NTRK fusions and concomitant immune and genomic landscape detected by DNA and RNA comprehensive genomic profiling in a large healthcare system

Introduction The use of next-generation sequencing (NGS) in clinical investigations has enabled the identification of actionable biomarkers across tumor histologies, paving the way for the development of pan-tumor therapies. Gene fusions involving NTRK1, NTRK2 , and NTRK3 (NTRK1/2/3) have emerged as rare yet clinically significant oncogenic drivers in a wide range of both pediatric and adult tumors due to high response rates to FDA-approved targeted therapies. Consequently, widespread testing for NTRK fusions is recommended across tumor types. However, data on NTRK fusions in cancer have predominantly been sourced from academic institutions and reference laboratories. Methods In this study, we investigated the frequency of NTRK fusions and co-occurring genomic alterations across solid tumor types in a large, real-world patient cohort that received DNA and RNA hybrid capture-based comprehensive genomic profiling (CGP) in the Providence community health system. Results Among 15,128 adult patients, CGP identified 30 pathogenic NTRK1/2/3 fusions, corresponding to a clinically actionable prevalence of 0.2% across 12 solid tumor types. An additional 11 NTRK fusions were classified as variants of unknown significance, and 8 of the identified NTRK fusions in the cohort were novel. The number of distinct and novel fusion partners identified demonstrates the genomic diversity of NTRK fusions observed in routine clinical practice. Discussion These findings highlight the value of RNA-based NGS, particularly when used alongside DNA NGS, to provide a comprehensive assessment of NTRK fusions and co-occurring gene alterations. Implementation of combined DNA and RNA CGP in a community health system setting enables detection of both known and novel NTRK fusions and can inform clinical care of cancer patients.