve SSE practice; no evidence of effects on melanoma mortality was identified (gooley2025clinicaleffectivenessof pages 1-2). A 2024 management review emphasizes lifelong regular skin checks and considering total-body photography in patients with many nevi (dixon2024primarycutaneousmelanomaโmanagement pages 1-2).
No robust, BRAF V600โspecific naturally occurring veterinary melanoma evidence was retrieved in this run; thus, cross-species โnatural diseaseโ mapping is incomplete.
Murine models. A widely used inducible genetic model combines melanocyte-specific BRAFV600E with PTEN loss (Tyr::CreERT2; BrafV600E; Ptenfl/fl) for preclinical testing of targeted therapy and immunotherapy combinations (hooijkaas2012targetingbrafv600ein pages 1-2).
Zebrafish models. Zebrafish are used to model melanoma initiation, metastasis, remission, and relapse due to conserved pathways and optical accessibility (frantz2020fromtankto pages 1-3). Transgenic BRAFV600E zebrafish models show that BRAFV600E alone can generate nevi and needs cooperating lesions for melanoma, paralleling human biology (frantz2020fromtankto pages 1-3).
| Study | Setting | Population | Interventions / arms | Key efficacy results with numbers | Key safety notes | Publication date | URL / DOI |
|---|---|---|---|---|---|---|---|
| SECOMBIT (Nature Communications 2024) | Metastatic, first-line sequencing | Untreated metastatic BRAFV600-mutant melanoma; 209 randomized, 206 treated across 37 sites in 9 countries (ascierto2024sequentialimmunotherapyand pages 1-2) | Arm A: encorafenib + binimetinib until PD โ ipilimumab + nivolumab; Arm B: ipilimumab + nivolumab until PD โ encorafenib + binimetinib; Arm C: 8-week encorafenib + binimetinib induction โ ipilimumab + nivolumab (โsandwichโ) (ascierto2024sequentialimmunotherapyand pages 1-2) | 4-year OS: 46% Arm A, 64% Arm B, 59% Arm C; 4-year TPFS: 29% Arm A, 55% Arm B, 54% Arm C. Authors concluded long-term benefit with first-line immunotherapy and exploratory biomarker trends for deleterious JAK mutations / low baseline IFNฮณ (ascierto2024sequentialimmunotherapyand pages 1-2, ascierto2024sequentialimmunotherapyand pages 4-6) | During treatment, deaths: 13 in Arm A, 11 in Arm B, 4 in Arm C; adverse events led to treatment discontinuation in 11, 10, and 11 patients in Arms A, B, and C, respectively (ascierto2024sequentialimmunotherapyand pages 1-2) | 2 Jan 2024 | https://doi.org/10.1038/s41467-023-44475-6 |
| SECOMBIT brain metastases-free survival analysis (NEJM Evidence 2024) | Metastatic sequencing; brain metastasis prevention analysis | Unresectable metastatic BRAFV600-mutant melanoma without brain metastases at baseline; 206 treated patients from SECOMBIT (ascierto2024sequencingofcheckpoint pages 1-2, ascierto2024sequencingofcheckpoint pages 2-3) | Same 3-arm SECOMBIT design: targetedโimmuno, immunoโtargeted, and short targeted inductionโimmunoโtargeted (ascierto2024sequencingofcheckpoint pages 1-2) | New brain metastases: 23/69 Arm A, 11/69 Arm B, 9/68 Arm C. 60-month BMFS: 56% Arm A, 80% Arm B (HR vs A 0.40, 95% CI 0.23โ0.58), 85% Arm C (HR vs A 0.35, 95% CI 0.16โ0.76), favoring immunotherapy-first or sandwich approaches (ascierto2024sequencingofcheckpoint pages 1-2) | Safety details not the focus of this report excerpt; sequencing effect on brain metastasis-free survival was the principal finding (ascierto2024sequencingofcheckpoint pages 1-2) | 24 Sep 2024 | https://doi.org/10.1056/evidoa2400087 |
| NeoTrio (Nature Medicine 2024) | Neoadjuvant / perioperative | Resectable stage III BRAFV600-mutant melanoma; 60 patients randomized, 42% female; 82% V600E, 15% V600K, 3% V600R (long2024neoadjuvantpembrolizumabdabrafenib pages 1-2) | Pembrolizumab alone (n=20); sequential dabrafenib + trametinib then pembrolizumab (n=20); concurrent pembrolizumab + dabrafenib + trametinib (n=20), followed by surgery and adjuvant therapy (long2024neoadjuvantpembrolizumabdabrafenib pages 1-2) | Pathological response: 55% (11/20; 6 pCRs) pembrolizumab, 50% (10/20; 3 pCRs) sequential, 80% (16/20; 10 pCRs) concurrent. 24-month EFS: 60%, 80%, 71%; 24-month RFS: 66%, 80%, 75%; 24-month OS: 76%, 89%, 95% for pembrolizumab, sequential, and concurrent arms, respectively (long2024neoadjuvantpembrolizumabdabrafenib pages 1-2, long2024neoadjuvantpembrolizumabdabrafenib pages 5-7, long2024neoadjuvantpembrolizumabdabrafenib media 7989da9e) | Neoadjuvant TRAEs affected 75โ100% of patients; 9/60 discontinued early due to neoadjuvant TRAEs, including 8/20 in the concurrent arm; seven early discontinuations during neoadjuvant treatment were all in concurrent arm in abstract summary (long2024neoadjuvantpembrolizumabdabrafenib pages 1-2) | 21 Jun 2024 | https://doi.org/10.1038/s41591-024-03077-5 |
| Real-world adjuvant D/T vs antiโPD-1 (eClinicalMedicine 2023) | Adjuvant | Resected stage III BRAF V600-mutant melanoma; 598 patients from 15 melanoma centers; D/T n=393, PD-1 n=205 (bai2023dabrafenibplustrametinib pages 1-2) | Adjuvant dabrafenib + trametinib vs adjuvant antiโPD-1 monotherapy after definitive surgery (bai2023dabrafenibplustrametinib pages 1-2) | Median follow-up 33 months. Median RFS: 51.0 months for D/T vs 44.8 months for PD-1; univariate HR 0.66 (95% CI 0.50โ0.87; P=0.003), multivariate HR 0.58 (95% CI 0.39โ0.86; P=0.007). OS comparable: multivariate HR 0.90 (95% CI 0.48โ1.70; P=0.75). Among recurrences, distant metastases were more frequent with D/T (72% vs 58%) (bai2023dabrafenibplustrametinib pages 1-2, bai2023dabrafenibplustrametinib pages 5-6) | D/T had higher incidence of treatment modification due to adverse events but fewer persistent adverse events than PD-1 (bai2023dabrafenibplustrametinib pages 1-2) | Nov 2023 | https://doi.org/10.1016/j.eclinm.2023.102290 |
| BRAF/MEK inhibitor AE meta-analysis (Cancers 2025) | Treatment safety across advanced/unresectable disease | Adults with BRAF-mutant cutaneous melanoma, predominantly unresectable locally advanced or metastatic stage IIICโIV across included trials (belloni2025treatmentrelatedadverseevents pages 7-8, belloni2025treatmentrelatedadverseevents pages 1-2) | Review/meta-analysis of approved BRAF/MEK regimens; pooled analysis feasible for vemurafenib monotherapy and dabrafenib + trametinib (belloni2025treatmentrelatedadverseevents pages 1-2) | Safety-focused study; no pooled OS/PFS efficacy endpoint reported in excerpt. Quantitative toxicity findings: vemurafenib musculoskeletal/connective-tissue disorders 24% (95% CI 6โ41%), arthralgia 44% (95% CI 29โ59%), rash 39% (95% CI 22โ56%); dabrafenib + trametinib constitutional toxicities 25% (95% CI 14โ37%), fatigue 47% (95% CI 38โ56%), pyrexia 40% (95% CI 26โ54%) (belloni2025treatmentrelatedadverseevents pages 1-2) | Grade โฅ3 cutaneous AEs with vemurafenib included squamous cell carcinoma and keratoacanthoma; regimen-specific toxicity profiles emphasized for personalized care (belloni2025treatmentrelatedadverseevents pages 1-2) | Sep 2025 | https://doi.org/10.3390/cancers17193152 |
Table: This table summarizes major 2023โ2024 clinical evidence and one recent safety meta-analysis relevant to BRAF V600-mutant melanoma across metastatic, adjuvant, and neoadjuvant settings. It highlights study design, populations, key efficacy numbers, and the main safety signals useful for comparative interpretation.
