Reproductive History and Risk of Second Primary
Breast Cancer: The WECARE Study
Joan A. Largent,1Marinela Capanu,2Leslie Bernstein,3Bryan Langholz,3Lene Mellemkjær,4
Kathleen E. Malone,5Colin B. Begg,2Robert W. Haile,3Charles F. Lynch,6
Hoda Anton-Culver,1Abigail Wolitzer,2and Jonine L. Bernstein2
1Epidemiology Division, Department of Medicine, University of California, Irvine, California;
Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York;
University of Southern California, Los Angeles, California;
Society, Copenhagen, Denmark;
Center, Seattle, Washington; and
2Department of Epidemiology and
3Department of Preventive Medicine,
4Institute of Cancer Epidemiology, Danish Cancer
5Division of Public Health Sciences, Fred Hutchinson Cancer Research
6Department of Epidemiology, University of Iowa, Iowa City, Iowa
Background: Women with an initial breast cancer diagnosis
are at elevated risk of developing subsequent cancer in the
contralateral breast. Studies of reproductive factors and
contralateral breast cancer (CBC) have provided inconsistent
Methods: We employed a case-control study nested within
five population-based cancer registries in the United States
and Denmark to examine associations between reproductive
history and CBC risk. Cases were women with asynchronous
CBC who had their first primary invasive breast cancer
before age 55 years. Two controls, who had only one primary
breast cancer diagnosis, were individually matched to each
case on age and year of diagnosis, race, and registry. A total
of 694 case-control triplets and 11 case-control pairs were
enrolled. Information regarding possible CBC risk factors
was obtained via telephone interviews. Multivariable con-
ditional logistic regression was used to estimate rate ratios
(RR) and 95% confidence intervals (95% CI) associated with
risk factors of interest.
Results: Increasing number of full-term pregnancies (FTP)
was inversely associated with CBC risk (P trend, 0.001).
Women who reported menarche before age 13 years had an
increased risk of CBC (RR, 1.26; 95% CI, 1.01-1.58). Age at
first FTP, breastfeeding history, and age at menopause were
not significantly associated with CBC risk.
Conclusions: These results suggest age at menarche and
parity, which are established risk factors for first primary
breast cancer, are associated with CBC, whereas other
reproductive risk factors associated with first primary breast
cancer, such as age at first FTP, are less important factors in
the development of CBC.
(Cancer Epidemiol Biomarkers
Women diagnosed with breast cancer have greater risk for a
second primary breast cancer than the general population of
women has for a first primary breast cancer (1). This risk
differential seems to be higher for women who are under age
45 at the time of their initial breast cancer diagnosis than it is
for older women (1-5). Several factors have been investigated
in relation to risk of contralateral breast cancer (CBC),
including genetic predisposition and family history (2, 3,
5-8), reproductive history (2-4, 7-9), histology of the first breast
cancer (3, 10, 11), treatment (3, 7, 9, 11), anthropometry (3, 4),
and race (11).
The impact of pregnancy on risk of a first primary breast
cancer has been extensively studied (12). Although having a
full-term pregnancy (FTP) is associated with reduced breast
cancer risk among postmenopausal women overall, women
who have their first term pregnancy in their 30s or 40s are at
somewhat higher breast cancer risk than nulliparous women.
The immediate effect of a term pregnancy seems to increase
a woman’s risk, with the duration of this elevated risk
decreasing with each subsequent pregnancy (13). Studies of
pregnancy history and risk of CBC have provided inconsistent
results with some reporting that late age at first FTP (2) and
low parity or nulliparity (2, 7, 9, 14) are associated with
increased risk of CBC, whereas others report no significant
associations between reproductive factors and CBC risk (4, 8, 15).
