BRAF

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

BRAF Biology

  • The BRAF gene belongs to the RAS-RAF-MEK-ERK signal transduction pathway, also called the MAPK pathway, and is involved in cell growth, differentiation, and proliferation.1-5
  • Proteins within the MAPK pathway are predominantly serine/threonine kinases that propagate the transduction pathway or activate downstream signal proteins for metabolism, mitosis, motility, and apoptosis.5,6
  • The 3 RAF proteins in humans are ARAF, BRAF, and CRAF; ARAF and CRAF require additional phosphorylation for full activity; subsequently, BRAF is the most active in humans.5

Etiology and Epidemiology

  • The most common BRAF mutation is V600E, which flips the protein into a constitutively active conformation.2,3,7
  • The mutated V600E protein stimulates ERK signaling in vivo.5
  • Other mutations cause reduced kinase activity, which activates wild-type CRAF and results in the same outcome of increased ERK signaling and tumorigenesis.5
  • BRAF V600E mutation status does not appear to correlate to survivability in biliary tract cancer (BTC).7 However, the power of studies to date has been low, so this conclusion may have limited applicability in light of future research.8
  • BRAF V600E mutations are shown to be present in approximately 5% to 7% of biliary tract cancers.9

BRAF V600E Testing

  • When to Test: Patients with unresectable or metastatic biliary tract cancers (BTCs) who are candidates for systemic therapy should receive comprehensive molecular profiling at diagnosis.1
  • Available Testing Methods: Common testing modalities are next-generation sequencing (NGS) or polymerase chain reaction (PCR) testing of tumor tissue.1 NGS can also be used on cell-free DNA to detect BRAF mutations.1
  • Guideline Recommendations for Testing: Experts recommend BRAF testing for patients with unresectable or metastatic gallbladder cancer, intrahepatic CCA, and extrahepatic CCA.1 BRAF V600E mutations appear exclusive to cholangiocarcinomas (CCAs), indicating that testing may provide nonspecific diagnostic support.1,7 Most intrahepatic CCAs are detected after the tumor is unresectable.7 Therefore, early detection of BRAF mutations provides an additional treatment option prior to metastasis.

BRAF V600E Targeted Therapy

  • Approved Agents: The first and currently only FDA-approved treatment for subsequent-line therapy for BRAF V600E–mutated BTC is dabrafenib with trametinib.1-3
  • Mechanism of Action: Dabrafenib is an inhibitor of mutated BRAF proteins, which are constitutively active; they stimulate tumor cell proliferation via the MAPK pathway.2 Trametinib is a reversible inhibitor of mitogen-activated protein kinase kinase 1 (MEK1) and MEK2.3 MEK proteins are upstream regulators of the MAPK pathway.3 Tumor cells that initially respond to dabrafenib can develop resistance via the MEK protein, providing the rationale for combination therapy.2,3,8

Learn more about Dabrafenib and Trametinib >

References

  1. NCCN. Clinical Practice Guidelines in Oncology. Biliary tract cancer, version 1.2024. Accessed March 9, 2024. https://www.nccn.org/professionals/physician_gls/pdf/btc.pdf
  2. TAFINLAR (dabrafenib). Prescribing information. Novartis; 2024. Accessed March 11, 2024. https://www.novartis.com/us-en/sites/novartis_us/files/tafinlar.pdf
  3. MEKINIST (trametinib). Prescribing information. Novartis; 2024. Accessed March 11, 2024. https://www.novartis.com/us-en/sites/novartis_us/files/mekinist.pdf
  4. Winstead E. FDA approves dabrafenib–trametinib for BRAF-positive cancers. National Cancer Institute. July 21, 2022. Accessed March 9, 2024. https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-dabrafenib-trametinib-braf-solid-tumors
  5. Wan PTC, Garnett MJ, Roe SM, et al; Cancer Genome Project. 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
  6. Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;75(1):50-83. doi:10.1128/MMBR.00031-10
  7. Goeppert B, Frauenschuh L, Renner M, et al. BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma. Mod Pathol. 2014;27(7):1028-1034. doi:10.1038/modpathol.2013.206
  8. Lamarca A, Barriuso J, McNamara MG, Valle JW. Molecular targeted therapies: Ready for “prime time” in biliary tract cancer. J Hepatol. 2020;73(1):170-185. doi:10.1016/j.jhep.2020.03.007
  9. 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.