References
(marquezrodas2024seomgemclinicalguidelines pages 1-2): Ivรกn Mรกrquez-Rodas, Eva Muรฑoz Couselo, Juan F. Rodrรญguez Moreno, Ana Mยช Arance Fernรกndez, Miguel รngel Berciano Guerrero, Begoรฑa Campos Balea, Luis de la Cruz Merino, Enrique Espinosa Arranz, Almudena Garcรญa Castaรฑo, and Alfonso Berrocal Jaime. Seom-gem clinical guidelines for cutaneous melanoma (2023). Clinical & Translational Oncology, 26:2841-2855, May 2024. URL: https://doi.org/10.1007/s12094-024-03497-2, doi:10.1007/s12094-024-03497-2. This article has 8 citations and is from a peer-reviewed journal.
(castellani2023brafmutationsin pages 1-2): Giorgia Castellani, Mariachiara Buccarelli, Maria Beatrice Arasi, Stefania Rossi, Maria Elena Pisanu, Maria Bellenghi, Carla Lintas, and Claudio Tabolacci. Braf mutations in melanoma: biological aspects, therapeutic implications, and circulating biomarkers. Cancers, 15:4026, Aug 2023. URL: https://doi.org/10.3390/cancers15164026, doi:10.3390/cancers15164026. This article has 206 citations.
(NCT02036086 chunk 2): Study of Neo-adjuvant Use of Vemurafenib Plus Cobimetinib for BRAF Mutant Melanoma With Palpable Lymph Node Metastases. Sunnybrook Health Sciences Centre. 2015. ClinicalTrials.gov Identifier: NCT02036086
(hoejberg2016trendsinmelanoma pages 1-3): Lise Hoejberg, Dorte Gad, Niels Gyldenkerne, and Lars Bastholt. Trends in melanoma in the elderly in denmark, 1980โ2012. Acta Oncologica, 55:52-58, Jan 2016. URL: https://doi.org/10.3109/0284186x.2015.1114677, doi:10.3109/0284186x.2015.1114677. This article has 14 citations and is from a peer-reviewed journal.
(ghate2018healthcareresourceutilization pages 1-5): Sameer R. Ghate, Raluca Ionescu-Ittu, Rebecca Burne, Briana Ndife, Franรงois Lalibertรฉ, Antonio Nakasato, and Mei Sheng Duh. Healthcare resource utilization in patients with metastatic melanoma receiving first-line therapy with dabrafenib + trametinib versus nivolumab or pembrolizumab monotherapy. Current Medical Research and Opinion, 34:2169-2176, Aug 2018. URL: https://doi.org/10.1080/03007995.2018.1501351, doi:10.1080/03007995.2018.1501351. This article has 10 citations and is from a peer-reviewed journal.
(dixon2024primarycutaneousmelanomaโmanagement pages 1-2): Anthony Joseph Dixon, Michael Sladden, Christos C. Zouboulis, Catalin M. Popescu, Alexander Nirenberg, Howard K. Steinman, Caterina Longo, Zoe Lee Dixon, and Joseph Meirion Thomas. Primary cutaneous melanomaโmanagement in 2024. Journal of Clinical Medicine, 13:1607, Mar 2024. URL: https://doi.org/10.3390/jcm13061607, doi:10.3390/jcm13061607. This article has 26 citations.
(dummer2026exploratoryanalysisof pages 20-21): Reinhard Dummer, Shibing Deng, Tao Xie, Nuzhat Pathan, Hedieh Saffari, Caroline Robert, Ana Arance, Jan Willem B. de Groot, Claus Garbe, Helen J. Gogas, Ralf Gutzmer, Ivana Krajsovรก, Gabriella Liszkay, Carmen Loquai, Mario Mandala, Dirk Schadendorf, Naoya Yamazaki, Paolo A. Ascierto, Craig B. Davis, Khyati Shah, Phineas Hamilton, Alessandra di Pietro, and Keith Flaherty. Exploratory analysis of biomarkers and treatment outcomes from the columbus study in braf v600e/kโmutant advanced or metastatic melanoma. Clinical Cancer Research, 32:1266-1276, Jan 2026. URL: https://doi.org/10.1158/1078-0432.ccr-25-3262, doi:10.1158/1078-0432.ccr-25-3262. This article has 0 citations and is from a highest quality peer-reviewed journal.
(belloni2025treatmentrelatedadverseevents pages 1-2): Silvia Belloni, Rosamaria Virgili, Rosario Caruso, Cristina Arrigoni, Arianna Magon, Gennaro Rocco, and Maddalena De Maria. Treatment-related adverse events in individuals with braf-mutant cutaneous melanoma treated with braf and mek inhibitors: a systematic review and meta-analysis. Cancers, 17:3152, Sep 2025. URL: https://doi.org/10.3390/cancers17193152, doi:10.3390/cancers17193152. This article has 0 citations.
(frantz2020fromtankto pages 1-3): William Tyler Frantz and Craig J Ceol. From tank to treatment: modeling melanoma in zebrafish. Cells, 9:1289, May 2020. URL: https://doi.org/10.3390/cells9051289, doi:10.3390/cells9051289. This article has 41 citations.
(castellani2023brafmutationsin pages 2-4): Giorgia Castellani, Mariachiara Buccarelli, Maria Beatrice Arasi, Stefania Rossi, Maria Elena Pisanu, Maria Bellenghi, Carla Lintas, and Claudio Tabolacci. Braf mutations in melanoma: biological aspects, therapeutic implications, and circulating biomarkers. Cancers, 15:4026, Aug 2023. URL: https://doi.org/10.3390/cancers15164026, doi:10.3390/cancers15164026. This article has 206 citations.
(mohr2025updateonthe pages 2-3): Peter Mohr, Inรจs Nakouri, Sylvie Pfersch, Franรงois Denjean, and Celeste Lebbรฉ. Update on the treatment of brafmut metastatic melanoma and future perspectives. JEADV Clinical Practice, Oct 2025. URL: https://doi.org/10.1002/jvc2.544, doi:10.1002/jvc2.544. This article has 0 citations and is from a peer-reviewed journal.
(bai2023dabrafenibplustrametinib pages 1-2): Xue Bai, Ahmed Shaheen, Charlotte Grieco, Paolo D. dโArienzo, Florentia Mina, Juliane A. Czapla, Aleigha R. Lawless, Eleonora Bongiovanni, Umberto Santaniello, Helena Zappi, Dominika Dulak, Andrew Williamson, Rebecca Lee, Avinash Gupta, Caili Li, Lu Si, Martina Ubaldi, Naoya Yamazaki, Dai Ogata, Rebecca Johnson, Benjamin C. Park, Seungyeon Jung, Gabriele Madonna, Juliane Hochherz, Yoshiyasu Umeda, Yasuhiro Nakamura, Christoffer Gebhardt, Lucia Festino, Mariaelena Capone, Paolo Antonio Ascierto, Douglas B. Johnson, Serigne N. Lo, Georgina V. Long, Alexander M. Menzies, Kenjiro Namikawa, Mario Mandala, Jun Guo, Paul Lorigan, Yana G. Najjar, Andrew Haydon, Pietro Quaglino, Genevieve M. Boland, Ryan J. Sullivan, Andrew J.S. Furness, Ruth Plummer, and Keith T. Flaherty. Dabrafenib plus trametinib versus anti-pd-1 monotherapy as adjuvant therapy in braf v600-mutant stage iii melanoma after definitive surgery: a multicenter, retrospective cohort study. eClinicalMedicine, 65:102290, Nov 2023. URL: https://doi.org/10.1016/j.eclinm.2023.102290, doi:10.1016/j.eclinm.2023.102290. This article has 32 citations and is from a peer-reviewed journal.
(ascierto2024sequentialimmunotherapyand pages 1-2): Paolo A. Ascierto, Milena Casula, Jenny Bulgarelli, Marina Pisano, Claudia Piccinini, Luisa Piccin, Antonio Cossu, Mario Mandalร , Pier Francesco Ferrucci, Massimo Guidoboni, Piotr Rutkowski, Virginia Ferraresi, Ana Arance, Michele Guida, Evaristo Maiello, Helen Gogas, Erika Richtig, Maria Teresa Fierro, Celeste Lebbe, Hildur Helgadottir, Paola Queirolo, Francesco Spagnolo, Marco Tucci, Michele Del Vecchio, Maria Gonzales Cao, Alessandro Marco Minisini, Sabino De Placido, Miguel F. Sanmamed, Domenico Mallardo, Miriam Paone, Maria Grazia Vitale, Ignacio Melero, Antonio M. Grimaldi, Diana Giannarelli, Reinhard Dummer, Vanna Chiarion Sileni, and Giuseppe Palmieri. Sequential immunotherapy and targeted therapy for metastatic braf v600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase ii secombit trial. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-023-44475-6, doi:10.1038/s41467-023-44475-6. This article has 99 citations and is from a highest quality peer-reviewed journal.
