Identifying and counseling women with BRCA mutations

February 22, 2016

Women with BRCA gene mutations face tough decisions but they have options.



One in 8 women will be diagnosed with breast cancer and 1 in 72 women will be diagnosed with ovarian cancer in her lifetime.1 Since the discovery of the BRCA1 and BRCA2 (BRCA) tumor suppressor genes in 1990 and 1994, respectively, the susceptibility of BRCA mutation carriers to breast, ovarian, pancreatic, and prostate cancer, and melanoma has been well established. Here we provide evidence-based recommendations on how to identify and counsel women with BRCA mutations.

More than 2000 variants of the BRCA1 and BRCA2 mutations with varying magnitudes of risk have been identified. The penetrance of BRCA mutations varies based on the specific mutation, but the overall breast and ovarian cancer risks for mutation carriers are approximately 65% to 85% and 39% to 46% respectively for BRCA1 and 45% to 85% and 10% to 27% respectively for BRCA2.2 The current literature may overestimate risk, because estimates are typically derived from highly selected families or ethnic groups. From 3% to 20% of mutations identified during full sequencing are variants of unknown significance (VUS). Ethnic minorities, especially African Americans, have higher rates of VUS, which poses a problem for counseling and treatment planning.3

Genetic counseling

Under the Affordable Care Act, genetic counseling and testing for BRCA mutations must be covered as preventative services in high-risk individuals with a family history of breast, ovarian, tubal, and peritoneal cancer. Referral to a licensed genetic counselor improves adherence to national recommendations, but more importantly, it expands the family history and implications of a negative test.4

All women with epithelial ovarian, tubal, or peritoneal carcinoma, and breast cancer patients with strong family histories should be offered genetic counseling and testing (Table). The National Comprehensive Cancer Network (NCCN) suggests that high-risk individuals with a family history of 3 or more of the following cancers/conditions should be referred for genetic evaluation: pancreatic cancer; prostate cancer with Gleason score ≥7; sarcoma; adrenocortical carcinoma; brain tumor; endometrial , thyroid, or kidney cancer; dermatologic manifestation of Cowden syndrome and/or macrocephaly; hamartomatous polyps of the gastrointestinal tract, and diffuse gastric cancer.5

In a large retrospective trial, the relative risk for pancreatic cancer in BRCA mutation carriers was approximately 2.5-fold higher than in the general population.6 The relative risk of melanoma in BRCA2 carriers was 2.58 times that of the general population.7 A personal or family history of pancreatic cancer or melanoma should raise clinical suspicion for an underlying BRCA mutation. However, in individuals with known BRCA mutations without a significant family history, the risks of developing pancreatic cancer or melanoma are relatively low. Although NCCN has no specific surveillance recommendations for pancreatic cancer or melanoma and data on the efficacy of screening are insufficient, at our institution, we consider endoscopic ultrasound screening of the pancreas based on family history and recommend annual skin examination for women with BRCA2 mutations.


Screening and detection

When a woman is diagnosed with a deleterious BRCA mutation, she should be counseled about cancer screening and prevention. Breast self-exams and awareness are recommended starting at age 18, and clinical breast exams are recommended every 6 to 12 months starting at age 25. Despite a lack of randomized trials on the effectiveness of breast self-exams for cancer prevention in BRCA mutation carriers, regular palpation may help promote breast awareness.

Annual breast imaging should commence at age 25 with magnetic resonance imaging (MRI), adding mammography alternating every 6 months at age 30. In the Dutch MRISC Screening Study, MRI was more sensitive than mammography for detection of invasive breast cancer (66.7% for BRCA1 and 69.2% in BRCA2).8 Although the false-positive rate was lower with mammography (5%), MRI maintained an acceptable false-positive rate of 10% in BRCA mutation carriers.9 MRI was also more cost-effective than mammography in both BRCA1 and BRCA2 mutation carriers.10 BRCA mutation carriers who began surveillance with both mammography and MRI at age 25 were estimated to receive 4.6 to 8.2 false-positive results that necessitated further imaging or biopsy over their lifetimes.11 False-positive MRI results increased patients’ anxiety but did not affect their preferences regarding prophylactic mastectomy.12

