Men with metastatic prostate cancer could benefit from screening for mutations in certain genes that keep DNA error-free, including the “breast cancer” genes BRCA1 and BRCA2, according to a new study led by researchers at Fred Hutchinson Cancer Research Center and the University of Washington.
Published online Wednesday in The New England Journal of Medicine, the work shows men with metastatic prostate cancer are five times likelier to harbor inherited mutations in BRCA1/2 and other DNA-repair genes than the general population, irrespective of age or family history of prostate cancer.
Screening for these mutations could help men with prostate cancer get more tailored treatment, provide better clarity on their prognosis, and alert family members to their own cancer risks.
The high rate of inherited mutations in DNA-repair genes was previously unappreciated, making the results “pretty surprising,” said Dr. Pete Nelson, a Fred Hutch prostate cancer researcher and senior author on the study. Nelson also treats prostate cancer patients at Seattle Cancer Care Alliance.
The testing has the potential to do “double duty” by helping predict patients’ optimal treatment and nudging family members to look into their own cancer risk, said first author Dr. Colin Pritchard, a UW genetics researcher. Children or siblings of men with these mutations may also harbor them — as well as an increased risk of prostate, breast, ovarian and pancreatic cancer. Family members with mutations could benefit from earlier or more comprehensive screening strategies designed to catch cancer in its earliest stages.
The genetic tests could help the patients themselves as well — men with advanced disease who have inherited mutations, also known as germline mutations, may respond well to new drugs being tested in clinical trials.
“What we’re recommending to patients is that all men with metastatic prostate cancer should have germline testing” and seek a genetic counselor to help interpret the results, said Nelson.
A not-so-small niche
Study author Dr. Heather Cheng, also a Fred Hutch and UW prostate cancer researcher, had suspected for a while that a deeper understanding of the inherited mutations carried by men with prostate cancer could help doctors provide better treatments.
“But I thought it would be a small, quiet niche. An important niche, but small,” said Cheng. “But now we’re finding that many, many more men have these mutations [than we’d thought].”
Pritchard teamed up with Cheng, Nelson, and an international group of colleagues to ask how often inherited mutations in DNA repair genes occur in men with advanced prostate cancer in which tumors have metastasized, or spread far from the original site. The team pulled together genetic information from men with advanced prostate cancer across seven different groups of patients and several institutions, including Fred Hutch, UW and SCCA.
All told, they sifted through 20 DNA-repair genes and compared the mutations in tumor and healthy tissue of 692 men. They found that nearly 12 percent of men with metastatic prostate cancer had inherited mutations — that is, mutations present in both cancerous and healthy cells — in 16 of these genes.
The Cancer Genome Atlas, a federally-funded program cataloging genetic links to cancer, offers genetic information on men with localized prostate cancer. The team found that men with advanced prostate cancer had inherited mutations in these 16 genes at nearly twice the rate of men with localized, high-risk prostate cancer and nearly six times the rate of men with localized, low-to-intermediate risk disease.
In the men studied, the scientists didn’t find the rate of inherited mutations in DNA-repair genes to be higher in younger patients compared to older men, or in men with a family history of prostate cancer. They did find that men with metastatic prostate cancer are five times as likely as the general population to have germline mutations in the 16 genes. In particular, men with advanced prostate cancer have a nearly 18 times higher-than-average risk of carrying an inherited mutation in BRCA2, already well-known for increasing risk of breast and prostate cancer.
“The big take home is that inherited mutations in genes that are known to predispose to cancer, more than just prostate cancer, are much higher than we ever suspected,” said Pritchard. Some of the mutations, like those in BRCA2, will probably strongly increase men’s risk of prostate cancer, while mutations in other genes may raise the risk only moderately, he noted. Further research will help tease out these nuances.
