1791P Molecular profiling and prognostic relevance of low PTEN expression in metastatic hormone-sensitive prostate cancer patients

Alterations in PTEN are associated with aggressive behavior and treatment resistance in patients (pts) with castration-resistant prostate cancer (PC). The aim of this study is to characterize the molecular alterations related to PTEN low mRNA expression and its prognostic value in metastatic hormone-sensitive PC (mHSPC) pts. This is a multicenter retrospective study enrolling mHSPC pts. Alterations in PTEN were assessed by mRNA expression by nCounter platform, targeted sequencing, and protein by IHC in FFPE tumor samples. RNA-seq analysis was performed to assess differences in gene expression between low vs. high/medium PTEN expression tumors. PTEN expression was correlated with castration resistance-free survival (CRPC-FS) and overall survival (OS) by Kaplan Meier and multivariate Cox analysis. 218 pts were included: 125 treated with ADT + docetaxel (D) and 93 with ADT, with a median follow-up of 46 months (7-223). Median age was 66 years, 76% of pts presented de novo stage IV and 68% had high-volume disease. 54 pts were tested for PTEN expression and targeted sequencing. Pts with low PTEN expression (PTEN-low) had higher frequency of PTEN mutations (p<0.02) and lower IHC expression (p<0.01). RNAseq (n=66) differential expression analysis found 13 genes differentially expressed (padj<0.05) in PTEN-low vs the rest. In the functional analysis PTEN-low tumors had overexpression of several pathways including cell cycle, DNA repair, metabolism and immune reponse, and infraexpression of the androgen-response hallmark. In the whole cohort, PTEN-low (31%) was independently associated with lower CRPC-FS (13 vs. 20.5 m, HR 1.8 (95% CI, 1.3 – 2.5), p<0.001) and OS (40.1 vs 57.9 m, HR 1.7 (95% CI, 1.2 – 2.3) p=0.003). Moreover, PTEN-low pts treated with ADT+D or ADT presented similar CRPC-FS (12.1 and 14.6 m, respectively) or OS (38.8 and 41 m), while PTEN-high/mid treated with ADT+D had the largest CRPC-FS (21.9 m, p=0.01) and OS (60.1 m, p=0.032), suggesting that PTEN-low pts may not benefit from chemotherapy. Lower expression of PTEN correlates with a distinct molecular profile and a more aggressive disease in pts with mHSPC, supporting the development of new therapeutic strategies for these pts.