Annals of Internal Medicine
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. O’Meara, 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 Con-
sortium were analyzed with proportional hazards models by using
C urrent practice guidelines on mammography screening
differ in their recommendations for women in their
40s (1–3). The U.S. Preventive Services Task Force recom-
mends individualized, informed decision making about
when to start mammography screening based on a wom-
an’s values about benefits and harms (4). Risk-based
screening has been recommended for other health condi-
tions in the United States and may provide a similar
evidence-based approach for breast cancer. However, ap-
plying this approach to clinical practice has been problem-
atic because it is unclear how women and clinicians can
effectively consider individualized risk factor information
in their discussions of benefits and harms.
Microsimulation models of mammography screening
developed as part of the Cancer Intervention and Surveil-
lance 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
benefits (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
benefit (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-
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Review
partly conditional Cox regression. Reference groups for comparisons
were set at U.S. population means.
Data Synthesis: Sixty-six studies provided data for estimates. Ex-
tremely 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 associ-
ated 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. www.annals.org
For author affiliations, see end of text.
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. How-
ever, studies generally included women of various ages,
measured and reported risk factors in different ways, and
provided wide ranges of risk estimates. Consequently, re-
sults of broad-based epidemiologic studies may not be clin-
ically 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
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© 2012 American College of Physicians 635
 Review Risk Factors for Breast Cancer for Women Aged 40 to 49 Years
Context
Knowing which factors influence breast cancer risk for
women younger than 50 years might help target screening
efforts.
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 (ⱖ2-fold increase); prior breast biopsy,
second-degree relatives with cancer, or heterogeneously
dense breasts (1.5- to 2.0-fold increase); current oral con-
traceptive 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 meta-
analysis is to determine what factors increase risk for inva-
sive breast cancer, specifically 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 cur-
rent 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 co-
hort, depending on the risk factor. This project was con-
ducted 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 Medicine’s Medical Subject
Headings keyword nomenclature to search MEDLINE
(1996 to the second week of November 2011), the Co-
chrane Central Register of Controlled Trials (fourth quar-
ter of 2011), and the Cochrane Database of Systematic
Reviews (fourth quarter of 2011) for relevant English-
language studies and systematic reviews. We also con-
ducted secondary referencing by manually reviewing refer-
ence 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 cur-
rent cohorts of women considering mammography screen-
ing and to correspond to the time frame of risk factor data
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collected by the Breast Cancer Surveillance Consortium
(BCSC) that were also used in this study.
Study Selection
We developed inclusion and exclusion criteria for ab-
stracts 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 defined specifically
for each risk factor, including eligibility of the data for
statistical meta-analysis. When sufficient 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 findings,
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 par-
ticipants were aged 40 to 49 years and all were younger
than 55 years. When studies reported outcomes by meno-
pausal status rather than age, we used results for premeno-
pausal 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 nonin-
vasive 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, fam-
ily history of breast cancer, breast density, prior breast pro-
cedures, and reproductive factors (age at menarche; parity;
age at birth of first child; breastfeeding; oral contraceptive
use; menopausal age, status, and type; and menopausal
hormone therapy). We included studies meeting the fol-
lowing criteria: studies of risk factors for recent or current
status that reflected exposure within 1 year of breast cancer
diagnosis; studies of physical activity that reported catego-
ries of exercise descriptively (inactive, some, or regular) or
quantified 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 meno-
pausal hormone therapy use that investigated any formula-
tion (combination, progestin, or estrogen only) and used
various definitions of ever and never use. We excluded
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 Risk Factors for Breast Cancer for Women Aged 40 to 49 Years