The number of breast cancer survivors is increasing due to
rising rates of both breast cancer incidence (16) and survival
(17). Identifying factors that are associated with an increased
risk of asynchronous CBC is therefore more important for
developing strategies of early detection of this outcome. To
resolve some of the inconsistencies of prior studies regarding
the relationship of pregnancy history to risk of CBC, we
employed a case-control study nested among a large sample of
breast cancer patients in five population-based cancer regis-
tries to examine further this relationship and to determine
whether the observed associations are modified by other risk
Materials and Methods
The WECARE Study is a multicenter, population-based nested
case-control study that involves a comparison of women with
asynchronous bilateral breast cancer, who serve as case
subjects, with women with unilateral breast cancer, who serve
as control subjects (18). All participants were identified
through a cohort of five population-based tumor registries,
four in the United States: Los Angeles County Cancer
Surveillance Program; Cancer Surveillance System of the Fred
Hutchinson Cancer Research Center (Seattle region); State
Health Registry of Iowa; and Cancer Surveillance Program of
Orange County/San Diego-Imperial Organization for Cancer
Control (Orange County/San Diego), all of which participate
in (or are members of) the National Cancer Institute
Surveillance, Epidemiology and End Results program. The
Cancer Epidemiol Biomarkers Prev 2007;16(5). May 2007
Received 12/4/06; revised 2/6/07; accepted 2/20/07.
Grant support: U01CA83178 and R01CA97397 from the NIH.
The costs of publication of this article were defrayed in part by the payment of page charges.
This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
Request for reprints: Joan Largent, Epidemiology Division, Department of Medicine,
University of California, Irvine, 224 Irvine Hall, Irvine, CA 92697-7555. Phone: 949-824-1351;
Fax: 949-824-1343. E-mail: firstname.lastname@example.org
Copyright D 2007 American Association for Cancer Research.
one participating Scandinavian registry was the Danish Breast
Cancer Cooperative Group Registry supplemented by data
from the Danish Cancer Registry.
Eligibility. Women were eligible as cases if they met the
following criteria: (a) diagnosed between January 1, 1985, and
December 31, 1999, with a first primary invasive breast cancer
that did not spread beyond the regional lymph nodes at
diagnosis and a second primary in situ or invasive breast
cancer diagnosed in the contralateral breast at least 1 year after
the first breast cancer diagnosis and before January 1, 2002; (b)
resided in the same study reporting area for both diagnoses; (c)
had no previous or intervening cancer diagnosis except
squamous cell or basal cell skin cancer or cervical carcinoma
in situ; (d) were alive at the time of contact, and able to provide
informed consent to complete the interview; and (e) were
under age 55 years at the time of diagnosis of the first primary
Two control subjects were individually matched to each case
on year of birth (5-year strata), year of diagnosis (4-year strata),
registry region, and race, and were counter-matched on
registry-reported radiation exposure (18). Counter-matching
was done so that two of the members of each case-control
triplet were reported to have radiation exposure by registry
records. This counter-matching was carried out to address the
hypotheses of the main study, designed to assess whether
genetic factors involved in DNA repair, in combination with
radiation exposure, were associated with an increased risk of
second primary breast cancer. In selecting controls, we created
an at-risk interval which was the elapsed time (in days)
between the matched case’s two diagnoses. This interval was
added to the date of breast cancer diagnosis for the control to
define her reference date for the purposes of eligibility (she
had to have lived in the same cancer-reporting region on that
date) and interview. In addition, controls had to meet the
following criteria: (a) diagnosed since January 1, 1985, with
first primary invasive breast cancer that did not spread beyond
the regional lymph nodes at diagnosis, while residing in one of
the study reporting areas; (b) no diagnosis of any other cancer
before her breast cancer diagnosis or in the defined at-risk
interval (other than squamous or basal cell skin carcinoma or
in situ cervical cancer); (c) alive at the time of contact and able
to provide informed consent to complete the interview; and (d)
no prophylactic mastectomy of the contralateral breast before
or within the at-risk interval.
