DNA-Repair Gene Mutations Might Guide Treatment for Metastatic Prostate Cancer

Metastatic prostate cancer is more strongly associated than localized disease with germline mutations in DNA repair genes like BRCA1 and BRCA2, according to a study published in TheNew England Journal of Medicine. The finding represents a “compelling argument” that prostate cancer guidelines should be updated to include germline gene testing for men with metastatic disease-even if they have no family history of prostate cancer, the study authors argued.

The team identified germline DNA-repair mutations in 11.8% of 692 men with metastatic prostate carcinoma versus 4.6% of 499 men with localized prostate carcinoma, including men with high-risk localized disease (P < .001), the researchers reported.

“The result is surprising and important for men with prostate cancer, as this information may prioritize certain therapies,” said senior study author Peter S. Nelson, MD, of the Fred Hutchinson Cancer Research Center in Seattle, in a news release.

Eighty-four germline mutations were identified at 16 DNA-repair loci among men with metastatic prostate cancer.

Mutations in specific genes were fairly infrequent and mutation frequencies did not correlate with family history of prostate cancer or patient age. For example, only 5.3% of men with metastasis had BRCA2 mutations, and BRCA1, ATM, CHEK2, RAD51D, and PALB2 mutations all occurred in fewer than 2%. Overall, however, men with metastatic prostate cancer were more than twice as likely as men with localized disease to harbor germline DNA-repair gene mutations.

Men with these mutations were also more likely to have first-degree relatives with non-prostate cancers (71% vs 50% among men without these mutations; odds ratio [OR], 2.4 [95% CI, 1.4-4.3]; P = .001). Cancers reported among their first-order relatives included breast, ovarian, pancreatic cancer, other gastrointestinal malignancies, and leukemia and lymphoma.

The family members of men with metastatic prostate cancer therefore should be considered for tests to detect inherited cancer-predisposing mutations, the authors argued.

“We already know a lot about some DNA repair genes such as BRCA2, but for others we are just beginning to understand how germline mutations contribute to prostate cancer risk and selection of optimal therapy,” noted a lead study author Colin C. Pritchard, MD, PhD, Associate Professor and Associate Director of the Genetics and Solid Tumors Laboratory at the University of Washington School of Medicine in Seattle.

Prostate cancer is “the most heritable of human malignancies” among adults, said one of the study’s lead coauthors, Michael F. Walsh, MD, of Memorial Sloan Kettering Cancer Center in New York, in a press release. The findings should allow prevention and early detection among patients’ family members, as well as selecting targeted treatments, Dr. Walsh said.

Prospective studies are required to confirm if these mutations predict treatment outcomes, the authors cautioned.