BRAF

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

BRAF Biology

  • The BRAF gene is located on chromosome 7, and its corresponding protein plays a role in the RAS-RAF-MEK-ERK (MAPK) signal transduction pathway.1-5
  • MAPK enzymes are activated through interaction with growth factors, cytokines, and hormones.4
  • More than a dozen known MAPK enzymes regulate cell differentiation, proliferation, and survival.4,5
  • BRAF and its family of proteins are serine/threonine kinases that target other MAPK proteins via phosphorylation.4,5
  • BRAF has 3 conserved regions (CRs) involved in protein function: CR1, CR2, and CR3.6
  • CR1 and CR3 interact to form an autoinhibitory complex, whereas CR2 functions as a hinge for this complex.6
  • Under normal conditions, RAS-GTP binds the CR1-CR3 complex and exposes the CR3 catalytic site for substrate activation.6
  • Once activated, BRAF is localized to the cell membrane.4

Etiology and Epidemiology

  • BRAF is a major driver of gene alteration in many types of cancer, including pancreatic malignancies, and the V600E mutation has been best characterized as a constitutive active driver mutation.4,6
  • Mutated BRAF can create a constitutively active protein that drives unregulated cell growth and division.1,4,6
  • Pathogenic BRAF variants, including class I/II mutations, deletions, and fusions, are present in 2% to 4% of advanced pancreatic cancer cases, occurring more frequently in KRAS wild-type vs KRAS-mutant tumors (30% vs 1.5%, respectively).3,7
  • BRAF V600E comprise approximately 17-28% of BRAF mutations in pancreatic cancer.

BRAF V600E Testing

When to Test:

  • Testing is recommended for patients with locally advanced or metastatic pancreatic cancer who are candidates for anticancer therapy.8

Available Testing Methods:

  • BRAF testing can be performed using immunohistochemistry (IHC) or, preferably, next-generation sequencing (NGS).8

Guideline Recommendations for Testing:

  • The National Comprehensive Cancer Network guidelines recommend testing for actionable somatic mutations including those involving BRAF for all patients with advanced pancreatic cancer regardless of the presence of metastases.8
  • The recommended testing method is NGS with an FDA-approved assay, although there is a growing consensus that RNA-based testing for fusion gene expression should be strongly considered as well.8

BRAF V600E Targeted Therapy

Approved Agents:

  • The only FDA-approved treatment for BRAF V600E–mutant pancreatic cancer is dabrafenib plus trametinib.1,2,7

Mechanism of Action:

  • Dabrafenib inhibits signals from the BRAF protein activated by the BRAF V600E mutation and prevents associated tumor growth.1
  • Trametinib complements this mechanism by inhibiting mitogen-activated extracellular-regulated kinase 1 (MEK1) and MEK2 that is activated by the mutated gene.2
  • The dual action prevents tumors from continuing to grow via the escape mechanism of MEK protein activating signals.9

Learn more about Dabrafenib and Trametinib >

References

  1. TAFINLAR (dabrafenib). Prescribing information. Novartis; 2024. Accessed March 11, 2024. https://www.novartis.com/us-en/sites/novartis_us/files/tafinlar.pdf
  2. MEKINIST (trametinib). Prescribing information. Novartis; 2024. Accessed March 11, 2024. https://www.novartis.com/us-en/sites/novartis_us/files/mekinist.pdf
  3. New study targets specific BRAF mutation. Let’s Win Pancreatic Cancer. July 27, 2023. Accessed March 11, 2024. https://letswinpc.org/research/target-braf-mutation/
  4. 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
  5. 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
  6. Zaman A, Wu W, Bivona TG. Targeting oncogenic BRAF: past, present, and future. Cancers (Basel). 2019;11(8):1197. doi:10.3390/cancers11081197
  7. Allen MJ, Zhang A, Bavi P, et al. Molecular characterisation of pancreatic ductal adenocarcinoma with NTRK fusions and review of the literature. J Clin Pathol. 2023;76(3):158-165. doi: 10.1136/jclinpath-2021-207781.
  8. NCCN. Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 1.2024. Accessed June 11, 2024. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  9. Winstead E. Dabrafenib-trametinib combination approved for solid tumors with BRAF mutations. American Cancer Society. July 21, 2022. Accessed March 9, 2024. https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-dabrafenib-trametinib-braf-solid-tumors