Across the five tumor registries, a total of 998 women with
bilateral breast cancer were eligible and approached for
inclusion in the study as cases, and 2,112 women with
unilateral breast cancer were eligible as controls. Of these
potential participants, 708 (71%) cases and 1,399 (66%) controls
completed the interview and had a blood sample drawn. In all,
we successfully recruited 694 counter-matched triplets (1 case:
2 controls), where two members of each triplet were exposed to
radiation according to the registry records. For 17 triplets, the
region or the race/ethnicity criteria was relaxed. We also
recruited 11 case-control pairs, of which 8 sets were discordant
on radiation exposure and 3 were concordant on exposure. We
were unable to recruit any controls for three cases. Of the 998
cases and 2,112 controls eligible and approached for the study,
reasons for nonparticipation, in sequence, were physician
refusal (0.5% cases, 1% controls), subject interview refusal (27%
cases, 31% controls), and subject blood draw refusal (3% cases,
Data Collection. All participants in the WECARE Study were
interviewed by telephone using a structured questionnaire.
The interview was conducted by a trained interviewer. The
questionnaire emphasized events occurring before the diag-
nosis of the first primary as well as those that occurred within
the at-risk period (before the reference date for the case or the
control subject). The focus of the questionnaire was on known
or suspected risk factors for breast cancer, including personal
demographics, medical history, family history, reproductive
history, use of hormones, body size, and alcohol intake. The
section on reproductive history included age at menarche,
number of pregnancies, pregnancy outcome, duration and end
date for each pregnancy, lactation history, menopausal status,
and age at menopause. Medical records, pathology reports,
and hospital charts were used to collect detailed treatment
information (chemotherapy, hormonal therapy, and radiation
therapy). Because the medical record data contained missing
values regarding chemotherapy (7%) and/or hormonal ther-
apy (10%), the treatment history variable was defined using
self-reported data for these subjects. Information on tumor
characteristics (including location in the breast, stage at
diagnosis, estrogen and progesterone receptor status, and
histology) was collected from medical records or cancer
registry records. The study protocol was approved by the
Institutional Review Boards at each study site and by the
ethical committee system in Denmark.
Statistical Methods. Two members of each triplet were
radiation exposed, and one was radiation unexposed, based
on treatment history information recorded in each of the
cancer registries (counter-matching design). Standard techni-
ques for analyzing counter-matched case-control studies (19)
were employed to investigate the individual and joint effects of
known risk factors on the development of CBC. Log-linear
(Cox) models for CBC rates were fit to the individually
matched triplet data using conditional logistic regression with
the inclusion of a log weight covariate in the model where
the coefficient of this log weight was fixed at 1 (i.e., an offset
in the model). These computed weights were incorporated in
the models to account for the sampling probability of counter-
matching. They are based on the number of radiation-exposed
and unexposed subjects within the sampled risk set. Aside
from this offset term, the analytic approach is identical to a
standard conditional logistic regression analysis for individu-
ally matched case-control studies.
In the current study, we focused on the following
reproductive variables: age at menarche (<13, z13 years);
pregnancy history (never pregnant, no FTP, and at least one
FTP); number of FTP (nulliparous, 1, 2, 3, 4+); age at first FTP
(<20, 20-24, 25-29, 30+ years or nulliparous); age at menopause
(premenopausal, postmenopausal age <45 years, postmeno-
pausal age z45 years), breast-fed (never/ever), and duration of
breastfeeding (1-3, 4-6, 7-23, 24+ months). A FTP was defined
as any stillbirth, livebirth, or multiple births with at least one
live birth. Menopausal status was determined by comparing
date or age at last period with reference date: if the subject
reported that she was still having periods, was having periods
within 12 months of the reference date, or was currently
pregnant, she was considered to be premenopausal; if subject
reported that her periods stopped at least 1 year before her
reference date, she was considered to be postmenopausal as of
the reference date. Pregnancy and lactation history were first
considered through the date of first breast cancer diagnosis
and then through the end date for the at-risk period (denoted
‘‘as of reference date,’’ the date of CBC diagnosis for the cases
and the corresponding date for the matched controls). Rate
ratios and corresponding 95% confidence intervals (95% CI)
were estimated by fitting univariate and multivariable condi-
tional logistic regression models accounting for the counter-
matched sampling. In the multivariable analyses, we included
all of the following risk factors: exact age at diagnosis of the
first primary breast cancer, family history of breast cancer (no
first-degree affected relatives, at least one first-degree affected
relative, adopted or unknown family history), histology of first
primary (lobular, medullary, ductal, or other) stage of the first
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Cancer Epidemiol Biomarkers Prev 2007;16(5). May 2007
primary (localized, regional), first primary treatment history of
chemotherapy and/or any hormone therapy (yes, no), and
radiation therapy (yes, no). Adjusted linear trend test P values
were obtained by including in the multivariable models
variables that assigned values 1, 2, 3, 4, etc. to the different
nominal categories. All statistical tests were two sided.