studies of nonoral forms of contraception and those eval-
uating formulations not applicable to the target population
(8).
We included studies that defined parity as the number
of full-term births, full-term pregnancies, live births, or
pregnancies lasting 6 months or more regardless of out-
come, consistent with standard medical definitions (9). We
included studies of breastfeeding that used a nonbreast-
feeding 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 Im-
aging Reporting and Data System (BI-RADS) classification
(1 ⫽ almost entirely fat, 2 ⫽ scattered fibroglandular den-
sities, 3 ⫽ heterogeneously dense, and 4 ⫽ extremely dense)
because of its clinical relevance to practice in the United States
(10).
Data Extraction and Quality Assessment
For the included studies, an investigator abstracted the
following data: study design, setting, participant character-
istics (including age, race and ethnicity, and diagnosis),
enrollment criteria, exposures (dose and duration), proce-
dures for data collection, number enrolled and number lost
to follow-up, methods of exposure and outcome ascertain-
ment, analytic methods (including adjustment for con-
founders), and results for each outcome. A second investi-
gator confirmed the accuracy of key data.
We used predefined criteria developed by the U.S.
Preventive Services Task Force to assess the quality of stud-
ies (11). Two investigators independently rated the quality
of each eligible study (good, fair, or poor), and final 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, out-
comes, timing of outcomes measurement, and setting) ap-
proach (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 deter-
mined 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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Review
Data Synthesis and Analysis
For eligible studies, we combined data in several meta-
analyses to obtain more precise estimates of the relation-
ship 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 po-
tential confounder in their analysis were included in the
meta-analysis. To determine the appropriateness of meta-
analysis, we considered clinical and methodological diver-
sity 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 esti-
mates 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 ex-
ample, reflected 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 es-
timates 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 defini-
tions of underweight (⬍18.5 kg/m2), normal weight (18.5
to ⬍25 kg/m2), overweight (25 to ⬍30 kg/m2), and obese
(ⱖ30 kg/m2) (13). We combined the underweight and
normal weight categories because too few women were in-
cluded in the underweight group. When studies catego-
rized 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 param-
eters 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 vari-
ation among studies. In general, when there is no variation
among studies, the random-effects model yields the same
results as a fixed-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 quantified by the total
number of adjusted variables and the number of adjusted
risk factors considered in the review as well as other study-
level variables, such as quality, study design, and breast
cancer type. We also conducted sensitivity analyses to as-
sess the robustness of results that considered variation from
different definitions of risk factors and reference groups,
inclusion of noninvasive breast cancer as an outcome, and
outlying studies. The results of the sensitivity analyses in-
dicated no major differences from the main analysis.
For specific risk factors (BMI, age at menarche, and
age at birth of first 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 pop-
ulation. 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 esti-
mates. Data describing distributions or means in the target
population were obtained from various sources represent-
ing U.S. national samples (16 –22) (Appendix Table, avail-
able 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 re-
ported in published studies. The BCSC is a national col-
laboration of 5 mammography registries and 2 affiliate 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 screen-
ing mammography. Risk factor data were obtained at the
time of each screening mammography and reported in cat-
egories similar to those defined by the systematic review.
Results for 380 585 women aged 40 to 49 years were pro-
vided in proportional hazards models adjusted for age,
race, family history of breast cancer, and BMI and stratified
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 mammogra-
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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 in-
vasive breast cancer; until they were censored at the first
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 identified 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
first birth, breastfeeding, and oral contraceptive use) pro-
vided data for meta-analysis. Two published meta-analyses
of family history of breast cancer reported results specifi-
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 Risk Factors for Breast Cancer for Women Aged 40 to 49 Years Review

