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Background Lung cancer molecular disparities may impact access to targeted therapies and immunotherapy. Although prior studies report variations in genetic alterations by ethnicity and smoking status, few offer subgroup analyses in diverse, underserved urban populations. This study evaluates the prevalence of key driver mutations (EGFR, KRAS, ALK, ROS1) and PD-L1 expression across ethnic groups and smoking status in a safety-net hospital cohort.Methods We conducted a cross-sectional study of patients diagnosed with lung cancer at a safety-net hospital in the Bronx, New York, from July 2022 to June 2024. Detailed chart review was used to stratify patients by ethnicity (Hispanic vs. non-Hispanic, including African American and Caucasian) and smoking status (smoker vs. non-smoker). Molecular profiling included next-generation sequencing (NGS) for EGFR, KRAS, ALK, and ROS1 mutations. PD-L1 expression was assessed via tumor proportion score (TPS), with >50% considered positive. Observed prevalence was compared to published reference data.Results Among 129 lung cancer patients (73 male [56.6%], 56 female [43.4%]), 72 (55.8%) were Hispanic, 46 (35.6%) African American, and 7 (5.4%) Caucasian. PD-L1 positivity among Hispanic patients was 62%. EGFR mutations were present in 46% of Hispanic non-smokers and 22% of non-Hispanic non-smokers. KRAS mutations were absent among Hispanic non-smokers but observed in 78% of non-Hispanic non-smokers. ALK rearrangements were detected in 10% of Hispanic smokers. ROS1 mutations were identified in 11% of non-Hispanic non-smokers.Conclusions Compared to published data, our findings suggest a high EGFR mutation rate in Hispanic non-smokers, comparable to rates observed in Asian populations and exceeding those typically reported in Caucasian cohorts. 1 2 We also observed an unexpectedly elevated KRAS mutation rate in non-Hispanic non-smokers.3 Additionally, ALK and ROS1 alterations appeared more prevalent in certain subgroups than previously reported.2 4 These disparities underscore the importance of inclusive molecular screening and the need for clinical trials that better represent underserved and ethnically diverse populations.References Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015;5(9):2892–2911.Arrieta O, Cardona AF, Bramuglia GF, Gallo A, Campos-Parra AD, Serrano S, et al. Genotyping non-small cell lung cancer in Latin America. J Thorac Oncol. 2011;6(11):1955–1959.Reita D, Pabst L, Pencreach E, Guérin E, Dano L, Rimelen V, et al. Direct targeting KRAS mutation in non-small cell lung cancer: focus on resistance. Cancers (Basel). 2022;14(5):1321.Zhu Q, Zhan P, Zhang X, Lv T, Song Y. Clinicopathologic characteristics of patients with ROS1 fusion gene in non-small cell lung cancer: a meta-analysis. Transl Lung Cancer Res. 2015;4(3):300–309.