Health Letter, August 2013
In May 2013, the actress Angelina Jolie announced in a column in The New York Times that she had undergone a preventive double mastectomy (removal of both breasts) after learning that she carries a defect of the BRCA1 gene, a genetic mutation that sharply increased her risk of developing breast cancer. Then in June, the U.S. Supreme Court ruled that a biotech company could not hold a patent on the BRCA1 and BRCA2 genes, effectively opening up patient access to affordable testing for all genetic mutations.
These stories have thrust the BRCA genes into the spotlight and led many women to consider testing themselves for these relatively rare genetic mutations that have been linked to several forms of cancer. For a small group of women, BRCA testing may help identify life-saving treatment. Yet for most, genetic testing will not lead to helpful information about the risk for breast cancer but is likely to trigger needless anxiety and perhaps even unnecessary removal of healthy organs. You can make smart decisions about testing by understanding BRCA mutations and available treatment options, as well as knowing what to expect from the test.
What is a BRCA mutation?
Normal BRCA1 and BRCA2 genes help prevent cancer by creating proteins that act as tumor suppressors by repairing damaged DNA. This in turn prevents further DNA mutations that can lead to cancer. Scientists have documented more than 500 forms of mutations to these BRCA genes, or changes to the gene sequencing. In most cases, these mutations disable the DNA-repairing protein, preventing it from performing its repair function and increasing the risk that the carrier of the mutation will develop certain types of cancer. However, not all BRCA mutations are negative: Some changes may have no effect on protein function or cancer risk, and at least one form actually reduces the risk of cancer.
The child of a parent with a BRCA mutation (mother or father) has about a 50 percent chance of inheriting the mutation. BRCA mutations are extremely rare in the general population. Researchers have estimated that roughly 1 in 300 to 800 women carry such mutations. However, individuals with family histories indicating a high risk of cancer are far more likely to carry the gene. Also, certain ethnic groups are more vulnerable: Among Ashkenazi Jewish men and women, an estimated 1 in 50 carry the gene.
People with harmful BRCA mutations have a dramatically increased risk of breast and ovarian cancer. Among the general population, women have only about a 13 percent lifetime risk of developing breast cancer. By contrast, among BRCA mutation carriers, the lifetime risk of breast cancer is 40 to 85 percent. For ovarian cancer, the lifetime risk among the general population is 1.5 percent, whereas the lifetime risk is between 25 to 65 percent for BRCA1 mutation carriers and 15 to 20 percent for BRCA2 mutation carriers. An individual person’s risk may be higher or lower based on that person’s own family history or lifestyle choices. Cancer risk is lower among those who live a healthy lifestyle, including exercising regularly, eating healthfully, reducing alcohol consumption and avoiding cancer-causing drugs.
However, having a healthy BRCA gene does not mean freedom from cancer risk. In fact, most women who develop breast or ovarian cancer do not have these mutations. Some may have other genetic mutations making their families more susceptible to cancer. More often, women diagnosed with cancer will have no family history of cancer at all and no identifiable genetic risk factors. Overall, only about 5 percent of women with breast cancer and 4 to 11 percent of women with ovarian cancer carry a BRCA mutation.
Interventions for those who test positive
Before you undergo any type of screening, always ask, “Is an effective treatment available for me if I test positive?” In the case of BRCA carriers, surgery is an effective treatment for preventing cancer, either double mastectomy (the surgery selected by Jolie) or removal of the ovaries with or without the fallopian tubes. Though effective, these surgeries are not without risks, and individuals may choose to delay surgery for various reasons, such as concerns about the health impact of early menopause or on the ability to have children.
Preventive removal of the ovaries and fallopian tubes reduces the risk of ovarian cancer by more than 80 percent. (The risk of being diagnosed is not entirely eliminated because women still get cancer in the abdominal cavity, which is sometimes diagnosed as ovarian cancer.) It also can reduce the risk of breast cancer when performed in younger women without prior breast cancer, although that benefit diminishes as women approach menopause. There also is evidence that preventive surgery reduces the risk of mortality. However, the procedure does not eliminate all risk of cancer and involves substantial risks, including impact on childbearing as well as premature estrogen deficiency (which may increase the risk of cardiovascular disease and other conditions) and exacerbated symptoms of menopause. These risks increase in younger women, and it may be reasonable for many young women to delay undergoing surgery until closer to the age of menopause.
Preventive removal of both breasts leads to a more than 90-percent reduction in breast cancer risk, although it is not yet clear whether this procedure leads to overall improvements in survival. The primary risks of the procedure include complications from the surgery itself or from breast implants if the patient chooses to have breast reconstruction.
Some women choose to undergo intensive annual or biannual screenings for breast cancer using Magnetic Resonance Imaging (MRI) or mammography. Though intensive screening can detect cancer, its effect on mortality is unknown, and it may lead to a high rate of unnecessary additional testing and surgery through the identification of false positives. Excessive exposure to radiation through repeated mammography screenings also slightly increases a woman’s risk of developing breast cancer.
Tamoxifen and raloxifene are two drugs the Food and Drug Administration approved to reduce the risk of cancer in some groups. However, these drugs have not been sufficiently tested to show whether they reduce the risk of cancer in women with BRCA mutations, and there is some evidence that tamoxifen is not effective among carriers of a faulty BRCA1 gene. Both drugs also are associated with substantial risks: Raloxifene is associated with an increased risk of blood clots, as well as hip and other fractures, and tamoxifen increases the risk of blood clots and endometrial cancer.
