BRAF V600E-Mutant Glioblastoma with Extracranial Metastases Responsive to Combined BRAF and MEK Targeted Inhibition: A Case Report

Abstract

Recent advancements in understanding the biology of glioblastomas (GBM) and increasing adoption of genomic sequencing in oncology practice have led to the discovery of several targetable mutations in these cancers. Among them, the BRAF V600E mutation can be found in approximately 3% of GBM. Despite the aggressive nature of GBM, metastatic disease is rarely observed. While there are growing data utilizing BRAF-targeting strategies in patients with GBM, data examining their efficacy in cases of metastatic GBM are lacking. We present the case of a 46-year-old female with GBM, isocitrate dehydrogenase (IDH)-wildtype and O⁶-methylguanine-DNA methyltransferase promoter (MGMT) unmethylated, BRAF V600E-mutant, and MYC amplified with extra-central nervous system spread to the spine and lung. Four months after completion of treatment with standard chemoradiation and temozolomide, the patient developed severe back pain, leading to the eventual discovery of her metastatic disease. Based on the presence of the BRAF V600E mutation, the patient was treated with and achieved an intracranial and systemic response to combination BRAF-MEK targeted inhibition for 9 months before evidence of progression.

Keywords: Actionable mutation; BRAF V600E-mutant; Glioblastoma; Metastatic; Targeted therapy.

Fig. 1

aHistologic section from a biopsy of a right T11 pedicle lesion revealing a primitive neoplasm with smooth chromatin and fine fibrillary background. Immunohistochemistry shows positivity for GFAP and OLIG2 (b, c). Additionally, the same cells were negative for desmin, CD99, CD138, CD45, synaptophysin, and chromogranin. WT-1 revealed cytoplasmic expression and cytokeratin AE1/AE3 showed variable reactivity representing aberrant antigen cross-reactivity.

Fig. 2

Histologic section from biopsy of a right T11 pedicle lesion (biopsy sample same as in Fig. 2) with immunohistochemistry showing positivity for BRAF V600E.

Fig. 3

MR images of the brain (upper panel) and sections of the spine (lower panel) demonstrating a radiographic response to combined BRAF and MEK targeted inhibition with dabrafenib and trametinib. T2/FLAIR (a, c) and T1 post-contrast (b, d) images of the brain show reduction in both extent of T2/FLAIR signal and contrast enhancement in response to treatment. A response to treatment was also seen in the thoracic spine (e–h). A measurable lesion is marked with an arrow. Note that the more caudal lesions had been previously irradiated, rendering assessment of response to dabrafenib and trametinib inconclusive.