BRCA screening

Screening can be initiated by population-based risk or by family history. When possible, the affected individual should first receive comprehensive sequencing of both BRCA1 and BRCA2 and then single-site testing offered to family members. Other options include comprehensive sequencing if the affected family member is unavailable or testing for “founder” mutations in certain populations.

A thorough family history assessment includes documentation of the age of diagnosis of a cancer, the site of the tumor, family members with multiple cancers or bilateral disease, and presence or absence of Jewish ancestry. In general, one does not have to verify diagnoses. Exceptions include (1) consideration of risk-reducing surgery when no mutation has been identified or (2) family history of either abdominal malignancies at young ages or sarcomas.[5] The US Preventive Services Task Force (USPSTF) concluded that there is adequate evidence that the net benefit of testing for potentially harmful BRCA mutations is moderate among women whose family history is associated with an increased risk. Testing should only be performed when a woman whose personal or family history suggests an increased risk of an inherited cancer susceptibility, when she has access to a health professional trained in genetic counseling and interpreting test results, and when test results will aid decision making.[6] The USPSTF recommends against routine genetic counseling or BRCA testing for women whose family history is not associated with an increased risk of potentially harmful BRCA mutations.

Several organizations have outlined recommendations for genetic screening and identifying at-risk women. For simplicity and the purposes of this chapter, discussion will focus on the recommendations outlined by the American Congress of Obstetricians and Gynecologists (ACOG). BRCA testing should be performed on any woman with a known BRCA mutation in the family or a risk of 20%–25% as estimated by the clinical criteria in Table 4-1. A woman may want to consider testing if she or a close relative has a personal history of any of the clinical criteria in Table 4-2.

Genetic screening may also be considered if a woman’s family history underrepresents female cancers due to adoption, few female relatives, or multiple family members with hysterectomies or oophorectomies at young ages. Family history should be reviewed periodically or at least every 5–10 years. Screening can be initiated as early as the age of consent, although ACOG recommends against screening women under age 21.[7]

Multiple risk stratification tools have been developed to help identify women who would benefit from a referral to genetic counseling. These tools include the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, and Family History Screen 7. Most of these tools have been found to be greater than 85% sensitive but have not been tested specifically among BRCA mutation carriers.[6] Other tools have been developed to predict the risk of deleterious BRCA mutations and include the Myriad Genetic Laboratories model, Couch model, Tyrer model, Pen II Risk model, and BRCAPRO. BRCAPRO is currently the most validated tool for assessing such a risk.[8] The USPSTF recommends against using breast cancer risk assessment models based on the Gail model (such as National Cancer Institute Breast Cancer Risk Assessment Tool) because they are not designed to assess which women should receive genetic counseling or BRCA testing. If using a risk assessment model, it is important to inform the patient of the uncertainties of estimation.

Several risk thresholds for genetic screening have been suggested but the USPSTF has found insufficient evidence to support a specific risk threshold for referral for genetic counseling or BRCA testing. ACOG and the Society of Gynecologic Oncology suggest a threshold of 20%–25%.[7] Women who are eligible for a genetics referral may be offered the option of accessing genetic testing during their initial management or at any time thereafter.[5]

Genetic counseling

Genetic counseling should occur prior to testing and should include pre- and post-test counseling. An important part of the counseling process is identification of affected family members who may be preferred candidates for testing. Other important components of counseling include the following: the natural history of the disorder, the inheritance pattern, options for screening, accuracy of testing, significance of possible results, options for surveillance and risk reduction, psychological and familial implications, cost, and legislation regarding genetic discrimination and privacy. The Genetic Information and Nondiscrimination Act of 2008 has made it illegal for health insurance providers or employers to use genetic information to make decisions about insurance eligibility or terms of employment. It is limited in that it does not apply to life insurance, disability insurance, or long-term care. Women should also be given information about sources of support, lifestyle advice, and any trials or studies. At the end of the visit, health professionals and counselors should send a written summary of a woman’s personal risk information and a reminder that her risk will change if her family history changes. Counseling should be performed by a trained provider. The necessary training to provide counseling has yet to be well defined. The National Cancer Institute Cancer Genetics Services Directory has a list of professionals who offer genetic counseling, cancer risk assessment, and genetic susceptibility testing (www.cancer.gov/cancertopics/genetics/directory).

