Clinical, radiological, and genomic features of BRAF V600E-mutated adult glioblastoma.

Abstract

2554 Background: Although uncommon, detection of a BRAF V600E mutation in adult patients with glioblastoma has become relevant given the increased availability of NGS and encouraging therapeutic activity of BRAF/MEK inhibitors. The clinical course, radiological characteristics and genetic mutations in this patient population has, however, not been well described. Methods: Adult patients treated at Dana-Farber Cancer Institute or Massachusetts General Hospital with glioblastoma diagnosed from 2013-2019 and an identified BRAF V600E mutation on immunohistochemistry staining or institutional NGS platform were included. Patient demographics, treatments and outcomes were collected retrospectively. Molecular diagnostics (Oncopanel or SNaPSHOT) and cytogenetics (array CGH) were reviewed for relevant mutations or copy number variants (CNV). Qualitative MRI data was analyzed using Visually Accessible Rembrandt Images (VASARI) feature set. Response assessment was performed using the RANO criteria. Results: Nineteen glioblastoma patients had a BRAF V600E mutation (16 on NGS and 19 on IHC). The median age at diagnosis was 41 (22-69) years; 13/19 were female, 12/19 were Caucasian. Only 1/19 had an IDH mutation; 10 of the 17 with known methylation status had MGMT unmethylated tumors. The most frequent mutations on NGS or CNV on array-CGH were TERT (12/16), CDKN2A (10/16), EGFR (7/16), PIK3R1 (6/16) and CKDN2B (6/16). Most tumors were well circumscribed (12/19) and all were contrast-enhancing on MRI. While no patient had clear leptomeningeal involvement at diagnosis, 11/19 eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following progression after standard of care therapy, with 3/6 patients showing partial response and 2 showing stable disease as their best response. PFS after BRAF/MEK inhibition ranged from 1.9 to 19 months. Grade 1 skin rash was present in 1 patient, but no other adverse events were reported. Median OS for the patients with confirmed deaths (15/19) was 22.6 (14.5 – 39.0) months. Conclusions: Compared to the general glioblastoma population, adult patients with BRAF V600E mutations are younger, more frequently female, and have a higher median OS despite a much higher incidence of leptomeningeal dissemination. Outcome following BRAF/MEK targeted therapy was encouraging. Understanding the natural history and features of these tumors may help better screen patients for BRAF/MEK inhibition and identify novel therapeutic strategies.