Original Article
Familial Clustering of Breast and Prostate Cancer and Risk of
Postmenopausal Breast Cancer in the Women’s Health
Initiative Study
Jennifer L. Beebe-Dimmer, MPH, PhD1,2; Cecilia Yee, MS1,2; Michele L. Cote, MPH, PhD1,2; Nancie Petrucelli, MS1,2;
Nynikka Palmer, MPH, DrPH3; Cathryn Bock, MPH, PhD1,2; Dorothy Lane, MD, MPH4; Ilir Agalliu, MD, ScD5;
Marcia L. Stefanick, PhD6; and Michael S. Simon, MD, MPH1,2
BACKGROUND: Evidence suggests that the risk of breast and prostate cancer is increased among those with a family history of the
same disease and particularly among first-degree relatives. However, less is known about the relationship between breast and prostate cancer within families and particularly among minority populations. METHODS: Analyses of participants in the Women’s Health
Initiative observational cohort who were free of breast cancer at the time of their baseline examination were conducted. Subjects
were followed for breast cancer through August 31, 2009. A Cox proportional hazards regression modeling approach was used to
estimate the risk of breast cancer associated with a family history of prostate cancer, breast cancer, and both among first-degree relatives. RESULTS: There were 78,171 eligible participants, and 3506 breast cancer cases were diagnosed during the study period. A
family history of prostate cancer was associated with a modest increase in breast cancer risk after adjustments for confounders
(adjusted hazard ratio [aHR], 1.14; 95% confidence interval [CI], 1.02-1.26). In a separate analysis examining the joint impact of both
cancers, a family history of both breast and prostate cancer was associated with a 78% increase in breast cancer risk (aHR, 1.78; 95%
CI, 1.45-2.19). Risk estimates associated with a family history of both breast and prostate cancer were higher among African American
women (aHR, 2.34; 95% CI, 1.09-5.02) versus white women (aHR, 1.66; 95% CI, 1.33-2.08). CONCLUSIONS: These findings suggest that
prostate cancer diagnosed among first-degree family members increases a woman’s risk of developing breast cancer. Future studies
are needed to determine the relative contributions of genes and a shared environment to the risk for both cancers. Cancer
C 2015 American Cancer Society.
2015;000:000-000. V
KEYWORDS: African American, aggregation, epidemiology, family history, genetics.
INTRODUCTION
Cancers of the breast and prostate are the most common invasive cancers diagnosed among women and men, respectively, in
the United States. It has been estimated that 232,670 new cases of breast cancer and 233,000 new cases of prostate cancer will
be diagnosed in the United States in 2014, and they will account for nearly 30% of all invasive cancers.1 A positive family history
is a well-established risk factor for both cancers, particularly when they are diagnosed among first-degree family members.2,3
The risk increases with an increasing number of affected relatives and is inversely associated with the age at diagnosis of affected
relatives.3,4 However, the relative risk for either breast or prostate cancer associated with the aggregation of both cancers within
families has not been thoroughly investigated. Evidence indicates clustering of breast and prostate cancer in predominantly
white populations5-8 and a similar or stronger phenomenon among African American families; however, the results for the latter
are based on a relatively small number of participants.9,10 These epidemiological observations may be explained by shared environments and/or genetics. The rationale of such studies hinges on the 2 cancers having similar biological mechanisms, and these
studies focus on exposure to endogenous sex-steroid hormone concentrations, insulin and insulin-like growth factors, and
inflammatory mediators (eg, adipokines) with mitogenic and potentially genotoxic effects on target tissues.
The current investigation focuses on the family history of prostate cancer and breast cancer among first-degree relatives and the risk of postmenopausal breast cancer among participants in the Women’s Health Initiative (WHI) Observational Study (OS). The results of case-control studies investigating the relationships between family cancer history and
Corresponding author: Jennifer L. Beebe-Dimmer, MPH, PhD, Karmanos Cancer Institute, 4100 John R Street, Detroit, MI 48201; Fax: (313) 578-4306;
[email protected]
1
Karmanos Cancer Institute, Detroit, Michigan; 2Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan; 3Department of Medicine,
University of California San Francisco, San Francisco, California; 4Department of Community and Behavioral Health, Stony Brook University, Stony Brook, New
York; 5Departments of Medicine and Population Health and Urology, Albert Einstein College of Medicine, Bronx, New York; 6Departments of Medicine and Obstetrics and Gynecology, Stanford University, Stanford, California.
