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

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

S. Puri: Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca, G1 Therapeutics; Financial Interests, Personal and Institutional, Invited Speaker: Onclive; Financial Interests, Institutional, Research Grant: 5 for the fight. A. Elliott: Non-Financial Interests, Personal and Institutional, Other, Employee: Caris. H.P. Soares: Financial Interests, Personal, Advisory Board, Consulting fees: Ipsen, TerSEra, AstraZeneca, Incyte. E. Lou: Financial Interests, Personal, Invited Speaker: GlaxoSmithKline, Daiichi Sankyo, Boston Scientific US; Financial Interests, Personal and Institutional, Invited Speaker: Novocure; Financial Interests, Personal and Institutional, Research Grant: Novocure; Financial Interests, Institutional, Research Grant: American Association for Cancer Research (AACR-Novocure Tumor-Treating Fields Research Award, Grant Number 19-60-62-LOU, American Cancer Society, The Randy Shaver Cancer Research and Community Fund, Minnesota Ovarian Cancer Alliance in 2019, 2021, and 2022; Non-Financial Interests, Personal, Advisory Board: Nomocan Pharmaceuticals, Minnetronix, LLC; Non-Financial Interests, Institutional, Principal Investigator: Celegene, Intima Biosciences. B. Halmos: Financial Interests, Personal and Institutional, Research Grant: Boehringer Ingelheim, AstraZeneca, Merck , BMS, Advaxis, Amgen, AbbVie, Daiichi, Pfizer, GSK, BeiGene, Janssen; Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Veracyte, Janssen, Takeda, Merck, BMS, Genetech, Pfizer, Eli Lilly. C.J. Langer: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Novocure, AstraZeneca, Takeda, Genetech/Roche, Merck, Gilead, GSK, Pfizer, Onclive, RTP, Regeneron, Sanofi-Aventis; Financial Interests, Institutional, Research Grant: Eli Lilly, Trizel, Merck, Takeda, Inovio, AstraZeneca, Oncocyte, Janssen, Amgen; Financial Interests, Institutional, Other, Medical Writing support: Novartis ; Financial Interests, Personal, Other, DSMC: Eli Lilly, Amgen, Oncocyte Dx. D. Uprety: Financial Interests, Personal, Advisory Board: Daiichi Sankyo Inc, AstraZeneca, Sanofi. S. Darabi: Financial Interests, Personal, Invited Speaker: Oncolense; Financial Interests, Personal, Advisory Board: Bayer. P. Walker: Non-Financial Interests, Personal and Institutional, Other, Employee: Caris. W. El-Deiry: Financial Interests, Personal, Stocks/Shares: Oncoceutics, p53 Therapeutics, Chimerix; Financial Interests, Personal, Research Grant: D&D Pharmatech; Financial Interests, Personal, Other: Patent on TIC10. A. VanderWalde: Non-Financial Interests, Personal and Institutional, Other, Employee: Caris; Financial Interests, Personal and Institutional, Research Grant: AACR stand up to Cancer Grant; Financial Interests, Personal, Advisory Board: BMS, George Clinical, Elsevier. S. Liu: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Boehringer Ingelheim, BMS, Daiichi Sankyo, Eisai, Elevation Oncology, Genetech Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Eli Lilly Merck, Novartis, Regeneron, Sanofi, Takeda, Turning point therapeutics; Financial Interests, Institutional, Research Grant: Alkermes, Bayer, Blueprint, BMS, Elevation Oncology, Genetech, Gilead, Merck, Merus, Nuvalent Pfizer, Rain Therapeutics, RAPT, Turning Point Therapeutics. All other authors have declared no conflicts of interest.