Annals of Internal Medicine

Review

Risk Factors for Breast Cancer for Women Aged 40 to 49 Years

A Systematic Review and Meta-analysis
Heidi D. Nelson, MD, MPH; Bernadette Zakher, MBBS; Amy Cantor, MD, MPH; Rongwei Fu, PhD; Jessica Griffin, MS; Ellen S. OMeara, PhD; Diana S.M. Buist, PhD, MPH; Karla Kerlikowske, MD, MS; Nicolien T. van Ravesteyn, MSc; Amy Trentham-Dietz, PhD; Jeanne S. Mandelblatt, MD, MPH; and Diana L. Miglioretti, PhD

Background: Identifying risk factors for breast cancer specific to women in their 40s could inform screening decisions. Purpose: To determine what factors increase risk for breast cancer in women aged 40 to 49 years and the magnitude of risk for each factor. Data Sources: MEDLINE (January 1996 to the second week of November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth quarter of 2011), Scopus, reference lists of published studies, and the Breast Cancer Surveillance Consortium. Study Selection: English-language studies and systematic reviews of risk factors for breast cancer in women aged 40 to 49 years. Additional inclusion criteria were applied for each risk factor. Data Extraction: Data on participants, study design, analysis, follow-up, and outcomes were abstracted. Study quality was rated by using established criteria, and only studies rated as good or fair were included. Results were summarized by using meta-analysis when sufficient studies were available or from the best evidence based on study quality, size, and applicability when meta-analysis was not possible. Data from the Breast Cancer Surveillance Consortium were analyzed with proportional hazards models by using

partly conditional Cox regression. Reference groups for comparisons were set at U.S. population means. Data Synthesis: Sixty-six studies provided data for estimates. Extremely dense breasts on mammography or first-degree relatives with breast cancer were associated with at least a 2-fold increase in risk for breast cancer. Prior breast biopsy, second-degree relatives with breast cancer, or heterogeneously dense breasts were associated with a 1.5- to 2.0-fold increased risk; current use of oral contraceptives, nulliparity, and age 30 years or older at first birth were associated with a 1.0- to 1.5-fold increased risk. Limitations: Studies varied by measures, reference groups, and adjustment for confounders, which could bias combined estimates. Effects of multiple risk factors were not considered. Conclusion: Extremely dense breasts and first-degree relatives with breast cancer were each associated with at least a 2-fold increase in risk for breast cancer in women aged 40 to 49 years. Identification of these risk factors may be useful for personalized mammography screening. Primary Funding Source: National Cancer Institute.
Ann Intern Med. 2012;156:635-648. For author affiliations, see end of text. www.annals.org

urrent practice guidelines on mammography screening differ in their recommendations for women in their 40s (13). The U.S. Preventive Services Task Force recommends individualized, informed decision making about when to start mammography screening based on a womans values about benets and harms (4). Risk-based screening has been recommended for other health conditions in the United States and may provide a similar evidence-based approach for breast cancer. However, applying this approach to clinical practice has been problematic because it is unclear how women and clinicians can effectively consider individualized risk factor information in their discussions of benets and harms. Microsimulation models of mammography screening developed as part of the Cancer Intervention and Surveillance Modeling Network (CISNET) indicated that women with approximately 2-fold increased risk for breast cancer who started biennial screening at age 40 years had similar benets (life-years gained) and harms (false-positive results) as average-risk women who started screening at age 50 years (5). The risk threshold was higher when the CISNET models considered reduction in breast cancer deaths as a benet (risk ratio [RR], 3.3) or annual rather than biennial screening (RR, 4.3). These results suggest that identifying women with at least a 2-fold increased risk for breast can-

cer could be useful in determining whether to initiate mammography screening before age 50 years. Much research has been published describing personal and clinical risk factors associated with breast cancer. However, studies generally included women of various ages, measured and reported risk factors in different ways, and provided wide ranges of risk estimates. Consequently, results of broad-based epidemiologic studies may not be clinically applicable to the screening decisions of individual women and in some cases may be misleading.

See also: Print Editors Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636 Editorial comment. . . . . . . . . . . . . . . . . . . . . . . . . . 662 Related article. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 Web-Only Appendix Table Supplement CME quiz (preview on page I-29) Conversion of graphics into slides
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Review
Context

Risk Factors for Breast Cancer for Women Aged 40 to 49 Years

Knowing which factors influence breast cancer risk for women younger than 50 years might help target screening efforts.

collected by the Breast Cancer Surveillance Consortium (BCSC) that were also used in this study.
Study Selection

Contribution
This review found that the following factors increased risk for breast cancer in women aged 40 to 49 years: extremely dense breasts or first-degree relatives with breast cancer (2-fold increase); prior breast biopsy, second-degree relatives with cancer, or heterogeneously dense breasts (1.5- to 2.0-fold increase); current oral contraceptive use, nulliparity, and age 30 years or older at first birth (1.0- to 1.5-fold increase).

Caution
Confounding may have affected some risk estimates.

Implication
Risk factor information could help personalize decisions about breast cancer screening in women aged 40 to 49 years. The Editors

The purpose of this systematic review and metaanalysis is to determine what factors increase risk for invasive breast cancer, specically for women aged 40 to 49 years, and to estimate the magnitude of risk for each factor compared with average-risk women. It focuses on women who are eligible for screening mammography under current practice guidelines in the United States and considers average-risk women to be those without the risk factor or who represent the mean or majority of women in the cohort, depending on the risk factor. This project was conducted in collaboration with development of the CISNET models of mammography screening based on increasing levels of risk and builds on previous work (6, 7).

METHODS
Data Sources and Searches

A standard protocol was developed and followed for this review. In conjunction with a research librarian, we used the National Library of Medicines Medical Subject Headings keyword nomenclature to search MEDLINE (1996 to the second week of November 2011), the Cochrane Central Register of Controlled Trials (fourth quarter of 2011), and the Cochrane Database of Systematic Reviews (fourth quarter of 2011) for relevant Englishlanguage studies and systematic reviews. We also conducted secondary referencing by manually reviewing reference lists of papers and by using Scopus to search citations of key studies. Searches included studies published during the past 16 years to provide data that are relevant to current cohorts of women considering mammography screening and to correspond to the time frame of risk factor data
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We developed inclusion and exclusion criteria for abstracts and articles based on the target population, risk factors, and outcome measures. We included randomized, controlled trials; observational studies; systematic reviews; and meta-analyses. After an initial review of abstracts, we retrieved full-text articles and conducted a second review by using additional inclusion criteria dened specically for each risk factor, including eligibility of the data for statistical meta-analysis. When sufcient studies were not available for a meta-analysis, we used the best evidence as determined by consensus among the investigators on the basis of study quality, size, and applicability. The target population consisted of women aged 40 to 49 years who were eligible for screening mammography. Studies were excluded if they enrolled women who were not candidates for routine screening because they had prior breast or ovarian cancer, ductal carcinoma in situ or other noninvasive breast cancer, current breast physical ndings, presence of deleterious BRCA1/BRCA2 mutations in self or relatives, or prior chest radiation for such conditions as lymphoma. Included studies were conducted in countries with patient populations and health care services similar to those of the United States to ensure applicability. Studies that reported outcomes in age groups that differed from the 40- to 49-year age category were included if most participants were aged 40 to 49 years and all were younger than 55 years. When studies reported outcomes by menopausal status rather than age, we used results for premenopausal women as long as the group included a majority of women in their 40s. The main outcome measure was incidence of invasive breast cancer at age 40 to 49 years or invasive and noninvasive breast cancer as a combined outcome when this was the only measure reported in a study. Risk factors included race and ethnicity, body mass index (BMI), physical activity, alcohol use, smoking, family history of breast cancer, breast density, prior breast procedures, and reproductive factors (age at menarche; parity; age at birth of rst child; breastfeeding; oral contraceptive use; menopausal age, status, and type; and menopausal hormone therapy). We included studies meeting the following criteria: studies of risk factors for recent or current status that reected exposure within 1 year of breast cancer diagnosis; studies of physical activity that reported categories of exercise descriptively (inactive, some, or regular) or quantied by metabolic equivalents; studies of alcohol use and smoking that reported use status (current, former, or never), recency, and amounts of use (drinks per week or packs per day); and studies of oral contraceptive and menopausal hormone therapy use that investigated any formulation (combination, progestin, or estrogen only) and used various denitions of ever and never use. We excluded
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Risk Factors for Breast Cancer for Women Aged 40 to 49 Years