Interpretation of possible results

Possible results of BRCA mutation testing are positive, true-negative, uninformative-negative, or variant of uncertain clinical significance (VUS). A positive result means that a potentially harmful mutation has been detected. A true-negative result is the lack of identification of a potentially harmful mutation in a woman with a family history of a known BRCA mutation. She can be reassured that her breast cancer risk is generally not increased compared to the general population. An uninformative-negative result is the lack of identification of a potentially harmful mutation in a woman without a known family history of a BRCA mutation. The presence of a significant family history of breast or ovarian cancer in a patient who receives a negative result may be explained by the presence of a BRCA deletion that the patient did not inherit, an undetectable BRCA mutation or other yet unidentified cancer susceptibility gene, or an affected relative with a sporadic cancer and no inherited predisposition in the family. Twelve percent of high-risk families without a BRCA1 or BRCA2 coding-region mutation may have other clinically important genomic rearrangements.[9]

The least defined result of BRCA testing is a VUS, which is a genetic mutation that has not yet been established as potentially harmful. The rate of identification of a VUS is 2%–13% and the harms associated with the result are not yet known.[10] As genetic research continues, VUS continue to be reclassified and women updated of their risk assessment. In one study, 56% of VUS were reclassified after a median of 39 months, longer than the median time to prophylactic oophorectomy (18.6 months) and prophylactic mastectomy (20.1 months).[11] Due to the lack of understanding of the risk of VUS and the known surgical risk or prophylactic oophorectomy and mastectomy, clinicians should consider managing such women based on their personal and family history.

Surveillance of BRCA carriers

Once a BRCA mutation is identified, treatment may include intensive surveillance, chemoprevention, or risk-reducing surgery. Evidence is lacking on the effect of intensive screening for BRCA-related cancer on clinical outcomes. Breast surveillance is typically initiated at age 25 or sooner depending on family history and includes clinical breast exams every three to six months, annual MRI, and annual mammography. The sensitivity of mammography seems to be lower in BRCA mutation carriers than in other high-risk women and may be due to a higher breast density, differences in morphologic features, or more frequent development of interval malignancies.[12] MRI use in breast cancer surveillance increases cancer detection rates in high-risk women. A meta-analysis concluded that combined use of MRI and mammography had higher sensitivity for detecting breast cancer than mammography alone.[13]

Ovarian cancer screening includes annual or semiannual CA125 and transvaginal ultrasound.[2] ACOG recommends initiation at age 30–35, or 5–10 years earlier than the earliest age of diagnosis of ovarian cancer in the family. There is generally poor compliance with surveillance as rates decline even one year after testing; standardization of care is needed.[14] Compliance was associated with the number of relatives with ovarian cancer, perceived risk of ovarian cancer, and Jewish ancestry.[15] Evidence exists that surveillance does not change the stage of ovarian cancer at the time of diagnosis, reduce the woman’s overall mortality, or decrease the number of ovarian cancer deaths. Screening can lead to harm such as complications from major surgical interventions in women who do not have cancer. Fifteen percent of women who underwent surgery for a false positive finding had a serious complication.[16] The USPSTF therefore recommends against ovarian cancer screening of asymptomatic women without a known BRCA mutation.

Breast cancer chemoprevention

Women at high or moderate risk of breast cancer with no personal history of breast cancer should be given information regarding the risks and benefits of chemoprevention, the extent of risk reduction, the side effects of medications, and the alternative options. Tamoxifen, raloxifene, and most recently the aromatase inhibitor exemestane have been found to decrease breast cancer incidence among moderate to high-risk women, but so far their effects seem to be limited to hormone-sensitive breast cancers. In a subset analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention trial (P-1 trial), tamoxifen decreased the risk of breast cancer by 62% in BRCA2 carriers but not in BRCA1 carriers.[17] This risk reduction is similar to tamoxifen’s effect in estrogen-receptor positive breast cancer patients which correlates with the fact that 65%–79% of tumors in BRCA2 carriers are estrogen-receptor positive, whereas only 10%–24% of tumors in BRCA1 carriers are estrogen-receptor positive.[17] Data on the use of breast chemoprevention among BRCA mutation carriers is limited and the number of BRCA mutation carriers in the P-1 trial is very small.

In summary, the USPSTF found sufficient evidence to recommend offering chemoprevention with tamoxifen for five years to premenopausal women and postmenopausal women with or without a uterus at high risk of breast cancer but no personal history of breast cancer and no history of thromboembolic disease or endometrial cancer.[5] Postmenopausal women with a uterus may also be offered chemoprevention with raloxifene. There is evidence to support considering prescribing chemoprevention to women at moderate risk of breast cancer as well.

Health-care professionals must use chemoprevention with caution due to a proven risk of venous thromboembolism (VTE) and endometrial cancer. Tamoxifen and raloxifene increase the risk of VTEs by four to seven events per 1,000 women over five years.[18] The risk is greater with tamoxifen than raloxifene and greater in older women. Tamoxifen increases the risk for endometrial cancer by four more cases per 1,000 women.[18] Tamoxifen or raloxifene should not be continued beyond five years and women must be informed to stop treatment at least two months before trying to conceive or at least 6 weeks before elective surgery.[5] Women who have a high risk of breast cancer but no personal history of breast cancer and have had a bilateral mastectomy should not be offered chemoprevention.

