5 Gene Mutations and Breast Cancer Risk: Overview and Management
Summary
Hereditary breast cancer accounts for 5 to 10% of all cases of breast cancer. It is characterized by young age at diagnosis (< 50 years), bilateral breast cancers, and having first-degree relatives with breast, ovarian, or pancreatic cancer. High-risk screening for breast cancer includes twice yearly physical examination and mammography alternated with breast MRI every 6 months. Breast MRI is more sensitive that mammography and allows for earlier detection of breast cancer.
Bilateral prophylactic mastectomy (BPM) confers a 90 to 95% risk reduction in mutation carriers. BPM is associated with reduced cancer distress and anxiety and satisfaction with outcomes. There is a potential negative impact on body image and sexual function. Data regarding the safety of prophylactic nipple-sparing mastectomy in high-risk women are limited by small sample size and short follow-up.
Key Teaching Points
Hereditary breast cancer accounts for 5 to 10% of all cases of breast cancer. It is characterized by young age at diagnosis (< 50 years), bilateral breast cancers, and having first-degree relatives with breast, ovarian, or pancreatic cancer.
Breast MRI is more sensitive than mammography and allows earlier detection of breast cancer in BRCA mutation carriers.
Tamoxifen can reduce the risk of breast cancer in BRCA2 mutation carriers.
Prophylactic oophorectomy before the age of 40 is associated with a 50% reduction in breast cancer in BRCA1/2 carriers.
Bilateral prophylactic mastectomy (BPM) confers a 90 to 95% risk reduction in mutation carriers.
Data regarding the safety of prophylactic nipple-sparing mastectomy are limited by small sample size and short follow-up.
BPM is associated with reduced cancer distress, anxiety, and satisfaction with outcomes. There is a potential negative impact on body image and sexual function.
5.1 Introduction
Some 5 to 10% of all cases of breast cancer and 25 to 40% of cases in patients younger than 35 years have a hereditary origin. It is characterized by young age at diagnosis (< 50 years), bilateral cancers, and having first-degree relatives with breast, ovarian, or pancreatic cancer. The current National Comprehensive Cancer Network guidelines for genetic testing are shown below.
National Comprehensive Cancer Network Guidelines for Genetic Testing for Breast Cancer
Young age (< 50 years).
Bilateral breast cancer.
First-degree relatives with breast, ovarian, pancreatic cancer.
Ashkenazi Jewish descent.
Triple negative breast cancer.
Male breast cancer.
The BRCA genes are tumor suppressor genes that are involved in DNA repair. Mutations in these genes result in increased risk of breast and ovarian cancer. They are inherited in an autosomal fashion and confer a 45 to 80% risk of developing breast cancer (▶Table 5.1). They are present in less than 1% of the general population, accounting for 5% of all breast cancers and 50% of hereditary breast cancer. Less common mutations in highly penetrant breast cancer–associated genes include TP53, PTEN, and PALB2. The development of multigene panels has found less common moderate penetrance genes, CDH1 and STK11, of which breast surgeons should be aware.
Currently, there are three prevention strategies employed in the management of women deemed at high risk of developing breast cancer:
Screening of high-risk patients.
Chemoprevention.
Prophylactic surgery.
5.2 High-Risk Screening
High-risk screening includes clinical breast examination semiannually, annual breast MRI beginning at age 25, and alternating magnetic resonance imaging (MRI) and digital mammography staggered at 6-month intervals. The American Cancer Society recommends surveillance of women with BRCA mutations to include breast MRI combined with mammography. This is based on the increased sensitivity of MRI compared to mammography. It seems to be a safe assumption that increased sensitivity would result in the detection of earlier cancers than mammography screening alone. Recent observational studies have found that screening by MRI with mammography was effective in detecting early-stage breast cancers among BRCA1 and BRCA2 mutation carriers.