cally for women in their 40s (26, 27). Single studies pro-
vided 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 Sup-
plement (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 significant in-
creased 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 specifically for under-
weight women were not provided by the published studies,
although the BCSC data indicated that risk for under-
weight women was not significantly different from that of
normal weight women.
Ten studies of physical activity met inclusion criteria
(45–54) but could not be combined in the meta-analysis
because they used different measures of activity and re-
ported results in dissimilar categories. All studies reported
no statistically significant differences in breast cancer risk
based on physical activity. Results from a large, good-
quality study designed to specifically 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 Systematic Review and Meta-analysis BCSC Breast Cancer Risk
Ratio (95% CI)*
Studies Breast Cancer Risk Heterogeneity
(Reference), n Ratio (95% CI)
I2, % P Value
Race and ethnicity
White 0 NA – – Reference group
Black 0 NA – – 1.04 (0.78–1.39)
Asian/Pacific Islander 0 NA – – 0.94 (0.78–1.12)
Hispanic 0 NA – – 1.10 (0.97–1.25)
Other/mixed 0 NA – – 0.95 (0.77–1.17)

Body mass index

⬍18.5 kg/m2 – – 1.28 (0.98–1.66)
Reference group Reference group†
18.5–24 kg/m2 – – Reference group
25–29 kg/m2 18 (17, 28–44) 0.86 (0.82–0.90) 0.0 0.73 0.92 (0.84–1.01)
ⱖ30 kg/m2 18 (17, 28–44) 0.74 (0.68–0.81) 1.3 0.44 0.74 (0.66–0.82)

Physical activity
Inactive Reference group Reference group – – NA
Some 1 (46) 1.09 (0.88–1.34) – – NA
Regular 1 (46) 1.15 (0.93–1.43) – – NA

Alcohol use‡
0 drinks/wk Reference group Reference group – – NA
⬍7 drinks/wk 3 (55, 61, 64) 1.03 (0.96–1.11) 0.0 0.74 NA
7–13 drinks/wk 3 (55, 61, 64) 1.14 (0.94–1.38) 0.0 0.75 NA
ⱖ14 drinks/wk 3 (55, 61, 64) 1.24 (0.87–1.78) 38.5 0.197 NA

Smoking use
Never Reference group Reference group – – NA
Ever 12 (31, 62, 65–74) 1.05 (0.98–1.13) 31.0 0.144 NA

Smoking status
Never Reference group Reference group – – NA
Current 7 (31, 62, 67, 70–73) 0.92 (0.84–1.02) 0.0 0.84 NA
Former 7 (31, 62, 67, 70–73) 1.11 (0.97–1.28) 47.8 0.074 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 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
49 Years

Risk Factor Systematic Review BCSC Breast Cancer Risk Ratio

(95% CI)*
Study Type or Number of Breast Cancer Risk Ratio
Studies (Reference) (95% CI)
First-degree relatives with breast cancer
0 Meta-analysis (26) Reference group Reference group
1 Meta-analysis (26) 2.14 (1.92–2.38)
2 Meta-analysis (26) 3.84 (2.37–6.22) None vs. any, 1.86 (1.69–2.06)
ⱖ3 Meta-analysis (26) 12.05 (1.70–85.16)

Age at diagnosis of first-degree relatives with breast cancer

None Meta-analysis (26) Reference group Reference group
⬍40 y Meta-analysis (26) 3.0 (1.8–4.9)
None vs. ⬍50 y, 2.17 (1.86–2.53)
40–49 y Meta-analysis (26) 2.0 (1.5–2.8)
50–59 y Meta-analysis (26) 2.3 (1.7–3.2)
None vs. ⱖ50 y, 1.68 (1.44–1.96)
ⱖ60 y Meta-analysis (26) 1.7 (1.3–2.1)

Second-degree relatives with breast cancer

0 Meta-analysis (27) Reference group NA
ⱖ1 Meta-analysis (27) 1.7 (1.4–2.0) NA

Breast density (BI-RADS category)†

1 1 (75) 0.46 (0.37–0.58) 0.41 (0.31–0.55)
2 1 (75) Reference group Reference group
3 1 (75) 1.62 (1.51–1.75) 1.75 (1.59–1.93)
4 1 (75) 2.04 (1.84–2.26) 2.33 (2.04–2.66)

Prior breast procedure‡

None 1 (76) Reference group Reference group
Any 1 (76) 1.87 (1.64–2.13) 1.51 (1.36–1.67)

