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

Abstract

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.

Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications

“…Undoubtedly, the role of the clinical geneticist is becoming increasingly important at the current stage of mCRPC management, and due to the prognostic value of the homologous recombination repair number, the indications for somatic and germline mutation testing in high-risk cancer will expand [168]. DDR mutations can be identified through the analysis of peripheral whole blood testing or tumor tissue.…”

Poly (ADP-ribose) Polymerase Inhibitors in Patients with Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis of Randomized Controlled Trials

“…It has been postulated that patients without HRR mutations may still derive potential benefits from PARP inhibition [33]. On the one hand, PARP inhibitors can attenuate the transcriptional activity of the androgen receptor (AR), thereby enhancing the inhibitory effects of ARi on AR pathways [34,35].…”

Editorial: Circulating biomarkers in prostate cancer

“…Homology recombination repair (HRR), the frequently altered DNA damage repair (DDR) mechanism in prostate cancer, involves genes like BRCA2. Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib and talazoparib, show antitumor activity in mCRPC with BRCA gene alterations ( 5 , 6 ). Genomic testing for HRR gene mutations, especially using ctDNA, is crucial for guiding PARP inhibitor treatment.…”