Review

studies of nonoral forms of contraception and those evaluating formulations not applicable to the target population (8). We included studies that dened parity as the number of full-term births, full-term pregnancies, live births, or pregnancies lasting 6 months or more regardless of outcome, consistent with standard medical denitions (9). We included studies of breastfeeding that used a nonbreastfeeding group of parous women as the reference category and determined breastfeeding activity (ever or never) and total duration. We included studies that reported menopausal status and history of hysterectomy or oophorectomy if the event preceded the breast cancer diagnosis in women in their 40s. We reviewed studies of mammographic breast density that used several methods to categorize density, but we reported results only from studies that used the Breast Imaging Reporting and Data System (BI-RADS) classication (1 almost entirely fat, 2 scattered broglandular densities, 3 heterogeneously dense, and 4 extremely dense) because of its clinical relevance to practice in the United States (10).
Data Extraction and Quality Assessment

Data Synthesis and Analysis

For the included studies, an investigator abstracted the following data: study design, setting, participant characteristics (including age, race and ethnicity, and diagnosis), enrollment criteria, exposures (dose and duration), procedures for data collection, number enrolled and number lost to follow-up, methods of exposure and outcome ascertainment, analytic methods (including adjustment for confounders), and results for each outcome. A second investigator conrmed the accuracy of key data. We used predened criteria developed by the U.S. Preventive Services Task Force to assess the quality of studies (11). Two investigators independently rated the quality of each eligible study (good, fair, or poor), and nal ratings were determined by consensus among raters. We used only studies rated as good or fair to determine risk estimates. We assessed applicability of studies by using the PICOTS (population, intervention, comparator, outcomes, timing of outcomes measurement, and setting) approach (12). In addition, applicability of case control studies was based on the control group population. For all studies, applicability was high if participants were recruited predominantly from community populations rather than clinical populations. For each risk factor, we also determined the consistency of results (that is, the degree of similarity in the effect sizes of the different studies). Studies were considered consistent if outcomes were generally in the same direction of effect and ranges of effect sizes were narrow. Applicability and consistency were determined by consensus of the investigators who reviewed the studies and conducted the meta-analyses.
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For eligible studies, we combined data in several metaanalyses to obtain more precise estimates of the relationship between risk factors and breast cancer. All included studies had cohort or case control designs, and only studies reporting estimates that adjusted for at least 1 potential confounder in their analysis were included in the meta-analysis. To determine the appropriateness of metaanalysis, we considered clinical and methodological diversity and assessed statistical heterogeneity. We abstracted or calculated estimates of RRs (odds ratio, rate ratio, or hazard ratio) and their SEs from each study and used them as the effect measures. Because the incidence of breast cancer was low, we considered the estimates of odds ratios to be equivalent to estimates of relative risks (rate ratio or hazard ratio). This assumed that the underlying event rates in the case control studies, for example, reected the low incidence rate in the population. For most risk factors, studies reported RRs based on similar cut points across included studies and we used estimates based on the reported cut points. For BMI, the cut points were too disparate to be combined as reported in the published studies. Therefore, we combined BMI categories to correspond to the World Health Organization denitions of underweight (18.5 kg/m2), normal weight (18.5 to 25 kg/m2), overweight (25 to 30 kg/m2), and obese (30 kg/m2) (13). We combined the underweight and normal weight categories because too few women were included in the underweight group. When studies categorized BMI by using other cut points, we calculated RRs by assuming that BMI is log-normally distributed and that a linear association exists between breast cancer risk and BMI on the logit scale. We estimated distribution parameters of BMI from published information in each study. We assessed the presence of statistical heterogeneity among the studies by using standard chi-square tests and the magnitude of heterogeneity by using the I2 statistic (14). We used a random-effects model to account for variation among studies. In general, when there is no variation among studies, the random-effects model yields the same results as a xed-effects model without a study effect (15). To explore heterogeneity, we used meta-regression to assess the effect of the degree of adjustment for confounders in the original studies. This was quantied by the total number of adjusted variables and the number of adjusted risk factors considered in the review as well as other studylevel variables, such as quality, study design, and breast cancer type. We also conducted sensitivity analyses to assess the robustness of results that considered variation from different denitions of risk factors and reference groups, inclusion of noninvasive breast cancer as an outcome, and outlying studies. The results of the sensitivity analyses indicated no major differences from the main analysis. For specic risk factors (BMI, age at menarche, and age at birth of rst child), we recalculated RRs from the meta-analysis by using reference groups that differed from
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Review

Risk Factors for Breast Cancer for Women Aged 40 to 49 Years

Figure. Summary of evidence search and selection.

BMI body mass index; OC oral contraceptive. * Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. Reference lists, Scopus, and studies suggested by experts. Some articles are included for more than 1 risk factor. Published meta-analyses. || No articles met inclusion criteria for race and ethnicity, menopausal stage and type (surgical or nonsurgical), age at menopause, and menopausal hormone use. Although some studies met inclusion criteria for the systematic review, they did not provide data for the meta-analysis because they used dissimilar categories or different measures from the other included studies.

the original studies to approximate average risk in the population. The new reference groups were chosen to align with the distribution or mean of risk factors in the target population to provide more clinically relevant risk estimates. Data describing distributions or means in the target population were obtained from various sources representing U.S. national samples (16 22) (Appendix Table, available at www.annals.org).
Comparison With BCSC Data

We included data from the BCSC to supplement the systematic review because some risk factors were not reported in published studies. The BCSC is a national collaboration of 5 mammography registries and 2 afliate sites in the United States that prospectively collects data on breast imaging, risk factors, and breast cancer outcomes (23). We analyzed BCSC data collected from 1994 to 2010 for women aged 40 to 49 years at the time of screening mammography. Risk factor data were obtained at the time of each screening mammography and reported in categories similar to those dened by the systematic review. Results for 380 585 women aged 40 to 49 years were provided in proportional hazards models adjusted for age, race, family history of breast cancer, and BMI and stratied by site. We used partly conditional Cox regression (24) to incorporate multiple observations per woman (allowing her to enter the analysis at each eligible screening mammogra638 1 May 2012 Annals of Internal Medicine Volume 156 Number 9

phy) and accounted for multiple observations per woman by using the robust sandwich estimator of the SE (25). Women were followed until they were diagnosed with invasive breast cancer; until they were censored at the rst occurrence of ductal carcinoma in situ, death, age 50 years, or end of complete cancer follow-up or eligibility for her site; or for 5 years after the examination date. Mean length of follow-up was 3.3 years. All analyses for the meta-analysis and BCSC data were performed by using Stata, version 11.0 (StataCorp, College Station, Texas), and were reported as RRs with 95% CIs.
Role of the Funding Source

The National Cancer Institute funded this work but had no additional role in the design, conduct, or reporting of the review and analysis.

