Background
Small cell lung cancer (SCLC) predominantly develops in patients with significant smoking history, but 6-8% of patients in recent SCLC datasets have no tobacco exposure. Prior reports have suggested that SCLC in never smoking patients may have unique genomic traits.

Methods
We retrospectively analyzed records from SCLC patients reporting “never smoking” (NS, n = 54) or “current/former smoking” (C/FS, n = 609) status. Tumors were sequenced with the Tempus xT assay, including a targeted DNA panel (595-648 genes) and whole exome capture RNA-seq. Tumor immune cell infiltration was estimated from RNA expression data. PD-L1 positivity was defined by tumor expression > 1% using 22C3 pharmDx IHC. Statistical significance was assessed with Pearsonʼs chi- squared test or Fisherʼs exact test, using a threshold of p < 0.05 or false discovery rate-adjusted q < 0.05.

Results
Compared with CF/S patients, NS patients were more likely to be female (70% vs 55%, p = 0.031). Tumors of NS patients had a lower prevalence of TP53 mutations (59% vs 85%, q < 0.001) but no significant difference in RB1 mutations (57% vs 63%, q = 0.600). Meanwhile, NS patients had a higher prevalence of EGFR (26% vs 2.6%, q < 0.001) and PIK3CA (15% vs 3.6%, q = 0.022) mutations. We also observed a trend towards higher rates of mutations in FGF4 (7.4% vs 1.6%, q = 0.100) and NF1 (7.4% vs 1.3%, q = 0.092). Gene fusions were infrequently found, with no notable difference across cohorts. With regard to the immune environment, NS patients had lower tumor mutation burden (2.59/Mb vs 4.99/Mb, p < 0.001) and a trend towards higher PD-L1 positivity (20% vs 9%, p = 0.086). NS tumors also had decreased immune cell infiltration (median 2% vs 10%, p = 0.008), and specifically a lower proportion of CD4+ and CD8+ T cells and higher proportion of macrophages.

Conclusions
The mutational landscape of SCLC in NS patients significantly differs from that of C/FS patients. Tumors of NS patients were more likely to harbor mutations in oncogenic drivers – such as EGFR and PIK3CA – and exhibited lower TMB and immune cell infiltration. These findings suggest that the occurrence of SCLC in NS patients may represent a distinct genomic entity and treatment implications should be further explored.

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