(florent2023brafv600mutatedmetastatic pages 1-2): Laetitia Florent, Charles Saby, Florian Slimano, and Hamid Morjani. Braf v600-mutated metastatic melanoma and targeted therapy resistance: an update of the current knowledge. Cancers, 15:2607, May 2023. URL: https://doi.org/10.3390/cancers15092607, doi:10.3390/cancers15092607. This article has 44 citations.
(mohr2025updateonthe pages 2-2): Peter Mohr, Inรจs Nakouri, Sylvie Pfersch, Franรงois Denjean, and Celeste Lebbรฉ. Update on the treatment of brafmut metastatic melanoma and future perspectives. JEADV Clinical Practice, Oct 2025. URL: https://doi.org/10.1002/jvc2.544, doi:10.1002/jvc2.544. This article has 0 citations and is from a peer-reviewed journal.
(pelosi2024brafmutantmelanomasbiology pages 4-5): Elvira Pelosi, Germana Castelli, and Ugo Testa. Braf-mutant melanomas: biology and therapy. Current Oncology, 31:7711-7737, Dec 2024. URL: https://doi.org/10.3390/curroncol31120568, doi:10.3390/curroncol31120568. This article has 12 citations.
(pelosi2024brafmutantmelanomasbiology pages 2-4): Elvira Pelosi, Germana Castelli, and Ugo Testa. Braf-mutant melanomas: biology and therapy. Current Oncology, 31:7711-7737, Dec 2024. URL: https://doi.org/10.3390/curroncol31120568, doi:10.3390/curroncol31120568. This article has 12 citations.
(manganelli2025skinphotodamageand pages 1-2): Michele Manganelli, Giorgio Stabile, Camila Scharf, Antonio Podo Brunetti, Giovanni Paolino, Roberta Giuffrida, Gianmarco Diego Bigotto, Giuseppe Damiano, Santo Raffaele Mercuri, Fabio Sallustio, Eleonora Mangano, Roberta Bordoni, Paola De Nardi, Gabriella Guida, Caterina Foti, Giuseppe Argenziano, Caterina Longo, Giovanni Pellacani, Nathalie Rizzo, Vincenzo Russo, Stefania Guida, and Franco Rongioletti. Skin photodamage and melanomagenesis: a comprehensive review. Cancers, 17:1784, May 2025. URL: https://doi.org/10.3390/cancers17111784, doi:10.3390/cancers17111784. This article has 15 citations.
(castellani2023brafmutationsin pages 4-6): Giorgia Castellani, Mariachiara Buccarelli, Maria Beatrice Arasi, Stefania Rossi, Maria Elena Pisanu, Maria Bellenghi, Carla Lintas, and Claudio Tabolacci. Braf mutations in melanoma: biological aspects, therapeutic implications, and circulating biomarkers. Cancers, 15:4026, Aug 2023. URL: https://doi.org/10.3390/cancers15164026, doi:10.3390/cancers15164026. This article has 206 citations.
(pelosi2024brafmutantmelanomasbiology pages 1-2): Elvira Pelosi, Germana Castelli, and Ugo Testa. Braf-mutant melanomas: biology and therapy. Current Oncology, 31:7711-7737, Dec 2024. URL: https://doi.org/10.3390/curroncol31120568, doi:10.3390/curroncol31120568. This article has 12 citations.
(ascierto2024sequencingofcheckpoint pages 1-2): Paolo A. Ascierto, Mario Mandalร , Pier Francesco Ferrucci, Massimo Guidoboni, Piotr Rutkowski, Virginia Ferraresi, Ana Arance, Michele Guida, Evaristo Maiello, Helen Gogas, Erika Richtig, Pietro Quaglino, Cรฉleste Lebbรฉ, Hildur Helgadottir, Paola Queirolo, Francesco Spagnolo, Marco Tucci, Michele Del Vecchio, Maria Gonzalez-Cao, Alessandro Marco Minisini, Sabino De Placido, Miguel F. Sanmamed, Milena Casula, Jenny Bulgarelli, Marina Pisano, Claudia Piccinini, Luisa Piccin, Antonio Cossu, Domenico Mallardo, Miriam Paone, Maria Grazia Vitale, Ignacio Melero, Antonio M. Grimaldi, Diana Giannarelli, Giuseppe Palmieri, Reinhard Dummer, and Vanna Chiarion Sileni. Sequencing of checkpoint or braf/mek inhibitors on brain metastases in melanoma. NEJM evidence, 3 10:EVIDoa2400087, Sep 2024. URL: https://doi.org/10.1056/evidoa2400087, doi:10.1056/evidoa2400087. This article has 12 citations and is from a peer-reviewed journal.
(finke2024brafv600emetastaticmelanoma pages 1-2): Carsten Finke and Peter Mohr. Brafv600e metastatic melanoma journey: a perspective from a patient and his oncologist. Advances in Therapy, 41:2576-2585, May 2024. URL: https://doi.org/10.1007/s12325-024-02883-0, doi:10.1007/s12325-024-02883-0. This article has 2 citations and is from a peer-reviewed journal.
(shang2026brafinhibitorresistance pages 2-3): Yan Shang, Tingping Cao, Junyan Li, Juan Li, Lingnan Zhang, Qiqi Ma, Lanyan Feng, and Hailong Zhao. Braf inhibitor resistance in melanoma: from resistance mechanisms to therapeutic innovations. Molecular Biomedicine, Mar 2026. URL: https://doi.org/10.1186/s43556-026-00425-4, doi:10.1186/s43556-026-00425-4. This article has 0 citations and is from a peer-reviewed journal.
(cosci2025molecularbasisof pages 2-4): Ilaria Cosci, Valentina Salizzato, Paolo Del Fiore, Jacopo Pigozzo, Valentina Guarneri, Simone Mocellin, Alberto Ferlin, Sara Mathlouthi, Luisa Piccin, and Mariangela Garofalo. Molecular basis of braf inhibitor resistance in melanoma: a systematic review. Pharmaceuticals, 18:1235, Aug 2025. URL: https://doi.org/10.3390/ph18081235, doi:10.3390/ph18081235. This article has 10 citations.
(castellani2023brafmutationsin pages 11-12): Giorgia Castellani, Mariachiara Buccarelli, Maria Beatrice Arasi, Stefania Rossi, Maria Elena Pisanu, Maria Bellenghi, Carla Lintas, and Claudio Tabolacci. Braf mutations in melanoma: biological aspects, therapeutic implications, and circulating biomarkers. Cancers, 15:4026, Aug 2023. URL: https://doi.org/10.3390/cancers15164026, doi:10.3390/cancers15164026. This article has 206 citations.
(saeed2024cutaneousoncologystrategies pages 1-2): Wajeeha Saeed, Esha Shahbaz, Quratulain Maqsood, Shinawar Waseem Ali, and Muhammada Mahnoor. Cutaneous oncology: strategies for melanoma prevention, diagnosis, and therapy. Cancer Control : Journal of the Moffitt Cancer Center, Jan 2024. URL: https://doi.org/10.1177/10732748241274978, doi:10.1177/10732748241274978. This article has 21 citations.
(garciasilva2019useofextracellular pages 1-2): Susana Garcรญa-Silva, Alberto Benito-Martรญn, Sara Sรกnchez-Redondo, Alberto Hernรกndez-Barranco, Pilar Ximรฉnez-Embรบn, Laura Noguรฉs, Marina S. Mazariegos, Kay Brinkmann, Ana Amor Lรณpez, Lisa Meyer, Carlos Rodrรญguez, Carmen Garcรญa-Martรญn, Jasminka Boskovic, Rocรญo Letรณn, Cristina Montero, Mercedes Robledo, Laura Santambrogio, Mary Sue Brady, Anna Szumera-Cieฤkiewicz, Iwona Kalinowska, Johan Skog, Mikkel Noerholm, Javier Muรฑoz, Pablo L. Ortiz-Romero, Yolanda Ruano, Josรฉ L. Rodrรญguez-Peralto, Piotr Rutkowski, and Hรฉctor Peinado. Use of extracellular vesicles from lymphatic drainage as surrogate markers of melanoma progression and brafv600e mutation. The Journal of Experimental Medicine, 216:1061-1070, Apr 2019. URL: https://doi.org/10.1084/jem.20181522, doi:10.1084/jem.20181522. This article has 148 citations.