RESULTS
A total of 9036 abstracts were identied by search criteria; of these, 884 full-text articles were reviewed and 95 met the inclusion criteria as well as the criteria for good or fair quality (Figure). Sixty-one studies of 8 risk factors (BMI, alcohol use, smoking, age at menarche, parity, age at rst birth, breastfeeding, and oral contraceptive use) provided data for meta-analysis. Two published meta-analyses of family history of breast cancer reported results speciwww.annals.org

Risk Factors for Breast Cancer for Women Aged 40 to 49 Years

Review

cally for women in their 40s (26, 27). Single studies provided estimates for 3 risk factors because either they were the only studies that met the inclusion and quality criteria for the risk factor (prior breast procedure) or studies did not provide data that could be used in a meta-analysis (breast density and physical activity). Individual studies providing data for risk estimates are described in the Supplement (available at www.annals.org). Data from the BCSC provided the only estimates for 3 risk factors that had no published studies that met the inclusion criteria (race and ethnicity, menopausal status and type, and menopausal hormone therapy). No data were available to evaluate age at menopause.
Personal Risk Factors

Personal risk factors included race and ethnicity, BMI, physical activity, alcohol use, and smoking (Table 1). Data from the BCSC indicated no statistically signicant increased risks for breast cancer by race and ethnicity when white race was used as the reference group.

For BMI, a meta-analysis of 18 studies (17, 28 44) indicated reduced risks for women in the overweight (RR, 0.86 [95% CI, 0.82 to 0.90]) and obese (RR, 0.74 [CI, 0.68 to 0.81]) categories compared with women in the normal and underweight category. Results were similar for overweight and obese categories in the BCSC, but the CI included 1.0 for overweight. Data specically for underweight women were not provided by the published studies, although the BCSC data indicated that risk for underweight women was not signicantly different from that of normal weight women. Ten studies of physical activity met inclusion criteria (4554) but could not be combined in the meta-analysis because they used different measures of activity and reported results in dissimilar categories. All studies reported no statistically signicant differences in breast cancer risk based on physical activity. Results from a large, goodquality study designed to specically assess the relationship between physical activity and premenopausal breast cancer

Table 1. Breast Cancer Risk Associated With Personal Factors for Women Aged 40 to 49 Years
Risk Factor Studies (Reference), n Race and ethnicity White Black Asian/Pacific Islander Hispanic Other/mixed Body mass index 18.5 kg/m2 18.524 kg/m2 2529 kg/m2 30 kg/m2 Physical activity Inactive Some Regular Alcohol use 0 drinks/wk 7 drinks/wk 713 drinks/wk 14 drinks/wk Smoking use Never Ever Smoking status Never Current Former Systematic Review and Meta-analysis Breast Cancer Risk Ratio (95% CI) Heterogeneity BCSC Breast Cancer Risk Ratio (95% CI)*

I2, %
0 0 0 0 0 NA NA NA NA NA

P Value
Reference group 1.04 (0.781.39) 0.94 (0.781.12) 1.10 (0.971.25) 0.95 (0.771.17)

Reference group 18 (17, 2844) 18 (17, 2844)

Reference group 0.86 (0.820.90) 0.74 (0.680.81)

0.0 1.3

0.73 0.44

1.28 (0.981.66) Reference group 0.92 (0.841.01) 0.74 (0.660.82)

Reference group 1 (46) 1 (46)

Reference group 1.09 (0.881.34) 1.15 (0.931.43)

NA NA NA

Reference group 3 (55, 61, 64) 3 (55, 61, 64) 3 (55, 61, 64)

Reference group 1.03 (0.961.11) 1.14 (0.941.38) 1.24 (0.871.78)

0.0 0.0 38.5

0.74 0.75 0.197

NA NA NA NA

Reference group 12 (31, 62, 6574)

Reference group 1.05 (0.981.13)

31.0

0.144

NA NA

Reference group 7 (31, 62, 67, 7073) 7 (31, 62, 67, 7073)

Reference group 0.92 (0.841.02) 1.11 (0.971.28)

0.0 47.8

0.84 0.074

NA NA NA

BCSC Breast Cancer Surveillance Consortium; NA not available. * Model included age, race, body mass index, family history of breast cancer, and site. Numbers of women included in estimates varied by risk factor because of missing data. Included body mass index 25 kg/m2. Among women using alcohol within 5 y.
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Review
49 Years
Risk Factor

Risk Factors for Breast Cancer for Women Aged 40 to 49 Years

Table 2. Breast Cancer Risk Associated With Family History, Breast Density, and Breast Procedures for Women Aged 40 to

Systematic Review Study Type or Number of Studies (Reference) Breast Cancer Risk Ratio (95% CI) Reference group 2.14 (1.922.38) 3.84 (2.376.22) 12.05 (1.7085.16)

BCSC Breast Cancer Risk Ratio (95% CI)*

First-degree relatives with breast cancer 0 Meta-analysis (26) 1 Meta-analysis (26) 2 Meta-analysis (26) 3 Meta-analysis (26) Age at diagnosis of first-degree relatives with breast cancer None Meta-analysis (26) 40 y Meta-analysis (26) 4049 y Meta-analysis (26) 5059 y Meta-analysis (26) 60 y Meta-analysis (26) Second-degree relatives with breast cancer 0 Meta-analysis (27) 1 Meta-analysis (27) Breast density (BI-RADS category) 1 1 (75) 2 1 (75) 3 1 (75) 4 1 (75) Prior breast procedure None Any

Reference group None vs. any, 1.86 (1.692.06)

Reference group 3.0 (1.84.9) 2.0 (1.52.8) 2.3 (1.73.2) 1.7 (1.32.1)

Reference group None vs. 50 y, 2.17 (1.862.53) None vs. 50 y, 1.68 (1.441.96)

Reference group 1.7 (1.42.0)

NA NA

0.46 (0.370.58) Reference group 1.62 (1.511.75) 2.04 (1.842.26)

0.41 (0.310.55) Reference group 1.75 (1.591.93) 2.33 (2.042.66)

1 (76) 1 (76)

Reference group 1.87 (1.642.13)

Reference group 1.51 (1.361.67)

BCSC Breast Cancer Surveillance Consortium; BI-RADS Breast Imaging Reporting and Data System; NA not available. * Model included age, race, body mass index, family history of breast cancer, and site. Numbers of women included in estimates varied by risk factor because of missing data. 1 almost entirely fat; 2 broglandular densities; 3 heterogeneously dense; 4 extremely dense. Surgical and needle biopsies.