In BRCA mutation carriers, prophylactic mastectomy is estimated to reduce breast cancer risk by 90% to 100%.13 Either simple (total) mastectomy or subcutaneous mastectomy, which preserves the nipple-areolar complex, can be performed. Risks of prophylactic mastectomy include significant psychological side effects, especially regarding femininity and body image, and sexual dysfunction related to loss of nipple sensation if total mastectomy is performed. Dissatisfaction with the cosmetic appearance of the reconstruction and post-reconstruction pain are common complaints. If future fertility is desired, breastfeeding plans should be addressed preoperatively.14

Early detection of ovarian cancer has proven significantly more challenging. Because current imaging modalities and serum tests are insufficiently sensitive and specific, NCCN does not support routine ovarian cancer screening. Transvaginal ultrasound (TVUS) and serum CA-125 testing can be considered at age 30 to 35 years, at intervals left to the clinician’s discretion. The Risk of Ovarian Cancer Algorithm (ROCA) tracks CA-125 annually and calculates a risk estimate based on CA-125 trends and age. An elevated calculated risk triggers TVUS. The use of ROCA for ovarian cancer screening in high-risk women is being studied in an ongoing clinical trial, GOG-199.15


The accepted standard of care for BRCA carriers is to perform risk-reducing salpingo-oophorectomy (RRSO) at age 35 to 40, or at the completion of childbearing.5 Estimates suggest that RRSO decreases the risk of ovarian cancer by more than 90%, breast cancer risk by 50% when performed before menopause, and overall mortality for BRCA mutation carriers.2 RRSO includes an abdominal and pelvic survey, pelvic washings, and resection of the entirety of the bilateral fallopian tubes and ovaries. The surgical specimens are pathologically examined using a specific protocol. Occult malignancy has been found in the fallopian tubes or ovaries in up to 10% of RRSO specimens.16

Another consideration prior to RRSO is whether to perform concurrent hysterectomy. Patients who desire hormone replacement therapy (HRT) after RRSO may choose hysterectomy to avoid the necessity of progesterone. Although the Women’s Health Initiative study demonstrated a small increase in breast cancer risk with combination HRT over estrogen alone in the general population, this incremental effect has not been seen in BRCA carriers after RRSO.17 Concurrent hysterectomy would eliminate the risk of uterine cancer if the patient requires tamoxifen later. There is also mixed evidence that BRCA1 carriers may be at slightly increased risk for uterine papillary serous carcinomas.18 The major drawback of hysterectomy is additional surgical risk.

In BRCA mutation carriers, molecular and pathologic studies have suggested that the fallopian tube may be the site of pelvic serous carcinogenesis.19 Evidence is insufficient on the degree of ovarian cancer risk reduction, optimal timing, and extent of surgical removal on which to base a recommendation for routine salpingectomy alone in high-risk patients, although the American College of Obstetricians and Gynecologists and the Society of Gynecologic Oncology have endorsed consideration of salpingectomy (SGO Clinical Practice statement 2013, ACOG committee opinion #620, 2015). Salpingectomy alone does not reduce breast cancer risk. Salpingectomy and delayed oophorectomy have also been suggested to improve quality of life, but no randomized trials have been performed studying outcomes after this practice.



Other options

For women who have declined or want to delay surgical risk reduction, chemoprevention is also an option and may offer better quality of life. Tamoxifen and raloxifene are Food and Drug Administration-approved for chemoprevention of breast cancer in women with a Gail model risk estimate of more than 1.66% over 5 years. A limited study of 19 BRCA mutation carriers, only 8 of whom received tamoxifen, found that tamoxifen reduced the risk of estrogen receptor-positive breast cancers and reduced breast cancer risk by 62% in BRCA2 carriers.20 Other agents that have shown efficacy for prevention or recurrence of breast cancer, such as raloxifene, anastrazole, and exemestane, have not been well studied for primary chemoprophylaxis.