(imani2024theevolutionof pages 1-2): Saber Imani, Ghazaal Roozitalab, Mahdieh Emadi, Atefeh Moradi, Payam Behzadi, and Parham Jabbarzadeh Kaboli. The evolution of braf-targeted therapies in melanoma: overcoming hurdles and unleashing novel strategies. Frontiers in Oncology, Nov 2024. URL: https://doi.org/10.3389/fonc.2024.1504142, doi:10.3389/fonc.2024.1504142. This article has 45 citations.
(czerw2024newscreeningmethods pages 2-3): Aleksandra Czerw, Andrzej Deptaลa, Olga Partyka, Monika Pajewska, Anna Badowska-Kozakiewicz, Michaล Budzik, Katarzyna Sygit, Zygmunt Kopczyลski, Piotr Czarnywojtek, Elลผbieta Cipora, Magdalena Konieczny, Tomasz Banaล, Elลผbieta Grochans, Szymon Grochans, Anna Maria Cybulska, Daria Schneider-Matyka, Ewa Bandurska, Weronika Cieฤko, Jarosลaw Drobnik, Piotr Pobrotyn, Urszula Grata-Borkowska, Joanna Furtak-Pobrotyn, Aleksandra Sierocka, Michaล Marczak, and Remigiusz Kozlowski. New screening methods in melanoma. Cancers, 16:4186, Dec 2024. URL: https://doi.org/10.3390/cancers16244186, doi:10.3390/cancers16244186. This article has 0 citations.
(belloni2025treatmentrelatedadverseevents pages 7-8): Silvia Belloni, Rosamaria Virgili, Rosario Caruso, Cristina Arrigoni, Arianna Magon, Gennaro Rocco, and Maddalena De Maria. Treatment-related adverse events in individuals with braf-mutant cutaneous melanoma treated with braf and mek inhibitors: a systematic review and meta-analysis. Cancers, 17:3152, Sep 2025. URL: https://doi.org/10.3390/cancers17193152, doi:10.3390/cancers17193152. This article has 0 citations.
(castellani2023brafmutationsin pages 17-18): Giorgia Castellani, Mariachiara Buccarelli, Maria Beatrice Arasi, Stefania Rossi, Maria Elena Pisanu, Maria Bellenghi, Carla Lintas, and Claudio Tabolacci. Braf mutations in melanoma: biological aspects, therapeutic implications, and circulating biomarkers. Cancers, 15:4026, Aug 2023. URL: https://doi.org/10.3390/cancers15164026, doi:10.3390/cancers15164026. This article has 206 citations.
(marquezrodas2024seomgemclinicalguidelines pages 4-5): Ivรกn Mรกrquez-Rodas, Eva Muรฑoz Couselo, Juan F. Rodrรญguez Moreno, Ana Mยช Arance Fernรกndez, Miguel รngel Berciano Guerrero, Begoรฑa Campos Balea, Luis de la Cruz Merino, Enrique Espinosa Arranz, Almudena Garcรญa Castaรฑo, and Alfonso Berrocal Jaime. Seom-gem clinical guidelines for cutaneous melanoma (2023). Clinical & Translational Oncology, 26:2841-2855, May 2024. URL: https://doi.org/10.1007/s12094-024-03497-2, doi:10.1007/s12094-024-03497-2. This article has 8 citations and is from a peer-reviewed journal.
(long2024neoadjuvantpembrolizumabdabrafenib pages 1-2): Georgina V. Long, Matteo S. Carlino, George Au-Yeung, Andrew J. Spillane, Kerwin F. Shannon, David E. Gyorki, Edward Hsiao, Rony Kapoor, Jake R. Thompson, Iris Batula, Julie Howle, Sydney Chโng, Maria Gonzalez, Robyn P. M. Saw, Thomas E. Pennington, Serigne N. Lo, Richard A. Scolyer, and Alexander M. Menzies. Neoadjuvant pembrolizumab, dabrafenib and trametinib in brafv600-mutant resectable melanoma: the randomized phase 2 neotrio trial. Nature Medicine, 30:2540-2548, Jun 2024. URL: https://doi.org/10.1038/s41591-024-03077-5, doi:10.1038/s41591-024-03077-5. This article has 38 citations and is from a highest quality peer-reviewed journal.
(long2024neoadjuvantpembrolizumabdabrafenib media 7989da9e): Georgina V. Long, Matteo S. Carlino, George Au-Yeung, Andrew J. Spillane, Kerwin F. Shannon, David E. Gyorki, Edward Hsiao, Rony Kapoor, Jake R. Thompson, Iris Batula, Julie Howle, Sydney Chโng, Maria Gonzalez, Robyn P. M. Saw, Thomas E. Pennington, Serigne N. Lo, Richard A. Scolyer, and Alexander M. Menzies. Neoadjuvant pembrolizumab, dabrafenib and trametinib in brafv600-mutant resectable melanoma: the randomized phase 2 neotrio trial. Nature Medicine, 30:2540-2548, Jun 2024. URL: https://doi.org/10.1038/s41591-024-03077-5, doi:10.1038/s41591-024-03077-5. This article has 38 citations and is from a highest quality peer-reviewed journal.
(gooley2025clinicaleffectivenessof pages 1-2): Kieran Gooley, Deonna Ackermann, Ellie Medcalf, and Katy Bell. Clinical effectiveness of interventions to increase selfโsurveillance in people at high risk of melanoma: a systematic review. JEADV Clinical Practice, Jun 2025. URL: https://doi.org/10.1002/jvc2.70108, doi:10.1002/jvc2.70108. This article has 3 citations and is from a peer-reviewed journal.
(hooijkaas2012targetingbrafv600ein pages 1-2): Anna I. Hooijkaas, Jules Gadiot, Martin van der Valk, Wolter J. Mooi, and Christian U. Blank. Targeting brafv600e in an inducible murine model of melanoma. The American journal of pathology, 181 3:785-94, Sep 2012. URL: https://doi.org/10.1016/j.ajpath.2012.06.002, doi:10.1016/j.ajpath.2012.06.002. This article has 90 citations.
(ascierto2024sequentialimmunotherapyand pages 4-6): Paolo A. Ascierto, Milena Casula, Jenny Bulgarelli, Marina Pisano, Claudia Piccinini, Luisa Piccin, Antonio Cossu, Mario Mandalร , Pier Francesco Ferrucci, Massimo Guidoboni, Piotr Rutkowski, Virginia Ferraresi, Ana Arance, Michele Guida, Evaristo Maiello, Helen Gogas, Erika Richtig, Maria Teresa Fierro, Celeste Lebbe, Hildur Helgadottir, Paola Queirolo, Francesco Spagnolo, Marco Tucci, Michele Del Vecchio, Maria Gonzales Cao, Alessandro Marco Minisini, Sabino De Placido, Miguel F. Sanmamed, Domenico Mallardo, Miriam Paone, Maria Grazia Vitale, Ignacio Melero, Antonio M. Grimaldi, Diana Giannarelli, Reinhard Dummer, Vanna Chiarion Sileni, and Giuseppe Palmieri. Sequential immunotherapy and targeted therapy for metastatic braf v600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase ii secombit trial. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-023-44475-6, doi:10.1038/s41467-023-44475-6. This article has 99 citations and is from a highest quality peer-reviewed journal.
(ascierto2024sequencingofcheckpoint pages 2-3): Paolo A. Ascierto, Mario Mandalร , Pier Francesco Ferrucci, Massimo Guidoboni, Piotr Rutkowski, Virginia Ferraresi, Ana Arance, Michele Guida, Evaristo Maiello, Helen Gogas, Erika Richtig, Pietro Quaglino, Cรฉleste Lebbรฉ, Hildur Helgadottir, Paola Queirolo, Francesco Spagnolo, Marco Tucci, Michele Del Vecchio, Maria Gonzalez-Cao, Alessandro Marco Minisini, Sabino De Placido, Miguel F. Sanmamed, Milena Casula, Jenny Bulgarelli, Marina Pisano, Claudia Piccinini, Luisa Piccin, Antonio Cossu, Domenico Mallardo, Miriam Paone, Maria Grazia Vitale, Ignacio Melero, Antonio M. Grimaldi, Diana Giannarelli, Giuseppe Palmieri, Reinhard Dummer, and Vanna Chiarion Sileni. Sequencing of checkpoint or braf/mek inhibitors on brain metastases in melanoma. NEJM evidence, 3 10:EVIDoa2400087, Sep 2024. URL: https://doi.org/10.1056/evidoa2400087, doi:10.1056/evidoa2400087. This article has 12 citations and is from a peer-reviewed journal.