provided the estimates in Table 1 (46). Data on physical activity were not available from the BCSC. Although 12 studies reporting various measures of alcohol use met inclusion criteria (31, 36, 55 64), results from only 3 studies could be combined in the metaanalysis (55, 61, 64). Using no alcohol use as the reference group, results indicated higher risk estimates with increasing amounts of alcohol consumption; however, all CIs included 1.0. Smoking use (never vs. ever) and status (never vs. current or former) had no signicant associations with breast cancer based on meta-analyses of 12 studies of never versus ever use (31, 62, 6574) and 7 studies of never versus current or former use (31, 62, 67, 70 73). No BCSC data on alcohol use or smoking were available.
Family History, Breast Density, and Breast Procedures

In an analysis of data from 52 epidemiologic studies (26), breast cancer risk was signicantly increased for women with rst-degree relatives with breast cancer (RR for 1 relative, 2.14 [CI, 1.92 to 2.38]; 2 relatives, 3.84 [CI, 2.37 to 6.22]; and 3 relatives, 12.05 [CI, 1.70 to 85.16]) (Table 2). Data from the BCSC also showed higher risk for women with a rst-degree relative with breast cancer (RR, 1.86 [CI, 1.69 to 2.06]). In both the meta-analysis and the BCSC results, risk was higher among women with
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rst-degree relatives who were diagnosed at younger ages than those diagnosed at older ages. Risk ratios for women with relatives younger than 40 years compared with women with no rst-degree relatives were 3.0 (CI, 1.8 to 4.9) in the meta-analysis (26) and 2.17 (CI, 1.86 to 2.53) for women with relatives younger than 50 years in the BCSC. Risk was lower for women with relatives diagnosed at age 60 years or older (RR, 1.7 [CI, 1.3 to 2.1]) (26). In a meta-analysis of 2 studies (27), risk was also signicantly increased for women with 1 or more second-degree relatives compared with none (RR, 1.7 [CI, 1.4 to 2.0]). A published study of BCSC data reported risk estimates for breast cancer by using BI-RADS breast density categories and dened BI-RADS category 2 (scattered broglandular densities) as the reference group (75). Results indicated increased risk for categories 3 (RR, 1.62 [CI, 1.51 to 1.75]) and 4 (RR, 2.04 [CI, 1.84 to 2.26]) and reduced risk for category 1 (RR, 0.46 [CI, 0.37 to 0.58]). A published study of BCSC data reported increased breast cancer risk for women who had prior benign results on breast biopsy (RR, 1.87 [CI, 1.64 to 2.13]) (76). Additional BCSC data that included prior biopsies or neneedle aspirations also indicated increased risk (RR, 1.51 [CI, 1.36 to 1.67]).
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Risk Factors for Breast Cancer for Women Aged 40 to 49 Years

Review

Reproductive Factors

DISCUSSION
Sixty-six studies identied in the systematic review contributed data for breast cancer risk estimates for 13 unique risk factors, whereas data from the BCSC provided estimates for 11 risk factors, 3 of which were not included in published studies. Both sources provided estimates for some risk factors that were expressed in alternate ways, such as in dichotomous as well as ordinal categories. A summary of evidence for the systematic review describes the number and design of included studies; breast cancer outcomes; and ratings for quality, consistency, and applicability for each risk factor (Table 4). Overall, studies were consistent and applicability was high, largely because conditions of the study population were incorporated into inclusion criteria. Results indicated that women in their 40s with extremely dense breasts on mammography or at least 1 rst-degree relative with breast cancer had at least a 2-fold increased risk for breast cancer (Table 5). This level of risk corresponds to the risk threshold of the CISNET models, which demonstrated similar benets and harms for increased-risk women starting biennial screening at age 40 years and average-risk women starting at age 50 years (5). Risk was even higher among women with 2 or more rst-degree relatives with breast cancer or rst-degree relatives diagnosed before age 40 years. The following 3 factors were associated with a 1.5- to 2.0-fold increased risk: a prior benign breast biopsy result, a second-degree relative with breast cancer, and heterogeneously dense breast tissue. Current use of oral contraceptives, nulliparity, and rst birth at age 30 years or older were associated with a 1.0- to 1.5-fold increased risk, although some results differed by data sources, which suggests inconsistency. Several factors were associated with lower-than-average risk, including BMI of 25 kg/m2 or higher; low breast density; age 15 years or older at menarche; birth of 3 or more children; breastfeeding; perimenopausal or postmenopausal status; and use of menopausal, estrogen-only hormone therapy. Although the results of this review are consistent with previous research, our estimates of risk are unique and relevant to current clinical dilemmas about mammography screening for women in their 40s. Although most women who develop breast cancer have no known risk factors, information about risk may be particularly useful when making decisions about screening. Of note, several risk factors identied in single studies or in studies of women of various ages were not statistically signicant in our analysis. These ndings may be useful to women, clinicians, and health systems considering risk-based screening who nd a long list of potential risk factors difcult to navigate. Focusing on high breast density and rst-degree family history of breast cancer may be a more clinically feasible approach to personalized screening.
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Reproductive factors included age at menarche, parity, age at rst birth, breastfeeding, oral contraceptive use, menopausal status, and menopausal hormone therapy (Table 3). In our meta-analysis of 13 studies (31, 34, 45, 77 86), menarche at age 15 years or older was associated with reduced risk for breast cancer compared with the reference age of 13 years (RR, 0.87 [CI, 0.78 to 0.97]). Results from the BCSC were similar. A meta-analysis of 17 studies of parity (31, 34, 45, 74, 77 80, 8290) indicated that nulliparous women had a signicantly higher risk for breast cancer than parous women (RR, 1.16 [CI, 1.04 to 1.26]), similar to BCSC estimates (Table 3). In a meta-analysis of 13 studies (31, 34, 74, 77 80, 82, 84 87, 90), risk was signicantly reduced for women with 3 or more births compared with nulliparous women (RR, 0.73 [CI, 0.61 to 0.87]). In a meta-analysis of 5 studies of age at rst birth (34, 45, 77, 83, 88), women having their rst child at age 30 years or older had a higher risk for breast cancer than a reference group of women aged 25 to 29 years (RR, 1.20 [CI, 1.02 to 1.42]) but a slightly lower risk than nulliparous women (RR, 1.25 [CI, 1.08 to 1.46]). Results from the BCSC indicated no signicantly increased risk for these groups but did indicate decreased risk for women aged 20 years or younger at the time of the rst birth. In a meta-analysis of 14 studies (34, 74, 78, 80, 82, 83, 86, 90 96), breastfeeding was associated with reduced risk for breast cancer (RR, 0.87 [CI, 0.77 to 0.98]), particularly when it continued for 12 months or longer (RR, 0.85 [CI, 0.73 to 0.99]) (34, 78, 80, 82, 83, 9196). Breastfeeding data were not available from the BCSC. Twelve studies of oral contraceptive use provided estimates for the meta-analysis of ever use compared with never use (31, 74, 77, 78, 97104), and 8 studies provided estimates for recency of use, with the most recent category dened as within 5 years (77, 78, 99 104). None of these associations was statistically signicant, although all point estimates were increased (Table 3). Data from the BCSC indicated signicantly higher risk for breast cancer for current oral contraceptive use than for former or never use (RR, 1.30 [CI, 1.13 to 1.49]). Data from the BCSC showed reduced breast cancer risk for perimenopausal and postmenopausal women (either surgical or nonsurgical menopause) compared with premenopausal women. The BCSC data also indicated that women with no uterus currently using menopausal hormone therapy had a reduced risk for breast cancer compared with nonusers (RR, 0.70 [CI, 0.52 to 0.94]), whereas those with a uterus had no signicant association. Presumably, women without a uterus were using estrogen alone, whereas those with a uterus were using estrogen combined with progestin.
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Risk Factors for Breast Cancer for Women Aged 40 to 49 Years