What to expect from the test
In those who suspect they may carry a BRCA mutation that is known to be harmful, testing for the mutation can help identify high-risk patients and allow them to make appropriate decisions about preventive treatment. In rare cases, testing also may help relieve anxiety by revealing that a woman does not carry a mutation previously detected in a member of her family. Women who have avoided inheriting a family mutation have about the same low risk of ovarian cancer as the general population. They also have a lower risk of breast cancer than those who carry the mutation, although some studies suggest that they could remain at higher risk than people with no family history of breast cancer (this residual risk may be due to other genes in the family that contribute to cancer risk).
Yet cases such as these are rare. It is far more likely that a test will be uninformative than yield a concrete negative or positive result. In the most common scenario, a patient with a family history of cancer receives test results showing normal BRCA genes but is unable to rule out other, unrelated genetic mutations that could have caused her family’s cancer history. This could occur when other members of the patient’s family have not yet been tested for BRCA mutations or have all tested negative themselves.
Unhelpful results also may occur in rare cases in which tests reveal a BRCA mutation that has not been studied well enough to understand its effect on cancer risk. A patient with this mutation cannot know whether the mutation increases the risk of cancer or has a neutral or even protective effect.
Patients can experience increased anxiety as a result of testing, particularly if results are uninformative, which may lead to unnecessary additional screening, prophylactic surgery or other excessive treatment. For example, in one study of subjects undergoing BRCA testing, about 12 percent of the patients who received uninformative test results had their ovaries and fallopian tubes removed, and 2 percent of those with “true negative” results (confirmed absence of a known family mutation) also underwent this surgery. Many, if not most, of these surgeries were unnecessary, given that the lifetime risk of developing ovarian cancer for these women was either unknown or equal to the general population (1.5 percent).
Until recently, genetic testing for BRCA mutations was a costly process with potentially far-reaching implications for a patient’s health insurance coverage. Two recent changes to the legal landscape have the potential to profoundly change these economic concerns.
First, the Supreme Court’s June 2013 decision to strike down two patents on the BRCA1 and BRCA2 genes opened the door to companies wishing to manufacture generic BRCA tests at lower costs. The price of a single test, previously between $3,000 and $4,000, is likely to fall dramatically with the recent ruling.
Second, under the Affordable Care Act, new health insurance plans are required to cover BRCA testing as a form of preventive care for individuals at heightened risk of carrying the gene due to family history. Insurers also are prevented from raising rates or denying insurance to patients who test positive, based on a 2008 law preventing discrimination related to genetic test results. However, insurers may still decline to pay for related procedures, such as fertility treatments for women who wish to preserve their eggs before undergoing surgery or other preventive treatment.
Should I consider testing?
Patients who have been diagnosed with certain types of breast cancer should consider genetic testing in collaboration with their cancer treatment team. For women who have never had breast cancer, the question of whether to get tested depends on family history and an individual evaluation of cancer risk and treatment options.
The U.S. Preventive Services Task Force (USPSTF), an independent panel of experts that evaluates the best evidence on preventive health services, has recommended that women at high risk of cancer due to family history seek genetic counseling to help them make an informed decision about whether to test for BRCA mutations. There is no expert consensus on exactly who should be considered sufficiently high-risk to warrant genetic counseling. However, the USPSTF has identified specific patterns of family history that can help women decide whether to seek genetic counseling. (See the box below).
The USPSTF has estimated that only about 2 percent of adult women in the general population meet one of these criteria for increased risk. For the remaining 98 percent of women who do not meet these patterns, there is very low risk of carrying a harmful BRCA mutation. These women are still at risk of developing breast cancer that is not associated with a BRCA1 or BRCA2 mutation, but genetic testing is not likely to provide useful information to help them make treatment or prevention decisions. The USPSTF therefore recommends against genetic screening for these women.
Several companies advertise genetic testing for other mutations besides BRCA mutations. These tests are generally not as helpful in guiding treatment decisions because less is known about the impact these mutations have on cancer risk. As a result, the tests may cause women to undergo unnecessary prophylactic surgery or other high-risk preventive treatments.
Patients considering any form of genetic testing should ask their doctor for a referral to a health care provider who offers genetic counseling. Genetic counseling, if done correctly by a trained expert, can help women make informed decisions, improve their knowledge and perception of the absolute risk for breast and ovarian cancer, and reduce anxiety.
BRCA testing is not for everyone and should be considered only by patients with a firm understanding of what to expect. For a small number of patients at high risk for breast cancer, this test may be a critical step toward reducing cancer risks and living a longer, healthier life.
Identifying High Genetic Risk From Family History
The USPSTF recommends genetic counseling for women who meet any one of these criteria.
For all women:
- Two immediate family members (such as a sister, mother or daughter) with breast cancer, one of whom was diagnosed at age 50 or younger.
- Three immediate or second-degree family members (such as an aunt, grandmother or niece) on either side of the family diagnosed with breast cancer at any age.
- Both breast cancer and ovarian cancer among immediate or second-degree family members on either side of the family.
- An immediate family member with bilateral breast cancer (cancer in both breasts).
- Breast cancer in a male relative.
For women of Ashkenazi Jewish ancestry:
- An immediate family member with breast cancer.
- Two second-degree family members on the same side of the family with breast or ovarian cancer.