1752 Articles | JNCI Vol. 103, Issue 23 | December 7, 2011
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Breast cancer survivors have an estimated two to six times greater
risk of being diagnosed with a second primary breast cancer in their
contralateral breast compared with the risk of being diagnosed with
a first breast cancer for women in the general population (1).
Established strategies for preventing second primary breast cancers
include adjuvant hormonal therapy and prophylactic contralateral
mastectomy (2). Given the increasing number of breast cancer sur-
vivors, it is imperative to identify effective and well-tolerated ways to
prevent second primary breast cancers. One possible approach is the
use of bisphosphonates, which are commonly prescribed to prevent
osteoporosis-related comorbidities (3) and, more recently, to pre-
vent and treat bone metastasis and cancer treatment–induced bone
loss and comorbidity (4–7). There is a growing body of evidence
suggesting that bisphosphonates have additional direct and indirect
antitumor effects (8,9), including solo and synergistic (with cytotoxic
chemotherapy, selective estrogen receptor modulators, or aromatase
inhibitors) activities in breast cancer relapse prevention (10,11).
In addition, three recent studies (12–14) suggest that nitrogen-
containing bisphosphonates are associated with a reduced risk of
first breast cancer, and in preliminary data from the randomized
Austrian Breast and Colorectal Cancer Study Group trial 12 (ABCSG-
12) (15), slightly fewer incident contralateral breast cancers in the trial
arms that received adjuvant nitrogenous bisphosphonate therapy were
observed compared with arms that did not receive adjuvant nitroge-
nous bisphosphonate therapy. These findings motivated us to assess
the association between bisphosphonate use and the risk of contralat-
eral breast cancer using data from a population-based case–control
study that was conducted in women who had been diagnosed with a
first primary estrogen receptor–positive (ER+) breast cancer. To
our knowledge, this is the first population-based study to examine
the relationship between bisphosphonate use and the risk of con-
tralateral breast cancer among breast cancer survivors.
Participants and Methods
Study Design and Data Collection
The study design and data collection methods have been previously
described (16). In brief, we used the Surveillance, Epidemiology,
Bisphosphonate Use After Estrogen Receptor–Positive Breast
Cancer and Risk of Contralateral Breast Cancer
Genevieve M. Monsees, Kathleen E. Malone, Mei-Tzu C. Tang, Polly A. Newcomb, Christopher I. Li
Manuscript received June 15, 2011; revised August 25, 2011; accepted September 2, 2011.
Correspondence to: Genevieve M. Monsees, SD, MSc, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N.,
M4-B874, PO Box 19024, Seattle, WA 98109-1024 (e-mail: firstname.lastname@example.org).
Background A growing body of evidence suggests that nitrogenous bisphosphonates may reduce the risk of developing a
first breast cancer and may prevent metastases among breast cancer survivors. However, their impact on risk
of second primary contralateral breast cancer is uncertain.
Methods Within a nested case–control study among women diagnosed with a first primary estrogen receptor–positive
invasive breast cancer at ages 40–79 years, we assessed the association between post-diagnostic bisphospho-
nate use and risk of second primary contralateral breast cancer. We used multivariable-adjusted conditional
logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) comparing 351 contralateral
breast cancer case subjects with 662 control subjects (ie, breast cancer patients not diagnosed with contralateral
breast cancer) who were incidence density–matched on county; race/ethnicity; and age at, year of, and stage at
first breast cancer diagnosis. We performed sensitivity analyses with respect to bisphosphonate type and con-
founding by indication. All statistical tests were two-sided.
Results Current use of any nitrogenous bisphosphonate and use specifically of alendronate were both associated with
reduced risks of contralateral breast cancer compared with never use (OR = 0.41, 95% CI = 0.20 to 0.84 and
OR = 0.39, 95% CI = 0.18 to 0.88, respectively). The risk of contralateral breast cancer further declined with
longer durations of bisphosphonate use among current users (Ptrend = .03). Results were similar in analyses
restricted to patients with a history of osteoporosis or osteopenia.
Conclusions Bisphosphonate use was associated with a substantial reduction in risk of contralateral breast cancer. If this
finding is confirmed in additional studies, nitrogenous bisphosphonate therapy may be a feasible approach for
contralateral breast cancer risk reduction.
