10. What does an ambiguous BRCA1 or BRCA2 test result mean?

If genetic testing shows a change in BRCA1 or BRCA2 that has not been previously associated with cancer in other people, the person’s test result may be interpreted as “ambiguous” (uncertain). One study found that 10 percent of women who underwent BRCA1 and BRCA2 mutation testing had this type of ambiguous result (16).

Because everyone has genetic differences that are not associated with an increased risk of disease, it is sometimes not known whether a specific DNA change affects a person’s risk of developing cancer. As more research is conducted and more people are tested for BRCA1 or BRCA2 changes, scientists will learn more about these changes and cancer risk.

11. What are the options for a person who has a positive test result?

Several options are available for managing cancer risk in individuals who have a harmful BRCA1 or BRCA2 mutation. However, high-quality data on the effectiveness of these options are limited.

· Surveillance—Surveillance means cancer screening, or a way of detecting the disease early. Screening does not, however, change the risk of developing cancer. The goal is to find cancer early, when it may be most treatable.

Surveillance methods for breast cancer may include mammography and clinical breast exams. Studies are currently under way to test the effectiveness of other breast cancer screening methods, such as magnetic resonance imaging (MRI), in women with BRCA1 or BRCA2 mutations. With careful surveillance, many breast cancers will be diagnosed early enough to be successfully treated.

For ovarian cancer, surveillance methods may include transvaginal ultrasound, blood tests for CA–125 antigen, and clinical exams. Surveillance can sometimes find ovarian cancer at an early stage, but it is uncertain whether these methods can help reduce a woman’s chance of dying from this disease.

• Prophylactic Surgery—This type of surgery involves removing as much of the “at-risk” tissue as possible in order to reduce the chance of developing cancer. Bilateral prophylactic mastectomy (removal of healthy breasts) and prophylactic salpingo-oophorectomy (removal of healthy fallopian tubes and ovaries) do not, however, offer a guarantee against developing cancer. Because not all at-risk tissue can be removed by these procedures, some women have developed breast cancer, ovarian cancer, or primary peritoneal carcinomatosis (a type of cancer similar to ovarian cancer) even after prophylactic surgery. In addition, some evidence suggests that the amount of protection salpingo-oophorectomy provides against the development of breast and ovarian cancer may differ between carriers of BRCA1 and BRCA2 mutations (17).
• Risk Avoidance—Certain behaviors have been associated with breast and ovarian cancer risk in the general population (see Question 16). Research results on the benefits of modifying individual behaviors to reduce the risk of developing cancer among BRCA1 or BRCA2 mutation carriers are limited.
• Chemoprevention—This approach involves the use of natural or synthetic substances to reduce the risk of developing cancer or to reduce the chance that cancer will come back. For example, the drug tamoxifen has been shown in numerous clinical studies to reduce the risk of developing breast cancer by about 50 percent in women who are at increased risk of this disease and to reduce the recurrence of breast cancer in women undergoing treatment for a previously diagnosed breast tumor. As a result, tamoxifen was approved by the U.S. Food and Drug Administration (FDA) as a breast cancer treatment and to reduce the risk of breast cancer development in premenopausal and postmenopausal women who are at increased risk of this disease. Few studies, however, have evaluated the effectiveness of tamoxifen in women with BRCA1 or BRCA2 mutations. Data from three studies suggest that tamoxifen may be able to help lower the risk of breast cancer in BRCA1 and BRCA2 mutation carriers (18–20). Two of these studies examined the effectiveness of tamoxifen in helping to reduce the development of cancer in the opposite breast of women undergoing treatment for an initial breast cancer (19, 20).

Another drug, raloxifene, was shown in a large clinical trial sponsored by the National Cancer Institute (NCI) to reduce the risk of developing invasive breast cancer in postmenopausal women at increased risk of this disease by about the same amount as tamoxifen. As a result, raloxifene was approved by the FDA for breast cancer risk reduction in postmenopausal women. Since tamoxifen and raloxifene inhibit the growth of breast cancer cells in similar ways, raloxifene may be able to help reduce breast cancer risk in postmenopausal BRCA1 and BRCA2 mutation carriers. However, this has not been studied directly.

12. What are some of the benefits of genetic testing for breast and ovarian cancer risk?

There can be benefits to genetic testing, whether a person receives a positive or a negative result. The potential benefits of a negative result include a sense of relief and the possibility that special preventive checkups, tests, or surgeries may not be needed. A positive test result can bring relief from uncertainty and allow people to make informed decisions about their future, including taking steps to reduce their cancer risk. In addition, many people who have a positive test result may be able to participate in medical research that could, in the long run, help reduce deaths from breast cancer.