Early diagnosis of prostate cancer in healthy men with germline mutations in DNA Damage Response (DDR) pathways: A literature review and proposal for a screening strategy

Abstract

Introduction

Men with mutations in DNA damage response (DDR) pathways have a higher risk of developing prostate neoplasia compared to the general population. The best studied alterations are mutations in BRCA1/2, ATM and MMR-Lynch syndrome.

Material and methods

A review of the clinical and prognostic implications of mutations in DDR pathways, as well as an evaluation of the different screening strategies available for affected patients.

Objective

To propose an early diagnostic strategy for men with mutations in DDR pathways.

Results

Current guidelines do not provide clear, specific recommendations for this subgroup of men. Among mutations in the MMR pathway, the germline MSH2 mutation is most strongly associated with prostate cancer. Men with germline mutations in BRCA1/2, ATM, and MSH2 have a higher incidence of prostate neoplasia, tend to develop the disease at a younger age, and are more likely to have aggressive forms of the disease. Furthermore, men with BRCA1/2 mutations have a lower cancer-specific survival rate compared to the general population. In these patients, PSA levels have important limitations in detecting prostate cancer. Multiparametric MRI of the prostate may be more effective than periodic PSA testing.

Conclusions

Patients with mutations in DDR pathways are at increased risk for aggressive prostate neoplasms and require earlier and more intensive screening. PSA-based screening has notable limitations. A screening strategy incorporating multiparametric MRI could offer a more effective strategy for this patient group.