Combination oral contraceptive pills (OCP) may also benefit healthy women who have not yet undergone oophorectomy. Estimates of risk reduction range from 40% to 50% after 3 years of use to 36% for every 10 additional years of OCP use.21 Despite concerns that OCP formulations before 1975 may have increased breast cancer risk, this effect has not been seen with prolonged use of currently available OCP formulations.22 Chemoprevention should be offered to women who are not yet ready for surgery, but it is not recommended as a replacement for surgical prophylaxis.

Preserving fertility

In young women, a discussion of the patient’s reproductive plans should be initiated. BRCA mutation carriers may experience accelerated ovarian aging.23,24 Some BRCA mutation carriers may choose in vitro fertilization with preimplantation genetic diagnosis in order to avoid transmission of the BRCA mutation to future generations. No association has been seen between the use of assisted reproductive technology or infertility treatment and breast or ovarian cancer risk in BRCA mutation carriers.25 The protective effect of parity against ovarian cancer seen in the general population has not been consistently reported in BRCA mutation carriers.21 Breastfeeding for more than 1 year may be protective against breast cancer.26

In the general population, retrospective trials have linked obesity, alcohol abuse, and lack of exercise to increased breast cancer risk. In BRCA mutation carriers, weight loss may protect against breast cancer.21,26 Smoking has been found to have no effect or to be slightly protective against breast cancer.27 Practitioners should recommend that BRCA mutation carriers follow the same lifestyle recommendations as the general population.




Side effects of RRSO

Although RRSO reduces cancer risk in BRCA mutation carriers, major morbidities are associated with surgical menopause, with greater morbidity in younger women. The well-documented risks include increased overall mortality, cardiovascular disease (CVD), stroke, cognitive decline, depression or anxiety, climacteric symptoms, and osteoporosis.

Vasomotor and sexual side effects of RRSO have been found to be the most bothersome to patients. Almost 60% of women report vasomotor symptoms and 10% report decreased sexual pleasure, mostly related to vaginal dryness. Vasomotor and sexual side effects can be managed with HRT in women without a history of breast cancer. In BRCA carriers without a personal history of breast cancer, no increased risk of breast cancer was seen with short-term use of HRT after RRSO but the study was limited due to heterogeneous dosing strategies and short follow-up of only 2.6 years.28 However, in BRCA carriers with a personal history of breast cancer, HRT confers an unacceptably increased risk of breast cancer.29 In these women, options include lifestyle modifications, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, vaginal lubricants, and gabapentin.

Osteoporosis risk rises sharply with surgical menopause. In one study, within 29 months of RRSO, 55.6% of patients had developed osteopenia, 12.1% had osteoporosis, and, 4% had suffered an atraumatic fracture.30 HRT may partially mitigate these risks but the benefits are lost when therapy is discontinued. Post-RRSO patients should be routinely counseled about osteoporosis, risk factors such as smoking, poor nutrition, and excessive weight loss, and preventative measures including adequate calcium and vitamin D intake, weight-bearing exercises, and fall-prevention measures.

Cardiovascular mortality after RRSO has not been well studied. Elective oophorectomy has been associated with an increased risk of death from coronary heart disease in women before age 45 (RR 1.34 [1.13-1.60]), and especially in never-users of estrogen replacement in women before age 50 (RR 1.98 [1.18-3.32]).31 Changes in cardiovascular risk and the effects of HRT on cardiovascular risk after RRSO for BRCA mutations are areas of active research.


Identifying and counseling women with BRCA mutations is complicated and requires detailed knowledge of both current genetic counseling recommendations and state-of-the-art cancer prevention research. Regular breast cancer screening should be performed but ovarian cancer screening has not yet been shown to be beneficial. Prophylactic mastectomy, chemoprophylaxis with tamoxifen or OCPs, and lifestyle modifications may modulate breast and ovarian cancer risk, but RRSO is strongly recommended at age 35 to 40 or at the completion of childbearing. Special attention should be paid to psychological and social wellbeing, bone mineral density screening, and CVD screening in women who have undergone prophylactic surgery.



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