Aligning germline and somatic mutations in prostate cancer. Are genetics changing practice?

Abstract

To review the current status of germline and somatic (tumour) genetic testing for prostate cancer, and its relevance for clinical practice. A narrative synthesis of various molecular profiles related to their clinical context was carried out. Current guidelines for genetic testing and its feasibility in clinical practice were analysed. We reported the main identified genetic sequencing results or functional genomic scores for prostate cancer published in the literature or obtained from the French PROGENE study. The molecular alterations observed in prostate cancer are mostly linked to disruption of the androgen receptor (AR) pathway or DNA repair deficiency. The main known germline mutations affect the BRCA2 and HOXB13 genes, whereas AR and TP53 are the genes with most frequent somatic alterations in tumours from men with metastatic prostate cancer. Molecular tests are now available for detecting some of these germline or somatic alterations and sometimes recommended by guidelines, but their utilisation must combine rationality and feasibility. They can guide specific therapies, notably for the management of metastatic disease. Indeed, following androgen deprivation, targeted therapies for prostate cancer currently include PARP inhibitors, immune checkpoint inhibitors and PSMA guided radiotherapy. The genetic tests currently approved for targeted therapies remain limited to the detection of BRCA1 and BRCA2 mutation and DNA mismatch repair deficiency, while large panels are recommended for germline analyses, not only for inherited cancer predisposing syndrome, but also for metastatic prostate cancer. Further consensus aligning germline with somatic molecular analysis in metastatic prostate cancer is required, including genomics scars, emergent immunohistochemistry or functional pre-screen imaging. With rapid advances in knowledge and technology in the field, continuous updating of guidelines to help the clinical management of these individuals, and well conducted studies to evaluate the benefits of genetic testing are needed.