Association of circulating tumor cell RB1 loss RNA signature with outcomes and immune phenotypes in men with mCRPC.

• DOI: 10.1200/jco.2022.40.6_suppl.139
• Publication Date: 2022-02-16T21:35:25Z
• Authors: Jiaren Zhang; Bob Zimmermann; Giuseppe Galletti; Susan Halabi; Ada Gjyrezi; Qian Yang; Santosh Gupta; Andrea Sboner; Monika Anand; Daniel J. George; Simon Gregory; Seunghee Hong; Virginia Pascual; Clio P. Mavragani; Emmanuel S. Anton...; David M. Nanus; Scott T. Tagawa; Olivier Elemento; Andrew J. Armstrong; Paraskevi Giannak...
• Keywords: Circulating tumor cell; Enzalutamide

139 Background: Androgen receptor signaling inhibitors (ARSi) are a mainstay for patients with metastatic castration-resistant prostate cancer (mCRPC). However, patient response is heterogeneous and the molecular underpinnings of ARSi resistance not well elucidated. Methods: We performed transcriptome analysis circulating tumor cells (CTCs) peripheral blood mononuclear (PBMC) in context PROPHECY, prospective clinical trial men (n = 118) mCRPC treated abiraterone (Abi) or enzalutamide (Enza). obtained CTCs at baseline (before treatment) time progression on Abi/Enza, comprehensive transcriptomic CTC samples 40) correlated outcomes to identify mechanisms resistance. In addition, we also matching (PBMCs) order uncover potential involvement immune macroenvironment (CIME) The proportional hazard model was used determine prognostic significance these signatures predicting overall survival (OS) progression-free (PFS). Results: RNA-sequencing identified that RB loss concurrently enhanced E2F transcriptional networks were associated intrinsic Using single sample GSEA (ssGSEA) score, RB/E2F common signature short PFS (median 6.5 months) OS 24.5 (hazard ratio (HR) 3.5; 95% CI 1.5-8.2) mCRPC. further developed BRCA which validated SU2C cohort, by showing network reflected genomic alterations as it significantly enriched BRCA-altered vs unaltered patients. Generating ssGSEA scores PROPHECY cohort observed high experienced shorter (HR 2.42; 1-5.9). Through comparison profiles baseline, an inflammatory acquired Transcriptomic PBMCs enrichment inflammasome gene indicative activated innate immunity progression, concurrent downregulation CD8 T NK cells. Importantly, loss/E2F had significant positive association this CIME signatures. Conclusions: Taken together, data demonstrate liquid biopsy transcriptomics both can pathways paving way treatment optimization development novel precision therapies