Total numbers presented in the tables may vary slightly
due to missing information. To account for missing informa-
tion within a counter-matched set, a missing indicator variable
was included in the conditional logistic regression models
according to the methods proposed by Huberman and
Distributions of the matching factors and other characteristics
for the cases and controls are displayed in Table 1. The large
difference in frequencies of radiation exposure between cases
and controls was due to the counter-matching in the design
whereby each triplet was comprised of two exposed subjects
and one unexposed.
Women who experienced menarche before age 13 had a
modest and marginally significant increased risk of CBC [rate
ratio (RR), 1.26; 95% CI, 1.01-1.58; Table 2]. Gravidity and
menopausal status were not statistically significantly associat-
ed with CBC. The number of FTPs (as of reference date) was
inversely associated with risk (P trend = 0.001) and culminated
in a 50% reduction in risk of CBC for cases with four or more
FTPs. We observed an increased rate ratio for women who
were nulliparous or had their first FTP at age 30 or later in the
unadjusted analysis. If we consider these groups separately,
the rate ratio for the nulliparous group as compared with age
<20 is 1.46 (95% CI, 0.98-2.18), whereas the rate ratio for the
30+ group relative to age <20 is 1.62 (95% CI, 1.06-2.47).
However, after considering the number of term pregnancies
and other potential confounders in the multivariable model,
age at first FTP was not significantly associated with the risk
of CBC (P trend = 0.76). Analyses of the number of births
occurring before or after age 30 were also completed. As
Table 1. Characteristics of 2,107 women with unilateral and bilateral breast cancer included in the WECARE study
Bilateral (N = 708) Unilateral (N = 1,399)
Registry, n (%)
Orange County/San Diego
Los Angeles County
Race, n (%)
Subject’s age at first breast cancer diagnosis, mean (range)
Age at reference date*, mean (range)
At-risk period, mean (range)
46 (24, 55)
50 (27, 70)
5 (1, 16)
45 (23, 55)
50 (27, 69)
5 (1, 16)
Radiation treatment (registry), n (%)
No or unknown
First-degree family history of breast cancer, n (%)
Adopted or family history unknown
Number of mammograms in year before reference date*, n (%)
Histology of first breast cancer, n (%)
Ductal and other
Stage of first breast cancer, n (%)
Chemotherapy, n (%)
Hormone therapy, n (%)
*Reference date is date of contralateral breast cancer diagnosis for cases and corresponding date for controls.
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Cancer Epidemiol Biomarkers Prev 2007;16(5). May 2007
compared with nulliparous women, those with three or more
FTPs, all of which occurred before age 30, were observed to
have significantly reduced risk of CBC (RR, 0.6; 95% CI, 0.4-
0.9). However, women with FTPs after age 30 were not
observed to have significantly reduced risk of CBC as
compared with nulliparous women. We cannot rule out a
protective effect from having children after age 30; nonethe-
less, this may be modest in comparison to that conferred by
multiple FTPs occurring before age 30. Breastfeeding history
was not significantly associated with risk of CBC (P trend =
0.09 for duration of breastfeeding). The results for effects of
reproductive factors using date at first breast cancer diagnosis
as the reference date for cases and controls were of similar
magnitude as those presented, which include the at-risk period
(data not shown). We also conducted age-stratified (<45, z45
years) analyses of CBC risk, examining the impact on CBC risk
of age at first FTP, number of FTPs, and breastfeeding. The
association between the reproductive characteristics and the
risk of CBC did not differ by age (data not shown).
