Fordecades, it has been known that the mutations in the tumor suppressor genes BRCA1 and BRCA2 are associated with high risks of breast and ovarian cancer,but a new prospective cohort study provides the strongest evidence to date thatthese mutations are associated with the development of prostate cancer (PCa).

TheBRCA2 mutation appears to be morestrongly associated with PCa development than the BRCA1 mutation. In addition, the increased risk of PCa varies byfamily history of the malignancy and the location of the mutation within thegenes.

Ourstudy is unique in that we have recruited healthy men across the UK and Irelandwho have hereditary BRCA1 or BRCA2 mutations, and then followed themprospectively for up to 17 years to see if they would develop prostate cancer,said corresponding author Tommy Nyberg, a PhD candidate at the Centre forCancer Genetic Epidemiology at the University of Cambridge in the UK.

Thestudy, which was published in EuropeanUrology, included 376 male BRCA1 mutationcarriers and 447 male BRCA2 mutation carrierswho were identified in clinical genetics centers in the United Kingdom and Ireland.Of these, 16 BRCA1 and 26 BRCA2carriers were diagnosed with PCa during follow-up. Nyberg and his colleagues foundthat the risk of PCa is more strongly influenced by BRCA2 than BRCA1 mutations.The BRCA2 mutation is associated witha nearly 4.5-fold increased risk of PCa, whereas the BRCA1 mutation is associated with an approximately 2.4-foldincreased risk. This translates into estimated absolute lifetime risks fordeveloping prostate cancer of 60% for BRCA2and 29% for BRCA1 mutation carriers.We also found an association with more aggressive prostate cancer for men with BRCA2, but not BRCA1 mutations, Nyberg told Renal& Urology News.

Forthe men with BRCA1/2 mutations, therisk was greater for those from families where several family members had beendiagnosed with PCa than for those without such a family history. This probablyreflects the complex genetic landscape of prostate cancer susceptibility, withseveral genetic variants besides BRCA1/2mutations being known to influence the risk, Nyberg said.

Amongcarriers of the BRCA2 mutation, therisk of PCa increased nearly 1.7-fold with each relative diagnosed with PCa.Compared with the general population, BRCA2mutations in the so-called ovarian cancer cluster region (bounded by positionsc.2831 and c.6401) were associated with a nearly 2.5-fold higher incidence ofPCa, a lower risk increase than for mutations elsewhere in the BRCA2 gene. BRCA2 mutations outside this region were associated with a 5.9-foldrelative risk of PCa. Additionally, the BRCA2mutation was associated with a 5-fold increased incidence of Gleason score 7PCa and 3-fold increased incidence of Gleason 6 or less PCa. The mutation alsowas associated with almost 3.9-fold increased incidence of PCa mortality.

Isee the primary clinical application of our research as facilitating geneticcounseling and the early detection of prostate cancer, Nyberg said. Men whoare discovered to carry a hereditary BRCA2mutation, even if currently healthy, are at considerable risk of developingprostate cancer during their lifetime. A greater understanding of genetic riskvariants is continuously occurring, and consequently genetic counseling forprostate cancer is getting more and more accurate.

AnthonyV. DAmico, MD, PhD, Chief of the Division of Genitourinary Radiation Oncologyat Dana-Farber Cancer Institute and Professor of Radiation Oncology at HarvardMedical School in Boston said drugs already are available that target BRCA2 mutations. Studies are needed inmen who harbor BRCA mutations to investigate whether these drugs such as PARPinhibitors and platnium based chemotherapy can reduce the risk of metastasisand death from prostate cancer, Dr DAmico said.

Moreover,the new findings support recommendations that men with a significant familyhistory for PCa, especially those with multiple first-degree relatives with PCa,undergo genetic testing for the BRCA2mutation and then to be seen by a genetics counselor to be considered for screening at an earlier age than recommendedin standard guidelines.

Themajor implication here is that men with BRCA2in particular are at a significantly increased risk of developing clinicallymeaningful prostate cancer, and this risk might be influenced by factors suchas family history and the type of mutation that is inherited, said Amar U.Kishan, MD, Assistant Professor of Radiation Oncology at the David GeffenSchool of Medicine of UCLA.

Althoughthe therapeutic implications of the new findings are unclear, it istheoretically possible that men with mutations in DNA repair genes may derivebenefit from drugs such as poly (ADP-ribose) polymerase (PARP) inhibitors, butthe data to support such a strategy are limited to patients with advanced,metastatic castration-resistant PCa. In this setting, olaparib and rucaparibare approved for men with BRCA1/2mutant-tumors, though these mutations can be either inherited or restricted tothe tumor, Dr Kishan said. Whether men with an inherited BRCA2 mutation, whodevelop an aggressive but early stage prostate cancer, would benefit from thistype of therapy, in combination with surgery or radiotherapy, is not known.Several studies are investigating this concept.

ToddMorgan, MD, Associate Professor of Urology and Chief of the Division ofUrologic Oncology at the University of Michigan in Ann Arbor, said the new studyadds important data to help guide patient counseling and may allow for improvedearly detection strategies in men with BRCA1/2 mutations. At his institution, DrMorgan and his colleagues have implemented an early detection clinic for menwith BRCA1 or BRCA2 mutations, which is modeled after similar clinics for femalecarriers of these mutations (https://www.rogelcancercenter.org/cancer-genetics/prostate-cancer-risk-clinic).

Medicaloncologist David Wise, MD, PhD of NYU Langone Health in New York, said the newfindings may change the conversation for men carrying the BRCA2 germline mutation. Based on this study and others, newguidelines are needed to personalize prostate cancer screening for men carryingthe BRCA2 germline mutation. Clinicaltrials testing PARP inhibitors, already FDA approved for ovarian and breastcancer, are ongoing in BRCA2-associatedprostate cancer. Based on promising data from these clinical trials, the FDAhas granted breakthrough therapy status for two PARP inhibitors, rucaparib andolaparib, for men with castration-resistant prostate cancer, Dr Wise said.

Reference

NybergT, Frost D, Barrowdale D, et al. Prostate cancer risks for male BRCA1 andBRCA2 mutation carriers: A prospective cohort study [published online September5, 2019]. Eur Urol. https://doi.org/10.1016/j.eururo.2019.08.025

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Prospective Study Characterizes PCa Risk Linked to BRCA1, BRCA2 Mutations - Renal and Urology News

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