(Editor's note Sept. 20, 2024: the GENTleMEN study closed to accrual in 2024. There are other prostate cancer-related studies available through Fred Hutch. One is the Prostate Cancer Registry of Outcomes and Germline Mutations for Improved Survival and Treatment Effectiveness Study, also known as the PROMISE study.)
Prostate cancer may be written in some men’s genes — but so could instructions for more effective treatments and better risk awareness for their family members. As part of the GENTleMEN study (GENetic Testing for MEN with prostate cancer), researchers at Fred Hutchinson Cancer Research Center and the University of Washington are offering free genetic testing to men with advanced prostate cancer to see if they’ve inherited alterations in genes linked to this disease.
A positive test could bring immediate benefits: certain therapies, not commonly used in prostate cancer, work particularly well against tumors with these types of mutations. Additionally, a positive test tells family members something about their own potential cancer risk, which is higher if they have also inherited the same mutation.
“[We set up this study] to remove barriers and improve access [to genetic testing and precision oncology] throughout the state of Washington,” said Dr. Heather Cheng, a Fred Hutch and UW researcher and prostate cancer specialist at Seattle Cancer Care Alliance who directs the SCCA’s Prostate Cancer Genetics Clinic. She co-leads the GENTleMEN study with UW colleague Dr. Bruce Montgomery.
The GENTleMEN study enables men with metastatic prostate cancer to access genetic testing and counseling via the web. Participants who test positive can share their results with their oncologists and family members and will have access to genetic counseling by phone or face-to-face at SCCA.
Because test results could have big implications for both patients and family members, Cheng strongly recommends that participants who have access to genetic counseling complement their study enrollment with a visit to a genetic counselor. She envisions the study being most helpful to the many patients who don’t have ready access to a genetic counselor. The study team can help facilitate genetic counseling follow-up, especially if participants test positive or have a family history of cancer.
The GENTleMEN study grew out of recent findings from an international collaborative research project led by Drs. Pete Nelson and Colin Pritchard at the Hutch and UW, and included Cheng and Montgomery. The team found that nearly 12 percent of men with advanced prostate cancer have inherited mutations in genes that are important for keeping DNA pristine and error-free — meaning that they’d received these genetic mistakes from a parent and carried them long before a tumor formed. They also found that men with metastatic prostate cancer were five times more likely to have inherited these kinds of mutations than men in the general population.
“We thought this high number of men with inherited mutations [in DNA-repair genes] made it worthwhile to screen all men with advanced prostate cancer,” said Nelson. The results “could impact their own treatment and have clear implications for their family.”
Perhaps the most well-known examples of DNA-repair genes are BRCA1 and BRCA2; certain hiccups in the sequences of these two genes increase women’s risk of breast and ovarian cancer. But men don’t duck this risk. For example, some BRCA2 mutations also put men at higher risk — for prostate cancer, but male breast and pancreatic cancer as well. (BRCA mutations raise the risk of pancreatic cancer for women, too).
“We need to get away from the idea that BRCA is just attached to breast and ovarian cancer [risk],” said Montgomery. “It’s about patients and their families and inherited risk.”
Mark Meerschaert knows this only too well. The Michigan State University statistics professor learned that he carried a BRCA2 mutation after he was diagnosed with prostate cancer in 2013 — but the news was no shock. One of his male relatives had already tested positive for mutated BRCA2 after developing breast cancer a few years earlier.
“When medical oncologists look at my family history, they usually all have the same reaction, which is, ‘Well, that’s a typical BRCA2 family tree,’” Meerschaert said. Meerschaert’s father and nearly all of his father’s 11 brothers and sisters experienced some form of cancer.
Because hobbled DNA-repair genes raise the risk of so many cancers, Montgomery and Cheng hope that if a man tests positive through the GENTleMEN study, his family members will also get tested. Then, they’ll have a better sense of their own cancer risk and what steps could safeguard their future health. The genetic counseling offered through the study can help men weigh their options.
Meerschaert encouraged his family members to find out if they carry the same mutation. If he’d known about his BRCA2 status earlier, he said, he might have undergone more stringent screening to catch potential tumors earlier. Confronted with the risk of other cancers, he includes screening steps, such as breast self-exams, that would never have occurred to him previously.
