Abstract A013: Genomic prognostic biomarkers in prostate cancer from the AACR GENIE cohort

Abstract INTRODUCTION: Prostate cancer (PC) shows marked heterogeneity in clinical outcomes, from indolent to highly aggressive disease. Alterations in TP53, PTEN, RB1, and DNA damage repair genes are linked to poor patient outcomes, yet how the interaction and co-occurrence of these alterations impact prognosis remains unclear. We leveraged the AACR Project GENIE prostate cancer cohort to assess the prognostic impact of individual and concomitant gene alterations, focusing on key PC drivers (BRCA2, TP53, PTEN, RB1). METHODS: the study was conducted in two stages: (i) identification of candidate alterations at individual gene level through a systematic literature review, followed by analyzing the prevalence and co-occurrence of genes in the AACR Project GENIE Public Release (PR) dataset. (ii) Prognostic analysis of the pre-selected biomarkers in the AACR Project GENIE Biopharma Collaborative (BPC) cohort. Analyses were performed in three clinical settings (entire BPC cohort, n=1114; subgroup of patients with localized disease at diagnosis, n=837; and subgroup of patients with metastatic PC with a biopsy collected before or at the time of mPC, n=455) using two statistical approaches: univariate analysis (UA) and inverse probability weighting using propensity scores (PS). Cox models were applied to estimate overall survival hazard ratios (HRs). RESULTS: after integrating the findings from the systematic review with the analysis of the GENIE PR (n=5684), 107 individual genes and 122 co-occurring alterations were selected for study. In the GENIE BPC (n=1114 patients) 75% were M0 at diagnosis, and 67% presented metastatic PC at any time. Alteration prevalence was: TP53, 25%; PTEN, 15%; BRCA2, 4%; RB1, 4%; co-alterations included, PTEN-TP53 (6.4%), RB1-TP53 (2.1%), PTEN-RB1 (1.3%), and BRCA2-TP53 (1.2%). All four key genes showed a statistically significant prognostic impact in the entire cohort with UA (BRCA2, HR:1.9; TP53, HR:2.6; PTEN, HR:2.4; RB1, HR:4.1, all p