Executive Summary

Biological Function

BRAF encodes a cytosolic serine-threonine kinase (B-Raf) of the MAPK/ERK pathway that regulates cell proliferation and survival. The gene is located at 7q34 and the protein presents three conserved domains (CR1–CR3). B-Raf is activated by RAS-GTP binding, dimerizes and phosphorylates MEK1/2, activating ERK1/2 and promoting growth signals.

Main Epidemiology

~50% Cutaneous melanomas
~45% Papillary thyroid carcinoma
8-12% Metastatic colorectal cancer
1-2% Lung adenocarcinomas
~100% Hairy cell leukemia

IECC ONE-ME® Scoring System

The IECC ONE-ME® System evaluates biomarkers in three fundamental clinical dimensions through scientifically validated quantitative scales.

Diagnostic Score (Dx)

Evaluates: Capacity to confirm/rule out disease

Criteria: Sensitivity/Specificity

Prognostic Score (Px)

Evaluates: Capacity to predict clinical evolution

Criteria: Hazard Ratio (HR)

Predictive Score (Prd)

Evaluates: Capacity to predict therapeutic response

Criteria: PPV/NPV

IECC ONE-ME® Scores for BRAF Alterations

BRAF Alteration	Dx Score	Px Score	Prd Score	Total IECC	Evidence Level
BRAF V600E	6 /6	5 /6	6 /6	17 /18	A
BRAF V600K	5 /6	4 /6	5 /6	14 /18	A
Class II (non-V600)	4 /6	3 /6	3 /6	10 /18	B
Class III (non-V600)	3 /6	2 /6	2 /6	7 /18	C
BRAF Fusions	5 /6	4 /6	3 /6	12 /18	A

BRAF Mutations Epidemiology

Cutaneous Melanoma

Frequency: ~50%

V600E: 80-90%

V600K: 10-20%

Papillary Thyroid Carcinoma

Frequency: ~45%

Asian series: up to 70-80%

Metastatic Colorectal Cancer

Frequency: 8-12%

Almost always V600E

Profile: Right colon, elderly women

NSCLC Adenocarcinoma

Frequency: 1-2%

Mainly V600E

Main BRAF Alterations

BRAF V600E (p.Val600Glu)

Total Score: 17/18

Location: Exon 15 (CR3 domain)
Frequency: 80-90% of BRAF mutations
Activity: Constitutively active, RAS-independent
Clinical Significance: Diagnostic biomarker and therapeutic predictor
Treatment: BRAF/MEK inhibitors, excellent response

BRAF V600K (p.Val600Lys)

Total Score: 14/18

Location: Exon 15 (CR3 domain)
Frequency: 5-20% of BRAF mutations
Activity: Activating, similar to V600E
Clinical Significance: Reliable therapeutic predictor
Treatment: Similar response to V600E with inhibitors

Class II (non-V600)

Total Score: 10/18

Examples: K601E, L597Q, G469A
Activity: Intermediate-high, requires dimerization
RAS Dependence: Independent
Clinical Significance: Moderate predictor
Treatment: MEK inhibitors preferably

Class III (non-V600)

Total Score: 7/18

Examples: D594G/N, G466V/E
Activity: Inactive or weakly active
RAS Dependence: RAS-dependent
Clinical Significance: Limited predictor
Treatment: Resistant to BRAF inhibitors

BRAF Gene Fusions

Total Score: 12/18

Examples: KIAA1549-BRAF, FAM131B-BRAF
Mechanism: N-terminal regulatory domain deletion
Frequency: >80% pilocytic astrocytomas
Clinical Significance: Diagnostic biomarker for gliomas
Treatment: MEK inhibitors, new therapies in development

BRAF-Targeted Therapies

BRAF V600+ Melanoma

First Line

Dabrafenib + Trametinib: ORR ~70%, PFS ~11 months
Vemurafenib + Cobimetinib: ORR ~64%, PFS ~9.9 months
Encorafenib + Binimetinib: ORR ~63%, PFS ~14.9 months

Adjuvant

Dabrafenib + Trametinib (COMBI-AD): HR relapse 0.47

BRAF V600E NSCLC

First Line

Dabrafenib + Trametinib: ORR ~64%, PFS ~10 months
FDA/EMA approved as standard

Characteristics

Effective in smokers and non-smokers
Alternative to chemotherapy + immunotherapy

BRAF V600E Metastatic CRC

Second Line (BEACON)

Encorafenib + Cetuximab ± Binimetinib
ORR: 26% vs 2%, OS: 9.0 vs 5.4 months (HR 0.52)

First Line (BREAKWATER)

Encorafenib + Cetuximab + mFOLFOX6
OS: 30.3 vs 15.1 months (HR 0.49), ORR: 66%

Hairy Cell Leukemia

Relapses

Vemurafenib: ORR ~96% (phase II)
Rapid and sustained responses

Characteristics

100% of cases have BRAF V600E
Excellent diagnostic biomarker

Diagnostic Algorithms

Detection Methods

NGS Recommended

Most complete method, detects all BRAF variants

Real-time PCR Routine

Fast and specific for V600E/V600K

IHC VE1 Screening

Specific for V600E, rapid result

Liquid Biopsy Monitoring

ctDNA for follow-up and resistance

Metastatic Melanoma Algorithm

Step 1: Stage IV diagnosis

Test BRAF immediately

Step 2: Preferred method

NGS if available, PCR/IHC if urgent

Step 3: V600+ result

Choose between immunotherapy or targeted therapy according to tumor burden

Metastatic CRC Algorithm

Step 1: Complete molecular panel

RAS, BRAF, MSI, HER2 at diagnosis

Step 2: BRAF V600E+

Differentiate sporadic (~60% MSI-H) vs Lynch (0% with BRAF+)

Step 3: Treatment

1L: Triplet + anti-EGFR | 2L+: Anti-EGFR + BRAF/MEKi

Quantified Bibliography IECC ONE-ME®

IECC ONE-ME® Bibliographic Quantification System

Impact Factor (JCR 2024)

IF >15 Top World Journals - Maximum
IF 5-15 High Impact - High
IF 2-5 Moderate Impact - Moderate
IF <2 Basic Impact - Basic

Number of Citations (Web of Science)

>500 Fundamental Study - Fundamental
100-500 Very Influential - Influential
50-100 Recognized - Recognized
<50 Emerging - Emerging

Main Validated References

Chapman PB, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation.

N Engl J Med. 2011;364(26):2507-16. (BRIM-3 Trial)

Pivotal study demonstrating vemurafenib efficacy vs dacarbazine in BRAF V600E+ melanoma

IF: 176.1 Citations: >2847 Level A

Robert C, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib.

N Engl J Med. 2015;372(1):30-39. (COMBI-v Trial)

Demonstrated superiority of BRAF+MEK combination vs BRAF monotherapy

IF: 176.1 Citations: >1923 Level A

Kopetz S, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E–mutated colorectal cancer.

N Engl J Med. 2019;381(17):1632-43. (BEACON CRC Trial)

Established new standard for BRAF V600E+ metastatic CRC after first line

IF: 176.1 Citations: >847 Level A