Authors
A. Mohamed, E. Teslow, E. Jaeger, M. Stoppler, S.L Asa, S.H. Tirumani, L. Qiubai, A. Mahipal, D. Bajor, S. Chakrabarti, J.E. Selfridge, M. Lumish, M. Conces, R.S. Hoehn, J. Winter, J. Ammori, J. Hardacre, L.E. Henke, A. Dowlati
BACKGROUND: Small cell neuroendocrine carcinomas (SC-NECs) are uncommon but aggressive tumors with poor prognosis. Although both small cell lung cancer (SCLC) and extrapulmonary small cell NEC (EP-SCNEC) have similar histological and morphological characteristics, whether they are biologically distinct is still unknown. We assessed and compared the genomic profiles of SCLC and EP-SC-NECs to identify distinct mutations that may allow for more personalized therapeutic options.
METHODS: Patients with a histological diagnosis of SC-NEC were identified from the de-identified Tempus realworld multimodal database and stratified by primary tumor site and categorized as SCLC or EP-SCNEC. Patient demographic/clinical characteristics and genomic/transcriptomic data were described as N (%) or median (IQR), min, and max and compared between groups by Chi-squared/Fisher’s Exact tests or Wilcoxon rank-sum tests, as applicable. The prevalence of somatic mutations (SNVs, CNVs, and Fusions) was compared similarly, with a false-discovery rate correction for multiple comparisons. Analyses were two-sided, with statistical significance evaluated at the 0.05 alpha level.
RESULTS: 228 SCLC vs 186 EP-SC-NEC were compared. The two groups did not differ in age, race, or ethnicity when diagnosed. SCLC samples had significantly higher median TMB than EP-SC-NEC samples (5.0 vs 3.4 mut/MB, p<0.001). MSI-H was rare in both groups (SCLC 0.4% vs EP-SC-NEC 2.7%, p=0.10). There were significant differences in SNVs with TP53, RB1, EGFR, and NOTCH1 mutations more common and TERT, ARID1A, APC, FOXA1, and CTNNB1 mutations less common in SCLC (q<0.05). SCLC also had significantly fewer CCNE1 amplifications than EP-SC-NEC. Pathogenic fusions were also more frequent in EP-SC-NEC vs SCLC (q<0.001), with 24% of EP-SC-NEC fusions being TMPRSS2-ERG.
CONCLUSIONS: Despite the histological and morphological overlap between SCLC and EP-SC-NECs, our data revealed heterogeneous molecular characteristics between both groups. These distinct molecular signatures could impact therapeutic decisions for SC-NEC according to their site of origin.
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