BRAF Mutations and the Utility of RAF and MEK Inhibitors in Primary Brain Tumors

Abstract

BRAF mutations have been identified as targetable, oncogenic mutations in many cancers. Given the paucity of treatments for primary brain tumors and the poor prognosis associated with high-grade gliomas, BRAF mutations in glioma are of considerable interest. In this review, we present the spectrum of BRAF mutations and fusion alterations present in each class of primary brain tumor based on publicly available databases and publications. We also summarize clinical experience with RAF and MEK inhibitors in patients with primary brain tumors and describe ongoing clinical trials of RAF inhibitors in glioma. Sensitivity to RAF and MEK inhibitors varies among BRAF mutations and between tumor types as only class I BRAF V600 mutations are sensitive to clinically available RAF inhibitors. While class II and III BRAF mutations are found in primary brain tumors, further research is necessary to determine their sensitivity to third-generation RAF inhibitors and/or MEK inhibitors. We recommend that the neuro-oncologist consider using these drugs primarily in the setting of a clinical trial for patients with BRAF-altered glioma in order to advance our knowledge of their efficacy in this patient population.

New hints towards a precision medicine strategy for IDH wild-type glioblastoma

“…In particular, this alteration is observed in the rarer IDH-wt epithelioid (eGBM) subtype, with BRAFV600 mutations present in greater than 50% of these cases. 112 To date, targeting of mutant BRAF signalling has been studied in several trials, with both dabrafenib 113 and vemurafenib (NCT01524978) 114 showing promise in a small subset of BRAFV600 mutant tumours 114,115 ; The VE-BASKET study of BRAFV600 mutant, nonmelanoma cancers assessed the effect of vemurafenib in n ¼ 24 patients with gliomas. Vemurafenib treatment resulted in a durable antitumour response in a cohort of IDH1/2 wt low-grade gliomas, with the greatest effect seen in pleomorphic xanthoastrocytoma patients (n ¼ 7).…”

Clinical Relevance of BRAF V600E Mutation Status in Brain Tumors with a Focus on a Novel Management Algorithm

“…Compared with V600E, the remaining class I mutations occur far less frequently and, therefore, their clinical relevance is harder to assess [21]. V600E is present in a significant subset of CNS tumors (Table 1).…”

“…Class II mutations include several point mutations and fusions that activate MEK through RAS-independent dimerization. The most common point mutations include K601E/ N/T, L597Q/V, and G469A/V/R; however, their relative frequency in brain tumors remains unknown [21]. Among fusions, the most common is KIAA1549-BRAF, which is predominantly identified in low-grade gliomas.…”

BRAF V600E Detection in Liquid Biopsies from Pediatric Central Nervous System Tumors

“…This mutation appears in 33% of midline tumors, and has the highest incidence (66%) in pleomorphic xanthoastrocytomas [17]. The relevance of the BRAF V600E mutation presence in pediatric Low Grade Gliomas is that the 10-year progression-free survival rate decreases in almost 40% [18], however, the use of BRAF inhibitors as dabrafenib (GSK2118436), encorafenib (LGX818) and vemurafenib (PLX4032) have shown a successful response [19][20][21]. Although, several clinical trials in pediatric tumors are ongoing, dabrafenib is the most popular one used in clinical practice, as it has the highest effectivity in vitro and the highest brain distribution [22].…”