In this study, we found that earlier menarche and lower parity
were associated with risk of asynchronous CBC in women
diagnosed with a first primary breast cancer before age 55
years. Age at first FTP, breastfeeding history, and menopausal
status were not significantly associated with CBC risk.
Early menarche is considered a modest risk factor for first
primary breast cancer (21). Two prior studies assessed risk of
CBC in relation to age at menarche, and neither showed
increased risk of CBC with menarche before age 13 years
(4, 9). Combined with our results, these studies suggest
that early age at menarche has, at most, a modest impact on
Parity is a well-established risk factor for breast cancer
(21, 22). Our results showing a statistically significant decline
in risk of CBC with increasing number of FTPs agree with
those of the only population-based study to address this
previously (9), where an adjusted RR of 0.62 for CBC risk
associated with two or more FTPs was reported. It has been
proposed that this observed protective effect for multiple
FTPs is a result of the differentiation of breast stem cells
which occurs during each FTP, leaving the cells less
susceptible to carcinogenesis (23, 24). It is unclear whether
the increased protection observed with each additional
pregnancy is due to further differentiation of tissue with
each succeeding pregnancy or changes in the hormonal milieu
(25, 26) or a combination of factors. Our results further
indicate that the protective effect of multiple FTPs is more
pronounced when the pregnancies occur before age 30 years.
Interestingly, however, an association between an early age at
first FTP and CBC risk was not observed in the present
analysis after adjusting for number of FTPs and other
potential confounding factors. These findings suggest that
the number of FTPs is a more important determinant of CBC
risk than an early first FTP. In contrast, research examining
the relative influences of parity and age at first FTP on risk of
first primary breast cancer suggests these factors may be
Table 2. Risk factors for second primary CBC among WECARE subjects
Factor Bilateral (n)Unilateral (n) Unadjusted (weighted),
RR* (95% CI)
Age at menarche
Menopausal status (as of reference dateb)
Incomplete pregnancies only
At least one full-term pregnancy
Age at first FTP (as of reference dateb)
Nulliparous or 30+ y
Trend P value
Number of FTPs (as of reference dateb)
Trend P value
Breastfeeding (as of reference dateb)
Duration of breastfeeding (as of reference dateb)
1 to 3 mo
4 to 6 mo
7 to 23 mo
Trend P value
1.29 (1.04-1.60) 1.26 (1.01-1.58)
0.79 (0.64-0.99)0.82 (0.63-1.07)
*Rate ratios are adjusted for the counter-matching sampling.
cRate ratios are adjusted for the counter-matching sampling and for the following covariates: age at first diagnosis, age at menarche, age at menopause, number of full-
term pregnancies, family history of breast cancer, histology of the first primary, stage of the first primary, first primary treatment history and radiation therapy.
bReference date is the date of contralateral breast cancer diagnosis for the cases and the corresponding date for controls.
xRate ratios are adjusted for all the covariates listed above except for the number of full-term pregnancies.
Cancer Epidemiology, Biomarkers & Prevention 909
Cancer Epidemiol Biomarkers Prev 2007;16(5). May 2007
Breastfeeding has only a modest impact on risk of breast
cancer overall after the impact of parity is considered (27). The
findings of the present study agree with one previous study of
breastfeeding and CBC, which also found no statistically
significant association with CBC risk when number of
pregnancies breast-fed was considered (9). Together, these
results suggest that breastfeeding history is not an important
predictor of CBC risk.