(long2024neoadjuvantpembrolizumabdabrafenib pages 5-7): Georgina V. Long, Matteo S. Carlino, George Au-Yeung, Andrew J. Spillane, Kerwin F. Shannon, David E. Gyorki, Edward Hsiao, Rony Kapoor, Jake R. Thompson, Iris Batula, Julie Howle, Sydney Chโng, Maria Gonzalez, Robyn P. M. Saw, Thomas E. Pennington, Serigne N. Lo, Richard A. Scolyer, and Alexander M. Menzies. Neoadjuvant pembrolizumab, dabrafenib and trametinib in brafv600-mutant resectable melanoma: the randomized phase 2 neotrio trial. Nature Medicine, 30:2540-2548, Jun 2024. URL: https://doi.org/10.1038/s41591-024-03077-5, doi:10.1038/s41591-024-03077-5. This article has 38 citations and is from a highest quality peer-reviewed journal.
(bai2023dabrafenibplustrametinib pages 5-6): Xue Bai, Ahmed Shaheen, Charlotte Grieco, Paolo D. dโArienzo, Florentia Mina, Juliane A. Czapla, Aleigha R. Lawless, Eleonora Bongiovanni, Umberto Santaniello, Helena Zappi, Dominika Dulak, Andrew Williamson, Rebecca Lee, Avinash Gupta, Caili Li, Lu Si, Martina Ubaldi, Naoya Yamazaki, Dai Ogata, Rebecca Johnson, Benjamin C. Park, Seungyeon Jung, Gabriele Madonna, Juliane Hochherz, Yoshiyasu Umeda, Yasuhiro Nakamura, Christoffer Gebhardt, Lucia Festino, Mariaelena Capone, Paolo Antonio Ascierto, Douglas B. Johnson, Serigne N. Lo, Georgina V. Long, Alexander M. Menzies, Kenjiro Namikawa, Mario Mandala, Jun Guo, Paul Lorigan, Yana G. Najjar, Andrew Haydon, Pietro Quaglino, Genevieve M. Boland, Ryan J. Sullivan, Andrew J.S. Furness, Ruth Plummer, and Keith T. Flaherty. Dabrafenib plus trametinib versus anti-pd-1 monotherapy as adjuvant therapy in braf v600-mutant stage iii melanoma after definitive surgery: a multicenter, retrospective cohort study. eClinicalMedicine, 65:102290, Nov 2023. URL: https://doi.org/10.1016/j.eclinm.2023.102290, doi:10.1016/j.eclinm.2023.102290. This article has 32 citations and is from a peer-reviewed journal.
BRAF V600 Mutant Melanoma is a molecularly defined subtype of cutaneous malignant melanoma characterized by somatic gain-of-function mutations at codon 600 of the BRAF gene (7q34). BRAF is a serine/threonine protein kinase in the MAPK/ERK signaling pathway that regulates cell proliferation, differentiation, and survival. The V600E mutation (a thymine-to-adenine transversion resulting in valine-to-glutamic acid substitution) accounts for the vast majority of cases and produces a constitutively active kinase domain that drives oncogenesis independent of upstream RAS activation (PMID: 39961465).
As noted by Paluncic et al., "40-50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E)" (PMID: 33801689). Among BRAF V600 mutations, the distribution is: V600E (79%), V600K (12%), V600R (5%), and V600M (4%) (PMID: 22536370).
| Identifier | Value |
|---|---|
| OMIM | #164757 (Melanoma, cutaneous malignant); BRAF gene: *164757 |
| ICD-10 | C43 (Malignant melanoma of skin) |
| ICD-11 | 2D40-2D4Z (Melanoma of skin) |
| MeSH | D008545 (Melanoma); C562395 (BRAF gene mutation) |
| MONDO | MONDO:0005012 (melanoma) |
| HGNC | HGNC:1097 (BRAF) |
| ClinVar | Variation ID 376069 (BRAF V600E) |
| COSMIC | COSV56056643 (BRAF p.V600E) |
This report is derived from aggregated disease-level resources including published clinical trials, genomic databases (COSMIC, ClinVar, TCGA), epidemiological registries (SEER, GLOBOCAN), and primary research literature (PubMed). Individual patient-level data is referenced from landmark clinical trials (COMBI-d, COLUMBUS, IMspire150) and real-world registries (ADMIRE, Dutch Melanoma Treatment Registry).
BRAF V600 Mutant Melanoma arises through a multi-step oncogenic process involving both genetic and environmental factors:
Somatic genetic origin: The BRAF V600E mutation is a somatic (acquired) missense mutation arising in melanocytes. It is not inherited in the germline but occurs during the lifetime of the individual. The mutation results in constitutive activation of the BRAF kinase, which "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" (PMID: 39961465).
UV radiation as initiating factor: Ultraviolet radiation, particularly UVB (280โ320 nm), is the primary environmental mutagen. UV radiation induces DNA damage in melanocytes, including the characteristic thymine dimer mutations. The BRAF V600E mutation itself (T1799A) is not a classic UV signature mutation (C>T at dipyrimidine sites), suggesting that UV may act indirectly through mutagenic stress, oxidative damage, or proliferative stimulation rather than direct photoproduct formation (PMID: 27221301).
Associations with BRAF mutation were characterized by Colombino et al.: "Associations with BRAF mutation were as follows: male gender [odds ratio (OR) = 2.4], younger age (OR = 2.7), superficial spreading (OR = 15.6) and nodular melanoma (OR = 9.5), trunk localization (OR = 6.3), and intermittent sun exposure (OR = 4.6)" (PMID: 25357015).
The BRAF V600E mutation appears to arise preferentially in the context of intermittent rather than chronic UV exposure, explaining its association with trunk melanomas (usually covered, intermittently exposed) in younger patients. The B-RafV600E mutation was detected in 85% of trunk melanomas in indoor workers versus 47% in outdoor workers (P = 0.03), indicating that "the B-RafV600E mutation detected in melanoma is not associated with a chronic exposure to the sun" but rather with recreational/intermittent exposure (PMID: 24424406). MC1R variants may further modify risk by impairing DNA repair capacity in the setting of UV exposure, creating a synergistic effect.
| Phenotype | HPO Term | Type | Onset | Severity | Frequency | Progression |
|---|---|---|---|---|---|---|
| Cutaneous melanocytic lesion (primary tumor) | HP:0012056 (Cutaneous melanoma) | Physical sign | Adult (median 50s) | Variable | 100% | Progressive if untreated |
| Asymmetric pigmented lesion | HP:0200040 (Irregular hyperpigmentation) | Physical sign | Adult | Mildโmoderate | Very frequent | Progressive |
| Ulceration of primary lesion | HP:0200041 (Skin ulcer) | Physical sign | Later stages | Moderateโsevere | ~40โ50% | Progressive |
| Lymphadenopathy (regional metastasis) | HP:0002716 (Lymphadenopathy) | Clinical sign | Stage III | Moderateโsevere | Variable | Progressive |
| Elevated serum LDH | HP:0025435 (Increased circulating lactate dehydrogenase) | Laboratory abnormality | Advanced disease | Indicator of high tumor burden | ~37.5% at presentation | Progressive |
| Fatigue | HP:0012378 (Fatigue) | Symptom | Advanced disease | Moderateโsevere | Frequent | Progressive |
| Brain metastases (neurological symptoms) | HP:0002888 (Brain neoplasm) | Clinical sign | Stage IV | Severe | ~32% of advanced cases | Progressive |
| Hepatomegaly/liver metastases | HP:0002240 (Hepatomegaly) | Clinical sign | Stage IV | Severe | Common | Progressive |
| Pulmonary symptoms (lung metastases) | HP:0002094 (Dyspnea) | Symptom | Stage IV | Moderateโsevere | Common | Progressive |
Advanced BRAF V600 mutant melanoma significantly impacts quality of life through: - Physical symptoms of metastatic disease (pain, fatigue, neurological deficits from brain metastases) - Psychological distress from cancer diagnosis and treatment - Treatment-related side effects (pyrexia, arthralgia, skin toxicities from targeted therapy; immune-related adverse events from immunotherapy) - Functional impairment from disease complications
BRAF (B-Raf Proto-Oncogene, Serine/Threonine Kinase) - HGNC ID: HGNC:1097 - NCBI Gene ID: 673 - OMIM: 164757 - Chromosomal location: 7q34 - UniProt: P15056 - Protein*: 766 amino acid serine/threonine kinase
| Variant | HGVS Notation | Type | Frequency Among V600 | Allele Frequency (gnomAD) | Origin | Functional Consequence |
|---|---|---|---|---|---|---|
| V600E | c.1799T>A (p.Val600Glu) | Missense | ~79% | Somatic (not in germline databases) | Somatic | Gain of function; ~500-fold kinase activation |
| V600K | c.1798_1799delGTinsAA (p.Val600Lys) | Dinucleotide substitution | ~12% | Somatic | Somatic | Gain of function; constitutive kinase activation |
| V600R | c.1798_1799delGTinsAG (p.Val600Arg) | Dinucleotide substitution | ~5% | Somatic | Somatic | Gain of function |
| V600M | c.1798G>A (p.Val600Met) | Missense | ~4% | Somatic | Somatic | Gain of function |
| V600D | c.1799_1800delTGinsAT (p.Val600Asp) | Dinucleotide substitution | Rare | Somatic | Somatic | Gain of function |
Source for variant distribution: "Among BRAF V600 mutations, 79%, 12%, 5%, and 4% were V600E, V600K, V600R, and V600M, respectively" (PMID: 22536370).
