BRAF

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

BRAF Biology

  • The RAS-RAF-MEK-ERK pathway is an important protein kinase cascade that regulates cell differentiation, proliferation, and survival in response to hormones, cytokines, and growth factors.1,2
  • There are 3 functional RAF proteins in humans, including V-Raf murine sarcoma viral oncogene homolog B (BRAF).2
  • BRAF is a serine/threonine-specific protein kinase with 3 conserved domains: CR1, CR2, and CR3.3
  • The wild-type BRAF protein forms a strong hydrophobic interaction in residues 596-600, which keeps it in its inactive state.
  • BRAF becomes activated once the activation loop is phosphorylated, destabilizing the hydrophobic site and enabling downstream kinase activity.2

Etiology and Epidemiology

  • BRAF mutation is an acquired gene mutation identified most commonly in older patients (>60 years), proximal tumor location, locally advanced characteristics, and poor cell differentiation.1
  • The BRAF V600E mutation is present in 5% to 9% of patients with colorectal cancer.4
  • BRAF V600E mutations are associated with worse survival after recurrence in patients with stage III colon cancer and are associated with a shorter median progression-free and median overall survival than patients with wild-type BRAF tumors.5,6
  • Mutations in BRAF can result in constitutive activation of the BRAF gene, which stimulates tumor growth.7
  • BRAF mutations are more common in cancer types that also harbor RAS mutations, including colorectal cancer, borderline ovarian cancers, and malignant melanoma.8
  • This association occurs because activation of the RAS-RAF-MEK-ERK pathway can be achieved by cancer cells through mutation at various points along the pathway.6,8 Therefore, agents that target BRAF gain synergistic effects when combined with other agents that target kinases in the same pathway.

BRAF V600E Testing

When to Test:

  • All patients with metastatic CRC should receive molecular testing for BRAF mutations at the time of diagnosis.4

Available Testing Methods:

  • The preferred method for molecular testing is broad profiling using an NGS panel in a CLIA-certified laboratory, though immunohistochemistry (IHC) is also an option.4
  • Testing can be performed on either the primary tumor or metastatic lesions.4

Guideline Recommendations for Testing:

  • All patients with mCRC should undergo testing for KRAS/NRAS and BRAF mutations, HER2 amplifications, and MSI/MMR status; testing may be performed individually or via NGS (preferred).4

BRAF V600E Targeted Therapy

Approved Agents:

  • A single drug regimen is FDA-approved for treating adult patients with mCRC with a BRAF V600E mutation detected by an FDA-approved test after prior therapy: encorafenib in combination with cetuximab.7–10
  • NCCN guidelines version 1.2024 also recommend encorafenib in combination with panitumumab.4

Encorafenib with Cetuximab7:

  • FDA Approved Indication(s):
    • In combination with cetuximab and mFOLFOX6, for the treatment of patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA‑approved test. *This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
    • In combination, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.
  • Mechanism of Action:
    • Encorafenib is a kinase inhibitor of BRAF V600E, wild-type BRAF, and CRAF.6
    • Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor.11
  • Drug Information:
  • Patient Resources:

References

  1. Clancy C, Burke JP, Kalady MF, Coffey JC. BRAF mutation is associated with distinct clinicopathological characteristics in colorectal cancer: a systematic review and meta-analysis. Colorectal Dis. 2013;15(12):e711-e718. doi:10.1111/codi.12427
  2. 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
  3. Cutler RE, Stephens RM, Saracino MR, Morrison DK. Autoregulation of the Raf-1 serine/threonine kinase. Proc Natl Acad Sci USA. 1998;95(16):9214-9219. doi:10.1073/pnas.95.16.9214
  4. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 1.2024. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
  5. Sinicrope FA, Shi Q, Allegra CJ, et al. Association of DNA mismatch repair and mutations in BRAF and KRAS with survival after recurrence in stage III colon cancers. JAMA Oncol. 2017;3(4):472-480. doi:10.1001/jamaoncol.2016.5469
  6. Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361(1):98-99. doi:10.1056/nejmc0904160
  7. BRAFTOVI (Encorafenib). Prescribing information. Array BioPharma, Inc; 2023. https://labeling.pfizer.com/ShowLabeling.aspx?id=12990
  8. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-954. doi:10.1038/nature00766
  9. Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: Updated survival results and subgroup analyses from the BEACON study. J Clin Oncol. 2021;39(4):273-284. doi:10.1200/JCO.20.02088
  10. FDA approves encorafenib in combination with cetuximab for metastatic colorectal cancer with a BRAF V600E mutation. US FDA. Updated April 9, 2020. Accessed May 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-combination-cetuximab-metastatic-colorectal-cancer-braf-v600e-mutation
  11. ERBITUX (cetuximab). Prescribing information. Eli Lilly and Company; 2021. https://uspl.lilly.com/erbitux/erbitux.html#pi