Table 3. Breast Cancer Risk Associated With Reproductive Factors for Women Aged 40 to 49 Years
Risk Factor Studies (Reference), n Systematic Review and Meta-analysis Breast Cancer Risk Ratio (95% CI) Heterogeneity BCSC Breast Cancer Risk Ratio (95% CI)*

I 2, %
Age at menarche 12 y 13 y 14 y 15 y Parity Ever None Births 0 1 2 3 Age at first birth 20 y 2024 y 2529 y 30 y None Breastfeeding None Ever Breastfeeding duration None 12 mo 12 mo Oral contraceptive use None Ever Oral contraceptive status Former or none Current Recency of oral contraceptive use None 5 y 59 y 10 y Menopausal status Premenopausal Perimenopausal Postmenopausal, nonsurgical Postmenopausal, surgical Unknown, surgery Menopausal hormone therapy Former or none Current (no uterus) Current (uterus present) 10 (31, 34, 45, 77, 79, 80, 8285) Reference group 6 (31, 34, 45, 79, 84, 85) 9 (31, 34, 45, 78, 79, 81, 8486) 1.10 (0.981.23) Reference group 0.98 (0.871.10) 0.87 (0.780.97) 45.1 3.8 0

P Value
0.059 0.39 0.58 0.99 (0.881.12) Reference group 1.00 (0.851.17) 0.77 (0.630.94)

Reference group 17 (31, 34, 45, 74, 7780, 8290)

Reference group 1.16 (1.041.26)

80.3

0.001

Reference group 1.15 (1.031.28)

Reference group 13 (31, 34, 74, 7780, 82, 8487, 90) 13 (31, 34, 74, 7780, 82, 8487, 90) 13 (31, 34, 74, 7780, 82, 8487, 90)

Reference group 0.95 (0.811.11) 0.93 (0.771.12) 0.73 (0.610.87)

48.3 73.2 82.4

0.026 0.001 0.001

NA NA NA NA

4 (34, 45, 77, 83) 4 (34, 45, 77, 83) Reference group 5 (34, 45, 77, 83, 88) 5 (34, 45, 77, 83, 88)

0.96 (0.821.11) 0.96 (0.821.11) Reference group 1.20 (1.021.42) 1.25 (1.081.46)

0 0 17.9 0

0.81 0.62 0.30 0.55

0.78 (0.650.93) 0.87 (0.751.00) Reference group 1.02 (0.871.20) 1.08 (0.931.25)

Reference group 14 (34, 74, 78, 80, 82, 83, 86, 9096)

Reference group 0.87 (0.770.98)

68.5

0.001

NA NA

Reference group 11 (34, 78, 80, 82, 83, 9196) 11 (34, 78, 80, 82, 83, 9196)

Reference group 0.97 (0.871.08) 0.85 (0.730.99)

42.2 55.0

0.068 0.014

NA NA NA

Reference group 12 (31, 74, 77, 78, 97104)

Reference group 1.08 (0.961.23)

71.5

0.001

NA NA

0 0

NA NA

Reference group 1.30 (1.131.49)

Reference group 8 (77, 78, 99104) 8 (77, 78, 99104) 8 (77, 78, 99104)

Reference group 1.10 (0.931.29) 1.15 (0.941.40) 1.07 (0.951.19)

40.7 51.8 40.1

0.096 0.035 0.100

NA NA NA NA

0 0 0 0 0

NA NA NA NA NA

Reference group 0.70 (0.580.86) 0.59 (0.470.75) 0.58 (0.440.77) 0.67 (0.560.80)

0 0 0

NA NA NA

Reference group 0.70 (0.520.94) 0.90 (0.671.21)

BCSC Breast Cancer Surveillance Consortium; NA not available. * Model included age, race, body mass index, family history of breast cancer, and site. Numbers of women included in estimates varied by risk factor because of missing data. Among women who gave birth. Bilateral oophorectomy. Usually hysterectomy without bilateral oophorectomy. Assumed women without a uterus were using estrogen only and women with a uterus were using estrogen combined with progestin.

642 1 May 2012 Annals of Internal Medicine Volume 156 Number 9

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Risk Factors for Breast Cancer for Women Aged 40 to 49 Years

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Table 4. Summary of Evidence for Studies Providing Data for Risk Estimates
Studies by Design, n Cohort CaseControl Published Meta-analysis 0 Invasive Only 7 Studies by Breast Cancer Outcome, n Invasive and Noninvasive 7 Not Specified 4 Studies by Quality, n Good Fair Consistency* Applicability

Body mass index 9 9 Physical activity 1 0 Alcohol use 0

13

Consistent

High

Single study

High

Consistent

High

Smoking use 1 11 Smoking status 0 7

Consistent

High

Consistent

High

First-degree relative with breast cancer 0 0 1

Single study

High

Age at diagnosis of first-degree relative with breast cancer 0 0 1 1 Second-degree relative with breast cancer 0 0 1 Breast density 1 0 Prior breast procedure 1 0 Age at menarche 1 12 Parity 3

Single study

High

Single study

High

Single study

High

Single study

High

Consistent

High

14

13

Consistent

High

Number of births 2 11 Age at first birth 1 4 Breastfeeding 1 13 Breastfeeding duration 1 10 Oral contraceptive use 2 10

10

Consistent

High

Consistent

High

13

Consistent

High

10

Consistent

High

Consistent

High

Recency of oral contraceptive use 0 8 0

Consistent

High

* Consistency refers to the degree of similarity in the effect sizes of different studies within an evidence base. Studies were consistent if outcomes were generally in the same direction of effect and ranges of effect sizes were narrow. Applicability of case control studies was based on the control group population. For all studies, applicability was high if participants were recruited predominantly from community populations rather than clinical populations.

