Targeted Next-Generation Sequencing Reveals Exceptionally High Rates of Molecular Driver Mutations in Never-Smokers with Lung Adenocarcinoma

Abstract

Background: Historically, high rates of actionable driver mutations have been reported in never-smokers with lung adenocarcinoma (LUAD); however, in the era of modern, comprehensive cancer mutation sequencing, this relationship necessitates a more detailed analysis. Methods: All Mount Sinai patients between 01/01/2015 and 6/01/2020 with a diagnosis of LUAD of any stage with known smoking status who received genomic testing were included. Most patients were analyzed using the Sema4 hotspot panel or the OCAv3 NGS panel conducted at Sema4. Patients were considered fully genotyped if they were comprehensively analyzed for alterations in EGFR, KRAS, MET, ALK, RET, ROS1, BRAF, NTRK1-3, and ERBB2, otherwise they were considered partially genotyped.Findings236 never-smokers and 671 smokers met the above criteria. Of the never-smokers, 201 (85%) had a driver mutation with 175 (74%) considered actionable. Among smokers, 436 (65%) had an identified driver mutation with 268 (40%) actionable (p<0.0001). When comprehensively sequenced, 95% (70/74) of never-smokers had a driver mutation with 80% (59/74) actionable; whereas, for smokers, 73% (131/180) had a driver with only 44% (79/180) actionable (p<0.0001). Within mutations groups, EGFR G719X and KRAS G12Cs were more common to smokers. For stage IV patients harboring EGFR-mutant tumors treated with EGFR-directed therapies, never-smokers had significantly improved overall survival compared to smokers (HR=3.50; p=0.0066). In multivariable analysis, Asian ancestry and female gender remained significant predictors of 1) overall survival i n stage IV patients and 2) likelihood of harboring an actionable driver mutation. Interpretation: Comprehensive NGS revealed driver alterations in 95% of never-smokers, with the majority having an associated therapy available. All efforts should be exhausted to identify or rule out the presence of an actionable driver mutation in LUAD patients requiring systemic treatment. Funding: Center for Thoracic Oncology Seed funding Declaration of Interests: MIK, KLA, XZ, SG, MF, MR, HA, FMH, WKO, SN, EES, RC are employed by Sema4 and some declare ownership of stock options of Sema4. No other competing interests to declare. PCM has received honoraria from Guardant Health and Amgen. FRH served on advisory boards for Bristol-Myers Squibb, Merck, Novartis, Genentech, AstraZeneca/Daiichi, Sanofi/Regeneron, OncoCyte, Amgen. Patent: “EGFR copy number and Protein Expression as Predictive Biomarker for EGFR directed Therapy” Co-inventor. Patent through University of Colorado. (no royalties) Ethics Approval Statement: Study permission was granted by the Mount Sinai IRB. The procedures followed in this study were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration.