Hereditary breast and ovarian cancer syndrome is an inherited cancer-susceptibility syndrome characterized by multiple family members with breast cancer, ovarian cancer, or both; breast and ovarian cancers in one person; and breast cancer with an early age at onset. Genetic testing is available to identify women at increased risk of breast and ovarian cancers. These women may benefit from screening and prevention strategies to reduce their risk. The American College of Obstetricians and Gynecologists (ACOG) has produced guidelines for physicians caring for patients with BRCA1 and BRCA2 gene mutations.

BRCA1 and BRCA2 Mutations

Approximately 10 percent of ovarian cancer cases and 3 to 5 percent of breast cancer cases can be traced to germline mutations in the BRCA1 and BRCA2 genes. In the general population, about one in 300 to 800 persons carries a mutation in these genes; however, a specific mutation known as a “founder mutation” may occur more often in populations founded by a small ancestral group, including Ashkenazi (Eastern European) Jews, French Canadians, and Icelanders. An estimated one in 40 Ashkenazi Jews carries one of three founder mutations in the BRCA1 or BRCA2 gene.

A woman with a BRCA1 mutation has a 39 to 46 percent risk of developing ovarian cancer, and a woman with a BRCA2 mutation has a 12 to 20 percent risk of developing ovarian cancer. The lifetime risk of breast cancer for a woman with a BRCA1 or BRCA2 mutation is 65 to 74 percent. In women with breast cancer, the 10-year risk of developing ovarian cancer is 12.7 percent for women with a BRCA1 mutation and 6.8 percent for women with a BRCA2 mutation.

Risk Assessment and Counseling

The initial screening for hereditary breast and ovarian cancer syndrome should include specific questions about the patient's personal and family history of breast and ovarian cancers, risk assessment, education, and counseling. The patient may choose to include genetic testing after appropriate counseling. Two sets of clinical criteria have been developed to determine which patients would benefit from genetic risk assessment (Table 1). The first group includes women whose chance of having an inherited predisposition to breast and ovarian cancers is greater than 20 to 25 percent. Genetic risk assessment is recommended in these patients. The second group includes women whose chance of having an inherited predisposition to breast and ovarian cancers is greater than 5 to 10 percent. Genetic risk assessment may be helpful for these patients. Patients who have been diagnosed with high-grade serous ovarian cancer, primary peritoneal cancer, or fallopian tube cancer may also benefit from genetic risk assessment because of the high prevalence of BRCA1 or BRCA2 mutation in these populations.

As part of genetic counseling, physicians should discuss possible testing outcomes with patients, including positive, negative, and uninformative test results. Before testing, patients should be made aware of options for surveillance, chemoprevention, and risk-reducing surgery. It is also appropriate to discuss possible psychologic and familial implications of testing, as well as the expected costs and patients' insurance coverage. Another aspect of counseling may include a discussion of current legislation regarding genetic discrimination and the privacy of genetic information. The federal Genetic Information Nondiscrimination Act of 2008 protects patients from discrimination based on genetic information. Some states have laws providing similar protection, although these laws do not pertain to certain forms of insurance, such as life or disability insurance.

Genetic Testing

Testing generally begins with a family member who has ovarian cancer or early-onset breast cancer. Full sequencing of BRCA1 and BRCA2 is often performed because the mutation may be found along the entire length of both genes. If a specific mutation is identified, a single-site test can be recommended to look for the specific mutation. In patients from high-risk ethnic and geographic groups where specific gene alterations are already identified, common mutations can be tested instead of full sequence testing.

If no affected family member is available, patients may still benefit from testing. Counseling on screening or risk-reducing approaches is appropriate if a deleterious mutation is identified. If no deleterious mutation is identified, physicians should explain possible reasons for this, such as a mutation that the patient did not inherit is present in the family; an undetectable mutation is present in the family but it is unknown whether the patient shares this predisposition; or there is no inherited predisposition in the family. A physician with experience in caring for patients who may be at inherited risk can determine which option is most likely and which risk-reduction approach is appropriate for the patient.

Risk-Reduction Strategies

OVARIAN AND FALLOPIAN TUBE CANCERS

Strategies to reduce the risk of ovarian and fallopian tube cancers in women with known BRCA mutations include surveillance, chemoprevention, and surgery. Current screening procedures are not likely to detect ovarian cancer at an early enough stage to cure the disease. Patients should be informed that there is no evidence that screening will reduce mortality from ovarian cancer in high-risk populations. However, because of the high risk of ovarian and fallopian tube cancers in women with BRCA1 or BRCA2 mutations, periodic screening with cancer antigen (CA) 125 and transvaginal ultrasonography are appropriate. Screening should begin between 30 and 35 years of age, or five to 10 years earlier than the earliest age of first diagnosis of ovarian cancer in the patient's family.

Although studies have reported the benefits and magnitude of reduced risk of ovarian cancer with oral contraceptive use in women with a BRCA mutation, this has not been demonstrated consistently in the general low-risk population. Some studies have suggested that oral contraceptive use increases the risk of breast cancer in women with BRCA mutations. Physicians should discuss the risks and benefits of chemoprevention and oral contraceptives with patients who have BRCA1 or BRCA2 mutations. Parity has been associated with a lower risk of ovarian cancer in women with a BRCA mutation.

Risk-reducing salpingo-oophorectomy of normal ovaries and fallopian tubes should be offered to women by 40 years of age or after childbearing. This procedure has been shown to reduce the risk of ovarian, fallopian tube, and peritoneal cancers by 85 to 90 percent, as well as decrease overall mortality, in women with a BRCA mutation.

BREAST CANCER

Strategies to reduce the risk of breast cancer in women with known deleterious BRCA mutations include surveillance, chemoprevention, and surgery. Surveillance methods include semiannual clinical breast examination, annual mammography, and annual breast magnetic resonance imaging beginning at 25 years of age or earlier, based on the earliest age of onset in the patient's family.

Preliminary studies suggest that chemoprevention with tamoxifen may reduce the risk of breast cancer by 62 percent in women with BRCA2 mutations, although it does not reduce the risk in women with BRCA1 mutations. Prophylactic surgery with bilateral mastectomy has been shown to reduce the risk of breast cancer by more than 90 to 95 percent, depending on the type of mastectomy procedure. The most effective procedure is total mastectomy, which removes the entire breast tissue, nipple, and areola. Physicians should discuss the psychosocial effects and potential for complications with patients.

Risk-reducing salpingo-oophorectomy has demonstrated a reduction in the risk of breast cancer by 40 to 70 percent. This protection is likely limited to patients who are premenopausal at the time of surgery. Carriers of the BRCA2 mutation may experience a greater protective effect than carriers of the BRCA1 mutation. Studies suggest that the timing of risk-reducing salpingo-oophorectomy should be based on the patient's needs, such as the desire to preserve fertility and which gene mutation the patient carries. For example, carriers of the BRCA1 mutation are more likely to develop ovarian cancer by 50 years of age than carriers of the BRCA2 mutation.

Management for Women Without Identified BRCA Mutations

Current testing methods cannot identify all mutations that exist in BRCA genes. Studies suggest that breast cancer is caused by a BRCA mutation in less than one half of families with four or more cases of breast cancer but no cases of ovarian cancer. Women with a personal or family history of breast cancer who test negative for a BRCA mutation should be treated based on their family history. There is an increased risk of breast cancer in women with a family history of site-specific breast cancer who have no identified BRCA mutation. However, these women may not have an increased risk of ovarian cancer. Women at high risk of breast and ovarian cancers should maintain contact with their physician to keep informed of new research and improvements in testing technology.