As genetic risk stratification in prostate cancer, a leading cause of death and a partially hereditary disease, continues to be understood, researchers in a new literature review have compiled data on reducing mortality through early detection and prevention.
Data over the past decade has shown that rare pathogenic mutations (RPMs), particularly those involved in DNA damage repair (DDR), such as BRCA1And BRCA2, And ATM, increases 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, and 44% of them had BRCA2 mutations.
The presence of RPMs has been shown to have implications for early cancer detection, risk classification, treatment, and subsequent familial testing. For example, individuals who have BRCA2 Mutations are up to 8.6 times more likely to develop prostate cancer than the general population. The group highlighted important considerations of ancestry in the mutational landscape, where Jewish men of Ashkenazi ancestry are more likely to have RPMs in BRCA1 And BRCA2 And men of black and white race may harbor different RPMs with different mutation profiles.
Current data strongly support tailored screening and early detection strategies that take into account genetic risk. This is best illustrated by the IMPACT trial, in which men aged 40 to 69 years from families with BRCA1 or BRCA2 PSA undergone mutants [prostate-specific antigen] examination,” the researchers explained in European Urology. men with BRCA2 The mutation was diagnosed with prostate cancer more often and at a younger age than men from the same families who did not have it personally BRCA2 leap. BRCA2 Its carriers were more likely to develop aggressive prostate cancer. The increase in PCa among men with BRCA1 Mutations were not statistically significant in the published interim analysis. In a parallel group, the men whose RPMs were at MSH2 And MSH6 Similarly, they were found to have an increased risk of developing prostate cancer.”
Emphasis has also grown on the importance of genetic testing, with a general consensus that patients with localized, diffuse or high-grade disease should receive counseling about genetic testing. In cases of less aggressive localized disease, genetic testing should be considered if the individual has a family history of high-risk RPM; a family history of breast, ovarian, pancreatic, and/or prostate cancer; Ashkenazi Jewish descent. or has intraductal/cribriform tissues.
The identification of RPMs has been adopted in early detection guidelines by groups such as the National Comprehensive Cancer Network and the European Urological Association, including recommendations for screening age and joint decision-making.
Early detection strategies also focused on the genetic risk score (GRS), as the scale was associated with worse outcomes, including metastatic disease and mortality. The researchers note that in most current datasets, men with low-grade disease received radical treatment at high rates, and long-term data is not always available, making it difficult to identify men who experienced poor outcomes after a certain time period.
The group noted another challenge that GRS has not been shown to be specific for aggressive prostate cancer despite the strong association between GRSs and key endpoints. They highlighted the importance of having such a genetic marker, as it would predict the development of aggressive cancers while avoiding getting caught in those likely to develop slow-growing cancers.
“With genome-wide association studies now including hundreds of thousands of cases and controls, we need to consider why no prostate cancer risk variants of aggressive or lethal disease were found,” the researchers wrote. In part, this may reflect a lack of power, as case-control data sets often lack detailed information on disease aggressiveness at diagnosis or long-term follow-up. Alternative approaches and other data sets may yield insights. For example, there is evidence It is interesting to note that the genetic makeup of the germ line influences cancer development and tumor gene expression.”
The researchers also emphasized the importance of a healthy lifestyle in men with adequate RPM or high GRS, including by avoiding smoking, maintaining a healthy weight, exercising regularly, and eating healthily.
Seibert TM, Garraway IP, Plym A, et al. Prediction of genetic risk for prostate cancer: implications for early detection and prevention. Euro Urol. Published online January 4, 2023. doi: 10.1016/j.eururo.2022.12.021