ARTICLE

Longitudinal Measurement of Clinical

Mammographic Breast Density to Improve
Estimation of Breast Cancer Risk
Karla Kerlikowske, Laura Ichikawa, Diana L. Miglioretti, Diana S. M. Buist, Pamela M. Vacek,
Rebecca Smith-Bindman, Bonnie Yankaskas, Patricia A. Carney, Rachel Ballard-Barbash

For the National Institutes of Health Breast Cancer Surveillance Consortium

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Background Whether a change over time in clinically measured mammographic breast density influences breast
cancer risk is unknown.

Methods From January 1993 to December 2003, data that included American College of Radiology Breast Imaging
Reporting and Data System (BI-RADS) breast density categories (1–4 in order of increasing density) were
collected prospectively on 301 955 women aged 30 and older who were not using postmenopausal hor-
mone replacement therapy and underwent at least two screening mammography examinations; 2639 of the
women were diagnosed with breast cancer within 1 year of the last examination. Women’s first and last
BI-RADS breast density (average 3.2 years apart) and logistic regression were used to model the odds of
having invasive breast cancer or ductal carcinoma in situ diagnosed within 12 months of the last examination
by change in BI-RADS category. Rates of breast cancer adjusted for age, mammography registry, and time
between screening examinations were estimated from this model. All statistical tests were two-sided.

Results The rate (breast cancers per 1000 women) of breast cancer was higher if BI-RADS breast density category
increased from 1 to 2 (5.6, 95% confidence interval [CI] = 4.7 to 6.9) or 1 to 3 (9.9, 95% CI = 6.4 to 15.5)
compared to when it remained at BI-RADS density of 1 (3.0, 95% CI = 2.3 to 3.9; P<.001 for trend). Similar
and statistically significant trends between increased or decreased density and increased or decreased risk
of breast cancer, respectively, were observed for women whose breast density category was initially 2 or
3 and changed categories. BI-RADS density of 4 on the first examination was associated with a high rate
of breast cancer (range 9.1–13.4) that remained high even if breast density decreased.

Conclusion An increase in BI-RADS breast density category within 3 years may be associated with an increase in
breast cancer risk and a decrease in density category with a decrease in risk compared to breast cancer
risk in women in whom breast density category remains unchanged. Two longitudinal measures of
BI-RADS breast density may better predict a woman’s risk of breast cancer than a single measure.

J Natl Cancer Inst 2007;99:386–95

Breast density is one of the strongest predictors of breast cancer

risk. Women who have dense tissue occupying greater than 50%
of the area of a mammographic breast image have high breast den-
sity and are at three- to five-fold greater risk of breast cancer than
women with less than 25% dense area (1–5). About 30% of post-
menopausal women have high breast density, a frequency that is
greater than the frequency of most recognized risk factors; for
example, a family history of breast cancer occurs in only 10% of
women (6). Both quantitative (1–3,7,8) and qualitative (4,5,7–11)
Affiliations of authors: Departments of Epidemiology and Biostatistics (KK,
RSB) and Radiology (RSB), and General Internal Medicine Section, Department
of Veterans Affairs (KK), University of California, San Francisco, CA; Group
Health Center for Health Studies, Seattle, WA (LI, DLM, DSMB); Department
of Biostatistics, University of Washington, Seattle, WA (DLM); Departments
of Medical Biostatistics and Pathology, University of Vermont, College of
Medicine, Burlington, VT (PMV); Department of Radiology, University of North
Carolina, Chapel Hill, NC (BY); Departments of Family Medicine and Public
Health and Preventive Medicine, Oregon Health and Science University,
Portland, OR (PAC); Applied Research Program, Division of Cancer Control
and Population Sciences, National Cancer Institute, Bethesda, MD (RBB).

measures of breast density have been used to demonstrate the
association of increased breast density with increased risk of breast
cancer. Quantitative measurements of breast density are taken
mainly in research settings, and due to practical challenges, they
are not routinely used in clinical care. Instead, the American
College of Radiology Breast Imaging Reporting and Data System
Correspondence to: Karla Kerlikowske, MD, General Internal Medicine
Section, San Francisco Veterans Affairs Medical Center, 111A1, 4150 Clement
St, San Francisco, CA 94121 (e-mail: karla.kerlikowske@ucsf.edu).
See “Notes” following “References.”
DOI: 10.1093/jnci/djk066
© The Author 2007. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: journals.permissions@oxfordjournals.org.

