Genetic Aberrations of DNA Repair Pathways in Prostate Cancer: Translation to the Clinic

Abstract

Prostate cancer (PC) is the second most common cancer in men worldwide. Due to the large-scale sequencing efforts, there is currently a better understanding of the genomic landscape of PC. The identification of defects in DNA repair genes has led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients. The identification of molecularly defined subgroups of patients has also other clinical implications; for example, we now know that carriers of breast cancer 2 (BRCA2) pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rate; BRCA2 PSVs confer lower overall survival (OS). Distinct tumor PSV, methylation, and expression patterns have been identified in BRCA2 compared with non-BRCA2 mutant prostate tumors. Several DNA damage response and repair (DDR)-targeting agents are currently being evaluated either as single agents or in combination in patients with PC. In this review article, we highlight the biology and clinical implications of deleterious inherited or acquired DNA repair pathway aberrations in PC and offer an overview of new agents being developed for the treatment of PC.

The Feasibility of Implementing Mainstream Germline Genetic Testing in Routine Cancer Care—A Systematic Review

“…When the genetic test result has consequences for the treatment of cancer, it is important that turnaround times for genetic testing are minimized. For patients with ovarian cancer and prostate cancer for example, there is clear evidence that patients carrying a pathogenic variant in a BRCA gene have the highest response rates to PARP inhibitors [ 5 , 46 ]. The longest delay in the turnaround time for the standard genetic testing pathway is probably the time between referral and first appointment with a genetic counselor due to long waiting lists [ 47 ].…”

Perspectives on PARP Inhibitor Combinations for Ovarian Cancer

“…Germline BRCA mutations are also common in some particular scenarios of other malignancies, such as triple-negative breast cancer and metastatic castration resistance prostate cancer. In the latter one, germline BRCA mutations occur in 11-33% of the cases, which is considerably higher than the occurrence in localized disease ( 2 ).…”

Heat Shock Proteins in Benign Prostatic Hyperplasia and Prostate Cancer

“…It has been shown that combination therapy is associated with significantly higher rates of metastasis-free survival, compared with ADT alone [17]. Moreover, one of the new therapeutic perspectives is the use of the PPAR inhibitor, olaparib, which acts synergistically with the HSP90 inhibitor (AT13387), which has so far been confirmed in clinical trials in mCRPC patients [18]. The greatest problem in the treatment of prostate cancer is the resistance of these cells to treatment aimed at inducing apoptosis, controlling signaling pathways responsible for cell proliferation or modulating the activity of the androgen receptor.…”