DOI: 10.1002/cncr.29075, Received: June 17, 2014; Revised: August 25, 2014; Accepted: September 2, 2014, Published online Month 00, 2015 in Wiley Online
Library (wileyonlinelibrary.com)
Cancer
Month 00, 2015
1
Original Article
cancer risk can be influenced by recall bias. Thus, the
WHI OS represents an opportunity to estimate the breast
cancer risk associated with the reported family history
while reducing the impact of such bias. Furthermore, the
large sample size allows the examination of racial differences in the breast cancer risk associated with a positive family history of prostate and breast cancer.
MATERIALS AND METHODS
Study Population
The WHI consists of several clinical trials and an observational study with more than 168,000 US women enrolled.
The study details of the WHI have been previously published.11-13 Briefly, the WHI enrolled healthy, postmenopausal women who were 50 to 79 years old into a
randomized, controlled clinical trial of exogenous estrogen and progesterone with coronary artery disease as the
primary outcome. Women unwilling to participate or
considered ineligible for the initial clinical trial were given
an opportunity to participate in the WHI OS. The OS
was initially established to serve as a control for the clinical
trial and collected detailed information on the following:
demographics; medical history; family medical history at
the baseline interview; and risk factors for a number of
chronic diseases, including breast cancer.
The WHI OS enrolled 93,676 postmenopausal
women through 40 clinical centers throughout the United
States between October 1, 1993 and December 31, 1998.
The WHI OS protocol was reviewed by the institutional
review boards of each of the 40 centers, and informed consent was obtained from each participant locally. Each participant completed an interview and physical examination
at the baseline and at 3 years. Women were deemed ineligible to participate in the OS at the baseline if they had a
medical history that would affect participation or predicted mortality within 3 years of the baseline examination.13 Annual questionnaires were mailed to participants
to obtain follow-up data, and they focused primarily on
changes in medical history and in health behaviors. Breast
cancers were verified with medical records, and pathology
was reviewed centrally by trained WHI physician adjudicators.14 For the current study, women with confirmed
breast cancer at the baseline interview (n 5 4168) were
excluded. Follow-up documentation of incident breast
cancers was conducted through August 31, 2009.
Baseline Data Collection
At the baseline, all OS participants had their height,
weight, waist and hip circumference, and blood pressure
measured, and their body mass index (kg/m2) was calcu2
lated from measures of weight and height. Participants
also completed a comprehensive, standardized, selfadministered questionnaire collecting information on
their demographics (including self-reported race), occupation, lifestyle and behavioral risk factors (smoking, alcohol
consumption, and physical activity), and reproductive,
medical, and family history.
All participants were asked about their family medical history, including cancer. The most detailed cancer
family history data gathered from women were for breast
and colorectal cancer, primarily because of the impact of
these cancers on morbidity and mortality but also because
of their inclusion as secondary endpoints in 1 or more of
the clinical trial components. For both breast and colorectal cancer, the number of affected first-degree relatives
was recorded, the approximate age at diagnosis for each
affected relative was recorded, and the relationship to the
participant was recorded. For prostate cancer as well as endometrial, cervical, and ovarian cancers, only the number
of affected first-degree, full-blood relatives was recorded.
Statistical Analysis
All analyses were conducted with Statistical Analysis Systems version 9.2 (SAS Inc, Cary, NC). Descriptive statistics, including age, race/ethnicity, education, WHI
region, body mass index, smoking history, any hormone
therapy use, parity, age at first birth, hysterectomy,
oophorectomy, a history of benign breast disease, insurance coverage, mammography in the past 2 years, and
general health, were used to characterize the baseline characteristics of the study population. To identify potential
confounders, differences in the distribution of baseline
characteristics between breast cancer cases and noncases
were evaluated with chi-square tests and the associated P
values. P values less than .05 were considered statistically
significant. Cox proportional hazards regression was used
to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for breast cancer associated with having a family history of breast cancer and/or prostate cancer
with adjustments for important confounders. Baseline
characteristics that were significantly different between
breast cancer cases and noncases were included individually in subsequent regression models. If the inclusion of
those characteristics in the model changed the hazard
ratios (HRs) related to a family history by 10%, then
these characteristics were considered important confounding variables. Models were generated for all participants
combined and were stratified by race; for the latter analysis, participants of non-white, non–African American, or
unknown race were excluded. For all analyses, the family
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Breast and Prostate Cancer in WHI/Beebe-Dimmer et al
history was restricted to first-degree, full-blood relatives.