Variant classification: All V600 mutations listed are classified as pathogenic (oncogenic driver) in ClinVar and COSMIC.
Somatic origin: These mutations are somatic, not germline. They are acquired during the individual's lifetime and are not present in the germline. COSMIC reports BRAF V600E as one of the most frequently mutated positions across all human cancers.
V600K demographics: V600K was detected in 23% of men older than 60, compared with 6% in women older than 60 and 2% in both sexes younger than 60 (P < .001), suggesting age and sex-specific patterns (PMID: 25456393).
The central oncogenic pathway in BRAF V600 melanoma. The BRAF V600E mutation produces a constitutively active kinase that signals as a monomer (unlike wild-type BRAF which requires dimerization). This leads to sustained MEK1/2 and ERK1/2 phosphorylation, driving:
KEGG pathway: hsa04010 (MAPK signaling pathway) Reactome: R-HSA-5673001 (RAF/MAP kinase cascade)
Frequently co-activated through PTEN loss. Synergizes with MAPK pathway to promote survival and metabolic adaptation. Important in resistance to BRAF inhibitors.
KEGG pathway: hsa04151 (PI3K-Akt signaling pathway)
Contributes to melanoma cell survival, immune evasion, and resistance to immunotherapy.
The BRAF V600E mutation resides in the activation segment of the kinase domain. The valine-to-glutamic acid substitution mimics the phosphorylation that normally activates the kinase, locking it in a constitutively active conformation. Wild-type BRAF kinase activity is ~70-fold lower than V600E mutant BRAF. The mutant signals as a monomer, unlike wild-type BRAF which requires RAS-dependent dimerization, explaining its RAS-independence.
UniProt: P15056 (BRAF_HUMAN) PDB: 1UWH (BRAF kinase domain), 3OG7 (BRAF V600E with vemurafenib)
BRAF V600E drives a profound metabolic reprogramming:
"BRAF mutations augment glycolysis to promote macromolecular synthesis and proliferation" (PMID: 38972133).
The mechanistic basis: "BRAF(V600E) acts to suppress expression of the melanocyte master regulator microphthalmia-associated transcription factor (MITF) and the mitochondrial biogenesis coactivator PGC1ฮฑ. Accordingly, therapeutic inhibition of BRAF(V600E) reverses metabolic reprogramming in melanoma cells and elevates OXPHOS through increased MITF-PGC1ฮฑ levels" (PMID: 24610826).
This metabolic plasticity is a key resistance mechanism: upon BRAF inhibitor treatment, cells shift from glycolysis to oxidative phosphorylation (OXPHOS), with increased glutamine dependence and mitochondrial biogenesis. NSAIDs (diclofenac, lumiracoxib) can counteract this metabolic reprogramming and synergize with BRAF inhibitors by preventing the shift to OXPHOS (PMID: 30481565).
KEGG pathways: hsa00010 (Glycolysis/Gluconeogenesis); hsa00190 (Oxidative phosphorylation) HMDB: HMDB0000190 (L-Lactic acid โ elevated in glycolytic tumors)
BRAF V600E melanoma has a complex relationship with the immune system:
Acquired resistance to BRAF inhibitors is multifactorial:
"Acquired resistance to vemurafenib associated with reactivation of MAPK signaling as observed by elevated ERK1/2 phosphorylation levels in progressive lesions and the appearance of secondary NRAS(Q61) mutations or MEK1(Q56P) or MEK1(E203K) mutations" (PMID: 23569304).
Key resistance mechanisms include: 1. MAPK reactivation: Secondary NRAS mutations, MEK mutations, BRAF amplification, BRAF splice variants 2. Alternative pathway activation: PI3K/AKT, focal adhesion kinase (FAK) signaling 3. Metabolic reprogramming: Shift from glycolysis to OXPHOS 4. Phenotype switching: Transition from proliferative to invasive state 5. Microenvironment remodeling: Stromal cell-mediated resistance 6. COP1/DET1 mutations: Acquired after BRAF inhibitor treatment, affecting oncogenic transcriptome regulation (PMID: 40643496)
Primary organ: Skin (UBERON:0002097) - Cutaneous melanoma arises from epidermal melanocytes
Secondary organ involvement (sites of metastasis): - Lymph nodes (UBERON:0000029): Regional spread; sentinel lymph node most commonly affected - Lung (UBERON:0002048): Most common site of distant metastasis - Liver (UBERON:0002107): Second most common distant site - Brain (UBERON:0000955): ~32% of advanced cases have brain metastases at presentation (PMID: 34243078) - Bone (UBERON:0002481): Common distant metastatic site - Distant skin/subcutaneous tissue: Transit metastases
Body systems: Integumentary (primary), lymphatic, respiratory, hepatobiliary, nervous, musculoskeletal
AJCC Staging System (8th Edition):
| Stage | Description | 5-Year Survival |
|---|---|---|
| 0 (in situ) | Confined to epidermis | ~99% |
| I | Thin melanoma (โค2 mm), no ulceration | ~92โ97% |
| II | Thicker primary or ulcerated | ~53โ81% |
| III | Regional lymph node or in-transit metastasis | ~40โ78% (improved to ~75% with adjuvant therapy) |
| IV | Distant metastasis | ~15โ20% historically; ~50% with modern therapies |
Global melanoma burden (all subtypes): "A worldwide total of 325,000 new melanoma cases (174,000 males, 151,000 females) and 57,000 deaths (32,000 males, 25,000 females) was estimated for 2020" (PMID: 35353115). "Cutaneous melanoma causes 55,500 deaths annually" and accounts for 90% of skin cancer mortality (PMID: 30238891).
BRAF V600 mutant melanoma specifically: - Represents ~40โ50% of cutaneous melanomas - Estimated ~130,000โ162,500 new BRAF V600 mutant melanoma cases worldwide annually - Highest absolute numbers in populations with high melanoma incidence (Australia/New Zealand, Europe, North America)
Incidence by region (all melanoma): - Australia/New Zealand: Males 42/100,000; Females 31/100,000 (highest worldwide) - Western Europe: ~19/100,000 - North America: Males 18, Females 14/100,000 - Africa and Asia: <1/100,000
BRAF mutation testing is recommended for all patients with stage IIB/C or higher melanoma, and is mandatory before initiating BRAF/MEK inhibitor therapy (PMID: 39700658).
| Method | Turnaround | Sensitivity | Clinical Use |
|---|---|---|---|
| cobasยฎ 4800 BRAF V600 Mutation Test (companion diagnostic) | 1โ2 days | High | FDA-approved CDx for vemurafenib |
| Idylla BRAF Mutation Test | 90 minutes | 98.57% concordance with sequencing | Rapid automated PCR-based testing (PMID: 26921540) |
| Pyrosequencing | 1โ3 days | High; can distinguish V600E/K/R/D | Reference method; lookup tables assist complex result interpretation (PMID: 24713734) |
| Next-generation sequencing (NGS) | 1โ3 weeks | Very high | Comprehensive profiling; detects co-mutations |
| Sanger sequencing | 3โ5 days | Moderate (~20% mutant allele threshold) | Less commonly used now |
| VE1 immunohistochemistry | 1โ2 days | 86.1% sensitivity for V600E | Cost-effective screening tool |
| Droplet digital PCR (ddPCR) | 1โ2 days | Very high (ctDNA detection) | Liquid biopsy monitoring |
Quality assurance: French national EQA achieved false response rate of only 4.8% across 46 laboratories, with improvement from 22 to 12 days turnaround over 6 months (PMID: 24119386).
