Breast Cancer Screening and Prevention

Breast cancer is the most common nonskin cancer in women, accounting for about 23% of all cases of cancer in women. For U.S. women, the cumulative lifetime risk for invasive breast cancer is 12% (1, 2). In addition to sex, age is a major risk factor: The 10-year risks of invasive breast cancer at ages 40, 50, and 60 years are 1.5%, 2.3%, and 3.5%, respectively. Black women more commonly present with advanced disease and have a higher mortality than white women (3). In 2016, about 250000 U.S. women are estimated to develop breast cancer and 40000 to die of it. Risk Assessment What factors increase risk for breast cancer? Risk status is an important criterion for applying screening and prevention guidelines, which generally apply to average-risk women. Thus, provider assessment of individual risk is a starting point for conversations with patients about screening. Menstrual and reproductive factors (such as age at menopause and age at first live birth) convey modest increases in relative risk (RR) (1.52.0). One population-based analysis estimated that these factors together account for 40% of breast cancer cases (4). This study also estimated that modifiable risk factors (such as postmenopausal obesity, exercise, and alcohol use) account for an additional 40% of cases. About 10% of breast cancers are associated with a positive family history (5). Less than 4 years of postmenopausal estrogen-progestin combination therapy does not seem to increase risk for breast cancer risk (Table 1) (6-11). Table 1. Risk Factors for Breast Cancer Breast density refers to the proportion of all breast tissue, including the adipose component, that can be radiographically identified as glandular and connective tissue. Breast density is largely determined by genetics, although exogenous hormones increase density, and density decreases with age. Compared with women with breasts categorized as fatty or nondense (<10% glandular component), women with breasts categorized as extremely dense (>75% glandular component) have an RR for breast cancer of 45 (7). Familial and genetic factors increase risk, especially as the number of first-degree relatives rises (9). The most common genetic mutations associated with breast cancer are the BRCA1 and BRCA2 mutations, which occur in about 1 in 300500 women in the general population (12). Mutations in these genes are more common in families who have had onset of breast cancer at younger ages, bilateral breast cancer, male breast cancer, ovarian cancer, multiple cases of breast cancer, and Ashkenazi Jewish ancestry. The risk for breast cancer by age 70 years is about 65% for women with BRCA1 mutations and 45% for women with BRCA2 mutations (13). Women who had chest radiation therapy during childhood or adolescence, generally for Hodgkin disease, have an extremely high risk for breast cancer (8). Women with benign biopsies have an increased risk for breast cancer, especially with biopsy results of atypical ductal hyperplasia and lobular neoplasia. Are there tools that can help patients and physicians judge the risk? A statistical model, the Breast Cancer Risk Assessment Tool (BRCAT) from the National Cancer Institute, is the first widely used breast cancer calculator designed for the general population of women (14). This model includes age, race, familial and reproductive risk factors, and breast biopsy information. Although less accurate for women with markedly positive family histories and women older than 70 years, the main limitation of the BRCAT is its omission of breast density as a risk factor. The Breast Cancer Surveillance Consortium (BCSC) developed a simple, validated calculator that includes age, race, family history, breast biopsy history, and breast density as risk factors (15). The importance of breast density and age can be illustrated with this calculator (Table 2). Table 2. Five-Year Risk for Breast Cancer According to the Breast Cancer Surveillance Consortium Calculator* For women with family histories of breast cancer, the Ontario Family History Assessment tool, the Manchester Scoring System, the Referral Screening Tool, the Pedigree Assessment Tool, and the Family History Screen 7 are clinically useful (16). Because the age to start screening and the interval between screenings often depend on individualized decision-making, decision aids help clinicians and patients understand risk estimates and facilitate conversations (17). For example, www.breastscreeningdecisions. com helps women aged 4049 years visualize the effect of screening mammography. It also offers the opportunity to create a summary of personal values about breast cancer screening (see the Box: Breast Cancer Screening Values), which they can print for conversations with their provider. Other nonWeb-based decision aids are also available. Breast Cancer Screening Values Willingness to undergo interventions to detect breast cancer early Perception of mammograms as painful or inconvenient Desire for