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 ⫽ fibroglandular 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 al-
cohol use met inclusion criteria (31, 36, 55– 64), results
from only 3 studies could be combined in the meta-
analysis (55, 61, 64). Using no alcohol use as the reference
group, results indicated higher risk estimates with increas-
ing amounts of alcohol consumption; however, all CIs in-
cluded 1.0. Smoking use (never vs. ever) and status (never
vs. current or former) had no significant associations with
breast cancer based on meta-analyses of 12 studies of never
versus ever use (31, 62, 65–74) 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 significantly increased for
women with first-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 ⱖ3 relatives, 12.05 [CI, 1.70 to 85.16])
(Table 2). Data from the BCSC also showed higher risk
for women with a first-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
640 1 May 2012 Annals of Internal Medicine Volume 156 • Number 9
first-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 first-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 significantly
increased for women with 1 or more second-degree rela-
tives compared with none (RR, 1.7 [CI, 1.4 to 2.0]).
A published study of BCSC data reported risk esti-
mates for breast cancer by using BI-RADS breast density
categories and defined BI-RADS category 2 (scattered fi-
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). Ad-
ditional BCSC data that included prior biopsies or fine-
needle 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
Reproductive Factors
Reproductive factors included age at menarche, parity,
age at first birth, breastfeeding, oral contraceptive use,
menopausal status, and menopausal hormone therapy (Ta-
ble 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 ref-
erence age of 13 years (RR, 0.87 [CI, 0.78 to 0.97]). Re-
sults from the BCSC were similar.
A meta-analysis of 17 studies of parity (31, 34, 45, 74,
77– 80, 82–90) indicated that nulliparous women had a
significantly 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 significantly re-
duced 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 first birth (34, 45, 77,
83, 88), women having their first 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 significantly increased risk for these groups
but did indicate decreased risk for women aged 20 years or
younger at the time of the first birth.
In a meta-analysis of 14 studies (34, 74, 78, 80, 82,
83, 86, 90 –96), breastfeeding was associated with re-
duced 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, 91–96). Breastfeeding data were not available from
the BCSC.
Twelve studies of oral contraceptive use provided esti-
mates for the meta-analysis of ever use compared with
never use (31, 74, 77, 78, 97–104), and 8 studies provided
estimates for recency of use, with the most recent category
defined as within 5 years (77, 78, 99 –104). None of these
associations was statistically significant, although all point
estimates were increased (Table 3). Data from the BCSC
indicated significantly higher risk for breast cancer for cur-
rent 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 (ei-
ther surgical or nonsurgical menopause) compared with
premenopausal women. The BCSC data also indicated that
women with no uterus currently using menopausal hor-
mone therapy had a reduced risk for breast cancer com-
pared with nonusers (RR, 0.70 [CI, 0.52 to 0.94]),
whereas those with a uterus had no significant 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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Review
DISCUSSION
Sixty-six studies identified 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 appli-
cability for each risk factor (Table 4). Overall, studies were
consistent and applicability was high, largely because con-
ditions of the study population were incorporated into in-
clusion criteria.
Results indicated that women in their 40s with extremely
dense breasts on mammography or at least 1 first-degree rela-
tive 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 benefits and harms for increased-risk women start-
ing 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 first-degree relatives with
breast cancer or first-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 heteroge-
neously dense breast tissue. Current use of oral contracep-
tives, nulliparity, and first birth at age 30 years or older
were associated with a 1.0- to 1.5-fold increased risk, al-
though some results differed by data sources, which sug-
gests 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 men-
arche; birth of 3 or more children; breastfeeding; peri-
menopausal or postmenopausal status; and use of meno-
pausal, estrogen-only hormone therapy.
Although the results of this review are consistent with
previous research, our estimates of risk are unique and rel-
evant 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 identified in single studies or in studies of women of
various ages were not statistically significant in our analysis.
These findings may be useful to women, clinicians, and
health systems considering risk-based screening who find a
long list of potential risk factors difficult to navigate. Fo-
cusing on high breast density and first-degree family his-
tory of breast cancer may be a more clinically feasible ap-
proach to personalized screening.
1 May 2012 Annals of Internal Medicine Volume 156 • Number 9 641
 Review 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 Systematic Review and Meta-analysis BCSC Breast Cancer Risk
Ratio (95% CI)*
Studies (Reference), n Breast Cancer Risk Heterogeneity
Ratio (95% CI)
I 2, % P Value
Age at menarche
ⱕ12 y 10 (31, 34, 45, 77, 79, 80, 82–85) 1.10 (0.98–1.23) 45.1 0.059 0.99 (0.88–1.12)
13 y Reference group Reference group – – Reference group
14 y 6 (31, 34, 45, 79, 84, 85) 0.98 (0.87–1.10) 3.8 0.39 1.00 (0.85–1.17)
ⱖ15 y 9 (31, 34, 45, 78, 79, 81, 84–86) 0.87 (0.78–0.97) 0 0.58 0.77 (0.63–0.94)

