New data on BRCA mutations and prophylactic surgeries


  • Carrie Printz

Treatment choice is highly individual

Barbara, aged 44 years, always knew that breast cancer ran in her family. She lost her mother to the disease when she was 9 years old, and her mother's first cousin also died of it. When the cousin's daughter developed breast cancer and tested positive for the BRCA1 mutation, it became clear that Barbara's mother also had been a carrier. Still, after both Barbara's siblings and her maternal aunt and uncle all tested negative, she thought she was safe. She was wrong. “I had the same genetic mutation as my cousin, who was then fighting a difficult battle against ovarian cancer,” she says.

Barbara did not hesitate to undergo a total hysterectomy at age 41 followed by a double mastectomy at age 42. “When I learned my high probability of getting cancer, I was not going to play Russian roulette,” she adds. “To me, there was no decision. Quite honestly, I should have done it when I was younger.” She put off taking the test because she had hoped to marry and have children before having to deal with the possibility of the surgeries, but, with her cousin dying of ovarian cancer, she could put it off no longer.

A Difficult Choice

Many women who test positive for BRCA1/2 genetic mutations confront the same choice. Although not all of them will develop breast or ovarian cancer, they do have a 60% lifetime risk of developing breast cancer (5 times higher than the general population) and a 15% to 40% risk of developing ovarian cancer, compared with a 1.4% risk for the general population, according to the National Cancer Institute (NCI), although these risk percentages may change with further research.

Because ovarian cancer has such a poor prognosis and no proven screening methods, oophorectomy is considered a mandate for patients who carry BRCA1/2 mutations and who have completed their childbearing or are aged 40 years and older. Prophylactic mastectomies are an individual choice, experts note.

Some women, particularly those who are young, have not completed their families, and have never had cancer, may opt for intensive screenings, including both mammograms and magnetic resonance imaging (MRI), versus undergoing a bilateral mastectomy. Others may not want to wait. “You have to individualize these recommendations in the context of women's lives,” says Susan Domchek, MD, director of the Cancer Risk Evaluation Program at the University of Pennsylvania's Abramson Cancer Center in Philadelphia.

She points to a recent study that compared survival outcomes of patients who underwent oophorectomy and prophylactic mastectomy versus those treated with oophorectomy and intensive breast screenings using sophisticated computermodeling.1 The difference in mortality was small, and MRI screening with oophorectomy at age 40 was found to be very effective in improving survival. The study's authors are developing a program that will enable BRCA mutation carriers to enter their own data to estimate differences in projected survival based on risk reduction choices.

Dr. Domchek and colleagues have conducted a number of studies related to the BRCA1/2 mutations. When the mutations were first discovered in the mid-90s, many people questioned the value of testing if it was only going to cause anxiety and stress among those who tested positive. “It was our job in the research community to prove that there are interventions that can reduce the risk of cancer,” she says.

A Look at the Data

Early studies were retrospective in nature, but Dr. Domchek and colleagues recently published a study that prospectively examined women with the mutations who had not had prior breast cancers and who opted to have their ovaries or breasts removed.2 The study followed approximately 2500 women with these genetic mutations identified between 1974 and 2008. Participants were followed until the end of 2009. The median follow-up for women was 3.65 years among those who underwent surgery and 4.29 years in controls who did not undergo surgery.

Of the 257 women who underwent risk-reducing mastectomies, no breast cancers were diagnosed, whereas 7% of women who did not opt for the mastectomies were diagnosed with breast cancer. Of the 993 women who underwent salpingo-oophorectomies, 1.1% were subsequently diagnosed with ovarian cancer, 11.4% were subsequently diagnosed with breast cancer, and 3% subsequently died from any cause; in women who did not undergo the surgery, 5.8% were diagnosed with ovarian cancer,19.2% were diagnosed with breast cancer, and 10% died.

In the United States, approximately 20% of BRCA1/2 mutation carriers who have not had cancer opt for prophylactic mastectomies. In addition, approximately 40% to 45% percent of women with prior breast cancers choose oophorectomies, with that rate noted to increase significantly by age 50, Dr. Domchek says. She points out that there continue to be many unknowns. For example, the long-term effects of oophorectomy on women's bone and cardiovascular health are unknown and researchers do not know the optimum age at which to remove the ovaries.

The conclusion, she says, is “there should no longer be a sense of nihilism about genetic testing forBRCA1/2. If we can identify the women who have these genetic mutations, we can improve their overall mortality with these interventions.”

Future Interventions

A key goal for future research is to determine why some BRCA1/2 carriers develop breast cancer at age 30, others at age 50, and others never develop it. There may be other genetic modifiers that are inherited that might alter disease development, which would require specific recommendations for individual risk profiles, Dr. Domchek notes.

Improving screening methods for ovarian cancer and developing Preventive medicines for cancer also are priorities. Researchers are interested in studying poly adenosine diphosphate-ribose polymerase inhibitors in women with BRCA1/2 mutations. In addition, ensuring that the “right ”women are tested for the mutations is another important goal. “There are women who get tested who have never had cancer, but the right person to test is their mother or sister who has had cancer—that gives us much more information and is more cost-effective,” Dr. Domchek explains. “We need to educate providers about how best to evaluate these families.” Although most women will test negative for these mutations, the challenge is to find out what is going on in the remaining families with a history of these diseases, she adds.