Researchers recommend major change in treatment

Leading American and British cancer researchers are urging that all men with advanced prostate cancer strongly consider being tested for inherited gene mutations - both to help steer their treatment and to alert family members who themselves might be at increased risk for a range of cancers.

This new recommendation, which represents a major change in approach, was prompted by a study published recently in the New England Journal of Medicine. The researchers found that almost 12 percent of men with advanced cancer had defects in genes that are designed to fix damage to DNA, compared to 4.6 percent of patients with disease that hadn't spread.

The study involved almost 700 men in the United States and Britain. Researchers looked for mutations in well-known DNA-repair genes such as BRCA1 and BRCA2, which are typically linked to breast and ovarian cancers, as well as in more obscure genes called CHEK2 and ATM. The most common defects involved the BRCA2 gene. The frequency of the mutations did not differ significantly based on age or family history of prostate cancer.

"The study has a simple message," said senior co-author Kenneth Offit, who is chief of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center. "Those individuals with advanced prostate cancer should consider getting genetic testing, regardless of family history."

Currently, only men with a family history of prostate cancer are offered such testing; insurers are unlikely to cover it for other patients. But based on the results of the study, Offit and other researchers said they will press for a change in clinical guidelines. Should that occur, much wider reimbursement would likely follow.

Knowing a patient has a DNA-repair-gene mutation could be critically important in deciding which treatment to use, said senior co-author Peter Nelson, a member of the Human Biology, Clinical Research and Public Health Sciences divisions at Fred Hutchinson Cancer Research Center.

A new class of drugs called PARP inhibitors, which is being used for women with BRCA-related ovarian cancer, is showing promise against advanced prostate cancer in clinical trials and may be the first targeted therapy approved for that disease. Platinum-based chemotherapy, also used for ovarian cancer, could benefit these men, too, Nelson said.

The researchers stressed that genetic testing could be important to families as well. A high proportion of men with the genetic abnormality had close relatives with cancers other than prostate cancer compared with the study group that did not have a mutation. So a man aware that he has an inherited mutation could serve as a "sentinel" for relatives who might share the same defect, prompting them to learn their genetic status. A woman whose brother knows of his own BRCA mutation, for example, might decide to get tested and, if the result is positive, have preventive surgery or take other steps to reduce her risk of ovarian cancer.

"You have the opportunity to prevent ovarian cancer in the family of a man with prostate cancer," Offit said. "This is a very remarkable."

Each year, nearly 200,000 American men are diagnosed with prostate cancer and 27,000 die from the disease. There is wide diversity in how the disease progresses - or whether it progresses at all.

Experts now realize that many men can live for decades with early-stage tumors that pose little threat; these patients, they say, should not be subjected to unnecessary treatments that can have severe side effects. Other patients, however, develop metastatic cancer that spreads throughout the body and desperately need more effective treatments.

The new study is part of a growing body of research showing the harmful effects of mutations in the DNA-repair genes. Another recent study found that women with BRCA1 mutations face a higher risk of a deadly type of uterine cancer.

Still unpublished are results from another team also focusing on inherited gene defects. Brian Helfand, a urologic oncologist with NorthShore University HealthSystem in Evanston, Illinois, said researchers there and at Johns Hopkins University are studying three mutations most frequently implicated in localized and advanced prostate cancer and their frequency in whites, African Americans and Asians.

"We have discovered similar results that suggest that knowledge of these mutations can have significant potential in terms of prostate cancer screening and treatment," Helfand said. "It's really opening our eyes."

Nancy Dawson, a medical oncologist at Georgetown Lombardi Comprehensive Cancer Center who was not involved in the study, said she was especially interested in the finding that many of the men with mutations had close family members with a wide range of malignancies - including breast, ovarian, pancreatic and other gastrointestinal cancers, and leukemia and lymphoma.

"It was well known that men with prostate cancer were more likely to have a close relative with prostate cancer," she said. "But this has a broader implication. There are subtle links to other cancers that need to be explored."

Dawson said the recommendation that all men with advanced disease be tested was "appropriate," adding that many of her patients already are requesting it. But, she added, "I'd be nervous if everyone rushes out to test. You have to get this in the guidelines and get insurers to agree to pay for it before we go out and tell our patients to do it and someone comes in with a big bill that isn't covered."

Besides Memorial Sloan Kettering and Fred Hutchinson, other institutions involved in the study were the University of Washington School of Medicine, University of Michigan, Dana-Farber Cancer Institute, Weill Cornell Medical College and the Institute of Cancer Research and Royal Marsden Hospital in London.

The research was funded in part by Stand Up To Cancer, the Prostate Cancer Foundation, National Institutes of Health and the Department of Defense.