One in nine (12%) men with metastatic prostate cancer carry inherited mutations in DNA damage repair (DDR) genes, reports a new study funded in part by the Prostate Cancer Foundation These practice-changing findings suggest that all metastatic prostate cancer patients should undergo screening for DDR defects, and that families of men found to have these mutations seek genetic counseling.
These results were published on Wednesday, July 6, 2016 in the New England Journal of Medicine.
“The implications of these groundbreaking findings are profound,” said Jonathan W. Simons, MD, president and CEO, Prostate Cancer Foundation. “Not only will they advance precision medicine for prostate cancer by identifying who may benefit from targeted treatment, but also new recommendations for screening can help determine who is at the greatest risk for this disease so we can intervene. Also, we estimate more than 12,000 U.S. families facing prostate cancer are carrying these genes in their children and grandchildren.”
“I think every man today with metastatic prostate cancer should have genetic testing, regardless of age or family history,” said Peter Nelson, MD, of Fred Hutchinson Cancer Research Center, and Professor of Medical Oncology at the University of Washington and the Genitourinary Oncology Clinical Research Director of the Seattle Cancer Care Alliance. Nelson led the study on behalf of the PCF International Prostate Cancer Dream Team.
Breaks in DNA occur thousands of times in each cell cycle, and normal cells have about half a dozen ways to combat DNA damage. However, cells with mutated DDR genes have deficient repair pathways, leading to the accumulation of mutations that can promote tumor formation.
Most notable of these are defects in BRCA1/2 genes, which are infamous for increasing a woman’s risk of breast and ovarian cancer. In the study, Nelson and colleagues found that BRCA2 specifically represented 44% of all identified mutations, making it the most common heritable mutation in men with advanced prostate cancer.
Prostate cancer patients with DDR mutations may benefit from targeted treatment with a relatively new class of drugs known as PARP inhibitors. Olaparib, a PARP inhibitor initially approved for the treatment of BRCA-mutated ovarian cancer, received breakthrough status for the treatment of advanced prostate cancer earlier this year. DDR-mutated tumors may also be sensitive to platinum chemotherapy, such as cisplatin and carboplatin.
The presence of hereditary mutations in metastatic prostate cancer patients may warrant screening of family members, who may also carry these oncogenic defects. Genetic counseling of male and female relatives can help determine their own risk and recourse for prostate, breast, ovarian, and pancreatic cancers. The type of testing required by patients and their relatives will vary on an individual basis.
Importantly, due to the relative rarity of germline DDR defects in the general population, the study authors caution against the widespread implementation of genetic screening. At this time, they do not recommend genetic testing for men with localized, low-intermediate risk prostate cancer without a strong family history of prostate, breast, or other cancers. Moreover, they do not suggest that male relatives who test positive for DDR mutations undergo prophylactic prostatectomies, which can have many side effects that degrade quality of life. Rather, male carriers should get more intensive screening for prostate cancer beginning at a younger age.
About the Prostate Cancer Foundation
The Prostate Cancer Foundation (PCF) is the world’s leading philanthropic organization funding and accelerating prostate cancer research. Founded in 1993, PCF has raised more than $660 million and provided funding to more than 2,000 research programs at more than 200 cancer centers and universities. The PCF global research enterprise now extends to 19 countries. PCF advocates for greater awareness of prostate cancer and more efficient investment of governmental research funds for transformational cancer research. Its efforts have helped produce a 20-fold increase in government funding for prostate cancer