BRAF

  • v-Raf murine sarcoma viral oncogene homolog B (BRAF)
  • Gene Location: chromosome 7 (7q34)1

BRAF Biology

  • BRAF is a proto-oncogene located on chromosome 7 that encodes a serine/threonine-protein kinase involved in activation of the MAPK signaling pathway, a key regulator of cellular growth and proliferation.1

Etiology and Epidemiology

  • BRAF mutations, specifically the V600E mutation, play a pivotal role in the development and progression of non-small cell lung cancer (NSCLC).
  • Occurring in 1% to 2% of lung adenocarcinomas, BRAF mutations are commonly found in patients with a history of smoking.
  • These mutations contribute to the growth of cancer cells through enhanced signaling pathways.2,3
  • Targeted therapies, specifically BRAF-directed tyrosine kinase inhibitors (TKIs), are the standard treatment for patients with advanced NSCLC with BRAF mutations.4
  • However, affected patients often develop resistance to BRAF-targeted therapy due to intrinsic or extrinsic mechanisms.3

BRAF V600E Testing

  • When to Test: All patients with advanced or metastatic lung adenocarcinoma should undergo broad molecular profiling at diagnosis. Broad molecular profiling should also be considered for those with advanced or metastatic lung squamous cell carcinoma at diagnosis. In early-stage disease, testing at diagnosis should include assessment of PD-L1, EGFR, and ALK.4
  • Available Testing Methods: Real-time polymerase chain reaction (PCR), Sanger sequencing, and next-generation sequencing (NGS) are frequently used methods to detect BRAF mutations.2 NGS, increasingly preferred for its ability to simultaneously test multiple molecular alterations and applicability to liquid biopsy, is becoming the method of choice.
  • Guideline Testing Recommendations: The National Comprehensive Cancer Network (NCCN) guidelines recommend testing for BRAF mutations in patients with metastatic nonsquamous NSCLC based on efficacy data demonstrated with dabrafenib plus trametinib for patients with BRAF V600E mutations.4,5 Given that BRAF mutations are also present in squamous cell NSCLC, although less frequently than nonsquamous NSCLC, testing may also be considered in patients with metastatic NSCLC squamous cell carcinoma.5-8

BRAF V600E Targeted Therapy

  • Approved Agents: Two combination therapies using targeted TKIs have received FDA approval for the treatment of metastatic NSCLC with BRAF V600E mutations. Dabrafenib in combination with trametinib was granted full approval in 2017 following initial breakthrough therapy designation in 2015.9 The combination of encorafenib with binimetinib received approval in 2023 along with the FoundationOne CDx and FoundationOne Liquid CDx companion diagnostics.10
  • Mechanism of Action: Dabrafenib and encorafenib act by inhibiting BRAF V600E-mutated receptors. BRAF inhibitors are used in combination with one of 2 MEK inhibitors, trametinib or binimetinib, thereby allowing for dual targeting of kinases in the MAPK pathway.

Learn more about Dabrafenib and Trametinib >

Learn more about Encorafenib and Binimetinib >

References

  1. Kumar A, Kumar A. Non small-cell lung cancer-associated gene mutations and inhibitors. Adv in Cancer Biol. 2022;6:100076. doi: 0.1016/j.adcanc.2022.100076
  2. Guaitoli G, Zullo L, Tiseo M, Dankner M, Rose AA, Facchinetti F. Non-small-cell lung cancer: how to manage BRAF-mutated disease. Drugs Context. 2023;12:2022-11-3. doi:10.7573/dic.2022-11-3
  3. Yan N, Guo S, Zhang H, Zhang Z, Shen S, Li X. BRAF-mutated non-small cell lung cancer: current treatment status and future perspective. Front Oncol. 2022;12:863043. doi:10.3389/fonc.2022.863043
  4. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer, version 3.2024. Accessed April 8, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  5. Planchard D, Besse B, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17(7):984-993. doi:10.1016/S1470-2045(16)30146-2
  6. Lam VK, Tran HT, Banks KC, et al. Targeted tissue and cell-free tumor DNA sequencing of advanced lung squamous-cell carcinoma reveals clinically significant prevalence of actionable alterations. Clin Lung Cancer. 2019;20(1):30-36.e3. doi:10.1016/j.cllc.2018.08.020
  7. Sands JM, Nguyen T, Shivdasani P, et al. Next-generation sequencing informs diagnosis and identifies unexpected therapeutic targets in lung squamous cell carcinomas. Lung Cancer. 2020;140:35-41. doi:10.1016/j.lungcan.2019.12.005
  8. Gautschi O, Milia J, Cabarrou B, et al. Targeted therapy for patients with BRAF-mutant lung cancer: results from the European EURAF Cohort. J Thorac Oncol. 2015;10(10):1451-1457. doi:10.1097/JTO.0000000000000625
  9. FDA grants regular approval to dabrafenib and trametinib combination for metastatic NSCLC with BRAF V600E mutation. US FDA. Updated June 22, 2017. Accessed April 9,2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-dabrafenib-and-trametinib-combination-metastatic-nsclc-braf-v600e
  10. FDA approves encorafenib with binimetinib for metastatic non-small cell lung cancer with a BRAF V600E mutation. FDA. Updated October 11, 2023. Accessed April 9, 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/resources-information-approved-drugs

Additional Reading

Ambrosini-Spaltro A, Rengucci C, Capelli L, et al. Clinicopathological features of non-small cell lung carcinoma with BRAF mutation. Curr Oncol. 2023;30(11):10019-10032. Published 2023 Nov 19. doi:10.3390/curroncol30110728

Gibson AJW, Pabani A, Dean ML, Martos G, Cheung WY, Navani V. Real-world treatment patterns and effectiveness of targeted and immune checkpoint inhibitor-based systemic therapy in BRAF mutation-positive NSCLC. JTO Clin Res Rep. 2023;4(3):100460. doi: 10.1016/j.jtocrr.2022.100460

Iaccarino A, Pisapia P, Pepe F, et al. Liquid biopsy for BRAF mutations testing in non-small cell lung cancer: a retrospective study. J Clin Pathol. 2022;75(1):58-60. doi:10.1136/jclinpath-2020-207107

Puri M, Gawri K, Dawar R. Therapeutic strategies for BRAF mutation in non-small cell lung cancer: a review. Front Oncol. 2023;13:1141876. doi:10.3389/fonc.2023.1141876

Sui JSY, Ladanyi M, Rudin CM, et al. Clinicopathologic and mutational landscape of BRAF V600E-mutant non–small cell lung carcinoma. J Clin Oncol. 2022;40(16 supp):9084. doi:10.1200/JCO.2022.40.16_suppl.9084