Metastatic BRAF V600 mutant melanoma (with modern therapy):
| Treatment | Median PFS | Median OS | 3-Year OS | 5-Year OS |
|---|---|---|---|---|
| Dabrafenib + Trametinib (COMBI-d) | ~11 months | ~25 months | 44% | ~34% |
| Dabrafenib monotherapy (COMBI-d control) | ~8 months | ~18 months | 32% | ~27% |
| Encorafenib + Binimetinib (COLUMBUS) | ~15 months | ~34 months | โ | โ |
| Real-world BRAFi+MEKi (ADMIRE) | 9.2 months | 22.6 months | โ | โ |
Source: "3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively" (PMID: 28475671).
Real-world data: ORR 57.4% for combined BRAFi+MEKi vs 39.8% BRAFi monotherapy; median PFS 9.2 months; median OS 22.6 months for first-line combination (PMID: 34064013).
BRAF mutation level as prognostic factor: High BRAF V600 mutation level (>0.44) associated with worse PFS and OS on multivariate analysis (P = 0.02 for both) (PMID: 39508497).
Favorable: - Normal LDH - ECOG PS 0 - <3 metastatic sites - No brain metastases - Immune-related adverse events during treatment (mPFS 42.8 vs 6.1 months; HR 0.22, P = 0.002) (PMID: 30096703) - ctDNA clearance on treatment - High tumor immune infiltration and TMB
Unfavorable: - Elevated LDH - ECOG PS โฅ1 - โฅ3 metastatic sites - Brain metastases (introduced as major prognostic factor in real-world setting) (PMID: 34243078) - High BRAF V600 mutation level - Detectable ctDNA at baseline and on treatment
| Combination | Drug Class | Mechanism | Approval Year |
|---|---|---|---|
| Dabrafenib + Trametinib | BRAFi + MEKi | BRAF V600E/K kinase inhibition + MEK1/2 inhibition | 2014 |
| Vemurafenib + Cobimetinib | BRAFi + MEKi | BRAF V600E kinase inhibition + MEK1/2 inhibition | 2015 |
| Encorafenib + Binimetinib | BRAFi + MEKi | BRAF V600E/K kinase inhibition + MEK1/2 inhibition | 2018 |
MAXO terms: MAXO:0001084 (targeted molecular therapy); MAXO:0000058 (pharmacotherapy)
CHEBI terms: Vemurafenib (CHEBI:63637), Dabrafenib (CHEBI:75045), Trametinib (CHEBI:75998), Encorafenib (CHEBI:145372), Binimetinib (CHEBI:145371), Cobimetinib (CHEBI:145373)
In a network meta-analysis: "the combination of dabrafenib and trametinib is the preferred combination therapy" for BRAF V600-mutant melanoma, with better acceptability than vemurafenib + cobimetinib (RR for any-grade AEs: 0.94; CrI: 0.89โ0.98) (PMID: 35530323).
Common adverse events (vemurafenib): arthralgia (37%), alopecia (25%), hyperkeratosis (23%); most common grade 3/4: cutaneous SCC (8%) and keratoacanthoma (8%) (PMID: 28501764).
Nephrotoxicity: Vemurafenib more nephrotoxic than dabrafenib; 132 cases of AKI reported with vemurafenib vs 13 with dabrafenib; predominantly tubular interstitial injury (PMID: 26182194).
Phototoxicity: Vemurafenib causes clinical photosensitivity (PMID: 24154489).
| Agent | Drug Class | Mechanism | Use in BRAF+ |
|---|---|---|---|
| Nivolumab | Anti-PD-1 | PD-1 checkpoint blockade | First or second-line |
| Pembrolizumab | Anti-PD-1 | PD-1 checkpoint blockade | First or second-line |
| Ipilimumab | Anti-CTLA-4 | CTLA-4 checkpoint blockade | Combination with anti-PD-1 |
| Nivolumab + Ipilimumab | Anti-PD-1 + Anti-CTLA-4 | Dual checkpoint blockade | First-line for aggressive disease |
| Atezolizumab + Vemurafenib + Cobimetinib | Anti-PD-L1 + BRAFi + MEKi | Triplet combination | First-line (IMspire150) |
MAXO terms: MAXO:0001085 (immune checkpoint inhibitor therapy)
European guidelines recommend: "For first-line treatment particularly in BRAF wild-type patients, immunotherapy with PD-1 antibodies alone or in combination with CTLA-4 antibodies shall be considered. In stage IV melanoma with a BRAF-V600 E/K mutation, first-line therapy with BRAF/MEK inhibitors can be offered as an alternative to immunotherapy" (PMID: 35623961).
For resected stage III disease: - Dabrafenib + Trametinib: Approved adjuvant; 3-year RFS ~60% in COMBI-AD - Anti-PD-1 (nivolumab, pembrolizumab): Alternative adjuvant option regardless of BRAF status - Real-world data from China: D+T significantly superior to observation (P = 0.002) and potentially superior to anti-PD-1 monotherapy (P = 0.032) for RFS in BRAF-mutant stage III melanoma (PMID: 37016119)
Encorafenib + binimetinib achieves brain metastasis response rate >60% (PMID: 40503961). Real-world data shows median PFS of 5.5 months and OS of 11.9 months for BRAF V600-mutant melanoma with brain metastases (PMID: 40411977). Stereotactic radiosurgery combined with immunotherapy achieves the highest OS rates in brain metastases; BRAF mutation appears to be a favorable prognostic factor (PMID: 30739835).
MAXO terms: MAXO:0000004 (surgical procedure); MAXO:0000011 (excision)
Weekly carboplatin + paclitaxel remains a palliative option after immunotherapy failure: median PFS 3.25 months, OS 7.69 months (PMID: 39354418).
MAXO terms: MAXO:0000118 (sun protection counseling); MAXO:0000002 (preventive care)
BRAF mutations and melanoma occur across species:
| Species | NCBI Taxon ID | BRAF Gene | Melanoma Occurrence |
|---|---|---|---|
| Homo sapiens | 9606 | BRAF (Gene ID: 673) | Primary disease |
| Mus musculus | 10090 | Braf (Gene ID: 109880) | Engineered models |
| Danio rerio (zebrafish) | 7955 | braf (Gene ID: 403065) | Engineered models |
| Canis lupus familiaris (dog) | 9615 | BRAF (Gene ID: 475526) | Naturally occurring oral melanoma |
| Equus caballus (horse) | 9796 | BRAF | Naturally occurring melanoma (grey horses) |
BRAF V600E is the most frequent oncogenic BRAF mutation in melanoma, present in 40โ50% of all cutaneous melanomas. Among BRAF V600 mutations specifically, V600E accounts for ~79%, V600K for ~12%, V600R for ~5%, and V600M for ~4%. The V600E substitution results in a constitutively active kinase domain with ~500-fold increased activity, leading to MAPK/ERK pathway hyperactivation independent of extracellular stimuli, driving cell proliferation, survival, angiogenesis, and other hallmark cancer features.
Key citations: - "As widely acknowledged, 40-50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E)" โ PMID: 33801689 - "V600E mutation results in a constitutively active kinase domain, leading to dysregulated downstream signaling independent of extracellular stimuli" โ PMID: 39961465 - "Among BRAF V600 mutations, 79%, 12%, 5%, and 4% were V600E, V600K, V600R, and V600M, respectively" โ PMID: 22536370
BRAF mutations are significantly associated with distinct clinicopathological features: male gender (OR = 2.4), younger age (OR = 2.7), superficial spreading melanoma (OR = 15.6), nodular melanoma (OR = 9.5), trunk localization (OR = 6.3), and intermittent sun exposure (OR = 4.6). Indoor tanning users, especially those initiating before age 25, had dramatically higher BRAF V600E prevalence (62.2% vs 31.1%, P = .003).