386 Articles | JNCI Vol. 99, Issue 5 | March 7, 2007

(BI-RADS) ordinal breast density categories are routinely col-
lected in clinical practice in the United States (12).
The extent of breast density can be modified by several factors.
Increasing age and menopause (13–15) are independent contribu-
tors to a decrease in breast density (16). Elevated body mass index
has been found to be associated with low breast density, whereas
increased age at first birth has been associated with high breast
density (17–20). Pregnancy at an early age decreases breast density,
and this beneficial effect appears to be permanent (18,21).
Postmenopausal hormone therapies that include both estrogen and
progesterone are associated with an increase in breast density that
decreases upon discontinuation of therapy (14,22,23). Intervention
trials have shown that decreases in breast density are associated
with tamoxifen treatment (24–26), a therapy proven to decrease
breast cancer risk (27,28).
These studies suggest that breast density may decrease over
time and that it may be modified by risk factors and interven-
tions, but they do not provide information on the association of
changes in breast density with breast cancer risk. A small study
used a computerized method to quantify breast density from digi-
tized films collected for a 10-year period from 108 postmeno-
pausal breast cancer patients and 400 control subjects (29). It
observed a trend of greater risk of breast cancer among women
who had low density initially that increased over time compared
to women with low breast density that remained low. It also
found that, among women with high density that decreased over
time, there was no evidence of decreased breast cancer risk rela-
tive to that in women whose high density persisted. A recent
longitudinal investigation of patients who were preponderantly
Hawaiian and Japanese did not find a difference in the rate of
change in percent density between women with and without
breast cancer (30).
The goal of this study was to determine whether a change in
breast density as reflected in a change in BI-RADS category was
associated with breast cancer risk in a population of 301 955
women who underwent screening mammography, of whom 2639
were diagnosed with breast cancer. The underlying hypothesis
was that decreases in breast density over time are associated with
a lower risk of breast cancer and that increases are associated with
a higher risk of breast cancer relative to women with unchanging
density.
Methods
Data Sources
Data were pooled from seven mammography registries that par-
ticipated in the Breast Cancer Surveillance Consortium (31)
(http://breastscreening.cancer.gov) supported by the National
Cancer Institute (NCI): San Francisco Mammography Registry,
Group Health’s Breast Cancer Surveillance, Colorado Mam-
mography Advocacy Project, Vermont Breast Cancer Surveillance
System, New Hampshire Mammography Network, Carolina
Mammography Registry, and New Mexico Mammography
Registry. These registries collect information on screening and
diagnostic mammography examinations performed in their defined
catchment areas. Each mammography registry annually links
women in their registry to a state tumor registry or regional
jnci.oxfordjournals.org
CONT E XT AND CAVE AT S
Prior knowledge
High mammographic breast density as measured by the radiolo-
gist in the clinic is strongly associated with an increased risk of
breast cancer. It was not known whether temporal increases or
decreases in a woman’s breast density affects her risk of develop-
ing breast cancer.
Study design
The risk of breast cancer was estimated from clinical breast density
data that was collected prospectively from registries linked to state
tumor registries or regional SEER program data on breast cancer
incidence.
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Contribution
This study showed that two breast density measurements sepa-
rated by an average of 3 years predicted the odds that a women
would develop breast cancer more accurately than one measure.
Implications
Both current and previous breast density measurements should be
used by clinicians when evaluating risk with patients.
Limitations
Further study will be required to determine the relative contribu-
tions of the increased accuracy provided by two measures on the
one hand and real changes in breast density on the other to the
apparent association of temporal changes in breast density and
breast cancer risk.
Surveillance, Epidemiology, and End Results (SEER) program to
obtain population-based cancer data. Some registries additionally
link to pathology databases. Each registry obtains annual approval
from their Institutional Review Board for consenting processes
or a waiver of consent, enrollment of participants, and ongoing
data linkages for research purposes. All registries have received
a Federal Certificate of Confidentiality that protects the identities
of research participants.
Subjects
We defined screening mammography as a bilateral examination
indicated by the radiologist as being performed for screening
among women without a history of breast cancer and without
breast implants. The accessible study sample (N = 518 739)
included women aged 30 years and older who underwent at least
two screening mammography examinations between January 1,
1993, and December 31, 2003, that were more than 9 months
apart. Both examinations had to include a BI-RADS breast
density measure (12) that was assigned in clinical practice by a
radiologist at the time of screening mammography. Screening
examinations that occurred after December 2003 were not included
to ensure that there would be at least 12 months for reporting
cancers to tumor registries after the most recent screening exami-
nation. Women who indicated they were using postmenopausal
hormone therapy at the time of any mammography examination
during the study period were excluded (N = 216 504). With the
exclusion of women of invalid age or incomplete cancer diagnosis
information (N = 280), the final study sample consisted of 301 955
women.
JNCI | Articles 387
Measurements and Definitions
Demographic information and a self-reported breast health history
were obtained at the time of each screening examination by having
women complete a questionnaire that requested information on
menopausal status, history of breast cancer in first-degree relatives
(mother, sister, or daughter), history of oophorectomy, age at first
live birth, and height and weight. Women were considered to have
a family history of breast cancer if they reported having at least one
first-degree relative with breast cancer. Women were considered
to be postmenopausal if both ovaries had been removed, if they
reported that their menstrual periods had stopped permanently, or
if they were aged 55 years or older.
If a woman had more than two screening mammography exam-
inations with BI-RADS density measures during the study period,
we used breast density measures from the earliest screening exami-
nation (first) and most recent examination (last) and demographic
and clinical characteristics obtained at the time of the last exam-
ination. If data on demographic and/or clinical characteristics
were missing on the last screening examination, we used the last
known value obtained before the last screening examination. Time
between mammography examinations was determined using dates
of the first and last screening examination.
The association of breast density with breast cancer risk was
assessed using four breast density measures that were based on the
BI-RADS breast density categories assigned at the first and/or last
screening examination for each woman. The BI-RADS categories
were 1 = almost entirely fat (also referred to as low density), 2 =
scattered fibroglandular densities (average density), 3 = heteroge-
neously dense (high density), 4 = extremely dense (very high den-
sity) (12). The first measure was the BI-RADS category assigned
to the first screening examination for each woman. The second
measure was the BI-RADS category assigned to the last screening
examination for each woman. The third measure was the average
of the BI-RADS categories from the first and last screening
examination. The fourth measure was a summary measure that
consisted of classifying women into 1 of 16 possible combinations
of BI-RADS categories assigned to the first and last screenings.
Women were considered to have breast cancer if reports from
a breast pathology database, SEER program, or state tumor regis-
try showed any invasive carcinoma or ductal carcinoma in situ
(DCIS) within one year of their last screening examination in the
study period. Women with lobular carcinoma in situ only were not
considered to have breast cancer.
Statistical Analysis
All analyses were performed using women as the unit of analysis.
Frequency distributions of various risk factors—age, ethnicity,
family history, age at first birth, menopausal status, body mass
index, and time between first and last screening examination—
were determined for women with and without breast cancer. We
also determined the frequency distributions of BI-RADS density
scores (from both the first and last screening examination), accord-
ing to decade of attained age and menopausal status for women
with and without breast cancer.
Multivariable logistic regression was used to assess the associa-
tion between breast density measures and breast cancer risk. All
models were adjusted for mammography registry, time between
388 Articles | JNCI
the two screening examinations (as a categorical variable [<2, 2 to
<3, 3 to <4, or ≥4 years]), and age (as a continuous variable with
both a linear and a quadratic term because breast cancer incidence
increases with age in a nonlinear fashion). All covariates included
in the models were statistically significant. We used BI-RADS
category 2 (scattered fibroglandular densities) as the referent
group when evaluating the association of first, last, and average
density measures with breast cancer risk since this group was the
most common. When evaluating the association of change in
BI-RADS category from first to last examination with cancer risk,
we stratified by BI-RADS category on the first examination and
used women whose density category did not change as the referent
group within each BI-RADS category. Because BI-RADS breast
density is a categorical measure, women with an observed change
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in clinically rated breast density may have had breast density values
between BI-RADS breast density categories. Therefore, we also
stratified women by the same average breast density of the first and
last screening examination, but different BI-RADS values at the
first and last examination to try to account for the effect of varia-
tion in assigning BI-RADS breast density categories by radiolo-
gists on observed associations between changes in breast density
and breast cancer risk. We used the Wald test to test for statisti-
cally significant linear trends within breast density groups. We
also tested for an interaction between age and change in breast
density and breast cancer risk and time between screening exami-
nations and change in breast density and breast cancer risk using a
linear regression model with age as a linear term and change in
breast density and time between screening examinations as cate-
gorical variables.
Adjusted breast cancer rates per 1000 women were calculated
from the logistic regression model using predicted margins, also
known as marginal standardization (32,33). Based on parameter
estimates from the logistic regression model, we estimated the
probability of breast cancer for each combination of age, mam-
mography registry, time between screens, and breast density. The
adjusted rates for each breast density category were then estimated
by calculating a weighted average of these probabilities based on
the proportion of women in the corresponding age group, mam-
mography registry, and time between screening examination strata
observed in the data. Confidence intervals (CIs) for the adjusted
rate of breast cancer were computed based on simulations. Each
simulation sampled values for each of the parameter estimates from
their estimated joint multivariable normal distribution. We ran
100 000 simulations, and the 2.5th and 97.5th percentiles from the
simulations were used to determine a 95% confidence interval.
We were not able to adjust for body mass index or age at first
birth due to missing values. In the final analysis, we also did not
adjust for race, family history of breast cancer, menopausal status
at last examination, or change in menopausal status over time
because including these variables in the models did not change the
overall results. We adjusted for misclassification of breast density
in each logistic regression model using an exact approach based on
the method of Reade-Christopher and Kupper (34). The misclas-
sification matrix used for adjustment was based on a study of the
rating of breast density of 324 women by 19 different radiologists.
Since the adjusted and unadjusted results were similar, we did not
adjust for misclassification in the final models.
Vol. 99, Issue 5 | March 7, 2007
 All statistical calculations were performed using SAS (version Table 1. Prevalence of risk factors and density measures among
9.1; SAS Institute, Cary, NC). Results of two-sided statistical tests women without breast cancer and with breast cancer within
12 months of the last screening mammography examination
in which P values were less than .05 were considered to be statisti-
cally significant. No breast cancer Breast cancer
Patient characteristic (N = 299 316) (N = 2639)
Age (y) % %
Results 30–39 2.3 0.8
40–49 36.3 23.6
Among 301 955 women aged 30 years and older who underwent at
50–59 24.1 22.4
least two screening mammography examinations, 2639 developed 60–69 15.0 18.9
breast cancer within 12 months of the last examination. Of these, ≥70 22.4 34.3
2089 were diagnosed with invasive breast cancer and 550 with DCIS. Race/Ethnicity*
In our sample, women with breast cancer, as compared to women White 80.6 84.2
Black 9.1 9.2
without breast cancer, were older and more likely to be white and Hispanic 5.2 2.5
have a family history of breast cancer and less likely to have given

