CLINICAL IMPACT OF DNA REPAIR DEFECTS IN PROSTATE CANCER
Speaker: Elena Castro Marcos
Spanish National Cancer Research Centre (CNIO)
Salón de Actos
Inherited mutations in several genes involved in DNA damage repair (DDR) have been reported to predispose men to prostate cancer including mutations in BRCA2, the genetic event that confers the greatest risk of the disease. Recent next generation sequencing studies have revealed that germline deleterious mutations in DDR genes are present in 8-12% of metastatic prostate cancer patients. This prevalence is significantly higher than the reported in localized prostate cancer (5%) or in the general population (3%) suggesting an association with aggressive disease. In fact, germline mutations in BRCA2 seem to be an independent poor prognostic factor for localised disease associated to shorter metastasis-free and cause-specific survival across different disease stages. Based on this evidence, some updated guidelines of clinical practice now recommend germline testing in all patients with high-risk localized or metastatic prostate cancer.
On the other hand, both germline and somatic DDR defects have been identified as potential predictive biomarkers for platinum-based chemotherapy and poly-ADP ribose polymerase (PARP) inhibitors. Despite promising results with these drugs, resistance eventually occurs, and the data regarding the impact of DDR defects on the response to currently approved therapies for prostate cancer are limited and conflicting.
As a result of the recommendation of germline screening and the implementation of sequencing panels in clinical practice to seek for actionable genetic aberrations, the number of patients with identified DDR defects is likely to grow in the near future, arising a pressing need for a better understanding of the implications of these genomics events on the prognosis and treatment of prostate cancer patients.