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

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación (PI18/714).

Disclosure

O. Reig Torras: Financial Interests, Personal, Invited Speaker: BMS, Ipsen, Pfizer. A. Font Pous: Financial Interests, Personal and Institutional, Research Funding: AstraZeneca; Financial Interests, Institutional, Research Funding: Astellas, Pierre Fabre; Financial Interests, Personal, Advisory Role: Janssen, Roche. L. Ferrer-Mileo: Financial Interests, Personal, Invited Speaker: BMS. A. Sánchez-Font: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Bayer; Financial Interests, Personal, Invited Speaker: Janssen. A. Rodriguez-Vida: Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Advisory Board: Bayer, BMS, MSD; Financial Interests, Personal, Speaker, Consultant, Advisor: Roche. M. Figols Gorina: Financial Interests, Personal, Speaker’s Bureau: Pfizer, Ipsen. M.A. Climent Duran: Financial Interests, Personal, Invited Speaker: BMS, Astellas; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Role: Roche, Novartis, Pfizer. E. Gonzalez Billalabeitia: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Astellas, Janssen, Bayer. B. Mellado Gonzalez: Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Invited Speaker: BMS, Pfizer; Financial Interests, Personal and Institutional, Research Funding: Janssen; Financial Interests, Institutional, Research Funding: Bayer, Pfizer. All other authors have declared no conflicts of interest.