889MO Comparative expression of driver transcription factors in extra-pulmonary small cell carcinoma

Abstract

Extra-pulmonary small cell carcinomas (EPSCC) are aggressive neuroendocrine tumors that are clinicopathologically distinct from small cell lung cancer (SCLC). Recent data suggest that transcriptionally-defined SCLC subtypes exhibit different underlying biology and therapeutic vulnerabilities. With limited data available on the EPSCC transcriptomic landscape, we analyzed gene expression profiles and its correlation with clinical outcomes across EPSCC anatomic sites. DNA (592 genes/whole-exome) and RNA (whole transcriptome) sequencing were performed for 1070 small cell carcinoma (SCC) patient (pt) samples that underwent molecular profiling at Caris Life Sciences (Phoenix, AZ). Samples were stratified into 5 subtypes based on the relative expression of key transcription factors (TFs): ASCL1, NEUROD1, YAP1, POU2F3, and Mixed. Real-world survival information was available for 111 pts treated with etoposide+platinum (EP) therapy. Overall survival (OS) was obtained from insurance claims & Kaplan-Meier estimates. Statistical significance is determined by Chi-square & Wilcoxon rank sum tests. EPSCC comprised 28.8% (n=308) of SCCs evaluated; most common primary sites included gynecologic (GYN, 21.8%, n=67), prostate (16.6%, n=51), bladder (15.9%, n=49) and colorectal (10.1%, n=31). Each primary site had a unique distribution of molecular subtypes relative to SCLC. ASCL1 was less frequent in GYN and bladder SCC (13.4% and 16.3%) compared to SCLC (35.7%), with bladder SCC enriched in NEUROD1 and POU2F3 (30.6% and 22.4% vs SCLC 17.5% and 6.4%, P<0.05). YAP1 was most common in GYN SCC (35.8% vs SCLC 20.7%, P<0.05). For both SCLC and EPSCC, low YAP1 was associated with improved OS (SCLC HR 2.1, P=0.05; EPSCC HR 4.3, P=0.02), and high NEUROD1 trended towards improved OS (SCLC HR 0.6, P=0.12; EPSCC HR 0.4, P=0.10) from start of EP therapy. Our analysis revealed differential expression of key lineage-defining TFs in EPSCCs from various anatomic sites that looked distinct from SCLC. EPSCC and SCLC OS was similarly associated with TF expression, suggesting the underlying biology of SCLC and EPSCC subtypes might predict comparable therapeutic vulnerabilities.