Clinlab Navigator

BRAF Mutation

BRAF is a human gene that encodes a serine/threonine protein kinase in the mitogen activated protein kinase (MAPK) pathway. This pathway includes signaling molecules Ras, Raf, MEK and ERK. Normally, extracellular growth factors activate this pathway by binding to receptor tyrosine kinases. Activation of MAPK leads to transcription of genes that regulate cell division, growth and differentiation. Specific mutations in BRAF can constitutively stimulate this pathway independent of growth factors leading to excessive cell proliferation and survival. BRAF mutations are most commonly detected in melanoma and papillary thyroid cancer.

Patients with metastatic melanoma should be tested for the presence or absence of the V600 mutation in the BRAF gene. The presence of a V600E or V600K mutation predicts responsiveness to BRAF or MEK inhibitiors. Mutations in BRAF are present in approximately 50 percent of advanced melanomas. In 80 to 90 percent of cases, the mutation results in a substitution of glutamic acid for valine at amino acid 600 (V600E mutation). An alternative mutation is due to substitution of lysine for valine at this locus (V600K). Advanced melanomas with a mutation in BRAF are associated with a more aggressive clinical course.

Patients with BRAF mutations respond to vemurafenib (Zelboraf) and dabrafenib (Taflinar). Vemurafenib is a potent inhibitor of the kinase domain in mutant BRAF. Vemurafenib prolongs both progression-free and overall survival in melanoma patients whose tumors contain a V600 mutation. Dabrafenib is another BRAF kinase inhibitor approved by the FDA for treatment of patients with advanced melanoma that expresses the V600E mutation of BRAF. However, virtually every patient treated with an inhibitor of BRAF eventually has disease progression.

The MEK inhibitor trametinib (Mekinist) has significant clinical activity in melanoma patients whose tumor contains a V600 BRAF mutation. Trametinib has been approved by FDA for use as an initial therapy in combination with dabrafenib for patients whose melanoma contained a BRAF V600E or V600K mutation.

Mutations outside of codon 600 should not be treated with a BRAF inhibitor. The presence of BRAF mutations cannot be used as a diagnostic criterion for melanoma because they also occur in nevi.

The preferred tissue for testing is a metastatic tumor because this is the target that will be treated with systemic therapy. When a metastasis is not available, a primary tumor can be tested as long as sufficient tumor tissue is available.

AddThis Social Bookmark Button