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

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Prostate cancer (PC) prognosis and treatment can be influenced by genetic alterations.
• DNA damage response (DDR) and repair (DDR) gene pathogenetic variants (PVs) are implicated in PC development and progression.

Purpose of the Study:

• To analyze current findings, open questions, and future directions regarding DDR gene PVs in prostate cancer.
• To evaluate the clinical utility of identifying DDR gene PVs for therapeutic decisions and prognostic assessment.

Main Methods:

• Review and analysis of existing literature on DDR gene PVs in prostate cancer.
• Correlation of PV incidence with disease stage (metastatic vs. non-metastatic).
• Assessment of therapeutic responses to PARP inhibitors based on specific gene mutations.

Main Results:

• Higher incidence of PVs in homologous recombination repair (HRR) genes in metastatic PC (11-33%) compared to non-metastatic PC.
• BRCA2 mutations were more frequent than other DDR gene mutations in metastatic PC.
• Somatic or germline BRCA2 PVs enabled tailored therapy with PARP inhibitors in metastatic castration-resistant prostate cancer (mCRPC), improving radiologic progression-free survival (rPFS) and overall survival (OS).

Conclusions:

• Testing all metastatic PC patients for somatic and germline HRR mutations is proposed.
• Somatic testing on primary or historic samples (within 5 years) is preferred over metastatic biopsies.
• DDR PVs have prognostic value for high-risk non-metastatic PC, aiding in management and treatment planning.
• Future strategies include using poly-ADP-ribose polymerase (PARP) inhibitors in hormone-sensitive prostate cancer (HSPC) and combination therapies with androgen receptor signaling inhibitors (ARSI).