Parity
Ever Reference group Reference group – – Reference group
None 17 (31, 34, 45, 74, 77–80, 82–90) 1.16 (1.04–1.26) 80.3 ⬍0.001 1.15 (1.03–1.28)

Births
0 Reference group Reference group – – NA
1 13 (31, 34, 74, 77–80, 82, 84–87, 90) 0.95 (0.81–1.11) 48.3 0.026 NA
2 13 (31, 34, 74, 77–80, 82, 84–87, 90) 0.93 (0.77–1.12) 73.2 ⬍0.001 NA
ⱖ3 13 (31, 34, 74, 77–80, 82, 84–87, 90) 0.73 (0.61–0.87) 82.4 ⬍0.001 NA

Age at first birth

⬍20 y 4 (34, 45, 77, 83) 0.96 (0.82–1.11) 0 0.81 0.78 (0.65–0.93)
20–24 y 4 (34, 45, 77, 83) 0.96 (0.82–1.11) 0 0.62 0.87 (0.75–1.00)
25–29 y Reference group Reference group – – Reference group
ⱖ30 y 5 (34, 45, 77, 83, 88) 1.20 (1.02–1.42) 17.9 0.30 1.02 (0.87–1.20)
None 5 (34, 45, 77, 83, 88) 1.25 (1.08–1.46) 0 0.55 1.08 (0.93–1.25)

Breastfeeding†
None Reference group Reference group – – NA
Ever 14 (34, 74, 78, 80, 82, 83, 86, 90–96) 0.87 (0.77–0.98) 68.5 ⬍0.001 NA

Breastfeeding duration†
None Reference group Reference group – – NA
⬍12 mo 11 (34, 78, 80, 82, 83, 91–96) 0.97 (0.87–1.08) 42.2 0.068 NA
ⱖ12 mo 11 (34, 78, 80, 82, 83, 91–96) 0.85 (0.73–0.99) 55.0 0.014 NA

Oral contraceptive use

None Reference group Reference group – – NA
Ever 12 (31, 74, 77, 78, 97–104) 1.08 (0.96–1.23) 71.5 0.001 NA

Oral contraceptive status

Former or none 0 NA – – Reference group
Current 0 NA – – 1.30 (1.13–1.49)

Recency of oral contraceptive use

None Reference group Reference group – – NA
⬍5 y 8 (77, 78, 99–104) 1.10 (0.93–1.29) 40.7 0.096 NA
5–9 y 8 (77, 78, 99–104) 1.15 (0.94–1.40) 51.8 0.035 NA
ⱖ10 y 8 (77, 78, 99–104) 1.07 (0.95–1.19) 40.1 0.100 NA

Menopausal status
Premenopausal 0 NA – – Reference group
Perimenopausal 0 NA – – 0.70 (0.58–0.86)
Postmenopausal, nonsurgical 0 NA – – 0.59 (0.47–0.75)
Postmenopausal, surgical‡ 0 NA – – 0.58 (0.44–0.77)
Unknown, surgery§ 0 NA – – 0.67 (0.56–0.80)

Menopausal hormone therapy㥋

Former or none 0 NA – – Reference group
Current (no uterus) 0 NA – – 0.70 (0.52–0.94)
Current (uterus present) 0 NA – – 0.90 (0.67–1.21)

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.
㛳 Assumed women without a uterus were using estrogen only and women 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 Review

