Abstract 1271P
Background
The rate and proportion of lung adenocarcinoma (LUAD) cases in never-smokers has increased dramatically. Using targeted NGS and a well-annotated case series of LUAD, we investigated relationships between the frequency and type of driver mutations with patient (pt) ethnicity, age, sex and outcomes based on smoking status.
Methods
From all LAUD pts treated at the Mount Sinai Health System (New York City, USA) from 2015-2020, LUAD pts of any stage with known smoking status and tumor molecular profiling were identified. Depending on the year, tumors were analyzed using a hotspot test or targeted NGS panel (OCAv3 conducted by Sema4, CT, USA) that included all NCCN-guideline molecular markers. Uni- and multi-variable statistical analysis included ethnicity, sex, age, stage, type of marker (Receptor Tyrosine Kinases [RTKs] vs MAPK pathway) and overall survival.
Results
A total of 907 pts with limited or comprehensive molecular analysis were identified, with 236 (26%) never-smokers and 671 (74%) smokers. Among never-smokers, 201 (85%) had driver mutations with 175 (74%) considered actionable with FDA-approved therapies or agents in phase III clinical trials. Among smokers, 436 (65%) had driver mutations with 268 (40%) actionable (p<0.0001). 254 pts had NGS sequencing. In this subgroup, 95% of never-smokers (70/74 pts) had an actionable mutation, with 70% (59/74 pts) treatable with an FDA-approved therapy. In smokers, these were signficantly lower at 73% (131/180) and 22% (79/180), respectively (p<0.0001). For stage IV patients with EGFRm tumors treated on EGFR TKI, never-smokers had significantly improved overall survival vs smokers (HR=3.50; p=0.0066). In multivariable analysis, smoking status, Asian ancestry and female gender were associated with 1) overall survival in stage IV, 2) likelihood of harboring an actionable driver mutation; and 3) the presence of RTK driver abnormalities (EGFR, MET, ERBB2, ALK, RET, ROS1). Asian, Black, Hispanic/Latino were less likely to harbor MAPK mutations (RAS, RAF).
Conclusions
Comprehensive NGS revealed driver alterations in 95% of never-smokers, with the majority having an associated therapy available. Beyond smoking status, ethnicity remained a significant predictor of mutation type and outcome after multivariable analysis.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Mount Sinai.
Funding
Sema4.
Disclosure
M. Klein: Financial Interests, Personal, Full or part-time Employment: Sema4. K. Ayers: Financial Interests, Personal, Full or part-time Employment: Sema4. A. Uzilov: Financial Interests, Personal, Full or part-time Employment: Sema4. X. Zhou: Financial Interests, Personal, Full or part-time Employment: Sema4. D. Corrigan: Financial Interests, Personal, Invited Speaker: Sema4. M. Dietz: Financial Interests, Personal, Full or part-time Employment: Sema4. M. Fink: Financial Interests, Personal, Full or part-time Employment: Sema4. S. Guin: Financial Interests, Personal, Full or part-time Employment: Sema4. N.S. Kip: Financial Interests, Personal, Full or part-time Employment: Sema4. M. Rossi: Financial Interests, Personal, Full or part-time Employment: Sema4. W. Oh: Financial Interests, Personal, Full or part-time Employment: Sema4. F. Hantash: Financial Interests, Personal, Full or part-time Employment: Sema4. S. Newman: Financial Interests, Personal, Full or part-time Employment: Sema4. E.E. Schadt: Financial Interests, Personal, Full or part-time Employment: Sema4. R. Chen: Financial Interests, Personal, Full or part-time Employment: Sema4. F. Hirsch: Other, Personal, Advisory Board, Consultant: AstraZeneca, Daiichi Sankyo; Other, Personal, Advisory Board, Consultant: Sanofi Regeneron; Other, Personal, Advisory Board, Consultant: Novartis; Other, Personal, Advisory Board, Consultant: Amgen; Other, Personal, Advisory Board, Consultant: Oncocyte; Other, Personal, Advisory Board, Consultant: VMS. All other authors have declared no conflicts of interest.