J Natl Cancer Inst 2011;103:1752–1760
JNCI | Articles 1753
and End Results (SEER) population-based cancer registry covering
Western Washington State to identify 17 628 women who were
40–79 years old and resided in the four-county Seattle–Puget
Sound region when they were diagnosed with a first primary inva-
sive, localized or regional SEER historic stage (17) ER+ breast
cancer between January 1, 1990, and September 30, 2005. This
study (and the parent study) was restricted by age and to ER+
breast cancers to focus on women who were most likely to have
received tamoxifen therapy (the primary exposure of the parent
study) (16). Within this cohort, we identified 446 women who
were diagnosed from July 1, 1990, to March 31, 2007, with a sec-
ond primary invasive contralateral breast cancer 6 or more
months after their first breast cancer diagnosis (case subjects). Of
these women, 369 (83%) were enrolled. Eligible control subjects
were women who were alive and residing in the county in which
they were diagnosed with a first primary ER+ breast cancer and
who had not developed a contralateral breast cancer for at least
the period between their matched case subject’s first breast cancer
and subsequent contralateral breast cancer diagnosis. Of 982 eli-
gible control subjects, 734 (75%) were enrolled. An average of
two control subjects were matched to each case subject on age at
and year of first breast cancer diagnosis, race/ethnicity, SEER
historic stage of first breast cancer (localized vs regional) (17), and
county of residence at first breast cancer diagnosis. To prevent a
survivor bias, eligible women were included in the study regard-
less of vital status at the time of case and control subject ascertain-
ment. Deceased women (n = 246) were enrolled through a waiver
of consent granted by the Fred Hutchinson Cancer Research
Center’s Institutional Review Board. Primary study data were
collected through SEER and detailed medical record reviews.
Women who were alive at the time of the parent study provided
verbal informed consent (n = 857). This study was approved by
the Fred Hutchinson Cancer Research Center Institutional
Information on bisphosphonate use between the index date
(date of first breast cancer diagnosis) and the reference date (case
subject reference date: date of contralateral breast cancer diagno-
sis; control subject reference date: date of the matched case
subject’s contralateral breast cancer diagnosis) was abstracted from
the medical records of the oncology and/or primary care provider
for 351 (95%) of the 369 matched case–control sets (351 case sub-
jects and 662 control subjects). Data on potential confounders and
effect modifiers came from several sources, including SEER (eg,
age, year of diagnosis, SEER historic stage, and county of resi-
dence), interviewer-administered telephone questionnaires (eg, a
variety of established breast cancer risk factors and treatments),
and the medical record abstractions described above (ie, detailed
information on breast cancer treatments, medical history). Sources
of the information for all variables are annotated in Table 1.
For descriptive purposes, we derived the American Joint
Committee on Cancer (AJCC) stage of the initial breast cancer
diagnosis. AJCC stage derivations for diagnoses made before 2004
were made according to version 1.1 of the SEER Program:
Comparative Staging Guide for Cancer (18); subsequent diagnoses
were staged according to the 10th edition of the North American
Association for Central Cancer Registries Standards for Cancer
Registries Volume II (19).
CONTEXT AND CAVEATS
Nitrogenous bisphosphonates are commonly prescribed to prevent
osteoporosis-related comorbidities and, more recently, to prevent
and treat bone metastasis and cancer treatment–induced bone
loss and comorbidity. A growing body of evidence suggests that
bisphosphonates have additional direct and indirect antitumor
effects, including the prevention of breast cancer relapse.
A nested case–control study among women diagnosed with a first
primary estrogen receptor–positive invasive breast cancer at ages
40–79 years that assessed the association between bisphosphonate
use after the first breast cancer diagnosis and the risk of second
primary contralateral breast cancer.
Current use of bisphosphonates and use for longer durations were
both associated with large reductions in the risk of contralateral
Nitrogenous bisphosphonate therapy may be a feasible approach
to reduce the risk of contralateral breast cancer.
The observed associations could be due to chance or residual
confounding. Factors that influence the ability to tolerate bisphos-
phonates or to adhere to their use could explain the observed
dose–response relationship with duration of use. The findings may
not be generalizable to risk of breast cancer recurrences, premeno-
pausal use of bisphosphonates, ER-negative or advanced-stage
breast cancer survivors, or use of nonnitrogenous bisphosphonates.
