Ever since inherited mutations in BRCA genes were first linked to breast and ovarian cancer two decades ago, this information has been used as a way to help empower women. Those who have the mutations but don’t yet have cancer can be screened more often or choose to have surgery to remove their breasts and ovaries as a preventive measure. For women already diagnosed, knowing they carry a mutation might encourage family members to have a genetic test to learn if they too are at increased risk.
But BRCA mutations don’t affect only women. Research has long suggested that men with inherited mutations in BRCA genes are at higher risk for prostate cancer. Until now, there has not been sufficient evidence for doctors to recommend routine testing for these kinds of mutations in men who have the disease.
New findings by a team of researchers at Memorial Sloan Kettering and five other institutions published in the New England Journal of Medicine (NEJM) provide that proof. The results suggest that all men with metastatic prostate cancer — regardless of age or family history — be tested for inherited mutations in genes that are responsible for DNA repair. These genes, which include the BRCA genes, correct errors that arise when cells duplicate their DNA before dividing.
It’s a discovery that doctors say could change clinical practice.
“We are at a point now where clinicians have specific therapies to offer people with heritable DNA-repair mutations,” explains MSK geneticist and pediatric oncologist Michael Walsh, the study’s co-lead author. “For someone with metastatic disease, getting tested provides a potential benefit.”
DNA-repair mutations have also been linked to breast cancer, ovarian cancer, and pancreatic cancer. The NEJM study found that DNA-repair mutations are significantly more frequent in men with advanced prostate cancer (11.8%) compared with men whose cancer has not spread beyond the prostate (4.6%). Researchers made the discovery by looking for mutations in 20 DNA-repair genes in 692 men with metastatic prostate cancer.
People with DNA-repair mutations are more likely to respond to certain therapies based on their genetic makeup. Women with breast cancer or ovarian cancer are increasingly being considered for PARP-inhibitor therapies — which target DNA repair in cancer cells — given their underlying genetic makeup. Now men with metastatic prostate cancer who are found to have DNA-repair mutations could be more likely to receive these treatments.
The payoff also goes beyond the individual patient. In the NEJM study, a high proportion of the prostate cancer patients with a DNA-repair abnormality had a first-degree relative — a parent, sibling, or child — with a different type of cancer. This information could prompt these relatives to be tested for inherited mutations as well as implement their own risk-reduction strategies.
Further research is needed to determine if the presence of DNA-repair mutations will help predict a prostate cancer patient’s clinical outcome. But the findings also suggest new lines of research that could shed light on how DNA-repair mutations contribute to other cancers.
“In addition to potentially changing clinical practice for prostate cancer, this study also showed that there are clusters of cancers other than prostate, breast, ovarian, and pancreatic in these families that were not expected and that will stimulate further research,” says Kenneth Offit, Chief of MSK’s Clinical Genetics Service and a co-senior author on the study.
A Wealth of Genomic Data
To explore the genomic and clinical links between DNA-repair mutations and advanced prostate cancer, MSK researchers used the powerful resources of the Robert and Kate Niehaus Center for Inherited Cancer Genomics, headed by Dr. Offit. The Niehaus Center makes use of genomic data obtained through next-generation gene sequencing, a cutting-edge technology that enables genomes to be profiled rapidly in great detail.
“One of the major aims of the Niehaus Center is not only to offer individuals genetic information to target treatment of their disease but also to provide genetic information to help with prevention in their families,” Dr. Offit says. “This is the first of what should be many examples of this benefit. It’s a true paradigm shift to think beyond the present and look for opportunities to prevent cancer in the next generation.”
The other institutions involved in the study were Fred Hutchinson Cancer Research Center, Dana-Farber Cancer Institute, the University of Washington School of Medicine, the University of Michigan, and the Institute of Cancer Research Royal Marsden Hospital in London.
Reference: Pritchard C, Mateo J, Walsh M, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. The New England Journal of Medicine. Abstract. July 6, 2016DOI: 10.1056/NEJMoa1603144