Because adjustments for the number of first-degree relatives did not change risk estimates, final models included
mutual adjustments for a family history of breast cancer,
prostate cancer, age, race, benign breast disease, hormone
therapy use, and hysterectomy.
RESULTS
The 78,171 WHI OS participants included in this study
were followed for a median of 132 months from the date
of enrollment with a median of 60 months between
enrollment and diagnosis for breast cancer cases. Table 1
describes the distribution of baseline characteristics
between the 3506 incident breast cancer cases diagnosed
between the baseline and August 31, 2009 and the 74,665
noncases followed during the same period in the WHI
observational cohort. Breast cancer cases were more likely
than noncases to be non-Hispanic white, collegeeducated, and hormone therapy users; to have a history of
benign breast disease; and to have had a mammogram
within 2 years of the baseline examination. The cases were
also less likely to smoke, to have children, and to have
undergone a hysterectomy. There were either marginal or
nonsignificant differences between cases and controls with
respect to the body mass index, WHI region, insurance
coverage, and self-reported health. The median age at the
baseline was 64 years for breast cancer cases and 63 years
for noncases; the median age at the time of the breast cancer diagnosis was 69 years (range, 50-90 years).
Self-reported family histories of both breast and
prostate cancer among first-degree family members in
breast cancer cases and noncases are provided in Table 2.
There were 11,608 women in the study who reported a
positive family history of breast cancer; 48.7% of these
women reported that their mother was diagnosed, 36.6%
reported a diagnosis for a sister, 4.6% reported a diagnosis
for a daughter, and the remaining 10.1% reported diagnoses for more than 1 first-degree relative. Cases were more
likely than noncases to report a family history of breast
cancer (20.5% and 14.6%, respectively), with an approximately 40% increase in risk associated with having a single
family member affected after adjustments for potential
confounders (aHR, 1.42; 95% CI, 1.30-1.55). Risk
increased further with multiple family members being
diagnosed with breast cancer (aHR, 1.66; 95% CI, 1.321.88). Breast cancer cases were more likely to report 1 or
more relatives diagnosed with prostate cancer in comparison with noncases (11.6% vs 10.1%). A family history of
prostate cancer in a first-degree relative (father, brother,
or son) was associated with a significant, albeit modest,
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Month 00, 2015
increase in breast cancer risk after adjustments for confounders, including a family history of breast cancer
(aHR, 1.14; 95% CI, 1.02-1.26). Women at the greatest
risk for breast cancer had a history of both breast and prostate cancer among first-degree family members, with an
approximately 80% increase in breast cancer risk in comparison with women with no family history of either
(aHR, 1.78; 95% CI, 1.45-2.19).
Table 3 provides race-stratified estimates of the
breast cancer risk associated with a family history of breast
and prostate cancer. Risk was greatest among African
American women with multiple affected first-degree family members (aHR, 2.85; 95% CI, 1.33-6.09). Although a
family history of prostate cancer was modestly predictive
of breast cancer risk in both white and African American
women, the association was statistically significant only in
white women. Lastly, African American women with a
family history of both breast and prostate cancer appeared
to be at greater risk for developing breast cancer (aHR,
2.34; 95% CI, 1.09-5.02) than their white counterparts
(aHR, 1.66; 95% CI, 1.33-2.08). However, the risk estimates were not significantly different as evidenced by the
overlapping CIs.
We also considered the impact of a family history of
other cancers (nonbreast, nonprostate) among first-degree
relatives on breast cancer risk and found no increase in
risk associated with a family history of any other cancer
(HR, 0.99; 95% CI, 0.91-1.07). A family history of colorectal cancer was associated with a marginal increase in
breast cancer risk (HR, 1.08; 95% CI, 0.99-1.18) after
adjustments for a family history of breast and prostate
cancer (Table 4). Interestingly, a family history among
first-degree relatives that included breast, prostate, and
colorectal cancer was associated with an approximately 2fold increase in breast cancer risk (HR, 2.06; 95% CI,
1.38-3.08).
