Early Surgery in BRCA1 Carriers Lowers Ovarian Cancer Risk

Roxanne Nelson

February 24, 2014

Women who carry the BRCA1 genetic mutation should undergo prophylactic oophorectomy by the age of 35 to achieve the greatest reduction in their risk for breast or ovarian cancer. This conclusion comes from a large international prospective study published online today in the Journal of Clinical Oncology.

But perhaps the most striking finding is the beneficial effect that prophylactic surgery has on all-cause mortality, which has been shown for the first time. By the age of 70, women who underwent the procedure had a significant reduction in their overall risk for death.

"To me, waiting to have oophorectomy until after 35 is too much of a chance to take," said lead author Steven Narod, MD, professor of medicine at the University of Toronto, in a statement. "These data are so striking that we believe prophylactic oophorectomy by age 35 should become a universal standard for women with BRCA1 mutations."

He noted that women with BRCA2 mutations do not appear to be at increased risk at such an early age. Such women "can safely delay surgery until their 40s, since their ovarian cancer risk is not as strong," he said.

Dr. Narod and his colleagues estimated that if BRCA1 carriers delay prophylactic surgery until the age of 40, their risk of developing ovarian cancer rises to 4.0%. Waiting until age 50 boosts this risk to 14.2%. Conversely, their data revealed only 1 case of ovarian cancer in a BRCA2 carrier that was diagnosed before the age of 50.

By comparison, they note, the overall lifetime risk for ovarian cancer in all women is only about 1.4%.

For women with both mutations, preventive surgery was associated with an 80% reduction in the risk for ovarian, fallopian tube, or peritoneal cancer, and a 77% reduction in all-cause mortality by the age of 70.

Dr. Narod noted that this 77% decrease in risk is even greater than the benefit of chemotherapy, and was equally strong for both BRCA1 and BRCA2 carriers.

They note that although the management of healthy BRCA mutation carriers is a multidisciplinary effort, with options that include chemoprevention and screening, preventive salpingo-oophorectomy is "acceptable by the majority of women" with these mutations, and that the rate of oophorectomy in carriers around the world is high. In addition, "patients report a high degree of satisfaction after surgery."

Support Previous Evidence

BRCA1 and BRCA2 mutations are currently the strongest known genetic risk factors for developing breast or epithelial ovarian cancer. However, for ovarian cancer, they seem like a double-edged sword; the mutations heighten the risk of developing the disease, but have been associated with improved survival.

Previous studies have confirmed the benefits of prophylactic mastectomy and salpingo-oophorectomy in women with BRCA1 and BRCA2 mutations. One study found that women who opted for prophylactic surgery had a greatly reduced risk for breast or ovarian cancer and a reduction in cancer-related mortality, as previously reported by Medscape Medical News.

Better Defines Risk

What this study does is better define the risk for women with BRCA1, said Joy Larsen-Haidle, MS, CGC, a genetic counselor at the Humphrey Cancer Center Robbinsdale in Minnesota. "We didn't have a good of a number before, just a general time frame and an estimate."

In an interview, she pointed out that an across-the-board recommendation isn't going to work. Instead, a multidisciplinary team that includes a genetic counselor can really help tailor the data to an individual.

"It is important to balance the risk and benefit as far as the timing of the surgery, and to balance the risk with potential life goals, such as having a family," said Larsen-Haidle, who is also president-elect of the National Society of Genetic Counselors.

"What this study also really highlights," she said, "is the awareness of family history and mutation status. Knowing that early in life and then acting on that information can really reduce mortality."

It is important to get an accurate risk assessment because "everything is not BRCA1 and BRCA2," said Larsen-Haidle. "We need to make sure that the patient understands the results of a genetic test and how they are going to affect choices made over a lifetime."

Study Details

However, Dr. Narod and colleagues are the first to show that prophylactic surgery in this population can have an overall mortality benefit.

Although up to 70% of American women who are mutation carriers will ultimately choose to have the procedure, the optimum age for undergoing this surgery has not been adequately studied.

The current work is an extension of the team's earlier research, which showed that oophorectomy was associated with a reduced risk for ovarian and fallopian tube cancer in high-risk women (JAMA. 2006;296:185-192). The original cohort of 1828 women has been extended to 5787 women, and the mean follow-up time has been lengthened from 3.5 to 5.6 years.

Women with BRCA mutations, identified from an international registry, completed questionnaires about their reproductive history, surgical history (including preventive oophorectomy and mastectomy), and hormone use. The women were followed from 1995 to 2011.

In this cohort, 2274 women did not undergo oophorectomy, 2123 had already undergone oophorectomy, and 1390 underwent oophorectomy during the study period. At a median follow-up of 5.6 years, there were 132 cases of ovarian cancer, 22 cases of fallopian tube cancer, and 32 cases of peritoneal cancer.

During the study period, there were 511 deaths — 333 from breast cancer, 68 from ovarian, fallopian tube, or peritoneal cancer, and the remainder from other causes.

Dr. Narod and colleagues conclude that their results indicate that genetic testing is likely to be beneficial in countries where "patients who test positive for a mutation have access to salpingo-oophorectomy, even if limited resources are available for other aspects of care."

Major Contribution

In a related editorial published online March 31, Phuong L. Mai, MD, Jennifer T. Loud, RN, DNP, and Mark H. Greene, MD, all from the National Cancer Institute, note that since "BRCA1 and BRCA2 were recognized to be the major underlying genetic basis of the hereditary breast and ovarian cancer syndrome, our understanding of cancer risk and its determinants as well as risk management options in this syndrome have improved tremendously, and the authors of the current publication have made major contributions to that effort."

However, they note that the long-term effects of risk-reducing salpingo-oophorectomy on overall health and quality of life are critical but unanswered questions. Salpingo-oophorectomy preformed before menopause has been shown, in the general population, to be associated with numerous health risks, including cardiovascular disease, bone loss/fracture, dementia, and mortality. The data are limited on the long-term sequelae in women at high risk, but the procedure has not been found to have any long-term adverse effects on overall quality of health. "Long-term follow-up data from this cohort and others have the potential to add substantially to our understanding of these important issues," they write.

This study was supported by grants from the Canadian Breast Cancer Research Alliance, the National Institutes of Health, and by the Ontario Ministry of Research and Innovation. The authors have disclosed no relevant financial relationships.

J Clin Oncol. Published online February 24 and March 31, 2014. Abstract, Editorial


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