“I don’t understand why someone wouldn’t want to know, Meerschaert said. Now, many members of his family have learned that they also carry the same cancer-predisposing variant of BRCA2.
As Meerschaert learned, testing positive for a DNA-repair mutation can lead to more targeted treatment. After an initial course of chemotherapy, his prostate tumor melted away — but then recurred in July 2016. Within the tumor, the normal copy of BRCA2 that Meerschaert had inherited from his mother had also been mutated. Meerschaert’s health declined quickly.
Meerschaert was an avid runner who was also in the midst of arranging an international scientific conference. “I was running three miles a day. Within three months [of my cancer recurrence], I couldn’t even stand for five minutes,” he recalled.
Now a patient of Cheng’s, Meerschaert is taking a type of chemotherapy known as a PARP inhibitor, a type of drug to which tumors with DNA-repair mutations are particularly sensitive. Already approved for advanced ovarian cancer, PARP inhibitors are still being tested against advanced prostate cancer, but Cheng and other researchers are excited about their potential.
Men who participate in the GENTleMEN study could well be steered toward a clinical trial similar to the one Meerschaert is in, said Cheng and Montgomery. But there are other drugs, already available and in use against certain subtypes of prostate cancer, that could benefit men with DNA-repair mutations. Patients could receive them from their local oncologists.
The possibility that a patient who tests positive for certain DNA-repair mutations will respond well to such drugs is “not theoretical,” said Cheng. “It’s very likely to be true.”
On his experimental therapy, Meerschaert has bounced back — from standing to walking, walking to occasional running. Though he’s selective about how he spends his now more-limited energy (and makes sure to maintain his health with a daily two-hour nap), Meerschaert said he has plenty with which to enjoy his life.
Once they’d established the link between inherited DNA-repair mutations and aggressive prostate cancer, Nelson, Pritchard and their team pushed for modifying screening guidelines for men with advanced prostate cancer. As a result, the National Comprehensive Cancer Network guidelines now recommend that men with metastatic prostate cancer receive testing for such mutations. But getting the testing and information to men who are eligible is another matter.
Cheng’s GENTleMEN study removes two of the largest barriers, said Montgomery: getting access to genetic counseling and getting approved for coverage of genetic testing.
The web-based, long-distance nature of the study could be the key to providing men access to this kind of care, regardless of where they’re located. One of the study’s goals is to assess how well a web-based approach works, said Cheng. In addition, they’ll try to build a full picture of the patients participating, including their family history and knowledge about these mutations. To do this, the team is building on prior work in other cancer fields.
“We know from breast and ovarian cancer that [web-based genetic counseling is] a reasonable option given that there are limited resources with genetic counselors in person,” she said.
And for those men who test positive for a DNA-repair mutation that is known to carry cancer risk, insurance generally covers face-to-face genetic counseling, Montgomery said.
Researchers in Seattle have spent many years carefully parsing different DNA-repair mutations and risks associated with breast and ovarian cancer, but the strength of those links to prostate cancer are only starting to be appreciated, Montgomery said.
“We’re in the Dark Ages compared to breast and ovarian cancer and really understanding which mutations raise the risk and by how much,” Nelson said. The GENTleMEN study is a first step toward gathering the information researchers need to paint a fuller picture of men’s cancer risk and appropriate preventive measures, he said. More studies are in the works by the cross-institutional prostate cancer research team at Fred Hutch and UW to begin addressing these questions.
And although the work already has resulted in changes to the NCCN guidelines, it will take time to translate these into changes in practice and insurance reimbursement, Nelson said.
Even as they look to the future, Cheng and Montgomery want the GENTleMEN study to make a difference in men’s lives now.
“We’re really invested in anybody anywhere who could know about this [trial] and have it make a difference,” Montgomery said.
The GENTleMEN study is supported by the Fred Hutch-UW Institute for Prostate Cancer Research and the Color Foundation.
Solid tumors are the focus of Seattle Translational Tumor Research, a network comprised of Fred Hutchinson Cancer Center, UW Medicine and Seattle Cancer Care Alliance. STTR is bridging laboratory sciences and patient care to provide the most precise treatment options for patients with solid-tumor cancers.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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