DISCUSSION
Findings from the WHI observational cohort suggest that
independently of a family history of breast cancer, a positive family history of prostate cancer among first-degree
relatives is associated with a modest increase in the risk of
breast cancer diagnosed after the age of 50 years. We
report, as have others, that women with a family history of
breast cancer are at an increased risk, with risk estimates
higher among women with multiple affected first-degree
family members. Our results also suggest that African
American women at the greatest risk for a diagnosis of
breast cancer have a family history of both breast and prostate cancer.
3
Original Article
TABLE 1. Baseline Characteristics of Breast Cancer
Cases and Noncases Participating in the Women’s
Health Initiative Observational Study
Characteristic
Total population
Age at baseline
<60 y
60-69 y
70 y
Age at diagnosis
<50-59 y
60-69 y
70-79 y
801 y
Race/ethnicity
Non-Hispanic white
Black
Other
Unknown
Education
No high school diploma
High school diploma/GED
College graduate or above
Unknown
Region
Northeast
South
Midwest
West
Body mass index
Underweight
to normal
(<18.5-24.9 kg/m2)
Overweight
(25.0-29.9 kg/m2)
Obese (30.0 kg/m2)
Unknown
Smoking
Never
Former
Current
Unknown
Hormone
replacement
therapy use
Never
Former
Current
Unknown
Parity
None (nulliparous)
1-2 term pregnancies
>2 term pregnancies
Unknown
Age at first
birth (full-term
pregnancy)
Never
<30 y
30 y
Unknown
Hysterectomy
No
4
Breast Cancer
Cases,
n (%) or
Median
(Range)a
Noncases,
n (%)
or Median
(Range)a
3506 (4.5)
74,665 (95.5)
Characteristic
Pb
.0001
1009 (28.8)
1653 (47.1)
844 (24.1)
24,428 (32.7)
32,785 (43.9)
17,452 (23.4)
403 (11.5)
1377 (39.3)
1417 (40.4)
309 (8.8)
—
—
—
—
.0001
3129 (89.2)
174 (5.0)
194 (5.5)
9 (0.3)
62,555 (83.8)
5627 (7.5)
6283 (8.4)
200 (0.3)
113 (3.2)
489 (13.9)
2879 (82.1)
25 (0.7)
3585 (4.8)
12,054 (16.1)
58,450 (78.3)
576 (0.8)
798 (22.8)
879 (25.1)
747 (21.3)
1082 (30.9)
17,464
18,952
16,458
21,791
1420 (40.5)
30,561 (40.9)
1180 (33.7)
25,171 (33.7)
867 (24.7)
39 (1.1)
18,081 (24.2)
853 (1.1)
1679 (47.9)
1579 (45.0)
212 (6.0)
36 (1.0)
37,897 (50.8)
31,390 (42.0)
4558 (6.1)
820 (1.1)
.0001
.19
(23.4)
(25.4)
(22.0)
(29.2)
.78
.0001
21,517 (28.8)
14,580 (19.5)
37,174 (49.8)
1394 (1.9)
506 (14.4)
1269 (36.2)
1710 (48.8)
21 (0.6)
9271 (12.4)
26,261 (35.2)
38,754 (51.9)
379 (0.5)
.0001
.0001
506 (14.4)
2378 (67.8)
339 (9.7)
283 (8.1)
9271 (12.4)
52,467 (70.3)
5603 (7.5)
7324 (9.8)
2219 (63.3)
43,591 (58.4)
Yes
Unknown
Oophorectomy
No
Yes
Unknown
History of benign breast
disease
No
Yes
Unknown
Family history of cancerc
No
Yes
Insurance
No
Yes
Unknown
Mammogram within 2 years
No
Yes
Unknown
Health in general
Poor/fair/good
Excellent/very good
Unknown
Age at baseline, y
Age at diagnosis, y
Body mass index, kg/m2
Breast Cancer
Cases,
n (%) or
Median
(Range)a
Noncases,
n (%)
or Median
(Range)a
1281 (36.5)
6 (0.2)
31,009 (41.5)
65 (0.1)
2536 (72.3)
933 (26.6)
37 (1.1)
52,331 (70.1)
21,497 (28.8)
837 (1.1)
Pb
.005
.0001
2412 (68.8)
1033 (29.5)
61 (1.7)
57,331 (76.8)
16,186 (21.7)
1148 (1.5)
2282 (65.1)
1224 (34.9)
46,529 (62.3)
28,136 (37.7)
95 (2.7)
3386 (96.6)
25 (0.7)
2509 (3.4)
71,432 (95.7)
724 (1.0)
361 (10.3)
3058 (87.2)
87 (2.5)
10,096 (13.5)
62,446 (83.6)
2123 (2.8)
1456 (41.5)
1800 (51.3)
250 (7.1)
64 (50-79)
69 (50-90)
26.1 (15-65.5)
27,777 (37.2)
38,910 (52.1)
7978 (10.7)
63 (49-81)
—
26 (11.9-69.9)
.0009
.034
.0001
.002
Abbreviation: GED, general educational development.