Our study has many strengths, including the large sample
size, the population-based subject ascertainment, the abstrac-
tion of medical records to confirm a cancer-free interval for
controls and treatment history for both cases and controls, and
strict individual matching of the cases and controls. However,
as with all case-control studies, our study has some potential
limitations. First, although our study is the largest population-
based case-control study conducted to date that included direct
interviews of patients, we nevertheless had limited statistical
power to detect modest relationships between age at first FTP
and CBC or between duration of breastfeeding and CBC.
Second, although we limited the potential for misclassification
of metastases as second primary breast cancer by restricting
this study to women with initial breast cancer diagnoses of
localized and regional disease and specified a minimum
interval of 1 year between the first and second diagnosis
among the cases, the possibility of misclassification remains.
Third, we conducted interviews with cases and controls, and
so we were able to include a woman’s history of reproductive
events both before first breast cancer diagnosis and during
her at-risk period before the cases’ second primary diagnoses.
However, by focusing on these reproductive events that are
important for developing a first primary breast cancer, we
may have missed some other factors that are predictors of a
second primary. Lastly, we required that all of our cases and
controls be alive so that we could obtain a blood sample.
Thus, we cannot rule out the potential for a survival bias in
our results. However, because we individually matched our
controls to our cases on both age and year of first breast
cancer diagnosis and restricted study eligibility to women
whose breast cancer had not spread beyond regional lymph
nodes at first diagnosis, this possibility is unlikely to
differentially affect the cases and controls in our study.
In summary, our findings suggest that among women
diagnosed with a first breast cancer before age 55 years,
multiparity and late menarche are inversely associated with
risk of CBC in a manner similar to the associations observed for
first primary breast cancers. However, other reproductive
factors basic to the epidemiology of first primary breast cancer
such as early age at first FTP and breastfeeding do not seem to
strongly influence CBC risk. Further research regarding
populations at risk for developing CBC may be useful in
developing strategies for primary and secondary prevention.
The WECARE Study collaborative group is made up of the following.
Principal investigator: Jonine L. Bernstein, Ph.D.
Co-principal investigators: Hoda Anton-Culver, Ph.D.; Colin Begg,
Ph.D.; Leslie Bernstein, Ph.D.; John Boice, Jr., Ph.D.; Anne-Lise
Børresen-Dale, Ph.D.; Marinela Capanu, Ph.D.; Patrick Concannon,
Ph.D.; Richard A. Gatti, Ph.D.; Robert W. Haile, Dr.P.H., Ph.D.; Bryan
M. Langholz, Ph.D.; Charles F. Lynch, M.D., Ph.D.; Kathleen E.
Malone, Ph.D.; Jørgen H. Olsen, M.D., D.M.Sc.; Barry Rosenstein,
Ph.D.; Roy E. Shore, Ph.D., Dr.P.H.; Marilyn Stovall, Ph.D.; Duncan C.
Thomas, Ph.D.; W. Douglas Thompson, Ph.D.
Coordinating center: Memorial Sloan-Kettering Cancer Center (New
York, NY) Jonine L. Bernstein, Ph.D. (WECARE Study P.I.), Xiaolin
Liang, M.D., M.S. (Informatics Specialist), Abigail Wolitzer, M.S.P.H.
(Project Director); National Cancer Institute (Bethesda, MD) Daniela
Seminara, Ph.D., M.P.H. (Program Officer).
Laboratories: Benaroya Research Institute at Virginia Mason
(Seattle, WA) Patrick Concannon, Ph.D. (P.I.), Sharon Teraoka, Ph.D.
(Laboratory Director), Eric R. Olson (Laboratory Manager); University
of Southern California (Los Angeles, CA) Robert W. Haile, Dr.P.H.
(P.I.), Anh T. Diep (Laboratory Director), Nianmin Zhou, M.D.