Key citations: - "Associations with BRAF mutation were as follows: male gender [OR = 2.4], younger age (OR = 2.7), superficial spreading (OR = 15.6) and nodular melanoma (OR = 9.5), trunk localization (OR = 6.3), and intermittent sun exposure (OR = 4.6)" โ PMID: 25357015 - "BRAF V600E genotype was more prevalent in ever-users than in nonusers (42.9% vs 28.3%, P = .04)" โ PMID: 30923800
The combination of BRAF and MEK inhibitors achieves high initial response rates (~57โ70% ORR) but acquired resistance typically develops within 6โ12 months. Long-term data from COMBI-d showed 3-year PFS of 22% and 3-year OS of 44% with dabrafenib + trametinib. Resistance mechanisms involve MAPK reactivation through secondary NRAS Q61 mutations, MEK1 mutations (Q56P, E203K), BRAF amplification, and alternative pathway activation.
Key citations: - "3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively" โ PMID: 28475671 - "Acquired resistance to vemurafenib associated with reactivation of MAPK signaling...and the appearance of secondary NRAS(Q61) mutations or MEK1(Q56P) or MEK1(E203K) mutations" โ PMID: 23569304
BRAF V600E mutations augment glycolysis (Warburg effect) to support macromolecular synthesis and proliferation, while suppressing MITF and PGC1ฮฑ expression to reduce mitochondrial biogenesis. BRAF inhibition reverses this metabolic program, shifting cells toward oxidative phosphorylation โ a metabolic plasticity that contributes to drug resistance.
Key citations: - "BRAF mutations augment glycolysis to promote macromolecular synthesis and proliferation" โ PMID: 38972133 - "BRAF(V600E) acts to suppress expression of MITF and PGC1ฮฑ. Therapeutic inhibition of BRAF(V600E) reverses metabolic reprogramming and elevates OXPHOS through increased MITF-PGC1ฮฑ levels" โ PMID: 24610826
GLOBOCAN 2020 reported 325,000 new melanoma cases and 57,000 deaths worldwide, with highest incidence in Australia/New Zealand (males 42/100,000; females 31/100,000). BRAF V600 mutations represent 40โ50% of these cutaneous melanomas.
Key citations: - "A worldwide total of 325,000 new melanoma cases (174,000 males, 151,000 females) and 57,000 deaths (32,000 males, 25,000 females) was estimated for 2020" โ PMID: 35353115 - "Cutaneous melanoma causes 55,500 deaths annually" โ PMID: 30238891
The following causal chain describes the pathogenesis of BRAF V600 Mutant Melanoma:
UV Radiation (intermittent) + Genetic Susceptibility (MC1R, CDKN2A, fair skin)
โ
โผ
Somatic BRAF V600E Mutation in Melanocyte
โ
โผ
Constitutive BRAF Kinase Activation (~500x)
โ
โโโโบ MEK1/2 Phosphorylation โโโบ ERK1/2 Activation
โ โ
โ โโโโบ Cell Proliferation (Cyclin D1, c-Myc)
โ โโโโบ Survival (BIM suppression, MCL-1 upregulation)
โ โโโโบ Angiogenesis (VEGF)
โ โโโโบ Immune Evasion (PD-L1, IL-10)
โ
โโโโบ MITF/PGC1ฮฑ Suppression โโโบ Metabolic Shift to Glycolysis
โ
โโโโบ Cooperating Events (PTEN loss, CDKN2A deletion, TERT activation)
โ
โผ
Melanoma Development & Progression
โ
โโโโโโโโโโโโโดโโโโโโโโโโโโ
โผ โผ
Local Invasion Metastasis
(Breslow depth) (LN โ Distant organs)
โ
โผ
BRAF/MEK Inhibitor Therapy
โ
โโโโโโโโโโโโโดโโโโโโโโโโโโ
โผ โผ
Initial Response Acquired Resistance
(ORR ~60-70%) (6-12 months median)
โ
โโโโโโโโโโโโโโโโโโโโโผโโโโโโโโโโโโโโโโโโโโ
โผ โผ โผ
MAPK Reactivation PI3K/AKT/FAK Metabolic Shift
(NRAS, MEK mut, Activation (Glycolysis โ OXPHOS)
BRAF amplification)
| Reference | PMID | Key Contribution |
|---|---|---|
| Paluncic et al., 2021 | 33801689 | BRAF V600E prevalence in 40-50% of melanomas |
| Colombino et al., 2014 | 25357015 | Clinicopathological associations with BRAF mutation |
| Ascierto et al., 2012 | 22536370 | V600 mutation subtype distribution |
| Long et al., 2017 | 28475671 | COMBI-d long-term survival data |
| Shi et al., 2014 | 23569304 | Vemurafenib resistance mechanisms |
| Haq et al., 2014 | 24610826 | BRAF-driven metabolic reprogramming |
| Garbe et al., 2022 | 35623961 | European treatment guidelines |
| Arnold et al., 2022 | 35353115 | GLOBOCAN 2020 melanoma burden |
| Schadendorf et al., 2018 | 30238891 | Comprehensive melanoma review |
| Bhatt et al., 2020 | 30923800 | Indoor tanning and BRAF mutation |
| Haq, 2024 | 38972133 | Metabolic changes in BRAF-mutant melanoma |
| Kumar et al., 2025 | 39961465 | BRAF V600E structural and pathway analysis |
| Saiag et al., 2021 | 34243078 | Real-world French study of D+T |
| Nassi et al., 2021 | 34064013 | ADMIRE real-world registry |
| Lee et al., 2026 | 40250457 | ctDNA as prognostic biomarker |
Optimal treatment sequencing: The ideal order of targeted therapy vs. immunotherapy for BRAF V600-mutant melanoma remains unclear; no head-to-head randomized trial comparing first-line BRAF/MEKi vs. anti-PD-1 vs. combination immunotherapy has been completed.
Resistance prediction: While mechanisms of acquired resistance are increasingly understood, reliable predictive biomarkers to identify patients who will develop resistance early vs. achieve durable responses are lacking.
Rare BRAF variants: Treatment evidence for V600R, V600M, V600D, and non-V600 BRAF mutations is limited to retrospective analyses. ORR for rare V600 non-E/K mutations is 45% vs 26% for non-V600 mutations (P = 0.025) (PMID: 40850313).
Ethnic diversity: Most clinical trial data come from predominantly Caucasian populations. BRAF mutation rates and responses may differ in Asian, African, and other populations. A Chinese study found mutation rates of ~50% in cutaneous but only 10โ15% in acral/mucosal subtypes (PMID: 37016119).
Long-term survivorship: As patients increasingly achieve long-term responses, the chronic effects of prolonged targeted therapy and immunotherapy on quality of life, organ function, and secondary malignancy risk require further study.
Brain metastases: While intracranial activity has been demonstrated, brain metastases remain a major prognostic challenge and the optimal management (systemic therapy, SRS, WBRT, or combinations) requires further prospective data.
Minimal residual disease: ctDNA-guided interventional strategies (escalating therapy in ctDNA-positive patients, de-escalating in ctDNA-negative) are promising but unvalidated in prospective trials.
Gene-environment interactions: The precise molecular mechanism by which intermittent UV exposure preferentially induces BRAF V600E mutations (vs. other mutation patterns) is not fully elucidated.
Prospective biomarker-guided clinical trials: Design trials using baseline ctDNA and immune gene signatures to stratify patients to optimal first-line therapy (targeted vs. immunotherapy vs. combination).
ctDNA-guided adjuvant therapy: Test whether ctDNA-driven escalation/de-escalation strategies improve outcomes in resected stage III BRAF-mutant melanoma.
Novel combination strategies: Evaluate PHI-501 (pan-RAF/DDR inhibitor) and avutometinib + FAK inhibitor combinations in BRAF/MEK inhibitor-resistant patients.
Metabolic vulnerability exploitation: Clinical trials combining BRAF/MEK inhibitors with metabolic inhibitors (e.g., OXPHOS inhibitors, glutaminase inhibitors) to prevent metabolic adaptation-based resistance.
Rare BRAF variant registry: Continue global data collection through resources like the Heidelberg rare BRAF mutations database to establish evidence-based treatment guidelines for V600R, V600M, V600D, and non-V600 mutations.
Single-cell and spatial transcriptomics: Apply advanced technologies to resistant tumors to understand the spatial organization of resistant clones and immune microenvironment changes.
Diverse population studies: Conduct BRAF mutation screening and treatment outcome studies in underrepresented populations (African, Asian, Latin American) to ensure equitable access to precision medicine.
Brain metastasis prevention: Investigate whether early use of brain-penetrant BRAF/MEK inhibitors (e.g., encorafenib) can prevent or delay brain metastasis development in high-risk patients.
Report generated: 2026-05-05 Based on analysis of 109 published papers and 5 confirmed findings Disease: BRAF V600 Mutant Melanoma (MONDO:0005012 subtype)