Efficacy of BRAF/MEK-inhibitor therapy for epithelioid glioblastoma with a novel BRAFV600 mutation

Abstract

Epithelioid glioblastoma (eGB), a very aggressive and rare brain tumour, is associated with a dismal median overall survival. Effective therapies for patients with eGB, particularly with leptomeningeal dissemination, are still lacking. Here, we describe a case of a 25-year-old male diagnosed with an intramedullary cervical tumour with subsequent leptomeningeal disease. Histopathology identified a highly necrotising, epithelioid-type tumour with high cell density, most compatible with the diagnosis of an eGB. DNA analysis revealed an unprecedented B-Raf protooncogene, serine/threonine kinase (BRAF) gene variant in exon 15 (ENST00000288602.6, c.1799_1810delinsATG, p.(V600_W604delinsDG)), triggering activation of the mitogen-activated protein kinase (MAPK) pathway. Consequently, we initiated MAPK inhibitor (MAPKi) therapy, utilizing a combination of BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. Liquid chromatography-tandem mass spectrometry analysis confirmed the drugs' presence in the patient's cerebrospinal fluid, indicating their capacity to cross the blood-brain barrier. Remarkably, the patient responded very well to therapy and transitioned from a near-comatose state to significantly improved health, sustained for over three months. This study highlights that MAPKi, particularly targeted towards novel BRAFV600 mutations, might offer promising advancements in eGB treatment strategies.

Keywords: BRAF mutation; Epithelioid glioblastoma; Leptomeningeal disease; MAPK inhibitors.

Fig. 1

Contrast-enhanced T1w magnetic resonance imaging (MRI) of the cervical myelon (a-d) and neurocranium (e-j). Row a-d show the course of spinal involvement: b depicts tumour progression with leptomeningeal (arrowhead) and parenchymal involvement (arrow) within 18 days. Subsequently, the therapy was initiated. c and d show regression of contrast enhancement within 15 days (c) and after 25 days (d). e-g show regression of intracranial involvement with leptomeningeal contrast enhancement of the pons and cranial nerves VII and VIII. h-j demonstrate decrease in ventricular width after therapy initiation and shunt implantation

Fig. 2

Immunohistochemistry analysis of epithelioid glioblastoma. FFPE tissue was stained with HE or with antibodies against EMA, Ki67, GFAP, S100, H3K28me3 and SMARCB1/INI1. A representative area at a magnification x 200 or x 400 (for HE) is shown, scale bar indicates 100–50 μm, respectively

Fig. 3

Immunohistochemistry analyses reveal activation of the MAPK pathway. FFPE tissue of the case was stained with HE or using antibodies against ERK and phospho-ERK (pERK). A representative area at a magnification x 100 is shown. Scale bar indicates 100 μm