(Laboratory Manager), Yong Liu, M.D. (Director of Blood Processing),
Evgenia Ter-Karapetova (Supervisor of Biospecimen Processing),
Andre Hernandez; Norwegian Radium Hospital (Oslo, Norway)
Anne-Lise Børresen-Dale, Ph.D. (P.I.), Laila Jansen (Laboratory
Manager); Mount Sinai School of Medicine (New York, NY) Barry
S. Rosenstein, Ph.D. (P.I.), David P. Atencio, Ph.D. (Laboratory
Manager); University of California at Los Angeles (Los Angeles,
CA) Richard A. Gatti, Ph.D. (Consultant); Memorial Sloan-Kettering
Cancer Center (New York, NY) Irene Orlow, Ph.D. (Laboratory
Director, Biorepository); Lund University (Lund, Sweden) A˚ke Borg,
Ph.D. Centers are listed, respectively, according to the volume of
samples genotyped and interviews completed.
Data Collection Centers: University of Southern California (Los
Angeles, CA) Leslie Bernstein, Ph.D. (P.I.), Laura Donnelly-Allen
(Project Manager); Danish Cancer Society (Copenhagen, Denmark)
Jørgen H. Olsen, M.D., D.M.Sc. (P.I.), Lene Mellemkjær, Ph.D., M.Sc.
(Project Manager); University of Iowa (Iowa City, IA) Charles F. Lynch,
M.D., Ph.D. (P.I.), Jeanne DeWall, M.A. (Project Manager); Fred
Hutchinson Cancer Research Center (Seattle, WA) Kathleen E. Malone,
Ph.D. (P.I.), Noemi Epstein (Project Manager); University of California
at Irvine (Irvine, CA) Hoda Anton-Culver, Ph.D. (P.I.), Joan Largent,
Ph.D., M.P.H. (Project Manager). Centers are listed, respectively,
according to the volume of samples genotyped and interviews
Radiation Measurement: University of Texas, M.D. Anderson
Cancer Center (Houston, TX) Marilyn Stovall, Ph.D. (P.I.), Susan
Smith, M.P.H. (Quality Assurance Dosimetry Supervisor); New York
University (New York, NY) Roy E. Shore, Ph.D., Dr.P.H. (Epidemiol-
ogist); International Epidemiology Institute (Rockville, MD) and
Vanderbilt University (Nashville, TN) John D. Boice, Jr., Sc.D.
Biostatistics Core: University of Southern California (Los Angeles,
CA) Bryan M. Langholz, Ph.D., Duncan C. Thomas, Ph.D.; Memorial
Sloan-Kettering Cancer Center (New York, NY) Colin Begg, Ph.D.,
Marinela Capanu, Ph.D.; University of Southern Maine (Portland, ME)
W. Douglas Thompson, Ph.D. (P.I.).
External Advisors: Stanford University (Palo Alto, CA) Alice
Chen Y, Semenciw R, Kliewer E, Shi Y, Mao Y. Incidence of second primary
breast cancer among women with a first primary in Manitoba, Canada.
Breast Cancer Res Treat 2001;67:35–40.
Vaittinen P, Hamminki K. Risk factors and age-incidence relationships for
contralateral breast cancer. Int J Cancer 2000;88:998–1002.
Chen Y, Thompson W, Semenciw R, Mao Y. Epidemiology of contralateral
breast cancer. Cancer Epidemiol Biomarkers Prev 1999;8:855–61.
Li CI, Malone KE, Porter PL, Daling JR. Epidemiologic and molecular risk
factors for contralateral breast cancer among young women. Br J Cancer
Fowble B, Hanlon A, Freedman G, Nicolaou N, Anderson P. Second cancers
after conservative surgery and radiation for stages I-II breast cancer:
identifying a subset of women at increased risk. Int J Radiat Oncol Biol Phys
Bernstein JL, Thompson WD, Risch N, Holford TR. The genetic
epidemiology of second primary breast cancer. Am J Epidemiol 1992;
Cook LS, White E, Schwartz SM, McKnight B, Daling JR, Weiss NS. A
population-based study of contralateral breast cancer following a first
primary breast cancer (Washington, United States). Cancer Causes Control
Horn PL, Thompson WD. Risk of contralateral breast cancer: associations
with factors related to initial breast cancer. Am J Epidemiol 1988;128:
Bernstein JL, Thompson WD, Risch N, Holford TR. Risk factors predicting
the incidence of second primary breast cancer among women diagnosed
with a first primary breast cancer. Am J Epidemiol 1992;136:925–36.