Use of oral contraceptives for chemoprevention

The use of oral contraceptives seems to be associated with a decreased risk of ovarian cancer. In a meta-analysis of BRCA1 and BRCA2 mutation carriers, use of oral contraceptives was associated with a significantly reduced risk of ovarian cancer [summary relative risk (SRR), 0.50, 95% CI 0.33–0.75] and no significantly increased risk of breast cancer (SRR 1.13, 95% CI 0.88–1.45).[19] Nonetheless, oral contraceptive use remains a controversial issue and the USPSTF recommends against the prescription of oral contraceptives solely for the purpose of ovarian cancer prevention. Instead, mutation carriers should receive counseling regarding their individualized risks and expected benefits with oral contraceptive use.

Risk-reducing surgery

Prophylactic mastectomy decreases the risk of breast cancer among patients with an inherited genetic predisposition and has the added benefit of also decreasing the risk of ovarian cancer. It is important, however, to counsel individuals that prophylactic surgery does not completely eliminate their risk given the remote chance that not all at-risk tissue is removed. Prior to surgery, a woman should receive counseling regarding the potential psychosocial and sexual consequences and the possibility of a histologic diagnosis of breast or ovarian cancer. She should be offered access to support groups before making her decision.

Breast cancer risk among BRCA mutation carriers can be decreased by as much as 85%–100% with prophylactic mastectomy and by 37%–100% with oophorectomy.[20, 21] In a large, prospective cohort study of BRCA mutation carriers, there were no cases of breast cancer during three years follow-up after prophylactic mastectomy. In those women who did not undergo prophylactic mastectomy, 7% were diagnosed with breast cancer during those three years.[22] Bilateral salpingo-oophorectomy (BSO) decreases breast cancer risk by up to 72% [23] Risk reduction is greater among BRCA1 mutation carriers than BRCA2 and is more pronounced if a woman is premenopausal at the time of surgery.[23] Short-term hormone therapy after BSO does not diminish the protective effect on breast cancer risk.[24]

If BRCA testing has not been performed but a woman is at high risk for breast cancer, bilateral mastectomy should be discussed but may only be appropriate for a small proportion of women and thus should be managed by a multidisciplinary team. In women without an identified inherited mutation, family history should be verified first. If it cannot be verified, the provider should seek agreement by a multidisciplinary team. Women who choose prophylactic mastectomy tend to be younger, have children, and report a greater number of breast and ovarian cancer among family members.[25]

The recommended surgery for maximizing ovarian cancer risk reduction in women with a genetic predisposition is BSO. The rates of risk and mortality reduction vary according to baseline cancer risks among mutation carriers. In one study of 5,783 BRCA mutation carriers, prophylactic oophorectomy was associated with an 80% reduction in ovarian, fallopian tube, or peritoneal cancer [hazard ratio (HR) 0.20, 95% CI 0.13–0.30, p <0.001] and a 77% reduction in all-cause mortality to age 70 years (HR 0.23, 95% CI 0.13–0.39, p <0.001).[21] Because there is approximately a 5% risk of histologic detection of ovarian cancer at the time of prophylactic oophorectomy in BRCA mutation carriers, it is prudent to routinely collect cytologic washings, peritoneal biopsies, and omental sampling during risk-reduction surgery.[26] Bilateral tubal ligation has also been shown to decrease ovarian cancer risk but not to the same degree as BSO.[2] There is also growing discussion around bilateral salpingectomy with ovarian sparing as a means to decrease risk until an at-risk individual is accepting of oophorectomy, but this approach is not yet supported by SGO as there is still insufficient data to support its use. In women without an identified inherited mutation, family history should be verified first and if it cannot be verified, the provider should seek agreement by a multidisciplinary team before proceeding with BSO.[5]

Risk-reducing BSO is recommended by age 35–40 or after completion of childbearing for women who are BRCA carriers or who have a high risk of ovarian cancer as defined by two or more first-degree relatives with ovarian cancer.[2] Despite a relatively low risk of ovarian cancer before age 50 in BRCA2 carriers (only 3%) compared to the higher risk of 10%–21% in BRCA1 carriers, timely removal of the ovaries is nevertheless recommended due the protective benefit it confers for breast cancer in this population.[7] Though the majority of BRCA carriers (74% in one study) undergo risk-reducing BSO, the majority do not do so by the recommended age of 40.[14] Premenopausal oophorectomy in women with an inherited or increased familial risk of ovarian cancer does not preclude them from participating in hormone therapy. In such women with no personal history of breast cancer, the USPSTF suggests that they should be offered appropriate hormone therapy to continue until the age of natural menopause in line with standard prescribing practices for the general population.