Table 4. Summary of Evidence for Studies Providing Data for Risk Estimates

Studies by Studies by Breast Cancer Studies by Consistency* Applicability†

Design, n Outcome, n Quality, n

Cohort Case–Control Published Invasive Invasive and Not Good Fair

Meta-analysis Only Noninvasive Specified
Body mass index
9 9 0 7 7 4 5 13 Consistent High

Physical activity
1 0 0 1 0 0 1 0 Single study High

Alcohol use
0 3 0 2 1 0 1 2 Consistent High

Smoking use
1 11 0 5 3 4 4 8 Consistent High

Smoking status
0 7 0 4 2 1 2 5 Consistent High

First-degree relative with breast cancer

0 0 1 1 0 0 1 0 Single study High

Age at diagnosis of first-degree relative with breast cancer

0 0 1 1 0 0 1 0 Single study High

Second-degree relative with breast cancer

0 0 1 0 1 0 0 1 Single study High

Breast density
1 0 0 0 1 0 1 0 Single study High

Prior breast procedure

1 0 0 0 1 0 1 0 Single study High

Age at menarche
1 12 0 4 6 3 4 9 Consistent High

Parity
3 14 0 6 7 4 4 13 Consistent High

Number of births
2 11 0 3 6 4 3 10 Consistent High

Age at first birth

1 4 0 2 2 1 2 3 Consistent High

Breastfeeding
1 13 0 3 5 6 1 13 Consistent High

Breastfeeding duration
1 10 0 2 5 4 1 10 Consistent High

Oral contraceptive use

2 10 0 7 2 3 5 7 Consistent High

Recency of oral contraceptive use

0 8 0 4 2 2 4 4 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 screen-
ing and prevention extends beyond mammography. Cur-
rent recommendations from the U.S. Preventive Services
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Task Force for women with family histories of breast can-
cer include genetic counseling and mutation testing if ap-
propriate (105) and consideration of medications to reduce
risk for primary breast cancer (106).
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 Review 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 Breast Cancer Risk Source (Reference)

Ratio (95% CI)
>2-fold increased risk
First-degree relatives with breast cancer
1 2.14 (1.92–2.38) (26)
2 3.84 (2.37–6.22) (26)
Any 1.86 (1.69–2.06) BCSC
Age of first-degree relative with breast cancer
⬍40 y 3.0 (1.8–4.9) (26)
⬍50 y 2.17 (1.86–2.53) BCSC
Breast density BI-RADS category 4 2.04 (1.84–2.26) (75)*

1.5- to 2.0-fold increased risk

Prior benign breast biopsy result 1.87 (1.64–2.13) (76)*
Second-degree relative with breast cancer 1.7 (1.4–2.0) (27)
Breast density BI-RADS category 3 1.62 (1.51–1.75) (75)*