10. Claus EB, Stowe M, Carter D, Holford T. The risk of contralateral breast
cancer among women diagnosed with ductal and lobular breast
carcinoma in situ: data from the Connecticut Tumor Registry. The Breast
11. Gao X, Fisher SG, Emami B. Risk of second primary cancer in the
contralateral breast in women treated for early-stage breast cancer:
a population-based study. Int J Radiat Oncol Biol Phys 2003;56:1038–45.
12. Kelsey JL, Gammon MD. The epidemiology of breast cancer. CA Cancer
J Clin 1991;41:146–65.
13. Liu Q, Wuu J, Mambe M, Hsieh S, Ekbom A, Hsieh C. Transient increase
910 The WECARE Study
Cancer Epidemiol Biomarkers Prev 2007;16(5). May 2007
in breast cancer risk after giving birth: postpartum period with the highest
risk (Sweden). Cancer Causes Control 2002;13:299–305.
14. Storm HH, Andersson M, Boice JD, Jr., et al. Adjuvant radiotherapy and risk
of contralateral breast cancer. J Natl Cancer Inst 1992;84:1245–50.
15. Boice JD, Jr., Harvey EB, Blettner M, Stovall M, Flannery JT. Cancer in the
contralateral breast after radiotherapy for breast cancer. N Engl J Med 1992;
16. American Cancer Society. Breast cancer facts & figures 2005–2006. Atlanta:
American Cancer Society, Inc.
17. Ries LAG, Harkins D, Krapcho M, et al., editors. SEER cancer statistics
review, 1975–2003, National Cancer Institute. Bethesda (MD). http://
seer.cancer.gov/csr/1975_2003/, based on November 2005 Surveillance,
Epidemiology and End Results (SEER) data submission, posted to the SEER
web site, 2006.
18. Bernstein JL, Langholz B, Haile RW, et al. Study design: evaluating gene-
environment interactions in the etiology of breast cancer—the WECARE
Study. Breast Cancer Res 2004;6:R199–214.
19. Langholz B: Counter-matching. Encyclopedia of biostatistics 2005, 2nd
edition, vol. 2, p. 1248–54.
20. Huberman M, Langholz B. Application of the missing-indicator method in
matched case-control studies with incomplete data. Am J Epidemiol 1999;
21. Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer.
Epidemiol Rev 1993;15:36–47.
22. Ursin G, Bernstein L, Wang Y, et al. Reproductive factors and breast cancer
risk in a study of white and African American women. Cancer 2004;101:
23. Lambe M, Hsieh C, Trichopoulos D, Ekbom A, Pavia M, Adami H. Transient
increase in the risk of breast cancer after giving birth. N Engl J Med 1994;331:
24. Russo J, Moral R, Balogh GA, Mailo D, Russo IH. The protective role of
pregnancy in breast cancer. Breast Cancer Res 2005;7:131–42.
25. Bernstein L, Pike MC, Ross RK, Judd HL, Brown JB, Henderson BE. Estrogen
and sex hormone binding globulin levels in nulliparous and parous women.
J Natl Cancer Inst 1985;74:741–5.
26. Bernstein L, Depue RH, Ross RK, Judd HL, Pike MC, Henderson BE.
Higher maternal levels of free estradiol in first compared to second preg-
nancy: a study of early gestational differences. J Natl Cancer Inst 1986;76:
27. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer
and breastfeeding: collaborative reanalysis of individual data from 47
epidemiological studies in 30 countries, including 50,302 women with
breast cancer and 96,973 women without the disease. Lancet 2002;360:
Cancer Epidemiology, Biomarkers & Prevention 911
Cancer Epidemiol Biomarkers Prev 2007;16(5). May 2007