recommendation about mammograms from provider Concern about individual breast cancer risk Clinical Bottom Line: Risk Assessment Breast cancer is common among U.S. women and increases with age. Other factors that increase risk include the duration of endogenous estrogen (which can be approximated by the age of menopause), breast density, proliferative breast disease, and family history. Genetic mutations are uncommon but increase risk substantially. Online calculators can help assess risk. We recommend that clinicians periodically assess risk, including collection of family history at least every 5 years, as a first step in mitigating high risk and to develop an individualized screening plan. Screening Who should be screened for breast cancer? Since many women who develop breast cancer do not fall into a clear high-risk group and because of the strong connection between age and risk for breast cancer, a consensus has emerged that women should be screened for breast cancer using primarily age-based protocols. High-risk women may benefit from modifications of these protocols. No low-risk groups (other than young age) have been identified in which screening can clearly be omitted. Is screening effective in reducing mortality? Eight large randomized trials (sometimes broken into 911 components) have studied mammography screening in the general population, including about 600000 women from the United States, Canada, United Kingdom, and Sweden. These studies were somewhat heterogeneous with regard to the age groups included, methods of randomization, intervals between screening, and methods of analysis. Nonetheless, meta-analyses have shown that when compared with controls, groups offered screening had a 15%20% reduction in risk for breast cancer mortality among all age groups (5, 18). For women aged 4059 years, the reduction in mortality was smaller and less statistically significant (Table 3) (18). For women aged 6069 years, the reduction was highly significant. For women aged 7074 years, the reduction was not significant, but far fewer women in this age group were studied. The estimated number of deaths prevented per 10000 women screened for 10 years ranged from 3 to 21 (Table 3). Table 3. Effectiveness of Mammography Screening on Breast Cancer Mortality by Age, Based on Results of Randomized, Controlled Trials None of the individual trials showed a reduction in all-cause mortality from screening, and a meta-analysis showed a combined RR of 0.99 (95% CI, 0.971.00) (19). Mammography screening was protective against advanced breast cancer (stage III or higher) among women aged 50 years or older (RR, 0.62 [CI, 0.460.83]). Four trials failed to show a reduction in the development of advanced breast cancer among women aged 3949 years (RR, 0.98 [CI, 0.741.37]). What are the harms? Most concern about breast cancer screening involves false-positive results and overdiagnosis. False-positive results lead to unnecessary follow-up tests and biopsies, as well as to some psychological distress. False-positive results have been shown to increase anxiety symptoms and psychological distress for up to 2 years after the mammogram but do not increase clinically diagnosed depression or anxiety. To diagnose 1 case of invasive breast cancer, hundreds of women must be screened, dozens of women will have false-positive results, and 310 women will have a biopsy. Since early diagnosis does not always prevent death, the number of procedures needed to prevent 1 death from breast cancer is correspondingly higher. The cumulative risk for at least 1 false-positive result after 10 years of annual screening is 50%60%, and the cumulative risk over 10 years of an unnecessary biopsy attributable to screening is 7%10% (5, 17). Overdiagnosis is early diagnosis of cancer that would never have progressed to clinical importance in the absence of screening. Although many overdiagnosed cases are ductal carcinoma in situ, it is now believed that some invasive cancers represent overdiagnosis as well. Overdiagnosis is a serious issue because the patient is subjected to the harms of treatment without any benefit, since the tumor would not have caused the patient harm if not detected. Once the cancer is diagnosed, there is no way to determine whether it is a case of overdiagnosis; the evidence showing overdiagnosis comes from studying the number of cancers diagnosed in screened women compared with those diagnosed in similar but unscreened women. Estimates of the percentage of overdiagnosed cancers are wide-ranging, but the best data estimate that about 10%20% of breast cancer cases diagnosed in screened women represent overdiagnosis (5, 17). Another potential harm of screening mammography is radiation exposure. Increased risk for radiation-induced cancer has been demonstrated in studies of women who have had therapeutic chest irradiation for Hodgkin lymphoma and/or frequent chest radiography and computed tomography. A recent estimate of the number of deaths due to radiation-ind