DNA and RNA-based next-generation sequencing for companion diagnostic rearrangement detection in solid tumors

BACKGROUND: While a well-designed next-generation sequencing-based DNA (DNA-NGS) comprehensive genomic profiling assay can be robust for detecting genomic rearrangements (RE), concurrent RNA-based NGS (RNA-NGS) may improve overall sensitivity. PATIENTS & METHODS: We examined detection rates of tissue sequencing-based companion diagnostic (CDx) RE (ALK, BRAF, FGFR2/3, METEx14, NTRK1/2/3, NRG1, RET, and ROS1) in a retrospective cohort of 5129 patients who received DNA- and RNA-NGS in parallel in order to quantify the added value of concurrent DNA- and RNA-NGS over DNA-NGS alone. RESULTS: The prevalence of CDx gene RE was 3.3% (N = 171) across solid tumors and 2.0% (N = 101) within approved tumor types (ITT) across both DNA and RNA. 20% of CDx RE ITT and 26% of CDx gene RE across solid tumors were detected with RNA-NGS only. Detection of NRG1 and NTRK fusions was most improved due to the challenges of baiting these genes on DNA-NGS with 67% of NRG1 RE+ non-small cell lung cancer (NSCLC) and 67% of NTRK RE+ solid tumors identified on RNA alone. A small proportion (4% ITT and 5% across all solid tumors) of CDx gene RE were detected in DNA alone in samples in which RNA could not be sequenced. CONCLUSION: A higher rate of CDx RE detection-most significantly for NRG1 and NTRK fusions-was observed using concurrent DNA-NGS and RNA-NGS compared to DNA-NGS alone. Our results highlight the complementary nature of these methods. Given the substantial clinical benefit of RE-targeted therapies, an integrated DNA/RNA profiling strategy should be part of routine clinical care.