A narrative review of BRAF alterations in human tumors: diagnostic and predictive implications

Abstract

: BRAF is a ubiquitous oncogene in human tumors; oncogenic mutations give rise to a broad biologic spectrum of clonal proliferations depending on cellular context and tumor suppressor gene co-mutation. The BRAF V600E mutation, a class 1 variant, is the best-understood alteration in the gene, but despite that, extensive pre-clinical and empiric study has been required to optimize combinatorial therapies in order to overcome bypass and downstream signaling induced by BRAF inhibitor monotherapy in tumors with this mutation. Class 2 and 3 BRAF variants predominate in certain tumors such as non-small cell lung carcinoma (NSCLC) and are associated with distinct clinicopathologic features including resistance to RAF inhibitors and co-mutation with other genes in the RTK/RAS/MAPK pathway. Clinical trials of BRAF inhibitors in some of the most common malignancies, including melanoma, colorectal cancers, and lung cancers, have led to a number of FDA-approved combination RAF-MEK or RAF-EGFR inhibitors, with substantial implications for improved survival and quality of life in a large number of cancer patients. Mutational testing for BRAF V600E is required for selection of patients with BRAF inhibitor therapies; rapid screening for the mutation may be carried out using mutation-specific immunohistochemistry, whereas next generation sequencing is an optimal testing strategy in order to identify relevant co-mutations and mutational patterns (such as mismatch repair status) likely to influence therapeutic selection and outcomes.