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Asian/Native Hawaiian/ 3.4 2.5
birth before the age of 30 years (Table 1). For about half of all women, Pacific Islander
3 or more years had elapsed between the first and last screen. American Indian/Alaskan native 0.5 0.4
Other/mixed races 1.1 1.2
The frequency distribution of the four BI-RADS breast density
First-degree family history of 15.8 22.5
categories at the first and last screen was calculated for different breast cancer*,†
age categories and according to menopausal status (premenopausal Age at first live birth*
or postmenopausal) among women with and without breast cancer Nulliparous or ≥30 y 31.5 32.7
(Table 2). Among women without breast cancer, women aged 70 Postmenopausal* 55.4 68.5
Body mass index (m/kg2)*
years and older were four times more likely to be assigned to the
<18.5 1.6 1.5
lowest breast density category (category 1) and six times less likely 18.5 to <25 42.8 42.1
to be assigned to the highest breast density category (category 4) 25 to <30 30.1 29.4
than were women aged 30–39 years. Thus, breast density decreased 30 to <35 15.2 17.2
35 to <40 6.3 6.9
with age. Women who developed breast cancer were more likely
≥40 3.8 2.9
to have BI-RADS breast density categories of 3 or 4 on the first Time between first and last
and last screen than women without breast cancer of similar age screening examination (y)
and menopausal status (Table 2). <2 27.9 32.4
The frequency distribution of breast density measures (values at 2 to <3 22.6 24.0
3 to <4 17.4 18.3
the first screening, last screening, or the average of the values
4 to <5 14.0 11.4
obtained at first and last screenings) among women of all ages who ≥5 18.1 13.8
did or did not have breast cancer is shown in Table 3, along with
the adjusted rate of breast cancer calculated from the logistic * Some data were missing in the categories of race, family history, age at first
live birth, menopausal status, and body mass index. Percentages among
regression model based on these data. A total of 51.3% of women
women with and without breast cancer, respectively, were: race, 8.8%
with breast cancer had a BI-RADS breast density of 3 or 4 on the and 8.1%; family history, 5.5% and 7.6%; age at first live birth, 41.4% and
last screening examination compared with 46.4% of those without 39.3%; menopausal status, 2.8% and 2.2%; body mass index, 46.6% and
45.7%.
breast cancer. The odds ratios (ORs) for experiencing breast can-
† First-degree relative with breast cancer was defined as mother, sister, or
cer for women with a given value of breast density were calculated
daughter with breast cancer.
relative to women with a breast density of 2 on first or last screen
or after averaging first and last screens. Compared with women
assigned to a BI-RADS breast density category of 2 on the last average of 1—to 12.6, 95% CI = 10.6 to 15.2, for those with an
examination, women with a BI-RADS category of 1 on the last average of 4.
examination had a lower rate of breast cancer (3.5 versus 7.2 cases The frequency distribution of the 16 possible combinations of
per 1000 women, OR = 0.49. 95% CI = 0.40 to 0.59), while women first and last breast density values for women with and without
with a BI-RADS 4 had a higher rate of breast cancer (11.5 cases per breast cancer and the adjusted rate of breast cancer for women in
1000 women, OR = 1.61, 95% CI = 1.38 to 1.87). The association each of these categories were calculated (Table 4). Odds ratios of
between breast cancer risk and BI-RADS breast density category developing breast cancer were calculated for women who started in
on the first screen was similar to that between breast cancer risk a given breast density category compared with women who experi-
and BI-RADS density on the last screen. enced no change serving as the referent group (Table 4). A total of
When BI-RADS measurements from the first and last screen- 19.6% of all women had an increase in breast density category and
ing examination were averaged, 61.4% of women who developed 18.5% had a decrease, with a median time of 3.2 years between
breast cancer had an average breast density greater than 2.0 com- screens. Of women with an initial BI-RADS breast density cate-
pared with 55.9% among those who did not (Table 3). The rate of gory of 1, 2, or 3, 22% had an increase in breast density category
breast cancer increased in a linear fashion with increases in the upon the last screening, and of women with an initial BI-RADS
average of the BI-RADS categories on the first and last examina- breast density category of 2, 3, or 4, 22% had a decrease. The
tion, ranging from 3.0, 95% CI = 2.3 to 3.9, for women with an majority of women had a BI-RADS breast density category of 2 or

jnci.oxfordjournals.org JNCI | Articles 389

Table 2. Distribution of breast density on first and last screening mammography examination by age, menopausal status,
and cancer status

No breast cancer Breast cancer†

Patient characteristic BI-RADS density* First screen (%) Last screen (%) First screen (%) Last screen (%)
Age group‡ (y)
Age 30–39 (N = 24 346) (N = 95)
1 4.0 3.8 0.0 0.0
2 34.2 32.1 27.4 20.0
3 45.0 49.3 39.0 56.8
4 16.7 14.9 33.7 23.2
Age 40–49 (N = 122 035) (N = 772)
1 4.9 4.8 0.9 1.3
2 36.1 35.6 27.2 24.7
3 44.6 47.6 49.6 57.1
4 14.5 12.1 22.3 16.8

