BRAF

  • V-RAF murine sarcoma viral oncogene homolog B1 (BRAF)
  • Gene Location: chromosome 7 (7q34)

BRAF Biology

  • The v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) gene was discovered in 1988, and it encodes a kinase protein in the RAS-RAF-MEK-ERK signal transduction pathway.1-4
  • BRAF is located on chromosome 7 and belongs to the RAF family of serine/threonine-specific protein kinases but is the only one known to be a proto-oncogene in humans.4
  • Under normal circumstances, RAF proteins participate in the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation and differentiation.1
  • Activated BRAF phosphorylates MEK proteins, which subsequently activate ERK proteins, which activate cellular transcription factors.1,4
  • BRAF contains 3 conserved regions: CR1, CR2, and CR3. CR1 and CR3 produce autoinhibitory interaction for BRAF, with CR2 functioning as a hinge of the other conserved regions.5

Etiology and Epidemiology

  • The most common BRAF mutation is V600E, resulting in constitutively activated BRAF kinases that stimulate tumor growth.1-3,6
  • Nearly all BRAF mutations occur within 2 different protein locations, exons 11 and 15, resulting in the loss of the autoinhibitory region combined with targeting BRAF to the plasma membrane.1,4
  • The prevalence of BRAF V600E mutations in gastric cancer is relatively low, ranging from 0% to 12% in different studies.4,6
  • Due to the rarity of BRAF mutations in gastric cancer, the role of mutation status and clinicopathological variables is unclear.4
  • BRAF is a known predictor of poor prognosis in colorectal cancer (CRC) to EGFR-targeted agents, but the predictive value in gastric cancer is unknown.4
  • Gastric cancer is characterized by high tumor heterogeneity, so biomarker testing has a high impact on appropriate treatment selection.7,8

BRAF V600E Testing

  • When to Test: Patients with gastric cancer should undergo testing for BRAF mutations and other relevant biomarkers at the time of diagnosis using next-generation sequencing (NGS) at the discretion of the physician.8
  • Available Testing Methods: BRAF testing can be performed using immunohistochemistry (IHC) or, preferably, next-generation sequencing (NGS).8
  • Guideline Testing Recommendations: Biomarker testing for gastric cancer should start with IHC and targeted PCR, followed by NGS testing. If tissue is limited or a biopsy isn't feasible, sequential single biomarker testing may deplete the sample. In these cases, comprehensive genomic profiling via a validated NGS assay is advised. Key biomarkers for interrogation include HER2 overexpression, PD-L1 expression, microsatellite instability, tumor mutational burden, NTRK fusion, RET fusion, and BRAF V600E mutation.8

BRAF V600E Targeted Therapy

  • Approved Agents: Gastric cancer accounts for only about 1.5% of new cancer cases in the United States each year.9 The relative rarity means that targeted treatments are limited, and most treatments include traditional chemotherapy.8 Currently, the only FDA-approved treatment for gastric cancer with a BRAF V600E mutation is dabrafenib plus trametinib.2,3,10-12
  • Mechanism of Action: Dabrafenib inhibits mutated BRAF kinases and wild-type BRAF, deactivating the BRAF cascade that promotes cell growth and differentiation.2 Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2, deactivating upstream regulation of the extracellular signal-related kinase (ERK) pathway.3

Learn more about Dabrafenib and Trametinib >

References

  1. Wan PTC, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855-867. doi:10.1016/s0092-8674(04)00215-6
  2. TAFINLAR (dabrafenib). Prescribing information. GSK; 2024. Accessed May 5, 2024. https://www.novartis.com/us-en/sites/novartis_us/files/tafinlar.pdf
  3. MEKINIST (trametinib). Prescribing information. Novartis; 2024. Accessed May 5, 2024. https://www.novartis.com/us-en/sites/novartis_us/files/mekinist.pdf
  4. Hewitt LC, Hutchins GG, Melotte V, Saito Y, Grabsch HI. KRAS, BRAF and gastric cancer. Transl Gastrointest Cancer. 2015;4(6). doi:10.3978/j.issn.2224-4778.2015.09.08
  5. Zaman A, Wu W, Bivona TG. Targeting oncogenic BRAF: past, present, and future. Cancers (Basel). 2019;11(8):1197. doi:10.3390/cancers11081197
  6. Choi YY, Noh SH, Cheong JH. Molecular dimensions of gastric cancer: translational and clinical perspectives. J Pathol Transl Med. 2016;50(1):1-9. doi:10.4132/jptm.2015.09.10
  7. Van Grieken NCT, Aoyma T, Chambers PA, et al. KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results from a large international multicentre study. Br J Cancer. 2013;108(7):1495-1501. doi:10.1038/bjc.2013.109
  8. National Comprehensive Cancer Network. NCCN guidelines version 1.2024: gastric cancer. 2024. Accessed May 5, 2024. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
  9. Zhu X, Pigazzi A, Zell J, Lu Y. Changing disparity of gastric cancer incidence by histological types in US race-specific populations. Cancer Control. 2020;27(1):1073274820977152. doi:10.1177/1073274820977152
  10. National Comprehensive Cancer Network. NCCN guidelines version 1.2024: pancreatic adenocarcinoma. 2024. Accessed May 5, 2024. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  11. Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAF V600E mutations: results of the NCI-MATCH trial subprotocol H. J Clin Oncol. 2020;38(33):3895-3904. doi:10.1200/JCO.20.00762
  12. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial. Nat Med. 2023;29(5):1103-1112. doi:10.1038/s41591-023-02321-8