Comprehensive molecular profiling of squamous non-small cell lung cancer reveals high incidence of actionable genomic alterations among patients with no history of smoking

Background: Next-generation sequencing (NGS) to detect actionable genomic driver alterations (AGAs) is critical to appropriate management of non-small cell lung cancer (NSCLC), but is inconsistently performed for squamous NSCLC (sqNSCLC). Molecular characterization of sqNSCLC by smoking status has not been well-reported. We analyzed a large cohort of sqNSCLC utilizing NGS to elucidate molecular differences in sqNSCLC by smoking status. Methods: sqNSCLC was profiled by NGS using a 592 gene panel. Smoking status was obtained from medical records. Genomic alterations, mutation burden, PD-L1 immunohistochemistry, gene set enrichment analyses (GSEA), immune-cell infiltration, and clinical outcomes were compared between never- and ever-smokers. Fisher's exact, Mann-Whitney U or t-tests were used, where appropriate. Statistical significance was defined as p < 0.05 with q < 0.05 or FDR < 0.25, where appropriate. Results: 2,891 patients with sqNSCLC were included, of which 2862 (98%) were ever-smokers and 63 (2%) were never-smokers. AGAs were detected in 22.2% (14/63) of never-smokers and 2.4% (69/2828) of ever-smokers. Never-smokers had a significantly higher prevalence of actionable MET and EGFR mutations compared to ever-smokers (9.5% vs 0.4% and 7.9% vs 0.4%, respectively), though actionable alterations were detected in both cohorts. GSEA revealed significantly enriched expression of interferon-α, interferon-γ and IL-6/JAK/STAT pathways in never-smokers. Conclusion: A high frequency of AGAs were detected in never-smokers with sqNSCLC, with significantly increased prevalence of actionable EGFR and MET alterations compared to ever-smokers. Our findings indicate that, analogous to the diagnostic algorithm for non-squamous NSCLC, NGS testing to inform frontline treatment decision-making is critical for never-smokers with sqNSCLC.