Warner et al performed a prospective observational study of MRI screening in high-risk women. Overall, the number of breast cancers detected was not significantly different in those screened with MRI compared to a control group that underwent routine screening. However, the cancers were detected at an earlier stage with more ductal carcinoma in situ and stage I disease and fewer stages II to IV tumors in MRI screened group (13.8 vs. 7.2% and 3.7 vs. 1.9%). Passaperuma et al performed a prospective screening trial of 496 women with BRCA mutations who had breast MRI and mammography annually. They demonstrated improved sensitivity of MRI over mammography (86 vs. 19%, p < 0.0001). Of those cancers detected by screening, 97% were stages 0 and I. Kriege et al have also observed a significantly lower incidence of positive axillary lymph nodes in patients whose cancers were detected by screening MRI.
Pearl
Breast MRI is more sensitive than mammography and allows earlier detection of breast cancer in BRCA mutation carriers.
5.3 Chemoprevention
The only agents approved for chemoprevention in high-risk women are tamoxifen, raloxifene, and exemestane. Randomized, controlled clinical trials have shown significant risk reduction for breast cancer in women at varying levels of family history but none of the trials specifically evaluated the impact on BRCA mutation carriers. These agents reduce the incidence of estrogen receptor (ER)-positive cancer and may not be appropriate for individuals at higher risk of ER-negative breast cancers such as those with BRCA1 mutations.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) P1 trial was the first large prevention trial in the United States. Over 13,000 women at high risk for breast cancer were randomized to tamoxifen or placebo for 5 years. It found a 49% risk reduction of estrogen responsive tumor in all age groups. In the subset of women with BRCA2 mutations, it showed similar reduction in ER-positive cancer as among all women in the trial. Tamoxifen use did not significantly reduce breast cancer risk among women with BRCA1 mutations. Two additional major chemoprevention trials did not address the effects of raloxifene and exemestane in women with BRCA mutations.
Studies examining the incidence of contralateral breast cancer in BRCA1/2 mutation carriers treated with tamoxifen for their primary breast cancer diagnosis provide additional evidence. They found that tamoxifen reduced contralateral breast cancer risk in BRCA1 mutation carriers by 13% and in BRCA mutation carriers by 27%.
Pearl
Tamoxifen appears to reduce the risk of breast cancer in women with BRCA2 mutations but has no impact in BRCA1 mutation carriers.
5.4 Prophylactic Surgery
5.4.1 Bilateral Salpingo-Oophorectomy
Prophylactic oophorectomy before the age of 40 is associated with a 50% reduction in breast cancer risk in BRCA1/2 mutation carriers. According to National Comprehensive Cancer Network (NCCN) guidelines, prophylactic salpingo-oophorectomy is recommended for all BRCA1/2 mutation carriers once childbearing is complete. The reduction in breast cancer is likely due to the decreased hormone exposure after removal of the ovaries.
Pearl
Prophylactic oophorectomy before the age of 40 is associated with a 50% reduction in breast cancer risk in BRCA1/2 mutation carriers.
5.4.2 Bilateral Prophylactic Mastectomy
There are no prospective randomized trials that examine the impact of bilateral prophylactic mastectomy (BPM) in patients with hereditary breast cancer syndromes. It is the most effective modality at decreasing the risk of breast cancer. Studies have shown a 90 to 95% risk reduction from traditional mastectomy in women with BRCA mutation.
The proportion of women choosing BPM varies greatly by country of origin and whether affected or unaffected mutation carriers. Metcalfe et al found overall proportion of BRCA1/2 mutation carriers opting for surgery varied from 2.7% in Poland to 36.3% in United States.
Cochrane’s review published in 2010 found that observational studies show that BPM is effective in reducing the incidence of breast cancer and death due to breast cancer. Proving a breast cancer survival advantage of BPM is difficult because the vast majority of women who develop breast cancer do not die of the disease. To overcome this deficiency, mathematical modeling has been used to compare risk-reducing surgery and high-risk screening. Kurian et al found a 7% survival gain for BPM performed at age 40 years, while another study estimated that BPM would be associated with 2 to 5.8 years of life gained depending on the age it was performed.
Pearl
Cochrane review published in 2010 found that observational studies show that bilateral prophylactic mastectomy is effective in reducing the incidence of breast cancer and death due to breast cancer.
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