Inherited mutations in DNA-repair genes, such as BRCA1 and BRCA2, are infrequent in the general population, but are known to predispose men to prostate cancer. However, previous research has not focused on the rate of these mutations in men with metastatic prostate cancer.
Researchers at the Fred Hutchinson Cancer Research Center published their results in the New England Journal of Medicine in July. In their study, more than 10% of men with aggressive prostate cancer that had spread outside of the prostate had inherited mutations in DNA-repair genes. The rate of the mutation was more than four times the rate in the general population, and more than twice the rate in men with localized prostate cancer.
Using genetics to tailor treatment options
The authors say that men with these mutations could benefit from targeted treatment such as PARP inhibitors or platinum chemotherapy drugs. PARP is an enzyme involved in DNA repair processes. Although PARP inhibitors are not yet approved for prostate cancer, they are under fast-track review by the FDA. The PARP inhibitor Lynparza (olaparib) has been granted Breakthrough Therapy designation by the US FDA for treatment of BRCA1/2 or ATM gene-mutated castrate resistant prostate cancer.
Platinum chemotherapy is also not yet approved to treat prostate cancer, but a study published in June in European Urology suggested that men with prostate cancer and DNA-repair mutations might respond well to the therapy. Platinum chemotherapy drugs are already approved for patients with these mutations who have ovarian cancer.
Details of the study
Key results from the study were that nearly 12% of men with metastatic prostate cancer had germline mutations in one of 20 DNA-repair genes— regardless of age or family history of prostate cancer. Men with metastatic prostate cancer were five times as likely to have the inherited mutations in DNA- repair genes than the general population. Men with advanced prostate cancer were 18 times more likely to carry a BRCA2 mutation than men without prostate cancer.
The researchers examined data from 692 men with metastatic prostate cancer Advancements in care that previously seemed out of reach are now a possibility in the current era of scientific and technological discovery in medicine. included in seven case series across several institutions. Men included in the study were not chosen due to family history of prostate cancer or age. Different genetic screening assays produced the same percentage of men with inherited mutations.
Affecting the family
Mutations in some DNA-repair genes predispose to other kinds of cancers, including breast, ovarian and pancreatic cancers. If appropriate, family members of men with advanced prostate cancer who have the inherited gene mutations may be eligible for genetic testing, counseling and enrollment in research studies.
"The result is surprising and important for men with prostate cancer, as this information may prioritize certain therapies. It is also important for family members, as they may have inherited a gene that predisposes them to developing one of several types of cancer, and heightened awareness could enhance early detection and treatment. These findings present a compelling argument for updating prostate cancer guidelines to include germline DNA testing as a part of standard care for men with metastatic prostate cancer."
– Dr. Peter Nelson, study author, from the Fred Hutchinson Cancer Research Center and professor of medical oncology at the University of Washington School of Medicine
at Brigham and Women's Hospital