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Age 50–59 (N = 55 422) (N = 507)
1 10.5 10.4 4.3 3.6
2 49.1 49.8 45.8 47.3
3 34.5 35.3 44.0 43.4
4 6.0 4.5 5.9 5.7
Age 60–69 (N = 47 521) (N = 567)
1 16.8 14.4 11.5 7.6
2 57.2 56.4 58.2 56.8
3 23.5 26.8 27.2 33.5
4 2.5 2.4 3.2 2.1
Age ≥70 (N = 49 992) (N = 698)
1 17.7 14.4 12.3 6.9
2 57.1 56.6 56.5 56.3
3 22.9 26.3 28.4 34.2
4 2.4 2.7 2.9 2.6
Menopausal status§
Premenopausal/ (N = 111 318) (N = 694)
premenopausal
1 4.4 4.1 0.9 1.0
2 34.6 33.5 26.8 23.5
3 45.5 49.0 47.6 57.9
4 15.5 13.5 24.8 17.6
Premenopausal/ (N = 17 609) (N = 112)
postmenopausal
1 6.6 7.2 3.6 3.6
2 39.6 43.3 29.5 39.3
3 41.7 42.1 52.7 44.6
4 12.2 7.4 14.3 12.5
Postmenopausal/ (N = 133 754) (N = 1582)
postmenopausal
1 15.9 13.7 10.6 6.6
2 55.6 55.1 56.1 55.4
3 25.3 28.2 30.0 35.3
4 3.2 3.0 3.4 2.7

* BI-RADS (American College of Radiology Breast Imaging Reporting and Data System) 1 = almost entirely fat; 2 = scattered fibroglandular densities;
3 = heterogeneously dense; 4 = extremely dense.
† Breast cancer diagnosed after most recent or last screening mammography examination.
‡ Age at last screening mammography examination.
§ Menopausal status at first/last screening mammography examination.

3 on the first and last examination, and this was true of women
with and without breast cancer: 30.0% of women without breast
cancer and 29.4% of women with breast cancer had BI-RADS
scores of 2 on the first and last screens, and 22.9% of women with-
out breast cancer and 24.3% women with breast cancer had scores
of 3 on both screens (Table 4).
The rate (per 1000 women) of breast cancer was higher if
BI-RADS breast density category increased from 1 to 2 (5.6, 95%
CI = 4.7 to 6.9) or 1 to 3 (9.9, 95% CI = 6.4 to 15.5) compared to
when it remained at BI-RADS density of 1 (3.0, 95% CI = 2.3 to
3.9; P<.001 for trend, Table 4). Women were at higher risk of
breast cancer if their BI-RADS breast density category increased
from 2 to 3 (9.7 breast cancers per 1000 women, 95% CI = 8.7 to
10.9) and lower risk if their BI-RADS category decreased from
2 to 1 (4.0, 95% CI = 3.1 to 5.2) compared to women who
remained at BI-RADS 2 (6.9, 95% CI = 6.4 to 7.5; P = .004 for

390 Articles | JNCI Vol. 99, Issue 5 | March 7, 2007

Table 3. Measures of breast density associated with breast cancer risk

No breast cancer Breast cancer Adjusted rate of breast cancer Odds ratio
Breast density measure N = 299 316 (column %) N = 2639 (column %) per 1000 women (95% CI) (95% CI)
At first screen*
1 9.9 6.8 4.6 (4.0 to 5.4) 0.63 (0.54 to 0.74)
2 45.2 45.2 7.3 (6.8 to 7.8) 1.00 (referent)
3 35.8 37.7 9.5 (8.9 to 10.3) 1.32 (1.21 to 1.44)
4 9.2 10.3 12.6 (11.1 to 14.3) 1.75 (1.52 to 2.00)
At last screen*
1 8.9 4.5 3.5 (2.9 to 4.2) 0.49 (0.40 to 0.59)
2 44.8 44.1 7.2 (6.7 to 7.7) 1.00 (referent)
3 38.6 43.3 10.1 (9.4 to 10.8) 1.41 (1.29 to 1.53)
4 7.8 8.0 11.5 (10.0 to 13.3) 1.61 (1.38 to 1.87)
Average of first and last
screen†

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1 4.6 2.1 3.0 (2.3 to 3.9) 0.43 (0.32 to 0.56)
1.5 8.6 6.2 4.9 (4.2 to 5.8) 0.71 (0.60 to 0.84)
2 30.8 30.3 6.9 (6.4 to 7.5) 1.00 (referent)
2.5 20.5 23.5 9.4 (8.7 to 10.3) 1.37 (1.23 to 1.53)
3 23.9 25.2 9.8 (9.0 to 10.7) 1.43 (1.28 to 1.59)
3.5 7.1 8.0 12.3 (10.8 to 14.2) 1.80 (1.54 to 2.11)
4 4.4 4.7 12.6 (10.6 to 15.2) 1.85 (1.51 to 2.24)

* Rates and odds ratios were adjusted for age at last screening mammography examination (continuous, linear, and quadratic terms), and mammography registry;
BI-RADS (American College of Radiology Breast Imaging Reporting and Data System) 1 = almost entirely fat; 2 = scattered fibroglandular densities;
3 = heterogeneously dense; 4 = extremely dense; CI = confidence interval.
† Rates and odds ratios were adjusted for age at last screening mammography examination (continuous, linear, and quadratic terms), mammography registry, and
time between mammography examinations.

trend). The rate of breast cancer was higher if BI-RADS density
category increased from 3 to 4 (10.8 per 1000 women, 95% CI =
8.6 to 13.5) and lower if density category decreased from 3 to 1
(4.5, 95% CI = 1.9 to 10.8), compared with when it remained at
BI-RADS density 3 (9.8, 95% CI = 9.0 to 10.7; P = .049 for trend).
Women with BI-RADS breast density category of 4 on the first
examination were at similar risk of breast cancer regardless of the
density category on the last examination (P = 0.87 for trend).
Most women remained at BI-RADS breast density category of
2 and were designated as average-risk women with a rate of breast
cancer of 6.9 per 1000 women (Table 4). Rate of breast cancer was
low among women with a BI-RADS breast density category of 1,
2, or 3 on the first examination and a 1 on the last examination
(Table 4). Compared with average-risk women, women had a
higher rate of breast cancer if they changed from a BI-RADS
breast density category of 1 to 3, or 2 to 3, or 2 to 4, or remained
at category 3, or changed from 3 to 2 or 3 to 4 (Table 4). Women
with a BI-RADS breast density of 4 on the first examination had
the highest rate of breast cancer. In this category, even women
who were assigned to a lower breast density category on the last
examination remained at high risk (Table 4).
Risk of breast cancer associated with change in BI-RADS breast
density categories was different by age (test for interaction, P = .03)
and similar by time between screening examinations (test for inter-
action, P = .74). Increases or decreases in risk of breast cancer
associated with change in BI-RADS breast density categories were
more prominent for women aged 50 years and older than for
women younger than age 50 years (Table 5).
We stratified women by the same average breast density of the
first and last screening examination, but different BI-RADS values
at the first and last examination to try to account for variation in
assigning BI-RADS breast density categories by radiologists
(data not shown). Among women who had an average BI-RADS
breast density of 1.5, those whose BI-RADS density decreased
from a 2 to 1 were at lower risk of breast cancer than women whose
BI-RADS increased from 1 to 2 (P = .03). Among women whose
BI-RADS density decreased from a 3 to 1 there was a trend of
lower risk of breast cancer than women whose BI-RADS density
increased from a 1 to 3 (P = .069). There were no additional differ-
ences among women with the same average density.
Discussion
In this analysis of data from more than 300 000 women, we found
that an increase in BI-RADS breast density category over a rela-
tively short period of time was associated with an increase in breast
cancer risk within 12 months after the last screening examination
and that a decrease in breast density category was associated with
a decrease in risk compared with women in whom breast density
category remains unchanged. This trend was seen for women ini-
tially assigned to BI-RADS breast density categories 1, 2, and 3 but
not for women in category 4, the highest density category.
Consistent with other studies (8–11), we found that a single mea-
sure of breast density, measured by BI-RADS category, was associ-
ated with breast cancer risk. In our study, women with a BI-RADS
breast density category of 1 were at decreased risk of breast cancer
and women with BI-RADS category of 3 and 4 were at increased
risk of breast cancer when compared to women with BI-RADS
breast density of 2, the most common density group. The choice of
those with BI-RADS breast density 2 as the referent group led to
lower estimates of increased relative risk associated with high breast
density than have been reported in prior studies that used the lowest

