Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer

TP53 , PTEN , and RB1 tumor suppressor genes (TSGs) are recurrently altered in treatment-resistant prostate cancer. Cooperative loss of two or more TSGs may drive more aggressive disease. To determine clinical outcomes of single and compound TSG alterations across the spectrum of prostate cancer. Massively parallel targeted sequencing using castration-sensitive prostate cancer (CSPC; localized [L] and metastatic [M1]) and castration-resistant prostate cancer (CRPC) specimens ( n = 285). TSG altered (TSG-alt) was any copy number loss or deleterious mutation of one or more TSGs ( TP53 , PTEN , and RB1 ). For L-CSPC, event-free survival (EFS) and time to CRPC were estimated. For M1-CSPC and M1-CRPC, overall survival (OS) was estimated. Cox regression models assessed the association between cumulative TSG hits (zero hits vs one hit vs two to three hits) and outcomes with multivariable analyses adjusted for clinicopathological factors. TSG variants increased with advanced disease (L-CSPC: 39%; M1-CSPC: 63%, M1-CRPC: 92%). TSG-alt L-CSPC had shorter EFS (median 2.6 yr, hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.22–3.13) and time to CRPC (median 9.5 mo, HR 3.36, 95% CI 1.01–11.16). Cumulative gene hits led to an incremental risk of relapse (EFS: one gene, HR 1.69, 95% CI 0.99–2.87; two to three genes, HR 2.70, 95% CI 1.43–5.08; both versus zero genes, p = 0.004). There was evidence of inferior OS with increasing TSG hits in the metastatic cohorts. Only four (8%) patients in the M1-CRPC cohort were TSG-neg, one of whom died after 5.2 yr. Multivariable analyses adjusting for mutational and copy number burden did not demonstrate a significant independent association of increasing gene hits and poorer outcomes. Deleterious TSG variants are associated with an increased risk of relapse (L) and death (M1) in CSPC. Poorer outcomes are seen with compound gene hits in both early and advanced disease, and this may in part reflect increasing global genomic instability. Men with prostate tumors with compound tumor suppressor gene mutations have poorer outcomes. These findings help identify patients with aggressive features who may benefit from intensified treatment. Alterations of TP53, PTEN, and RB1 tumor suppressor genes are present across the clinical spectrum of prostate cancer and are particularly frequent in metastatic and castration-resistant disease. Alterations are associated with poorer outcomes, with incremental risk seen with compound loss, thereby identifying at-risk patient subgroups in the early and advanced disease settings.