Family history is an important, well-established risk factor for breast cancer, and its role in breast cancer screening and prevention extends beyond mammography. Current recommendations from the U.S. Preventive Services
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Task Force for women with family histories of breast cancer include genetic counseling and mutation testing if appropriate (105) and consideration of medications to reduce risk for primary breast cancer (106).
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Risk Factors for Breast Cancer for Women Aged 40 to 49 Years

Table 5. Factors Significantly Associated With Increased Breast Cancer Risk for Women Aged 40 to 49 Years
Risk Factor >2-fold increased risk First-degree relatives with breast cancer 1 2 Any Age of first-degree relative with breast cancer 40 y 50 y Breast density BI-RADS category 4 1.5- to 2.0-fold increased risk Prior benign breast biopsy result Second-degree relative with breast cancer Breast density BI-RADS category 3 1.0- to 1.5-fold increased risk Current oral contraceptive use Nulliparity Age at first birth 30 y Breast Cancer Risk Ratio (95% CI) Source (Reference)

2.14 (1.922.38) 3.84 (2.376.22) 1.86 (1.692.06) 3.0 (1.84.9) 2.17 (1.862.53) 2.04 (1.842.26)

(26) (26) BCSC (26) BCSC (75)*

1.87 (1.642.13) 1.7 (1.42.0) 1.62 (1.511.75)

(76)* (27) (75)*

1.30 (1.131.49) 1.25 (1.081.46) 1.20 (1.021.42)

BCSC (34, 45, 77, 83, 88) (34, 45, 77, 83, 88)

BCSC Breast Cancer Surveillance Consortium; BI-RADS Breast Imaging Reporting and Data System. * BCSC estimates from published analyses; similar BCSC estimates calculated from primary data are provided in Table 2. Nulliparity was calculated in 2 ways (Table 3). Estimates indicating signicantly increased risk for nonparous compared with parous women were similar for the meta-analysis and the BCSC data. Estimates comparing ages at rst birth that included nonparous women provided signicant results for the meta-analysis only. Results were not statistically signicant for the BCSC data.

Several studies have reported associations between mammographic breast density and breast cancer (107 111), but only 1 met inclusion criteria for this review because it reported results with BI-RADS classications that are used in U.S. clinical practice and provided risk estimates specic to the target population (75). The use of breast density in screening and prevention is currently unclear, although research suggests that it may be important for estimating risk (111114) and for determining the age at which screening should begin and appropriate screening intervals (115). However, clinical trials of these strategies have not been done and use of breast density in current practice poses such challenges as variability of reporting among radiologists (116). Our risk estimates were derived from epidemiologic data, and their application in predicting individual risk has not been evaluated. They may be particularly useful for developing more complex risk prediction models. Although several such models exist (for example, the Gail model), they were not developed specically for women in their 40s, were not based on recent research, and have low discriminatory accuracy in predicting individual risk (117). Improving risk models and demonstrating their effectiveness in clinical applications are necessary future steps in this work. Although our risk estimates may be useful in informing clinical practice, effective methods to modify risk factors to reduce breast cancer incidence are largely untested. Our results indicated reduced breast cancer risk for women with BMIs in the overweight and obese categories. However, an inverse association has been found in postmeno644 1 May 2012 Annals of Internal Medicine Volume 156 Number 9

pausal women (118). Given the higher incidence of breast cancer in postmenopausal women, an appropriate clinical recommendation would be to modify weight gain after menopause rather than at a younger age. Some risk factors may reect underlying biological effects that cannot be modied for disease prevention purposes, such as parity. In contrast, breast density was reduced in high-risk women receiving tamoxifen in clinical trials (119). How to apply this information to individual patients is currently unclear. This evidence review and meta-analysis is limited in several ways. Studies reported different measures, dissimilar categories for exposures and outcomes, and reference groups that did not represent average risk in the target population. Studies also varied in the degree of adjustment for confounders in their risk estimates. All of these variations could lead to potential bias in the combined estimates of RRs. In addition, some women outside the targeted age group were included because studies provided data in categories that did not align with ours. Publication bias and selective reporting are also potential limitations but are difcult to assess. To address these issues, we developed inclusion criteria that considered the quality and applicability of studies consistently across risk factors, included only fair- or goodquality studies, selected best-evidence estimates for risk factors that lacked estimates from a meta-analysis, and redened reference groups to approximate the mean or distribution of the target population. In addition, we analyzed primary BCSC data to supplement or support the metaanalysis results. To address concerns of heterogeneity, we performed several sensitivity analyses, including an analysis
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Risk Factors for Breast Cancer for Women Aged 40 to 49 Years

Review

based on the degree of adjustment for confounders, and we found no important differences in results. Data in the meta-analysis and the BCSC were derived from observational studies that were subject to inherent potential biases, such as unmeasured and uncontrolled confounders. Our analysis was limited to the effects of individual risk factors, and we did not assess the risk associated with multiple concurrent factors. Our inclusion criteria led to the selection of studies enrolling a specically dened population, and results may not be applicable to different populations. Also, we focused on factors that increase risk for breast cancer in collaboration with the development of the CISNET models. Clinical application of our estimates of factors associated with reduced risk is limited because the CISNET models were not designed for similar reduced-risk scenarios. This comprehensive systematic review and metaanalysis of risk factors for breast cancer in women aged 40 to 49 years, as well as a primary analysis of the same risk factors using BCSC data, indicated that having either extremely dense breast tissue on mammography or rstdegree relatives with breast cancer is associated with at least a 2-fold increased risk for breast cancer. Identication of these risk factors may be useful for personalized mammography screening.
From the Oregon Evidence-based Practice Center, Oregon Health & Science University, and Providence Cancer Center, Portland, Oregon; Group Health Research Institute, Seattle, Washington; San Francisco Veterans Affairs Medical Center and University of California, San Francisco, California; Erasmus Medical Center, Rotterdam, the Netherlands; Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin; and Lombardi Comprehensive Cancer Center, Washington, DC.
Disclaimer: The content is solely the responsibility of the authors and

U01CA63736, U01CA70013, U01CA69976, U01CA63731, and U01CA70040). Providence Health & Services provided additional support for Dr. Nelson, and the Veterans Affairs Fellowship in Health Issues of Women Veterans provided support for Dr. Cantor. The collection of BCSC cancer data used in this study was supported in part by several state public health departments and cancer registries throughout the United States. For a full description of these sources, please see www.breastscreening .cancer.gov/work/acknowledgement.html.
Potential Conflicts of Interest: Dr. Nelson: Grant (money to institu-

tion): NCI; Support for travel to meetings for the study or other purposes (money to institution): NCI. Dr Fu: Grant (money to institution): AHRQ. Ms. Grifn: Grant (money to institution): NCI. Dr. OMeara: Grant (money to institution): NCI; Employment: Group Health Research Institute. Dr. Buist: Grant (money to institution): NCI. Ms. van Ravesteyn: Grant (money to institution): NCI. Dr. Trentham-Dietz: Grant (money to institution): NCI; Support for travel to meetings for the study or other purposes: NCI. Dr. Mandelblatt: Grant (money to institution): NCI; Support for travel to meetings for the study or other purposes (money to institution): NCI. Dr. Miglioretti: Grant (money to institution): NIH. Disclosures can be also viewed at www.acponline.org/authors/icmje /ConictOfInterestForms.do?msNumM11-2350.
Requests for Single Reprints: Heidi D. Nelson, MD, MPH, Oregon

Evidence-based Practice Center, Oregon Health & Science University, Mail Code BICC, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098; e-mail, nelsonh@ohsu.edu. Current author addresses and author contributions are available at www.annals.org.