jnci.oxfordjournals.org JNCI | Articles 391

Table 4. Rate of breast cancer per 1000 women and odds ratio of developing breast cancer based on first and last BI-RADS breast
density measure with first breast density measure as referent group by age

BI-RADS breast density Adjusted rate of

on first and last screen No breast cancer Breast cancer breast cancer per Level of breast
stratified by first density N = 299 316 N = 2639 1000 women† cancer risk by
measure* (column %) (column %) Odds ratio† (95% CI) (95% CI) density groups‡
First density = 1
1:1 4.6 2.1 1.0 (referent) 3.0 (2.3 to 3.9) Lower
1:2 4.7 4.0 1.9 (1.4 to 2.6) 5.6 (4.7 to 6.9) Average
1:3 0.5 0.7 3.4 (2.0 to 5.7) 9.9 (6.4 to 15.5) Higher
1:4 0.03 0 NE§ NE§
P for trend<.001
First density = 2
2:1 3.9 2.2 0.58 (0.44 to 0.76) 4.0 (3.1 to 5.2) Lower
2:2 30.0 29.4 1.0 (referent) 6.9 (6.4 to 7.5) Average

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2:3 11.0 13.2 1.4 (1.3 to 1.6) 9.7 (8.7 to 10.9) Higher
2:4 0.4 0.4 1.4 (0.75 to 2.6) 9.6 (5.2 to 17.8) Higher
P for trend = .004
First density = 3
3:1 0.3 0.2 0.45 (0.19 to 1.1) 4.5 (1.9 to 10.8) Lower
3:2 9.5 10.3 0.92 (0.80 to 1.1) 9.1 (8.0 to 10.3) Higher
3:3 22.9 24.3 1.0 (referent) 9.8 (9.0 to 10.7) Higher
3:4 3.0 2.9 1.1 (0.87 to 1.4) 10.8 (8.6 to 13.5) Higher
P for trend = .049
First density = 4
4:1 0.04 0.04 0.96 (0.13 to 7.0) 12.2 (1.7 to 80.9) Highest
4:2 0.6 0.5 0.72 (0.40 to 1.3) 9.1 (5.3 to 15.6) Higher
4:3 4.2 5.1 1.1 (0.83 to 1.4) 13.4 (11.3 to 16.0) Highest
4:4 4.4 4.7 1.0 (referent) 12.6 (10.6 to 15.2) Highest
P for trend = .87

* BI-RADS (American College of Radiology Breast Imaging Reporting and Data System) 1 = almost entirely fat; 2 = scattered fibroglandular densities;
3 = heterogeneously dense; 4 = extremely dense.
† Adjusted for age at last screening mammography examination (continuous, linear, and quadratic terms), mammography registry, and time between screening
mammography examinations.
‡ Lower risk = 4.9 cancers per 1000 women or less; average risk = more than 4.9 and up to 7.5 cancers per 1000 women; higher risk = more than 7.5 and up to 11.3
cancers per 1000 women; highest risk = more than 11.3 cancers per 1000 women. Groups correspond to 25th, 50th, and 75th percentiles of our study population.
§ NE = not estimable.

density group as the reference (1,3,9). We also found that both
recent and prior BI-RADS breast density measures were associated
with breast cancer risk, similar to what has been observed when
more quantitative measures of breast density were used (1).
A trend of greater risk of breast cancer among women who
started at low breast density and were found to have higher breast
density over time was reported by van Gils et al. (29). For women
who started at high density and whose measured breast density
decreased during the study period, these authors found no evi-
dence of decreased risk with decreased density, possibly because
of the small study sample size (108 postmenopausal breast cancer
patients and 400 control subjects) (29). We found that two
BI-RADS breast density measures may predict a women’s risk of
breast cancer more reliably than a single measure. Our results are
consistent with those of van Gils et al. in that we found a higher
rate of breast cancer among women who started at low breast den-
sity and in whom density increased over time relative to women
who remained at low density. Also, consistent with the van Gils
et al. study we found that presence of the highest breast density
category was associated with the highest rate of breast cancer even
if breast density decreased to a lower category over time. Contrary
to the results of van Gils et al., and possibly due to our much larger
sample size, we found that women with average or high density
(BI-RADS density category of 2 or 3) that decreased to a lower
BI-RADS density category had a lower rate of breast cancer than
women who stayed at average or high density.
A recent case–control study did not observe any association
between breast cancer and rate of change in percent density (30).
Compared to the results of Maskarinec et al. (30), our study had a
relatively large proportion of premenopausal women who have
been reported to have a higher rate of decline of breast density
over time, this and the large sample size may account for the
observed changes in density and associated breast cancer risk that
we report here (30). It is not known why some women may have
an increase in breast density over time with increasing age.
Decreasing weight, increased alcohol intake, or changes in diet or
medication may contribute to increasing breast density (35), and
their possible effects on changes in breast density over time war-
rant further study.
Mammographic density is highly influenced by genetic factors.
In a study of monozygotic and dizygotic twins from Australia,
Canada, and the United States, Boyd et al. (36) determined that
the majority (60%–75%) of the variation in the fraction of dense
tissue measured on mammograms in women between the ages of
40 and 70 years is controlled by genetic factors and that environ-
mental factors account for 20%–30% of the age-adjusted variation

392 Articles | JNCI Vol. 99, Issue 5 | March 7, 2007

Table 5. Rate of breast cancer per 1000 women based on first and last BI-RADS breast density measure with first breast density
measure as referent group by age

