1529MO - 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, 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 Pearson’s chi-squared test or Fisher’s 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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Ashok: Financial Interests, Personal, Full or part-time Employment, I am an employee of Tempus labs: Tempus Labs; Financial Interests, Personal, Stocks/Shares, I do have RSU from Tempus Labs: Tempus Labs. E. Mauer: Financial Interests, Institutional, Full or part-time Employment: Tempus Labs; Financial Interests, Personal, Stocks/Shares: Tempus Labs; Non-Financial Interests, Institutional, Proprietary Information: Tempus Labs. E.B. Garon: Financial Interests, Personal, Advisory Board: Novartis, Merck, BMS, EMD Serono, Regeneron, Sanofi, Natera, Shionogi, ABL Bio, Xilio, GSK, Boehringer Ingelheim, Eisai, Gilead, Eli Lilly, Personalis; Financial Interests, Institutional, Invited Speaker: Novartis, Merck, EMD Serono, Eli Lilly, Genetech, Iovance, Neon, Mirati, AstraZeneca, BMS, ABL Bio; Non-Financial Interests, Advisory Role, Scientific Advisory Board: Lungevity. A.E. Lisberg: Financial Interests, Personal, Research Grant: AstraZeneca, Daiichi Sankyo, Calithera Biosciences, Dracen Pharmaceuticals, WindMIL; Financial Interests, Personal, Advisory Board: Bristol-Meters Squibb, Leica Biosystems, Jazz Pharmaceuticals, Novocure, Pfizer, MorphoSys, Eli-Lilly, Oncocyte, Novartis, Regeneron, AstraZeneca; Financial Interests, Personal, Other, Employment (Immediate Family Member): Boston Scientific; Financial Interests, Personal, Stocks/Shares: Boston Scientific. J.W. Goldman: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Genentech, Eli Lilly, Janssen, AbbVie; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Genentech, Eli Lilly, Janssen, BMS, AbbVie. All other authors have declared no conflicts of interest.