a
Percentages may not add up to 100% because of rounding.
b
Chi-square test.
c
Nonprostate, nonbreast cancer.
.002
820 (23.4)
621 (17.7)
1984 (56.6)
81 (2.3)
TABLE 1. Continued
.001
Epidemiological studies consistently demonstrate
that a family history of the same tumor, particularly
among first-degree relatives, is a moderate to strong risk
factor for both breast and prostate cancer, with concordant estimates of relative risk ranging from 2.0 to 4.5.3,15
Reported estimates are even higher with multiple affected
relatives and/or relatives diagnosed with earlier onset disease (typically <50 years at the time of diagnosis for breast
cancer and <60 years for prostate cancer).3,4,16 Interestingly, the risk appears slightly higher for both cancers
when a full-blood sibling instead of a parent is affected
with the same disease, and this suggests some contribution
from the environment (particularly the early environment) and/or an interaction between 1 or more genes and
early environmental exposures playing an important role
in carcinogenesis.15,16
Comparatively, much less is known about the aggregation of breast and prostate cancer within families and
the discordant estimates of risk associated with a positive
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TABLE 2. Baseline Reported History of Breast and Prostate Cancer Among First-Degree, Full-Blood
Relatives and Breast Cancer Risk in the Women’s Health Initiative Observational Study
Family History of Cancer
Among First-Degree Relatives
Breast Cancer
Cases, n (%)
Noncases,
n (%)
3506
74,665
2787 (79.5)
636 (18.1)
83 (2.4)
Total (n 5 78,171)
Breast cancerb
None
1 relative
>1 relative
Prostate cancerb
None
1 or more relatives
Breast and prostate cancer
None
Breast only
Prostate only
Both
Crude RR
(95% CI)
Multivariate
RR (95% CI)a
63,776 (85.4)
9796 (13.1)
1093 (1.5)
Referent
1.47 (1.35-1.60)
1.75 (1.41-2.18)
Referent
1.42 (1.30-1.55)
1.66 (1.32-2.08)
3101 (88.4)
405 (11.6)
67,107 (89.9)
7558 (10.1)
Referent
1.14 (1.03-1.26)
Referent
1.14 (1.02-1.26)
2480 (70.7)
621 (17.7)
307 (8.8)
98 (2.8)
57,459 (77.0)
9648 (12.9)
6317 (8.5)
1241 (1.7)
Referent
1.48 (1.35-1.61)
1.12 (0.99-1.26)
1.81 (1.48-2.21)
Referent
1.42 (1.29-1.55)
1.10 (0.98-1.24)
1.78 (1.45-2.19)
Abbreviations: CI, confidence interval; RR, relative risk.
a
Models included age, race, benign breast disease, hormone replacement therapy usage, and hysterectomy.
b
Models were also mutually adjusted for a family history of breast cancer and prostate cancer among first-degree relatives.
family history. Our findings are similar to those of Sellers
et al,6 who reported that a family history of prostate cancer in a father or brother was associated with a modest
increase in postmenopausal breast cancer risk independent of the family history of breast cancer (relative risk,
1.19; 95% CI, 0.90-1.56), but a family history of both
breast and prostate cancer was associated with an approximately 2.0-fold increase in breast cancer risk.6 Both Turati et al17 and Gronberg et al18 reported an approximately
60% increase in the odds of a breast cancer diagnosis associated with a history of prostate cancer in any first-degree
relative. However, other studies have not observed significant increases in breast cancer risk associated with a family
history of prostate cancer.19-21 These discrepancies may
be attributed to differences in study design and/or the
composition of the study participants. In comparison, the
majority of studies,5,10,22-25 but not all,7,19,26,27 have
reported a significant independent association between a
positive family history of breast cancer among first-degree
relatives and the risk of prostate cancer.