Age < 50 y Age ≥ 50 y

BI-RADS breast
density on first and Adjusted rate Adjusted rate of
last screen stratified No breast cancer Breast cancer of breast cancer No breast cancer Breast cancer breast cancer per
by first density N = 115 367 N = 644 per 1000 women† N = 183 949 N = 1995 1000 women†
measure* (column %) (column %) (95% CI) (column %) (column %) (95% CI)
First density = 1
1:1 1.9 0.2 0.4 (0.2 to 7.7) 6.3 2.7 4.0 (3.1 to 5.2)
1:2 2.2 0.3 0.7 (0.6 to 2.7) 6.3 5.2 7.8 (6.5 to 9.5)
1:3 0.3 0.0 NE‡ 0.6 1.0 14.4 (9.0 to 23.2)
1:4 0.0 0.0 NE‡ 0.0 0.0 NE‡
P for trend = .98 P for trend<.001
First density = 2
2:1 1.9 0.6 1.7 (1.0 to 3.0) 5.1 2.7 5.2 (4.0 to 6.7)

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2:2 20.9 12.6 2.9 (2.6 to 3.6) 35.7 34.8 9.1 (8.5 to 10.0)
2:3 11.3 13.5 5.8 (5.5 to 8.3) 10.7 13.1 12.0 (10.6 to 13.8)
2:4 0.6 0.3 3.0 (1.1 to 6.2) 0.3 0.4 15.0 (8.1 to 28.9)
P for trend = .37 P for trend = .003
First density = 3
3:1 0.3 0.2 3.0 (1.2 to 7.6) 0.4 0.2 5.5 (2.0 to 14.4)
3:2 9.7 8.2 4.3 (3.3 to 5.0) 9.4 10.9 12.0 (0.6 to 14.0)
3:3 30.4 35.1 5.6 (5.3 to 6.6) 18.2 20.9 12.1 (10.9 to 13.4)
3:4 4.9 5.8 6.1 (4.5 to 7.2) 1.7 2.0 13.2 (10.9 to 13.4)
P for trend = .43 P for trend = .09
First density = 4
4:1 0.1 0.2 13.6 (2.0 to 25.8) 0.0 0.0 NE‡
4:2 0.8 0.6 4.0 (2.0 to 5.8) 0.4 0.5 12.7 (6.1 to 23.8)
4:3 6.6 9.8 7.6 (6.2 to 9.1) 2.7 3.6 16.4 (2.9 to 20.9)
4:4 8.0 12.7 8.3 (6.6 to 10.8) 2.1 2.1 12.0 (9.0 to 16.3)
P for trend = .78 P for trend = .96

* BI-RADS (American College of Radiology Breast Imaging Reporting and Data System) 1 = almost entirely fat; 2 = scattered fibroglandular densities;
3 = heterogeneously dense; 4 = extremely dense.
† Adjusted for age at last screening mammography examination (continuous, linear, and quadratic terms), mammography registry, and time between screening
mammography examinations.
‡ Not estimable.

in the percentage of dense tissue (2). Environmental factors that
influence breast density include menopausal status, weight, parity,
and exogenous and endogenous levels of hormones (18,21,23).
Women who become menopausal have an absolute decrease in
mean breast density of 5% within 1.5 years and 8% within 5 years
(16). Hormone therapy that includes estrogen plus progesterone
has been shown to increase BI-RADS breast density in approxi-
mately 16%–28% of menopausal women within the first year of
starting hormone therapy (14,22). Women at high risk for breast
cancer taking standard tamoxifen therapy for prevention have been
shown to have an absolute mean decrease in breast density of 5%
at 18 months and 7% at 52 months (26). We used a categorical
variable to assess breast density and found that a modest propor-
tion of women had an increase (19.6%) or decrease (18.5%) in
BI-RADS category within an average of 3 years. Thus, absolute
changes in breast density over time due to environmental factors
appear moderate, influence a modest proportion of women, and
can occur in a relatively short period of time. The proportion of
women who were observed in our study to change in BI-RADS
category was somewhat higher than in a study of women aged 67
years and older (22) that reported that 11.6% of women had an
increase and 6.5% a decrease, in BI-RADS category within an
average of 2 years. Our longer average time between screening
examinations and younger study population may account for the
differences between studies.
Our results are consistent with the hypothesis that women with
sustained levels of high breast density are at highest risk of breast
cancer and those with low levels of breast density over time are at
lowest risk. This is not surprising in that the extent of breast den-
sity reflects morphological differences that are related to breast
cancer risk. For example, high mammographic density is associ-
ated with greater total nuclear area of both epithelial and nonepi-
thelial cells (37). Furthermore, a greater percentage of epithelium
in benign tissue biopsies has been associated with an increased risk
of hyperplasia (with or without atypia) and/or carcinoma in situ,
and these histology findings are associated with increased risk of
breast cancer (38–41). Cumulative exposure to growth factors,
including higher plasma concentrations of insulin-like growth
factor 1 in premenopausal women and higher prolactin levels in
postmenopausal women (42,43), may influence proliferation of
epithelial and stromal cells in the breast. Thus, the long-standing
presence of extensive or high breast densities may reflect exposure
to hormones and growth factors that stimulate cell division in the
breast and may influence breast cancer risk. This suggests that
cumulative exposure to high breast densities could have a corre-
sponding effect of increasing the incidence of breast cancer (30).

