How the Analysis of the Pathogenetic Variants of DDR Genes Will Change the Management of Prostate Cancer Patients.

Herein, we analyze answers achieved, open questions, and future perspectives regarding the analysis of the pathogenetic variants (PV) of DNA damage response (and repair) (DDR) genes in prostate cancer (PC) patients. The incidence of PVs in homologous recombination repair (HRR) genes among men with metastatic PC varied between 11% and 33%, which was significantly higher than that in non-metastatic PC, and BRCA2 mutations were more frequent when compared to other DDR genes. The determination of the somatic or germline PVs of BRCA2 was able to define a tailored therapy using PARP inhibitors in metastatic castration-resistant prostate cancer (mCRPC) progression after first-line therapy, with significant improvements in the radiologic progression-free survival (rPFS) and overall survival (OS) rates. We propose testing all metastatic PC patients for somatic and germline HRR mutations. Somatic determination on the primary site or on historic paraffin preparations with a temporal distance of no longer than 5 years should be preferred over metastatic site biopsies. The prognostic use of DDR PVs will also be used in selected high-risk cases with non-metastatic stages to better arrange controls and therapeutic primary options. We anticipate that the use of poly-ADP-ribose polymerase (PARP) inhibitors in hormone-sensitive prostate cancer (HSPC) and in combination with androgen receptor signaling inhibitors (ARSI) will be new strategies.

International journal of molecular sciences. 2022 Dec 30*** epublish ***

Alessandro Sciarra, Marco Frisenda, Giulio Bevilacqua, Alessandro Gentilucci, Susanna Cattarino, Gianna Mariotti, Francesco Del Giudice, Giovanni Battista Di Pierro, Pietro Viscuso, Paolo Casale, Benjamin I Chung, Riccardo Autorino, Simone Crivellaro, Stefano Salciccia

Department "Materno Infantile e Scienze Urologiche", University Sapienza, 00161 Rome, Italy., Department of Urology, Humanitas Center, 20089 Milano, Italy., Department of Urology, University School of Stanford, Stanford, CA 94305, USA., Department of Urology, Rush University Medical Center, Chicago, IL 60612, USA., Department of Urology, University of Illinois Hospital, Chicago, IL 60612, USA.