Molecular Characterization of Oncogenic Gene Fusions in a Large Real-World Cohort of Solid Tumors

Abstract
Gene fusions are a class of important oncogenic drivers, with many matched FDA-approved targeted therapies across multiple solid tumors. However, the prevalence of fusions varies considerably by cancer type and assay. Fusion detection is technically challenging, and studies have shown that RNA-based next-generation sequencing (NGS) can improve fusion detection rates when used in conjunction with DNA-based NGS. In this study, we performed a retrospective pan-cancer analysis of 67,278 patients receiving both RNA- and DNA-NGS in 43 distinct solid-tumor cancer types, including: NSCLC (18.6%), colorectal cancer (18.2%), and breast cancer (13.1%). In this cohort, 1497 patients (2.2%) had at least one of nine fusions detected—each having an FDA-approved matched therapy in at least one indication. Three hundred and sixteen patients (21.1%) had a fusion detected (RET or NTRK1/2/3) with matched-targeted therapy approved in all cancer indications. Concurrent RNA- and DNA-NGS increased the detection of driver gene fusions by 21% compared to DNA-NGS alone. Gene fusions were observed in a range of cancers beyond their approved cancer indications: of 1,501 fusions detected, 29% (n=437) were detected outside of an FDA-approved indication. Finally, emerging fusion drivers with targets in drug development were found in an additional 218 patients, with combined RNA- and DNA-NGS increasing detection of these variants by 127%. Our findings support combined RNA-NGS and DNA-NGS to maximize detection of clinically actionable fusions with FDA-approved matched therapies, and potentially actionable fusions in non-FDA-approved indications or those matched to therapies in clinical development.