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.
Highlights
The RAF serine/threonine protein kinases have been studied extensively over the past 17 years since their initial discovery as oncogenes
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
That study found a better overall survival in secondary GBM with BRAF V600E mutation than without [92]. This may suggest a “cap” to BRAF V600E’s oncogenicity, making it a driver mutation that is relatively aggressive compared to other LGG but relatively mild compared to other driver mutations in pGBM
Summary
The RAF serine/threonine protein kinases have been studied extensively over the past 17 years since their initial discovery as oncogenes. Up-front combination of RAF and MEK survival inhibitors,in patients with advanced melanoma [8,9,10]. There are three combinations of andoccur may delay or prevent the common mechanisms of treatment-emergent resistance that inhibitors approved by improves the Unitedprogression-free. Nextglioma [11,12,13,14] This has led to anecdotal reports of positive responses, as well as positive clinical generation sequencing (NGS) of tumor specimens has experience enabled identification of other trial data, though most neuro-oncologists still have little with these drugs [15].mutations. We summarize the mutations in in the BRAF gene in primary brain tumors, but many of these do not respond to FDA-approved described to date in glioma provide anrapidly.
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