Brief Report: The Genomic Landscape of Small Cell Lung Cancer in Never-Smoking Patients.

Background: Small cell lung cancer (SCLC) predominantly develops in patients with significant smoking history, and patients who have no history of tobacco exposure remain understudied. Prior reports have suggested that SCLC in never-smoking patients may have unique genomic traits.

Methods: We retrospectively analyzed records from the Tempus clinicogenomic database to identify SCLC patients reporting "never smoking" (NS, n = 54) or "current/former smoking" (C/FS, n = 608) status. Tumors were sequenced with the Tempus xT assay, including a targeted 648-gene DNA panel and whole exome capture RNA-seq. Tumor immune cell infiltration was estimated from RNA expression data and PD-L1 expression status was determined by immunohistochemistry.

Results: Compared with CF/S patients, NS patients were more likely to be female (70% vs. 55%). Tumors of NS patients had a lower prevalence of TP53 mutations (59% vs. 85%) but no significant difference in RB1 mutations (57% vs. 63%). NS patients had a higher prevalence of EGFR (26% vs. 2.6%), PIK3CA (15% vs. 3.6%), and OS9 (5.6% vs. 0.0%) mutations. Similar findings were observed even after removing cases of transformation from non-small cell lung cancer (NSCLC) or combined SCLCNSCLC presentations. In addition, tumors of NS patients had a lower tumor mutation burden and decreased immune cell infiltration, including by CD4+ and CD8+ T cells.

Conclusion: The mutational landscape of SCLC in NS patients significantly differs from that of C/FS patients, suggesting that the occurrence of SCLC in NS patients may represent a distinct genomic entity.