1.0- to 1.5-fold increased risk

Current oral contraceptive use 1.30 (1.13–1.49) BCSC
Nulliparity† 1.25 (1.08–1.46) (34, 45, 77, 83, 88)
Age at first birth ⱖ30 y‡ 1.20 (1.02–1.42) (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 significantly increased risk for nonparous compared with parous women were similar for the
meta-analysis and the BCSC data. Estimates comparing ages at first birth that included nonparous women provided significant results for the meta-analysis only.
‡ Results were not statistically significant 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 be-
cause it reported results with BI-RADS classifications that
are used in U.S. clinical practice and provided risk esti-
mates specific to the target population (75). The use of
breast density in screening and prevention is currently un-
clear, although research suggests that it may be important
for estimating risk (111–114) 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. Al-
though several such models exist (for example, the Gail
model), they were not developed specifically 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 effective-
ness in clinical applications are necessary future steps in
this work.
Although our risk estimates may be useful in inform-
ing clinical practice, effective methods to modify risk fac-
tors 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. How-
ever, an inverse association has been found in postmeno-
644 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 reflect underlying biological effects that cannot be
modified 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 varia-
tions 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 cat-
egories that did not align with ours. Publication bias and
selective reporting are also potential limitations but are dif-
ficult to assess.
To address these issues, we developed inclusion criteria
that considered the quality and applicability of studies con-
sistently across risk factors, included only fair- or good-
quality studies, selected best-evidence estimates for risk
factors that lacked estimates from a meta-analysis, and re-
defined reference groups to approximate the mean or dis-
tribution of the target population. In addition, we analyzed
primary BCSC data to supplement or support the meta-
analysis 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
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 asso-
ciated with multiple concurrent factors. Our inclusion cri-
teria led to the selection of studies enrolling a specifically
defined population, and results may not be applicable to
different populations. Also, we focused on factors that in-
crease risk for breast cancer in collaboration with the de-
velopment of the CISNET models. Clinical application of
our estimates of factors associated with reduced risk is lim-
ited because the CISNET models were not designed for
similar reduced-risk scenarios.
This comprehensive systematic review and meta-
analysis 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 ex-
tremely dense breast tissue on mammography or first-
degree relatives with breast cancer is associated with at least
a 2-fold increased risk for breast cancer. Identification of
these risk factors may be useful for personalized mammog-
raphy 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 Fran-
cisco, 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
does not necessarily represent the official 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 Certifi-
cate of Confidentiality 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 pur-
poses 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, con-
ducted literature searches, and Katie Reitel, BA, provided assistance; all
are affiliated with Oregon Health & Science University.
Grant Support: By a National Cancer Institute Activities to Promote
Research Collaboration supplement (U01CA086076-10S1). Data collec-
tion was supported by the National Cancer Institute–funded BCSC co-
operative agreements (U01CA63740, U01CA86076, U01CA86082,
www.annals.org
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Review
U01CA63736, U01CA70013, U01CA69976, U01CA63731, and
U01CA70040). Providence Health & Services provided additional sup-
port 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. Griffin: Grant (money to institution): NCI. Dr. O’Meara: Grant
(money to institution): NCI; Employment: Group Health Research Insti-
tute. 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; Sup-
port for travel to meetings for the study or other purposes (money to institu-
tion): NCI. Dr. Miglioretti: Grant (money to institution): NIH.
Disclosures can be also viewed at www.acponline.org/authors/icmje
/ConflictOfInterestForms.do?msNum⫽M11-2350.
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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[PMID: 21483019]

