Men with Metastatic Prostate Cancer Should Be Considered for Germline Genetic Testing of DNA Repair Genes


Men with metastatic prostate cancer should be considered for germline genetic testing of DNA repair genes, regardless of age or family history, according to a team of researchers from Memorial Sloan Kettering Cancer Center (MSK), Fred Hutchinson Cancer Research Center, Dana-Farber Cancer Institute, University of Washington School of Medicine, University of Michigan, and the Institute of Cancer Research Royal Marsden Hospital.

In a study reported online in the New England Journal of Medicine on July 6, the researchers showed an association between advanced prostate cancer and mutations in DNA repair genes and observed that these mutations are significantly more frequent in advanced as opposed to localized disease (11.8 percent versus 4.6 percent).

Individuals shown to have germline cancer predisposition mutations may serve as sentinels that identify high-risk families. For example, of those who had a DNA repair abnormality, a very high proportion had a first-degree relative with cancers other than prostate cancer compared with the group that did not have DNA repair mutations. The identification of a germline DNA repair gene mutation provides critical information for relatives as well as for the patient, prompting a cascade of counseling to identify cancer predisposition and deploy risk-reduction strategies in family members. By thinking beyond the present and looking for opportunities to prevent cancer in the next generation, this work will create a large paradigm shift.

“With the exception of some cancer syndromes in children, prostate cancer is the most heritable of human malignancies,” said Michael F. Walsh, MD, co-lead author of the study and a geneticist and pediatric oncologist at MSK. “Historically, the main benefit of identifying cancer-causing mutations has been prevention and early detection in families. Now we can use inherited genomic information to target treatment, with specific therapies shown to be effective in those with specific genomic subsets of prostate cancer.”

MSK researchers utilized powerful new resources from MSK’s Niehaus Center for Inherited Cancer Genomics to explore the genomic and clinical links between DNA repair gene mutations and advanced prostate cancer.

“These findings are of interest for two reasons,” explained Kenneth Offit, MD, MPH, Chief of the Clinical Genetics Service, head of the Niehaus Center, and a co-senior author on the study. “First, these findings potentially change clinical practice because we now show that testing for these DNA repair genes should be offered to all men with advanced prostate cancer. The second important finding is that we see clusters of cancers other than prostate, breast, ovarian, and pancreatic in these families that were not expected and that will stimulate further research.”

Prospective studies are needed to determine if DNA repair gene mutations are predictive of clinical outcomes. This study was designed by Stand Up To Cancer (SU2C)-Prostate Cancer Foundation (PCF) Dream Team investigators and partially funded by SU2C-PCF Dream Team Translational Cancer Research Grant. MSK’s Charles Sawyers, MD, Chair of the Human Oncology and Pathogenesis Program, serves as a co-leader of the SU2C-PCF Dream Team. SU2C is a program of the Entertainment Industry Foundation whose scientific partner is the American Association for Cancer Research.