Risk Prediction for Risk Mitigation in Prostate Cancer Explored in New Study

As uptake of genetic risk stratification continues in prostate cancer, a leading cause of death and a partially heritable disease, researchers of a new literature review have compiled data on reducing mortality through early detection and prevention.

Data over the last decade have shown that rare pathogenic mutations (RPMs), particularly those in DNA damage repair (DDR), such as BRCA1, BRCA2, and ATM, increase the risk of prostate cancer. In one study, 11.8% of patients with metastatic disease had a pathogenic mutation in 1 of 16 genes involved in DDR, 44% of which were BRCA2 mutations.

The presence of RPMs has been shown to have implications for early cancer detection, risk stratification, treatment, and subsequent family testing. For example, individuals with BRCA2 mutations are up to 8.6 times more likely to develop prostate cancer than the general population. The group highlighted the important consideration of ancestry in the mutational landscape, as Jewish men of Ashkenazi descent are more likely to have RPMs in BRCA1 and BRCA2 and men of Black and White ethnicity may harbor different RPMs with different mutational profiles.

“Current data strongly support tailored screening and early detection strategies that account for genetic risk. This is best illustrated by the IMPACT trial, where men aged 40 to 69 years from families with BRCA1 or BRCA2 mutations underwent PSA [prostate-specific antigen] screening,” explained the researchers in European Urology. “Men with a BRCA2 mutation were diagnosed with prostate cancer more often and at a younger age than men from these same families who did not personally have a BRCA2 mutation. BRCA2 carriers were also more likely to have aggressive prostate cancer. The increase in PCa among men with BRCA1 mutations was not statistically significant in the published interim analysis. In a parallel cohort, men with RPMs in MSH2 and MSH6 were similarly found to have an increased risk of prostate cancer.”

Emphasis on the importance of genetic testing has also grown, with a general consensus that patients with metastatic or high-grade localized disease should receive genetic testing counseling. In cases of less aggressive localized disease, genetic testing should be considered if the individual has a family history of a high-risk RPM; a family history of breast, ovarian, pancreatic, and/or prostate cancer; has Ashkenazi Jewish ancestry; or has intraductal/cribriform histology.

The identification of RPMs in early detection guidelines has been adopted form groups like the National Comprehensive Cancer Network and European Association of Urology, including recommendations on screening age and shared decision-making.

Early detection strategies have also been centered on genetic risk score (GRS), as the measure has been associated with poorer outcomes, including metastatic disease and mortality. The researchers noted that in most current data sets, men with low-grade disease have historically received radical treatment at high rates and long-term data are not always available, making it challenging to determine which men experienced poor outcomes after a certain timepoint.

The group flagged another challenge in that no GRS has been shown to be specific for aggressive prostate cancer despite the strong association of GRSs with key end points. They highlighted the importance of having such a GRS, as it would predict the development of aggressive cancers while avoiding the capture of those likely to develop indolent cancers.

“With genome-wide association studies now including hundreds of thousands of cases and controls, we need to consider why common prostate cancer risk variants that are specific for aggressive or lethal disease have not been found,” wrote the researchers. “Partly, this may reflect a lack of power, as case-control datasets frequently lack detailed information on the aggressiveness of disease at diagnosis or long-term follow-up. Alternate approaches and other datasets may yield insights. For example, there is intriguing evidence that germline genetic composition influences cancer evolution and tumor gene expression.”

The researchers also emphasized the importance of a healthy lifestyle in men who harbor a relevant RPM or have a high GRS, including by avoiding smoking, maintaining a healthy weight, exercising regularly, and eating healthy.

Reference

Seibert TM, Garraway IP, Plym A, et al. Genetic risk prediction for prostate cancer: implications for early detection and prevention. Eur Urol. Published online January 4, 2023. doi:10.1016/j.eururo.2022.12.021