jnci.oxfordjournals.org JNCI | Articles 393

 Women with a change in BI-RADS category from 1 to 2 or
from 2 to 1 may have a breast density value between these two
measures. If the majority of women with a change in BI-RADS
category from 1 to 2 or from 2 to 1 had a similar average breast
density value of about 1.5, these two groups of women should have
similar breast cancer risk. In contrast, if the underlying breast
density in the majority of these women represents an actual change
in breast density, we would expect women who change from 1 to 2
to have a higher breast cancer risk than women who go from 2 to
1, as we observed in these groups of women. We also demon-
strated a trend of different breast cancer risk, albeit one that was
not statistically significant, among women with an average BI-
RADS breast density of 2.0 who changed from 1 to 3 or 3 to 1. The
fact that the direction of breast density change is predictive of risk
in categories of women for whom the average of the first and last
measurements is the same suggests that the observed changes in
BI-RADS breast density categories reflect actual changes whose
direction influences breast cancer risk.
Our study has both strengths and limitations. A major strength
of our study is the large number of women with two breast density
measures and the large number of breast cancers. A limitation of
our study is that the interrater agreement of the BI-RADS breast
density measure is moderate (44,45). Therefore, misclassification
of BI-RADS categories may have influenced our results, such that
some of the differences we observed could result in an under- or
overestimation of associations (46). In addition, some groups that
changed BI-RADS breast density category were very small and the
numbers of cancers in these groups were few, limiting our ability
to identify important associations. It is also not possible to deter-
mine from our data whether the observed risk of breast cancer is
due to changes in breast density, the combined effect of two den-
sity measurements, or both.
In this study, values for some variables associated with breast
density and breast cancer risk were missing. Body mass index, age
at first live birth, and race were the variables that were most often
lacking because some participating facilities did not consistently
collect this information. Adjusting for body mass index, age at first
live birth, family history of breast cancer, menopausal status,
change in menopausal status over time, and race did not substan-
tially alter the breast cancer risk estimates in this study for the
subset of women with covariate data available, consistent with
other studies (9,47). It is possible, however, that adjustment for
body mass index in the full cohort would have strengthened the
association of breast density and breast cancer risk, given its nega-
tive association with breast density and positive association with
breast cancer risk in postmenopausal women (48). In this study, we
excluded women receiving postmenopausal hormone therapy
because of a limited number of breast cancers among women who
were on hormone therapy for 5 or more years and had BI-RADS
density measures. Future analyses might examine the association of
change in density and breast cancer risk among women taking
postmenopausal hormone therapy.
BI-RADS density measures are routinely included in mammog-
raphy reports to practitioners, but they are not currently used to
estimate the risk of breast cancer at the time of screening mam-
mography. Risk models have shown that BI-RADS breast density is
a statistically significant addition to prediction of breast cancer in
394 Articles | JNCI
premenopausal and postmenopausal women (8,49). A model based
on breast density alone and adjusted for age and ethnicity is as accu-
rate as the Gail model in predicting breast cancer (8). Postmenopausal
women are rarely assessed for risk of developing breast cancer and
rarely receive preventive therapy, even if they are at high risk for
breast cancer (50,51). The assessment, concurrently with screening
mammography, of breast cancer risk based on breast density and
standard risk factors creates an opportunity to discuss with the
patient the risk of breast cancer in the next 5 years and, for those at
high risk, prevention strategies. Our study suggests that physicians
should take into account both current and previous breast density
measurements when evaluating risk with their patients.
In summary, we found that with average follow-up of three
years, a modest proportion of women change BI-RADS breast
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density category. An increase in BI-RADS breast density category
may be associated with increased breast cancer risk, and a decrease
may be associated with decreased breast cancer risk relative to the
level of risk when the breast density does not change. Thus, two
longitudinal measures of BI-RADS breast density may better
predict a woman's risk of breast cancer than a single measure.
References
(1) Byrne C, Schairer C, Wolfe J, Parekh N, Salane M, Brinton LA, et al.
Mammographic features and breast cancer risk: effects with time, age, and
menopause status. J Natl Cancer Inst 1995;87:1622–9.
(2) Boyd NF, Lockwood GA, Byng JW, Tritchler DL, Yaffe MJ. Mammo-
graphic densities and breast cancer risk. Cancer Epidemiol Biomarkers
Prev 1998;7:1133–44.
(3) Boyd NF, Byng JW, Jong RA, Fishell EK, Little LE, Miller AB, et al.
Quantitative classification of mammographic densities and breast cancer
risk: results from the Canadian National Breast Screening Study. J Natl
Cancer Inst 1995;87:670–5.
(4) Saftlas AF, Wolfe JN, Hoover RN, Brinton LA, Schairer C, Salane M,
et al. Mammographic parenchymal patterns as indicators of breast cancer
risk. Am J Epidemiol 1989;129:518–26.
(5) Wolfe JN, Saftlas AF, Salane M. Mammographic parenchymal patterns
and quantitative evaluation of mammographic densities: a case-control
study. AJR Am J Roentgenol 1987;148:1087–92.
(6) Colditz GA, Willett WC, Hunter DJ, Stampfer MJ, Manson JE,
Hennekens CH, et al. Family history, age, and risk of breast cancer. JAMA
1993;270:338–43.
(7) Prevrhal S, Shepherd JA, Smith-Bindman R, Cummings SR, Kerlikowske K.
Accuracy of mammographic breast density analysis: formal training of
operators with varying background. Cancer Epidemiol Biomarkers Prev
2002;11:1389–93.
(8) 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.
(9) Vacek PM, Geller B. A prospective study of breast cancer risk using rou-
tine mammographic breast density measurements. Cancer Epidemiol
Biomarkers Prev 2004;13:715–22.
(10) Ziv E, Tice J, Smith-Bindman R, Shepherd J, Cummings S, Kerlikowske K.
Mammographic density and estrogen receptor status of breast cancer.
Cancer Epidemiol Biomarkers Prev 2004;13:2090–5.
(11) Ziv E, Shepherd J, Smith-Bindman R, Kerlikowske K. Mammographic
breast density and family history of breast cancer. J Natl Cancer Inst
2003;95:556–8.
(12) American College of Radiology. The American College of Radiology
Breast Imaging Reporting and Data System (BI-RADS®). 3rd ed. Reston
(VA): American College of Radiology; 2003.
(13) Kerlikowske K, Grady D, Barclay J, Sickles EA, Ernster V. Effect of age,
breast density, and family history on the sensitivity of first screening mam-
mography? JAMA 1996;276:33–8.
Vol. 99, Issue 5 | March 7, 2007
(14) Greendale GA, Reboussin BA, Sie A, Singh HR, Olson LK, Gatewood O,
et al. Effects of estrogen and estrogen-progestin on mammographic
parenchymal density. Ann Intern Med 1999;130:262–9.
(15) Kerlikowske K, Miglioretti DL, Barbash R, Weaver D, Buist DSM,
