Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy

Abstract

Chromosomal rearrangements involving the NTRK1, NTRK2, and NTRK3 genes (NTRK genes), which encode the high-affinity nerve growth factor receptor (TRKA), brain-derived neurotrophic factor/neurotrophin-3 (BDNF/NT-3) growth factor receptor (TRKB), and neurotrophin-3 (NT-3) growth factor receptor (TRKC) tyrosine kinases (TRK proteins), act as oncogenic drivers in a broad range of pediatric and adult tumor types. NTRK gene fusions have been shown to be actionable genomic events that are predictive of response to TRK kinase inhibitors, making their routine detection an evolving clinical priority. In certain exceedingly rare tumor types, NTRK gene fusions may be seen in the overwhelming majority of cases, whereas in a range of common cancers, reported incidences are in the range of 0.1% to 2%. Herein, we review the structure of the three NTRK genes and the nature and incidence of NTRK gene fusions in different solid tumor types, and we summarize the clinical data showing the importance of identifying tumors harboring such genomic events. We also outline the laboratory techniques that can be used to diagnose NTRK gene fusions in clinical samples. Finally, we propose a diagnostic algorithm for solid tumors to facilitate the identification of patients with TRK fusion cancer. This algorithm accounts for the widely varying frequencies by tumor histology and the underlying prevalence of TRK expression in the absence of NTRK gene fusions and is based on a combination of fluorescence in situ hybridization, next-generation sequencing, and immunohistochemistry assays.