Few studies have reported on the impact of race and
family history on the risk of breast and prostate cancer.
TABLE 3. Race-Stratified Estimates of Breast Cancer Risk According to the Family History of Breast and
Prostate Cancer in the Women’s Health Initiative Observational Study
Family History of
Cancer Among
First-Degree
Relatives
White
Breast Cancer
Cases, n (%)
Noncases,
n (%)
3129
62,555
2488 (79.5)
578 (18.5)
63 (2.0)
53,134 (84.9)
8504 (13.6)
917 (1.5)
2766 (88.4)
363 (11.6)
2208 (70.6)
558 (17.8)
280 (8.9)
83 (2.7)
Total (n 5 71,485)
Breast cancerb
None
1 relative
>1 relative
Prostate cancerb
None
1 or more relatives
Breast and prostate cancer
None
Breast only
Prostate only
Both
Black
Multivariate
RR (95% CI)a
Breast Cancer
Cases, n (%)
Noncases,
n (%)
Multivariate
RR (95% CI)a
174
5627
Referent
1.41 (1.28-1.55)
1.46 (1.13-1.88)
138 (79.3)
29 (16.7)
7 (4.0)
4914 (87.3)
630 (11.2)
83 (1.5)
Referent
1.58 (1.05-2.37)
2.85 (1.33-6.09)
56,151 (89.8)
6404 (10.2)
Referent
1.13 (1.01-1.26)
151 (86.8)
23 (13.2)
4941 (87.8)
686 (12.2)
Referent
1.09 (0.70-1.69)
47,803 (76.4)
8348 (13.3)
5331 (8.5)
1073 (1.7)
Referent
1.40 (1.27-1.54)
1.11 (0.98-1.26)
1.66 (1.33-2.08)
122 (70.1)
29 (16.7)
16 (9.2)
7 (4.0)
4331 (77.0)
610 (10.8)
583 (10.4)
103 (1.8)
Referent
1.63 (1.08-2.46)
0.99 (0.59-1.67)
2.34 (1.09-5.02)
Abbreviations: CI, confidence interval; RR, relative risk.
a
Models included age, benign breast disease, hormone replacement therapy usage, and hysterectomy
b
Models were also mutually adjusted for a family history of breast cancer and prostate cancer among first-degree relatives
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5
Original Article
TABLE 4. Baseline Reported History of Breast and Colorectal Cancer Among First-Degree, Full-Blood Relatives and Breast Cancer Risk in the Women’s Health Initiative Observational Study
Family History of Cancer
Among First-Degree Relatives
Total (n 5 78,171)
Breast cancerb
None
1 relative
>1 relative
Colorectal cancerb
None
1 or more relatives
Breast and colorectal cancer
None
Breast only
Colorectal only
Both
Breast Cancer
Cases, n (%)
Noncases,
n (%)
Crude
RR (95% CI)
Multivariate
RR (95% CI)a
3506
74,665
2787 (79.5)
636 (18.1)
83 (2.4)
63,776 (85.4)
9796 (13.1)
1093 (1.5)
Referent
1.47 (1.35-1.60)
1.75 (1.41-2.18)
Referent
1.42 (1.30-1.55)
1.66 (1.32-2.08)
2931 (83.6)
575 (16.4)
63,328 (84.8)
11,337 (15.2)
Referent
1.08 (0.99-1.19)
Referent
1.08 (0.99-1.19)
2337 (66.7)
594 (16.9)
450 (12.9)
125 (3.6)
54,387 (72.8)
8941 (12.0)
9389 (12.6)
1948 (2.6)
Referent
1.53 (1.39-1.67)
1.11 (1.01-1.23)
1.51 (1.26-1.80)
Referent
1.47 (1.34-1.61)
1.11 (1.00-1.23)
1.47 (1.22-1.77)
Abbreviations: CI, confidence interval; RR, relative risk.
a
Models included age, race, benign breast disease, hormone replacement therapy usage, and hysterectomy.
b
Models were also mutually adjusted for a family history of breast cancer and colorectal cancer among first-degree relatives.
