Abstract 2244: Association of chromosomal instability with poor prognosis in metastatic hormone sensitive and castrate-resistant prostate cancer
Authors: Rebernick Ryan J. , Hammer Liat , McFarlane Matthew , Westbrook Thomas , Hazime Munna , Hammoud Tanya , Chiu Pin-en , Wu Yi-Mi , Robinson Dan , Spratt Daniel Eidelberg , Alva Ajjai S. , Jackson William C. , Reichert Zachery R. , Chinnaiyan Arul , Alumkal Joshi J. , Dess Robert T. , Cieslik Marcin 
Published: April 2023

Abstract
Introduction: Chromosomal instability (CIN) is a continuum of chromosomal gains and losses present in tumor cells. While increasing CIN is linked to poor patient outcomes in select cancers, the prognostic significance of CIN, and its association with molecular phenotypes and therapeutic response in advanced prostate cancer (PCa) is poorly understood. We characterize CIN in aggressive Pca by integrating DNA/RNA sequencing with detailed clinical information.
Methods: From 4/2005-7/2021, 290 men with advanced PCa underwent IRB-approved tissue collection for tumoral RNA-sequencing and tumor/normal whole exome sequencing. DNA/RNA sequencing data for 328 libraries across 304 biopsies was processed using Turnkey Precision Oncology. CIN was measured using the weighted genome integrity index (wGII). Driver mutations (ETS fusions, SPOP, FOXA1 class 1, and CDK12 mutations), TP53 mutations and AR amplification status were determined. GSEA and EPIC were used for pathway/immune deconvolution. Associations with overall survival (OS) from the time of biopsy were determined via multivariable analysis (MVA).
Results: 36 samples were from patients with localized disease (LD), 101 from metastatic hormone sensitive PCa (mHSPC) and 191 from metastatic castrate resistant PCa (mCRPC). wGII was associated with disease state: LD (median:0.28, IQR:[0.18-0.48]); mHSPCa (0.36, [0.21-0.58]); mCRPC (0.52, [0.35-0.62]) (p&lt;0.001). TP53 loss was associated with wGII, independent of disease state (p&lt;0.001). Strikingly, AR-amplifications were associated with increased wGII when controlled for disease state (p=2.2e-9). wGII was negatively associated with CD8+ T cell levels (R=-0.24,p=7.7e-4) and this remained significant on MVA adjusting for disease state and tumor purity (p=0.003). For mCRPC samples, GSEA of wGII-high tumors identified upregulation of EMT (q=6.8e-14) and downregulation of androgen response (q=2.7e-6). Additionally, wGII levels did not differ by prior exposure to enhanced hormonal agents or taxane therapy (p=0.82, p=0.70). Finally, high wGII was associated with worse OS when controlled for age, disease state, TP53 loss, AR amplification, and purity (HR: 3.28; 95% CI: 1.39-7.80, p=0.007).
Conclusions: We identify CIN as one of the strongest genetic predictors of poor patient outcomes in metastatic PCa. Future research is needed to identify therapeutic vulnerabilities in this newly-described genetic subset of aggressive prostate cancers.
Citation Format: Ryan J. Rebernick, Liat Hammer, Matthew McFarlane, Thomas Westbrook, Munna Hazime, Tanya Hammoud, Pin-en Chiu, Yi-Mi Wu, Dan Robinson, Daniel Eidelberg Spratt, Ajjai S. Alva, William C. Jackson, Zachery R. Reichert, Arul Chinnaiyan, Joshi J. Alumkal, Robert T. Dess, Marcin Cieslik. Association of chromosomal instability with poor prognosis in metastatic hormone sensitive and castrate-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2244.