Intercepting cancer
The findings have clear implications for men with advanced prostate cancer, said Nelson. Two classes of drugs, known as PARP inhibitors and platinum chemotherapy, best target cancer cells with mutations in DNA-repair genes. While PARP inhibitors are not yet approved for use in prostate cancer, they are under fast-track review by the FDA. Platinum chemotherapy is not commonly used to treat prostate cancer, but results coming out of current clinical trials, including a case study published last month by Cheng, Nelson, Pritchard and their UW colleague Dr. Bruce Montgomery, suggest that men with prostate cancer and DNA-repair mutations may respond well to platinum-based chemotherapy.
“For men with metastatic disease who are found to have these mutations, there are very clear treatment implications that would not otherwise be considered for prostate cancer. It would essentially expand [the patients’] toolbox of treatments,” said Cheng. She has set up a genetics clinic at SCCA to provide counseling and genetic testing for men diagnosed with advanced prostate cancer, which can be reached at (855) 557-0555.
At least one patient has already benefited from screening for inherited mutations in DNA-repair genes. Todd Braman had little hope that his disease could be tackled — until he began treatment with a PARP inhibitor. Braman, a participant in Nelson’s Stand Up to Cancer study, was found to have inherited a mutation in BRCA1. This prompted Braman’s daughter, Alicia, to undergo genetic screening and discover she carries the same mutation. Now that she knows of her increased cancer risk, Alicia Braman undergoes regular cancer screening at SCCA.
“The implications are big in terms of intercepting and preventing a cancer because [carriers of these mutations] are at high risk,” said Nelson.
Disease course for prostate cancer varies from slow-growing tumors in patients who would benefit from a light therapeutic touch to rapidly progressing, aggressive tumors. The genetic background of a patient and his prostate tumor can provide more precise information for guiding therapy, said Nelson. Oncologists’ ongoing struggle has been to determine who are the patients whose disease is aggressive and need aggressive therapy early — but the new findings could help untangle this issue by highlighting high-risk patients, said Pritchard.
Information on patients’ inherited mutations could also help steer decisions to intervene early in patients for whom they might otherwise have chosen an active surveillance, or wait-and-see, strategy, said Nelson.
BRCA mutations and cancer risk — not just for women
The findings highlight the risk that mutations in genes like BRCA1 and BRCA2 pose to men, not just women. The focus on the relationship of BRCA1 and BRCA2 to breast and ovarian cancers has led to the misunderstanding that these mutations only affect women or can only be inherited by women, said Cheng.
“But if prostate cancer had been studied first, they might be known as prostate cancer genes instead,” noted Pritchard.
However, more data needs to be collected on various DNA-repair mutations and how they influence cancer risk. While some mutations are well-studied, sometimes a “variant of uncertain significance” pops up. It’s extremely important, said Nelson, that patients receive the assistance of a genetic counselor, who is trained to navigate this kind of uncertainty. Genetic counselors also help patients deal with emotions that can be stirred up, said Cheng.
“I think these data really suggest that we need to engage men in discussions about genetics, where it has not been central before,” said Cheng. Because mutations in DNA-repair genes can raise the risk of several cancers (including male breast cancer), men should share their whole family’s cancer history with their doctors, said Nelson.
Next steps
Right now, typically only men from a family known to have BRCA1/2 mutations can have a germline genetic screening underwritten by insurance, so Nelson and his team hope the findings will lead to changes in the National Comprehensive Cancer Network guidelines (often followed by insurance companies) to include this screening.
Future work will also shed light on new cancer risk mutations and clarify how much a specific mutation may — or may not — impact cancer risk. In particular, Pritchard, Cheng, Nelson and their colleagues hope to determine which mutations predispose men to the most aggressive type of prostate cancer. They also hope to use information on patients’ genetics to direct men with these mutations to tailored treatment and clinical trials.
Even with this uncertainty, Pritchard said he would counsel men with metastatic prostate cancer to consider screening for inherited mutations in DNA-repair genes. “If a mutation is found, I would tell at-risk family members to get tested,” he said.
SCCA oncologists can discuss genetic screening and treatment options for men with advanced prostate cancer. Appointments can be made at (855) 557-0555.
Sabrina Richards is a staff writer at Fred Hutchinson Cancer Research Center. She has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