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does not necessarily represent the ofcial views of the National Cancer Institute or the National Institutes of Health.
Note: Each cancer registry and the Statistical Coordinating Center have

received institutional review board approval for either active or passive consenting processes or a waiver of consent to enroll participants, link data, and perform analytic studies. All procedures are compliant with the Health Insurance Portability and Accountability Act, and all registries and the Statistical Coordinating Center have received a federal Certicate of Condentiality and other protection for the identities of women, physicians, and facilities participating in this research. A list of the BCSC investigators and procedures for requesting BCSC data for research purposes is provided at http://breastscreening.cancer.gov/.
Acknowledgment: The authors thank the participating women, mam-

mography facilities, and radiologists for the data they have provided for this study. Rose Relevo, MLIS, MS, and Robin Paynter, MA-LIS, conducted literature searches, and Katie Reitel, BA, provided assistance; all are afliated with Oregon Health & Science University.
Grant Support: By a National Cancer Institute Activities to Promote Research Collaboration supplement (U01CA086076-10S1). Data collection was supported by the National Cancer Institutefunded BCSC cooperative agreements (U01CA63740, U01CA86076, U01CA86082,
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55. Berstad P, Ma H, Bernstein L, Ursin G. Alcohol intake and breast cancer risk among young women. Breast Cancer Res Treat. 2008;108:113-20. [PMID: 17468952] 56. Bowlin SJ, Leske MC, Varma A, Nasca P, Weinstein A, Caplan L. Breast cancer risk and alcohol consumption: results from a large case-control study. Int J Epidemiol. 1997;26:915-23. [PMID: 9363510] 57. Brinton LA, Gammon MD, Malone KE, Schoenberg JB, Daling JR, Coates RJ. Modication of oral contraceptive relationships on breast cancer risk by selected factors among younger women. Contraception. 1997;55:197-203. [PMID: 9179450] 58. Ferraroni M, Decarli A, Franceschi S, La Vecchia C. Alcohol consumption and risk of breast cancer: a multicentre Italian case-control study. Eur J Cancer. 1998;34:1403-9. [PMID: 9849424] 59. Garland M, Hunter DJ, Colditz GA, Spiegelman DL, Manson JE, Stampfer MJ, et al. Alcohol consumption in relation to breast cancer risk in a cohort of United States women 25-42 years of age. Cancer Epidemiol Biomarkers Prev. 1999;8:1017-21. [PMID: 10566558] 60. Ma nnisto S, Virtanen M, Kataja V, Uusitupa M, Pietinen P. Lifetime alcohol consumption and breast cancer: a case-control study in Finland. Public Health Nutr. 2000;3:11-8. [PMID: 10786719] 61. McDonald JA, Mandel MG, Marchbanks PA, Folger SG, Daling JR, Ursin G, et al. Alcohol exposure and breast cancer: results of the womens contraceptive and reproductive experiences study. Cancer Epidemiol Biomarkers Prev. 2004; 13:2106-16. [PMID: 15598768] 62. Brown LM, Gridley G, Wu AH, Falk RT, Hauptmann M, Kolonel LN, et al. Low level alcohol intake, cigarette smoking and risk of breast cancer in Asian-American women. Breast Cancer Res Treat. 2010;120:203-10. [PMID: 19597702] 63. Petri AL, Tjnneland A, Gamborg M, Johansen D, Hidrup S, Srensen TI, et al. Alcohol intake, type of beverage, and risk of breast cancer in pre- and postmenopausal women. Alcohol Clin Exp Res. 2004;28:1084-90. [PMID: 15252295] 64. Swanson CA, Coates RJ, Malone KE, Gammon MD, Schoenberg JB, Brogan DJ, et al. Alcohol consumption and breast cancer risk among women under age 45 years. Epidemiology. 1997;8:231-7. [PMID: 9115015] 65. Al-Delaimy WK, Cho E, Chen WY, Colditz G, Willet WC. A prospective study of smoking and risk of breast cancer in young adult women. Cancer Epidemiol Biomarkers Prev. 2004;13:398-404. [PMID: 15006915] 66. Band PR, Le ND, Fang R, Deschamps M. Carcinogenic and endocrine disrupting effects of cigarette smoke and risk of breast cancer. Lancet. 2002;360: 1044-9. [PMID: 12383984] 67. Baron JA, Newcomb PA, Longnecker MP, Mittendorf R, Storer BE, Clapp RW, et al. Cigarette smoking and breast cancer. Cancer Epidemiol Biomarkers Prev. 1996;5:399-403. [PMID: 9162307] 68. Braga C, Negri E, La Vecchia C, Filiberti R, Franceschi S. Cigarette smoking and the risk of breast cancer. Eur J Cancer Prev. 1996;5:159-64. [PMID: 8818604] 69. Gammon MD, Eng SM, Teitelbaum SL, Britton JA, Kabat GC, Hatch M, et al. Environmental tobacco smoke and breast cancer incidence. Environ Res. 2004;96:176-85. [PMID: 15325878] 70. Gammon MD, Schoenberg JB, Teitelbaum SL, Brinton LA, Potischman N, Swanson CA, et al. Cigarette smoking and breast cancer risk among young women (United States). Cancer Causes Control. 1998;9:583-90. [PMID: 10189043] 71. Kropp S, Chang-Claude J. Active and passive smoking and risk of breast cancer by age 50 years among German women. Am J Epidemiol. 2002;156:61626. [PMID: 12244030] 72. Prescott J, Ma H, Bernstein L, Ursin G. Cigarette smoking is not associated with breast cancer risk in young women. Cancer Epidemiol Biomarkers Prev. 2007;16:620-2. [PMID: 17372262] 73. Roddam AW, Pirie K, Pike MC, Chilvers C, Crossley B, Hermon C, et al. Active and passive smoking and the risk of breast cancer in women aged 36-45 years: a population based case-control study in the UK. Br J Cancer. 2007;97: 434-9. [PMID: 17579618] 74. Wrensch M, Chew T, Farren G, Barlow J, Belli F, Clarke C, et al. Risk factors for breast cancer in a population with high incidence rates. Breast Cancer Res. 2003;5:R88-102. [PMID: 12817999] 75. Kerlikowske K, Cook AJ, Buist DS, Cummings SR, Vachon C, Vacek P, et al. Breast cancer risk by breast density, menopause, and postmenopausal hormone therapy use. J Clin Oncol. 2010;28:3830-7. [PMID: 20644098] 76. Ashbeck EL, Rosenberg RD, Stauber PM, Key CR. Benign breast biopsy
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Mammographic density and breast cancer in three ethnic groups. Cancer Epidemiol Biomarkers Prev. 2003;12:332-8. [PMID: 12692108] 111. Vachon CM, van Gils CH, Sellers TA, Ghosh K, Pruthi S, Brandt KR, et al. Mammographic density, breast cancer risk and risk prediction. Breast Cancer Res. 2007;9:217. [PMID: 18190724] 112. Barlow WE, White E, Ballard-Barbash R, Vacek PM, Titus-Ernstoff L, Carney PA, et al. Prospective breast cancer risk prediction model for women undergoing screening mammography. J Natl Cancer Inst. 2006;98:1204-14. [PMID: 16954473] 113. Chen J, Pee D, Ayyagari R, Graubard B, Schairer C, Byrne C, et al. Projecting absolute invasive breast cancer risk in white women with a model that includes mammographic density. J Natl Cancer Inst. 2006;98:1215-26. [PMID: 16954474] 114. Tice JA, Cummings SR, Ziv E, Kerlikowske K. Mammographic breast density and the Gail model for breast cancer risk prediction in a screening population. Breast Cancer Res Treat. 2005;94:115-22. [PMID: 16261410] 115. Schousboe JT, Kerlikowske K, Loh A, Cummings SR. Personalizing mammography by breast density and other risk factors for breast cancer: analysis of health benets and cost-effectiveness. Ann Intern Med. 2011;155:10-20. [PMID: 21727289] 116. Nicholson BT, LoRusso AP, Smolkin M, Bovbjerg VE, Petroni GR, Harvey JA. Accuracy of assigned BI-RADS breast density category denitions. Acad Radiol. 2006;13:1143-9. [PMID: 16935726] 117. Nelson HD, Fu R, Humphrey L, Smith ME, Grifn JC, Nygren P. Comparative Effectiveness of Medications to Reduce Risk of Primary Breast Cancer in Women. Comparative Effectiveness Review (Prepared by Oregon Evidence-based Practice Center under contract 290-97-0018). Rockville, MD: Agency for Healthcare Research and Quality; September 2009. 118. van den Brandt PA, Spiegelman D, Yaun SS, Adami HO, Beeson L, Folsom AR, et al. Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol. 2000;152:514-27. [PMID: 10997541] 119. Cuzick J, Warwick J, Pinney E, Duffy SW, Cawthorn S, Howell A, et al. Tamoxifen-induced reduction in mammographic density and breast cancer risk reduction: a nested case-control study. J Natl Cancer Inst. 2011;103:744-52. [PMID: 21483019]