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 Annals of Internal Medicine
Current Author Addresses: Drs. Nelson, Zakher, Cantor, and Fu and
Ms. Griffin: 3181 SW Sam Jackson Park Road, Mail Code BICC, Port-
land, OR 97239.
Drs. O’Meara, Buist, and Miglioretti: 1730 Minor Avenue, Suite 1600,
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ton, DC 20007.
Author Contributions: Conception and design: H.D. Nelson, D.S.M.
Buist, K. Kerlikowske, N. van Ravesteyn, A. Trentham-Dietz, J. Man-
delblatt, D. Miglioretti.
Analysis and interpretation of the data: H.D. Nelson, B. Zakher, A.
Cantor, R. Fu, J. Griffin, E.S. O’Meara, D.S.M. Buist, K. Kerlikowske,
A. Trentham-Dietz, J. Mandelblatt.
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Critical revision of the article for important intellectual content: H.D.
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van Ravesteyn, A. Trentham-Dietz, J. Mandelblatt, D. Miglioretti.
Final approval of the article: H.D. Nelson, B. Zakher, R. Fu, J. Griffin,
E.S. O’Meara, D.S.M. Buist, K. Kerlikowske, N. van Ravesteyn, J. Man-
delblatt, D. Miglioretti.
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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. Griffin,
D.S.M. Buist.
Collection and assembly of data: H.D. Nelson, B. Zakher, A. Cantor, R.
Fu, J. Griffin, D.S.M. Buist, K. Kerlikowske, D. Miglioretti.
1 May 2012 Annals of Internal Medicine Volume 156 • Number 9 W-223
 Appendix Table. Population Distribution of Risk Factors for Appendix Table—Continued
Women Aged 40 to 49 Years
Risk Factor U.S. BCSC
Risk Factor U.S. BCSC Distribution Distribution
Distribution Distribution Parity
Race and ethnicity Ever NA 77%
None NA 23%
White NA 72%
Black NA 7%
Births
Asian/Pacific Islander NA 7%
0 NA NA
Hispanic NA 11%
1 NA NA
Other/mixed NA 3% 2 NA NA
ⱖ3 NA NA
Body mass index
⬍18.5 kg/m2 2% Age at first birth††
36%*
18.5–24 kg/m2 51% ⬍20 y NA 17%
25–29 kg/m2 26% 26% 20–24 y NA 22%
ⱖ30 kg/m2 38% 21% 25–29 y NA 17%
ⱖ30 y NA 14%
Physical activity None NA 29%
Inactive 37%† NA
Some 32% NA Breastfeeding
Regular 32% NA None 25%‡‡ NA
Ever 75% NA
Alcohol use
Breastfeeding duration§
0 drinks/wk 36%‡ NA
None 25%‡‡ NA
⬍7 drinks/wk 59% NA
⬍12 mo 53% NA
7–13 drinks/wk NA
5% ⱖ12 mo 22% NA
ⱖ14 drinks/wk NA
Oral contraceptive use
Smoking use None 18%§§ NA
Never 27%* NA Ever 82% NA
Ever 73% NA
Oral contraceptive status
Smoking status Former or none NA 92%
Never 27%* NA Current NA 8%
Current 29% NA
Former 44% NA Recency of oral contraceptive use
None NA NA
First-degree relatives with breast cancer ⬍5 y NA NA
0 90.7%§ 89% 5–9 y NA NA
1 8.6% 11% (ⱖ1) ⱖ10 y NA NA
2 0.6% –
Menopausal status
ⱖ3 0.1% –
Premenopausal NA 81%
Perimenopausal NA 3%
Age at diagnosis of first-degree relatives with breast cancer
Postmenopausal, nonsurgical NA 3%
None NA 92%
Postmenopausal, surgical 㛳 㛳 NA 5%
⬍40 y NA
4% (⬍50) Unknown, surgery¶¶ NA 8%
40–49 y NA
50–59 y NA
4% (ⱖ50) Menopausal hormone therapy***
ⱖ60 y NA
Former or none NA 93%
Current (no uterus) NA 4%
Second-degree relatives with breast cancer
Current (uterus present) NA 3%
None NA NA
ⱖ1 NA NA
BCSC ⫽ Breast Cancer Surveillance Consortium; BI-RADS ⫽ Breast Imaging
Reporting and Data System; NA ⫽ not available.
Breast density (BI-RADS category)㥋
* National Center for Health Statistics, 2011 (21).
1 NA 5% † Colditz and colleagues, 2003 (46).
2 NA 36% ‡ Substance Abuse and Mental Health Services Administration, 2008 (22).
3 NA 45% § Collaborative Group on Hormonal Factors in Breast Cancer, 2001 (26).
4 NA 13% 㛳 1 ⫽ almost entirely fat; 2 ⫽ fibroglandular densities; 3 ⫽ heterogeneously dense;
4 ⫽ extremely dense.
Prior breast procedure¶ ¶ Surgical and needle biopsies.
None NA 90% ** 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.
Any NA 10%
†† The mean age at first birth was 25 y in the U.S. sample (Matthews and
Hamilton, 2009 [18]).
Age at menarche** ‡‡ Centers for Disease Control and Prevention, 2010 (20).
ⱕ12 y NA 44% §§ Mosher and Jones, 2010 (19).
13 y NA 31% 㛳 㛳 Bilateral oophorectomy.
14 y NA 13% ¶¶ Usually hysterectomy without bilateral oophorectomy.
ⱖ15 y NA 12% *** Assumed women without a uterus were using estrogen only and women with
a uterus were using estrogen combined with progestin.

W-224 1 May 2012 Annals of Internal Medicine Volume 156 • Number 9 www.annals.org

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