Among those focused on concordant risk, studies of prostate cancer have reported that African American men in the
United States have a risk similar to that of white men with
comparable family histories.8,28 Alternatively, studies of
racial disparities in familial breast cancer are not as clear.
The Black Women’s Health Study and the Women’s Contraceptives and Reproductive Experiences (CARE) study
reported similar estimates of the relative risk associated
with a positive family history of breast cancer in African
American and white women. However, a subsequent report
from the CARE study found that after the age of 50 years,
risks diverge, with white women having a higher risk of
breast cancer in comparison with black women; this was
particularly true among those with more than 1 affected
first-degree relative.29 Two case-control studies focusing on
discordant risk in African Americans found that men with
prostate cancer were more likely to report a family history
of breast cancer in a sibling in comparison with controls.9,10 To our knowledge, the current investigation is the
first to report on racial differences in the risk of breast cancer associated with a family history of prostate cancer.
A genetic explanation for the familial clustering of
breast and prostate cancer is currently unknown, but
researchers have naturally focused on breast cancer 1
early-onset (BRCA1) and breast cancer 2 early-onset
(BRCA2) with the presence of prostate cancer in Ashkenazi Jewish families as well as those meeting criteria for hereditary breast and ovarian cancer syndrome. The results
of studies examining the association between either of
these genes and prostate cancer have been inconsistent.3034
It has been predicted that germline mutations in
6
BRCA1/2 can explain just a small proportion of the
observed clustering of breast and prostate cancer within
families, and BRCA2 has been linked to more aggressive
prostate cancer clinical features.31,32,35-41
The strengths of the current investigation primarily
lie in the WHI OS resource. The large population allowed
a precise estimation of the breast cancer risk associated with
a history of breast and prostate cancer among immediate
family members, particularly among those with a family
history of both cancers, which is a relatively rare occurrence
in the population (2%). In addition, the prospective nature of the study eliminated the possibility of a misclassification bias produced by differential recall of the family
history in breast cancer cases versus noncases. Other important strengths include the long-term follow-up of study participants with central adjudication of breast cancers.
Limitations include the relatively small number of African
American women with breast cancer in the study and the
reliance on self-reporting of the family history of cancer;
however, evidence suggests that self-reported cancer family
histories are generally accurate, particularly among firstdegree relatives.42 Because a family history of cancer was
assessed only at the baseline, any changes in family histories
of cancer were not captured in this analysis.
In summary, a family history of breast cancer and a
family history of prostate cancer were each independently
associated with the risk of breast cancer diagnosed after
the age of 50 years, with the greatest risk observed among
women with a family history of both breast and prostate
cancer among first-degree relatives. These findings deserve
further investigation and may have significant
Cancer
Month 00, 2015
Breast and Prostate Cancer in WHI/Beebe-Dimmer et al
implications because of the contribution of an inherited
predisposition for both cancers. Familial clustering of
these 2 cancers represents a unique phenotype in which to
identify new susceptibility genes. Furthermore, because
the contribution of a family history of prostate cancer to
breast cancer risk among relatives (and vice versa) is more
clearly elucidated, risk communication between the physician and the patient as well as the dissemination of this information from the patient to immediate relatives would
be important in shaping the health behaviors (such as
screening for early detection) of those family members,
even among those of the opposite sex.
FUNDING SUPPORT
The WHI is funded by the National Heart, Lung, and Blood Institute
(National Institutes of Health, US Department of Health and Human
Services) through contracts HHSN268201100046C, HHSN
268201100001C, HHSN268201100002C, HHSN268201100003C,
HHSN268201100004C, and HHSN271201100004C. Jennifer L.
Beebe-Dimmer, Michele L. Cote, Cathryn Bock, and Nancie Petrucelli receive funding as independent contractors from the WHI Midwest Regional Center.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
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