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Current Author Addresses: Drs. Nelson, Zakher, Cantor, and Fu and Ms. Grifn: 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239. Drs. OMeara, Buist, and Miglioretti: 1730 Minor Avenue, Suite 1600, Seattle, WA 98101. Dr. Kerlikowske: 4150 Clement Street, San Francisco, CA 94121. Ms. van Ravesteyn: PO Box 2040, Rotterdam 3000, the Netherlands. Dr. Trentham-Dietz: 307 WARF Building, 610 Walnut Street, Madison, WI 53726. Dr. Mandelblatt: Suite 4100, 3300 Whitehaven Street NW, Washington, DC 20007. Author Contributions: Conception and design: H.D. Nelson, D.S.M. Buist, K. Kerlikowske, N. van Ravesteyn, A. Trentham-Dietz, J. Mandelblatt, D. Miglioretti. Analysis and interpretation of the data: H.D. Nelson, B. Zakher, A. Cantor, R. Fu, J. Grifn, E.S. OMeara, D.S.M. Buist, K. Kerlikowske, A. Trentham-Dietz, J. Mandelblatt.

Drafting of the article: H.D. Nelson, B. Zakher, A. Cantor, R. Fu, J. Grifn, E.S. OMeara, K. Kerlikowske, J. Mandelblatt. Critical revision of the article for important intellectual content: H.D. Nelson, B. Zakher, A. Cantor, R. Fu, D.S.M. Buist, K. Kerlikowske, N. van Ravesteyn, A. Trentham-Dietz, J. Mandelblatt, D. Miglioretti. Final approval of the article: H.D. Nelson, B. Zakher, R. Fu, J. Grifn, E.S. OMeara, D.S.M. Buist, K. Kerlikowske, N. van Ravesteyn, J. Mandelblatt, D. Miglioretti. Provision of study materials or patients: H.D. Nelson, D.S.M. Buist, K. Kerlikowske. Statistical expertise: H.D. Nelson, R. Fu, K. Kerlikowske, D. Miglioretti. Obtaining of funding: H.D. Nelson, D.S.M. Buist, K. Kerlikowske, J. Mandelblatt, D. Miglioretti. Administrative, technical, or logistic support: H.D. Nelson, J. Grifn, D.S.M. Buist. Collection and assembly of data: H.D. Nelson, B. Zakher, A. Cantor, R. Fu, J. Grifn, D.S.M. Buist, K. Kerlikowske, D. Miglioretti.

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Appendix Table. Population Distribution of Risk Factors for

Women Aged 40 to 49 Years

Appendix TableContinued
Risk Factor U.S. Distribution NA NA BCSC Distribution 77% 23%

Risk Factor Race and ethnicity White Black Asian/Pacific Islander Hispanic Other/mixed Body mass index 18.5 kg/m2 18.524 kg/m2 2529 kg/m2 30 kg/m2 Physical activity Inactive Some Regular Alcohol use 0 drinks/wk 7 drinks/wk 713 drinks/wk 14 drinks/wk Smoking use Never Ever Smoking status Never Current Former

U.S. Distribution NA NA NA NA NA

BCSC Distribution 72% 7% 7% 11% 3%

Parity Ever None Births 0 1 2 3 Age at first birth 20 y 2024 y 2529 y 30 y None Breastfeeding None Ever Breastfeeding duration None 12 mo 12 mo Oral contraceptive use None Ever Oral contraceptive status Former or none Current Recency of oral contraceptive use None 5 y 59 y 10 y Menopausal status Premenopausal Perimenopausal Postmenopausal, nonsurgical Postmenopausal, surgical Unknown, surgery Menopausal hormone therapy*** Former or none Current (no uterus) Current (uterus present)

NA NA NA NA

NA NA NA NA

36%* 26% 38%

2% 51% 26% 21%

NA NA NA NA NA

17% 22% 17% 14% 29%

37% 32% 32%

NA NA NA

25% 75%

NA NA

36% 59% 5%

NA NA NA NA

25% 53% 22%

NA NA NA

27%* 73%

NA NA

18% 82%

NA NA

27%* 29% 44%

NA NA NA

NA NA

92% 8%

First-degree relatives with breast cancer 0 90.7% 1 8.6% 2 0.6% 3 0.1% Age at diagnosis of first-degree relatives with breast cancer None NA 40 y NA 4049 y NA 5059 y NA 60 y NA Second-degree relatives with breast cancer None NA 1 NA Breast density (BI-RADS category) 1 2 3 4 Prior breast procedure None Any Age at menarche** 12 y 13 y 14 y 15 y

89% 11% (1)

NA NA NA NA

NA NA NA NA

92% 4% (50) 4% (50)

NA NA NA NA NA

81% 3% 3% 5% 8%

NA NA

NA NA NA

93% 4% 3%

NA NA NA NA

5% 36% 45% 13%

NA NA

90% 10%

NA NA NA NA

44% 31% 13% 12%

BCSC Breast Cancer Surveillance Consortium; BI-RADS Breast Imaging Reporting and Data System; NA not available. * National Center for Health Statistics, 2011 (21). Colditz and colleagues, 2003 (46). Substance Abuse and Mental Health Services Administration, 2008 (22). Collaborative Group on Hormonal Factors in Breast Cancer, 2001 (26). 1 almost entirely fat; 2 broglandular densities; 3 heterogeneously dense; 4 extremely dense. Surgical and needle biopsies. ** The mean age at menarche was 12.5 y in the U.S. sample (Anderson and colleagues, 2003 [16]) and 12.8 y in the BCSC sample. The mean age at rst birth was 25 y in the U.S. sample (Matthews and Hamilton, 2009 [18]). Centers for Disease Control and Prevention, 2010 (20). Mosher and Jones, 2010 (19). Bilateral oophorectomy. Usually hysterectomy without bilateral oophorectomy. *** Assumed women without a uterus were using estrogen only and women with a uterus were using estrogen combined with progestin.

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