For decades, 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 that these mutations are associated with the development of prostate cancer (PCa).
The BRCA2 mutation appears to be more strongly associated with PCa development than the BRCA1 mutation. In addition, the increased risk of PCa varies by family history of the malignancy and the location of the mutation within the genes.
“Our study is unique in that we have recruited healthy men across the UK and Ireland who have hereditary BRCA1 or BRCA2 mutations, and then followed them prospectively for up to 17 years to see if they would develop prostate cancer,” said corresponding author Tommy Nyberg, a PhD candidate at the Centre for Cancer Genetic Epidemiology at the University of Cambridge in the UK.
The study, which was published in European Urology, included 376 male BRCA1 mutation carriers and 447 male BRCA2 mutation carriers who were identified in clinical genetics centers in the United Kingdom and Ireland. Of these, 16 BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. Nyberg and his colleagues found that the risk of PCa is more strongly influenced by BRCA2 than BRCA1 mutations. The BRCA2 mutation is associated with a nearly 4.5-fold increased risk of PCa, whereas the BRCA1 mutation is associated with an approximately 2.4-fold increased risk. “This translates into estimated absolute lifetime risks for developing prostate cancer of 60% for BRCA2 and 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.
For the men with BRCA1/2 mutations, the risk was greater for those from families where several family members had been diagnosed with PCa than for those without such a family history. “This probably reflects the complex genetic landscape of prostate cancer susceptibility, with several genetic variants besides BRCA1/2 mutations being known to influence the risk,” Nyberg said.
Among carriers of the BRCA2 mutation, the risk of PCa increased nearly 1.7-fold with each relative diagnosed with PCa. Compared with the general population, BRCA2 mutations in the so-called ovarian cancer cluster region (bounded by positions c.2831 and c.6401) were associated with a nearly 2.5-fold higher incidence of PCa, a lower risk increase than for mutations elsewhere in the BRCA2 gene. BRCA2 mutations outside this region were associated with a 5.9-fold relative risk of PCa. Additionally, the BRCA2 mutation was associated with a 5-fold increased incidence of Gleason score 7 PCa and 3-fold increased incidence of Gleason 6 or less PCa. The mutation also was associated with almost 3.9-fold increased incidence of PCa mortality.
“I see the primary clinical application of our research as facilitating genetic counseling and the early detection of prostate cancer,” Nyberg said. “Men who are discovered to carry a hereditary BRCA2 mutation, even if currently healthy, are at considerable risk of developing prostate cancer during their lifetime.” A greater understanding of genetic risk variants is continuously occurring, and consequently genetic counseling for prostate cancer is getting more and more accurate.
Anthony V. D’Amico, MD, PhD, Chief of the Division of Genitourinary Radiation Oncology at Dana-Farber Cancer Institute and Professor of Radiation Oncology at Harvard Medical School in Boston said drugs already are available that target BRCA2 mutations. “Studies are needed in men who harbor BRCA mutations to investigate whether these drugs such as PARP inhibitors and platnium based chemotherapy can reduce the risk of metastasis and death from prostate cancer,” Dr D’Amico said.
Moreover, the new findings support recommendations that men with a significant family history for PCa, especially those with multiple first-degree relatives with PCa, undergo genetic testing for the BRCA2 mutation and then to be seen by a genetics counselor to be considered for screening at an earlier age than recommended in standard guidelines.
“The major implication here is that men with BRCA2 in particular are at a significantly increased risk of developing clinically meaningful prostate cancer, and this risk might be influenced by factors such as family history and the type of mutation that is inherited,” said Amar U. Kishan, MD, Assistant Professor of Radiation Oncology at the David Geffen School of Medicine of UCLA.
Although the therapeutic implications of the new findings are unclear, it is theoretically possible that men with mutations in DNA repair genes may derive benefit from drugs such as poly (ADP-ribose) polymerase (PARP) inhibitors, but the data to support such a strategy are limited to patients with advanced, metastatic castration-resistant PCa. “In this setting, olaparib and rucaparib are approved for men with BRCA1/2 mutant-tumors, though these mutations can be either inherited or restricted to the tumor,” Dr Kishan said. “Whether men with an inherited BRCA2 mutation, who develop an aggressive but early stage prostate cancer, would benefit from this type of therapy, in combination with surgery or radiotherapy, is not known. Several studies are investigating this concept.”
Todd Morgan, MD, Associate Professor of Urology and Chief of the Division of Urologic Oncology at the University of Michigan in Ann Arbor, said the new study adds important data to help guide patient counseling and may allow for improved early detection strategies in men with BRCA1/2 mutations. At his institution, Dr Morgan and his colleagues have implemented an early detection clinic for men with BRCA1 or BRCA2 mutations, which is modeled after similar clinics for female carriers of these mutations (https://www.rogelcancercenter.org/cancer-genetics/prostate-cancer-risk-clinic).
Medical oncologist David Wise, MD, PhD of NYU Langone Health in New York, said the new findings may change the conversation for men carrying the BRCA2 germline mutation. “Based on this study and others, new guidelines are needed to personalize prostate cancer screening for men carrying the BRCA2 germline mutation. Clinical trials testing PARP inhibitors, already FDA approved for ovarian and breast cancer, are ongoing in BRCA2-associated prostate cancer. Based on promising data from these clinical trials, the FDA has granted breakthrough therapy status for two PARP inhibitors, rucaparib and olaparib, for men with castration-resistant prostate cancer,” Dr Wise said.
Nyberg T, Frost D, Barrowdale D, et al. Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: A prospective cohort study [published online September 5, 2019]. Eur Urol. https://doi.org/10.1016/j.eururo.2019.08.025