Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy

Abstract

Background: Standard therapies for high grade glioma have failed to substantially improve survival and are associated with significant morbidity. At relapse, high grade gliomas, such as glioblastoma multiforme, are refractory to therapy and universally fatal. BRAF V600E-mutations have been described in a modest 6% to 7% of primary central nervous system (CNS) tumors, but with increased prevalence in the pediatric population and in certain brain tumor subtypes. The use of BRAF inhibitors have transformed melanoma therapy however their use in brain tumors remains unproven.

Case presentation: We describe the pediatric case of a now 12 year old Caucasian male who originally presented at age 9 with a right fronto-parietal glioblastoma multiforme that recurred 2 ½ years from diagnosis. Molecular analysis of the primary tumor revealed a BRAF V600E mutation and the patient was placed on the BRAF inhibitor vemurafenib. A complete response was observed after 4 months of therapy and remains sustained at 6 months.

Conclusion: This is the first report of a complete response of relapsed glioblastoma multiforme to targeted BRAF inhibitor therapy. While not a predominant mutation in glioblastoma multiforme, the increased prevalence of BRAF V600 mutations in pediatric CNS tumors and certain subtypes marks a population to whom this therapy could be applied. Response to this therapy suggests that BRAF inhibitors can affect primary CNS lesions when a documented and targetable mutation is present.

Figure 1

Chronological changes on magnetic resonance imaging (MRI) document the tumor recurrence and response. Coronal MRI T1-weighted images with gadolinium-based contrast were taken at the following times: (A) diagnosis, (B) post-operatively, (C) after completion of radiation therapy, (D) while receiving adjuvant chemotherapy, (E) at completion of therapy, (F) 4 months after completion of therapy, (G) upon start of vemurafenib therapy at relapse, (H) after 2 months of vemurafenib therapy, and (I) after 4 months of vemurafenib therapy.

Figure 2

The diagnosis of glioblastoma (WHO grade IV) was rendered on histopathologic review. Histopathologic evaluation revealed a hypercellular astrocytic neoplasm which infiltrated the surrounding brain parenchyma. Mitotic activity (arrows) was abundant and microvascular proliferation (designated V) was present (A). Necrosis was encountered in the specimen, including pseudo-palisading necrosis (designated N) (B). While not a dominant appearance, focally the tumor had features of epithelioid glioblastoma (C).

Figure 3

Electropherogram derived from patient’s tumor sample showing a point mutation at codon 600 (GTG to GAG) resulting in a Valine (V) to Glutamic acid (E) substitution.