From the Editors
Bisphosphonate use was defined according to ever use, the recency
of use, and the cumulative duration of use following the first breast
cancer diagnosis. Ever use was defined as having used bisphospho-
nates for 6 months or longer between the index and reference
dates. Short-term use was defined as bisphosphonate use for fewer
than 6 months during this period, and never use was defined as
never having used bisphosphonates during this period. Current
users were defined as ever users who had used bisphosphonates
within 6 months of their reference date. Former users were defined
as ever users who last used bisphosphonates more than 6 months
before their reference date. This 6-month threshold was chosen to
define current use and short-term use because it reflects the min-
imum possible duration between the index and reference dates.
In analyses of the duration of use following the first breast can-
cer diagnosis, we assessed thresholds of 6, 12, and 24 months of
use. We restricted these analyses to women with greater than or
equal to 6, 12, or 24 months, respectively, between their index and
reference dates. Thresholds of 12 and 24 months were chosen to
facilitate interpretation and comparison of our findings to those of
We excluded from the analysis bisphosphonates that were
specifically given to treat breast cancer according to the medical
1760 Articles | JNCI Vol. 103, Issue 23 | December 7, 2011
17. Young JL Jr, Roffers SD, Ries LAG, Fritz AG, Hurlbut AA. SEER
Summary Staging Manual—2000: Codes and Coding Instructions. Bethesda,
MD: National Cancer Institute; 2001. NIH Pub. No. 01–4969.
18. Seiffert JE, Shambaugh EM, Weiss MA, et al. SEER Program: Comparative
Staging Guide for Cancer. Version 1.1. Bethesda, MD: National Cancer
Institute; 1993. NIH Pub. No. 93–3640.
19. Havener LA, Hultstrom D. North American Association for Central Cancer
Registries: Standards for Cancer Registries Volume II - Data Standards and
Data Dictionary. 10th ed. Version 11. Springfield, IL: North American
Association of Central Cancer Registries; 2004.
20. Gnant M, Mlineritsch B, Stoeger H, et al. Adjuvant endocrine therapy
plus zoledronic acid in premenopausal women with early-stage breast cancer:
62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol.
21. Coleman R, Woodward E, Brown J, et al. Safety of zoledronic acid and
incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a
randomised phase III trial (AZURE: BIG 01-04) for women with stage II/
III breast cancer. Breast Cancer Res Treat. 2011;127(2):429–438.
22. Coleman RE, Thorpe H, Cameron D, et al. Adjuvant treatment with
zoledronic acid in stage II/III breast cancer. The AZURE Trial (BIG
01/04). Abstract number S4–5. Presented at the 33rd Annual San Antonio
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24. Vestergaard P, Fischer L, Mele M, Mosekilde L, Christiansen P. Use of
bisphosphonates and risk of breast cancer. Calcif Tissue Int. 2011;88(4):
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This work was supported by the National Cancer Institute at the National
Institutes of Health (R01-CA097271 and T32-CA09168 to G.M.M.).
The authors wish to acknowledge the substantial contributions of Ms. Sarah
Taylor and Ms. Heather O’Brien in the conduct of this research study. Other
staff member making important contributions to this work are Elisabeth
Beaber, Nancy Blythe, Ann Bradshaw, Kay Byron, Fran Chard, Lora Cox,
Diane DeHart, Sue Ellingson, Carolyn Howard, Dick Jacke, Jean Jue, Eileen
Louie, Karen Lunna, Charlotte Palmberg, Amanda Phipps, Patty Pride, Babette
Siebold, Camille Taylor, Loni Tipton, Vicky Tran, and Michelle Zuanich.
Lastly, we want to acknowledge the time and generosity of all of the women who
participated in this research.
The study sponsor did not have any role in the design of the study; the
collection, analysis, or interpretation of the data; the decision to submit the ar-
ticle for publication; or the writing of the article.
Affiliations of authors: Division of Public Health Sciences, Fred Hutchinson
Cancer Research Center, Seattle, WA (GMM, KEM, M-TCT, PAN, CIL);
Department of Epidemiology, University of Washington, Seattle, WA (GMM,
KEM, PAN, CIL).