Clinical and radiographic response following targeting of BCAN-NTRK1 fusion in glioneuronal tumor

Abstract

Glioneuronal tumors constitute a histologically diverse group of primary central nervous system neoplasms that are typically slow-growing and managed conservatively. Genetic alterations associated with glioneuronal tumors include BRAF mutations and oncogenic fusions. To further characterize this group of tumors, we collected a cohort of 26 glioneuronal tumors and performed in-depth genomic analysis. We identified mutations in BRAF (34%) and oncogenic fusions (30%), consistent with previously published reports. In addition, we discovered novel oncogenic fusions involving members of the NTRK gene family in a subset of our cohort. One-patient with BCAN exon 13 fused to NTRK1 exon 11 initially underwent a subtotal resection for a 4th ventricular glioneuronal tumor but ultimately required additional therapy due to progressive, symptomatic disease. Given the patient's targetable fusion, the patient was enrolled on a clinical trial with entrectinib, a pan-Trk, ROS1, and ALK (anaplastic lymphoma kinase) inhibitor. The patient was treated for 11 months and during this time volumetric analysis of the lesion demonstrated a maximum reduction of 60% in the contrast-enhancing tumor compared to his pre-treatment magnetic resonance imaging study. The radiologic response was associated with resolution of his clinical symptoms and was maintained for 11 months on treatment. This report of a BCAN-NTRK1 fusion in glioneuronal tumors highlights its clinical importance as a novel, targetable alteration.

Fig. 1

NTRK fusion in glioneuronal tumors can be treated with Trk-inhibitors. a Fluorescence in situ hybridization (FISH) using split apart probes, with separation of the 5′ (green) and 3′ (red) NTRK1 signals, reveal abnormal rearrangement, with some red–green pairs showing a small green probe signal (arrows). b Schematic of three different NTRK-containing gene fusions discovered in the glioneuronal cohorts from MGH and Vancouver, involving either NTRK1 or NTRK2. Predicted active domains in the expression product are depicted below. TM transmembrane. c Sagittal (top) and axial (bottom) post-contrast T1-weighted MRI images of patient with BCAN-NTRK1 fusion just prior to treatment with entrectinib (left) and following 9 months on treatment (right). The T1-avid tumor visualized in dorsal pons and medulla has decreased in size during this time period. d Plot demonstrating tumor volume over time while patient was on treatment with entrectinib using MRI-derived volumetrics (see Methods). Baseline tumor volume was measured approximately 2 years prior to treatment. Tumor volume initially slowly increased, then expanded more rapidly coincident with onset of clinical symptoms. Treatment with entrectinib led to rapid and substantial decrease in tumor volume. Period on treatment denoted with thick black line