Letter to the Editor: “Family history and pathogenic/likely pathogenic germline variants in prostate cancer patients”

Dear Editor, We would like to thank the editors of The Prostate for the opportunity to respond to the letter submitted by Maida et al. concerning our article. As discussed by Maida et al., familial aggregation may be biased by the prevalence of clinical testing and may be a confounding factor with regard to assessing germline variants associated with prostate cancer risk. Beyond the clinical diagnostic factors, the assessment of familial aggregation, as discussed in the study limitations, is constrained by the self‐reported nature of family history. As a late‐onset disease, accurate medical family history is often lost to both time and changing clinical paradigms; thus, truly assessing family history is challenging. Beyond family history, clinically there are no definitive criteria to distinguish between prostate cancer associated with germline genetics and sporadic prostate cancer in the early phases, though cribriform and intraductal changes are associated with biallelic BRCA2 alterations. In advanced stages though phenotypic differences may appear, all patients are tested removing the possibility of bias. Despite the challenges of self‐reported family history, as shown in this study, a complete cancer family history remains a powerful tool in the ever‐evolving landscape of prostate cancer genetics. As noted in several major studies, pathogenic germline variants, especially in DNA repair pathways, have been shown to play a critical role in risk and progression in advanced prostate cancer. Germline variants have been shown to be more prevalent in advanced prostate cancer patients. Likewise in the present study, approximately 72% (n = 356) of all patients at this single institution went on to have metastases and of this group, 14% (n = 49) had a pathogenic germline variant which is consistent with published literature. We agree that more extensive research is warranted. Similarly, as noted by Maida et al., and as shown in this single‐ institution study, prostate family history may need to be evaluated more closely. Prostate cancer family history is associated with prostate risk, even when assessing second degree relatives. With nuanced family history collection, in the future, more robust risk stratification based on both clinical features and family history may be an attainable goal and improve patient outcomes as well as providing critical genetic information for families. Ultimately, more research is needed to quantify the effects of both disease and genetic heterogeneity and their relationship to the genetics of prostate cancer.