Barlow W, et al. Prognostic characteristics of breast cancer among post-
menopausal hormone users in a screened population. J Clin Oncol
2003;21:4314–21.
(16) Boyd NF, Martin L, Stone J, Little L, Minkin S, Yaffe M. A longitudinal
study of the effects of menopause on mammographic features. Cancer
Epidemiol Biomarkers Prev 2002;11:1048–53.
(17) White E, Velentgas P, Mandelson MT, Lehman CD, Elmore JG,
Porter P, et al. Variation in mammographic breast density by time in
menstrual cycle among women aged 40 to 49 years. J Natl Cancer Inst
1998;90:906–10.
(18) Vachon CM, Kuni CC, Anderson K, Anderson E, Sellers TA. Association
of mammographically defined percent breast density with epidemiologic
risk factors for breast cancer (United States). Cancer Causes Control
2000;11:653–62.
(19) Salminen TM, Hakama M, Heikkila MM, Saarenmaa IE. Favorable
change in mammographic parenchmal patterns and breast cancer risk fac-
tors. Int J Cancer 1998;78:410–4.
(20) Warwick J, Pinney E, Warren RML, Duffy SW, Howell A, Wilson M,
et al. Breast density and breast cancer risk factors in a high-risk population.
Breast 2003;12:10–6.
(21) El-Bastawissi AY, White E, Mandelson MT, Taplin SH. Reproductive
and hormonal factors associated with mammographic density by age
(United States). Cancer Causes Control 2000;11:955–63.
(22) Rutter CM , Mandelson MT , Laya MB , Seger DJ , Taplin S .
Changes in breast density associated with initiation, discontinuation,
and continuing use of hormone replacement therapy. JAMA 2001;285:
171–6.
(23) Greendale GA, Reboussin BA, Slone S, Wasilauskas C, Pike C, Ursin G.
Postmenopausal hormone therapy and change in mammographic density.
J Natl Cancer Inst 2003;95:30–7.
(24) Atkinson C, Warren R, Bingham SA, Day NE. Mammographic patterns
as a predictive biomarker of breast cancer risk: effect of tamoxifen. Cancer
Epidemiol Biomarkers Prev 1999;8:863–6.
(25) Chow CK, Venzon D, Jones EC, Premkumar A, O’Shaughnessy J,
Zujewski J. Effect of tamoxifen on mamographic density. Cancer Epidemiol
Biomarkers Prev 2000;9:917–21.
(26) Cuzick J, Warwick J, Pinney E, Warren RML, Duffy SW. Effect of
Tamoxifen on breast density in women at increased risk of breast cancer.
J Natl Cancer Inst 2004;96:621–8.
(27) Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M,
Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of
the national surgical adjuvant breast and bowel project P-1 study. J Natl
Cancer Inst 1998;90:1371–88.
(28) Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S, et al.
Overview of the main outcomes in breast cancer prevention trials. Lancet
2003;361:296–300.
(29) van Gils CH, Hendriks JHCL, Holland R, Karssemeijer N, Otten JDM,
Straatman H, et al. Changes in mammographic breast density and
concomitant changes in breast cancer risk. Eur J Cancer Prev 1999;8:
509–15.
(30) Maskarinec G, Pagano I, Lurie G, Kolonel LN. A longitudinal investiga-
tion of mammographic density: the multiethnic cohort. Cancer Epidemiol
Biomarkers Prev 2006;15:732–9.
(31) Ballard-Barbash R, Taplin SH, Yankaskas BC, Ernster VL, Rosenberg RD,
Carney PA, et al. Breast Cancer Surveillance Consortium: a national
mammography screening and outcomes database. AJR Am J Roentgenol
1997;169:1001–8.
(32) Lane P, Nelder J. Analysis of covariance and standardization as instances
of prediction. Biometrics 1982;38:613–21.
(33) Graubard B, Korn E. Predictive margins with survey data. Biometrics
1999;55:652–9.
(34) Reade-Christopher SJ, Kupper LL. Effects of exposure misclassification
on regression analyses of epidemiologic follow-up study data. Biometrics
1991;47:535–48.
jnci.oxfordjournals.org
(35) Boyd NF, Rommens JM, Vogt K, Lee V, Hopper JL, Yaffe MJ, et al.
Mammographic breast density as an intermediate phenotype for breast
cancer. Lancet Oncol 2005;6:798–808.
(36) Boyd NF, Dite GS, Stone J, Gunasekara A, English DR, McCredie MR,
et al. Heritability of mammographic density, a risk factor for breast cancer.
N Engl J Med 2002;347:886–94.
(37) Li T, Sun L, Miller N, Nicklee T, Woo J, Hulse-Smith L, et al. The
association of measured breast tissue characteristics with mammographic
density and other risk factors for breast cancer. Cancer Epidemiol
Biomarkers Prev 2005;14:343–9.
(38) Warner E, Lockwood GA, Tritchler DL, Boyd NF. The risk of breast
cancer associated with mammographic parenchymal patterns: a meta-
analysis of the published literature to examine the effect of method of
classification. Cancer Detect Prev 1992;16:67–72.
(39) Gertig DM, Stillman IE, Byrne C, Spiegelman D, Schnitt SJ,
Connolly JL, et al. Association of age and reproductive factors with
Downloaded from https://academic.oup.com/jnci/article/99/5/386/2522354 by guest on 04 December 2023
benign breast tissue composition. Cancer Epidemiol Biomarkers Prev
1999;8:873–9.
(40) Boyd NF, Jensen HM, Cooke G, Lee Han H, Lockwood GA, Miller AB.
Mammographic densities and the prevalence and incidence of histological
types of benign breast disease. Eur J Cancer Prev 2000;9:15–24.
(41) Hartmann L, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K,
et al. Benign breast disease and the risk of breast cancer. N Engl J Med
2005;353:229–37.
(42) Byrne C, Colditz GA, Willett WC, Speizer FE, Pollak M, Hankinson SE.
Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and
mammographic density. Cancer Res 2000;60:3744–8.
(43) Byrne C, Hankinson SE, Colditz GA, Willett W, Speizer FE. Plasma
prolactin and mammographic breast density in postmenopausal women.
Proc Am Assoc Cancer Res 2001;42:153.
(44) Kerlikowske K, Grady D, Barclay J, Frankel S, Ominsky S, Sickles EA,
et al. Variability and accuracy in mammographic interpretation using the
American College of Radiology Breast Imaging Reporting and Data
System (BI-RADS). J Natl Cancer Inst 1998;90:1801–9.
(45) Ciatto S, Houssami N, Apruzzese A, Bassetti E, Brancato B, Carozzi F,
et al. Categorizing breast mammographic density: intra- and interobserver
reproducibility of BI-RADS density categories. Breast 2005;14:269–75.
(46) Gustafson P. Measurement error and misclassification in statistics and
epidemiology: impacts and Bayesian adjustments. CRC Press; Boca Raton
(FL): 2004.
(47) McCormack VA, dos Santos Silva I. Breast density and parenchymal pat-
terns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol
Biomarkers Prev 2006;15:1159–69.
(48) Boyd NF, Martin LJ, Sun L, Gun H, Chiarelli A, Hislop G, et al. Body
size, mammographic density, and breast cancer risk. Cancer Epidemiol
Biomarkers Prev 2006;15:2086–92.
(49) Barlow W, White E, Ballard-Barbash R, Vacek PM, Titus-Ernstoff LT,
Carney PA, et al. A prospective breast cancer risk prediction model among
women undergoing screening mammography. J Natl Cancer Inst 2006;
98:1204–14.
(50) Kaplan C, Haas JS, Perez-Stable EJ, Somkin C, Gregorich S, Des Jarlais G,
et al. Breast cancer risk reduction options: awareness, discussion, and use
among women from four ethnic groups. Cancer Epidemiol Biomarkers
Prev 2006;15:162–6.
(51) Armstrong K, Quistberg A, Micco E, Domchek S, Guerra C. Prescription
of tamoxifen for breast cancer prevention by primary care physicians. Arch
Intern Med 2006;166:2260–5.
Notes
This work was supported by the NCI-supported Breast Cancer Surveillance
Consortium cooperative agreement (U01CA63740, U01CA86076,
U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731,
U01CA70040) and Dr K. Kerlikowske is also supported by PO1 CA107584.
The study sponsor had no role in the design of the study; the collection,
analysis, and interpretation of the data; the writing of the manuscript, or the
decision to publish.
Manuscript received June 16, 2006; revised December 19, 2006; accepted
January 6, 2007.
JNCI | Articles 395