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Available online http://breast-cancer-research.com/content/10/2/R38
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(page number not for citation purposes)
Vol 10 No 2
Research article
Nonsteroidal anti-inflammatory drugs and breast cancer risk in
the National Institutes of Health–AARP Diet and Health Study
Gretchen L Gierach
1,2
, James V Lacey Jr
1
, Arthur Schatzkin
3
, Michael F Leitzmann
3
,
Douglas Richesson
1
, Albert R Hollenbeck
4
and Louise A Brinton
1
1
Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of
Health, 6120 Executive Blvd, Suite 550, Rockville, MD 20852-7234, USA
2
Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute, National Institutes of Health, 6120 Executive Blvd,
Suite T-41, Bethesda, MD 20892-7361, USA
3
Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120
Executive Blvd, Suite 320, Rockville, MD 20852-7232, USA
4
Organizational and Tracking Research Department, AARP, 601 E Street NW, Washington, DC 20049, USA
Corresponding author: Gretchen L Gierach, gierachg@mail.nih.gov
Received: 17 Dec 2007 Revisions requested: 14 Feb 2008 Revisions received: 18 Mar 2008 Accepted: 30 Apr 2008 Published: 30 Apr 2008
Breast Cancer Research 2008, 10:R38 (doi:10.1186/bcr2089)
This article is online at: http://breast-cancer-research.com/content/10/2/R38
© 2008 Gierach et al.; licensee BioMed Central Ltd.
This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Introduction By inhibiting cyclooxygenase-2, nonsteroidal anti-
inflammatory drugs (NSAIDs) decrease aromatase activity and
might reduce breast cancer risk by suppressing estrogen
synthesis. Epidemiologic evidence for a protective role of
NSAIDs in breast cancer, however, is equivocal.
Methods We tested NSAID use for its association with breast
cancer incidence in the National Institutes of Health–AARP Diet
and Health Study, where 127,383 female AARP (formerly
known as the American Association of Retired Persons)
members with no history of cancer, aged 51 to 72 years,
completed a mailed questionnaire (1996 to 1997). We
estimated relative risks of breast cancer for NSAID exposures
using multivariate Cox proportional hazards regression models.
The state cancer registry and mortality index linkage identified
4,501 primary incident breast cancers through 31 December
2003, including 1,439 estrogen receptor (ER)-positive cancers
and 280 ER-negative cancers.
Results Proportional hazards models revealed no statistically
significant association between overall NSAIDs and total breast
cancer. As cyclooxygenase inhibition by aspirin (but not other
NSAIDs) is irreversible, we tested associations by NSAID type.
Although we observed no significant differences in risk for daily
use (versus nonuse) of aspirin (relative risk = 0.93, 95%
confidence interval = 0.85 to 1.01) or nonaspirin NSAIDS
(relative risk = 0.96, 95% confidence interval = 0.87 to 1.05),
risk of ER-positive breast cancer was significantly reduced with
daily aspirin use (relative risk = 0.84, 95% confidence interval =
0.71 to 0.98) – a relationship not observed for nonaspirin
NSAIDS. Neither aspirin nor nonaspirin NSAIDs were
associated with risk of ER-negative breast cancer.
Conclusion Breast cancer risk was not significantly associated
with NSAID use, but daily aspirin use was associated with a
modest reduction in ER-positive breast cancer. Our results
provide support for further evaluating relationships by NSAID
type and breast cancer subtype.
Introduction
Numerous epidemiologic studies have examined the associa-
tion between nonsteroidal anti-inflammatory drugs (NSAIDs)
and breast cancer, with equivocal results. Most, but not all,
case–control studies have found relative risk reductions from
20% to 40% [1-3] (reviewed in [4-7]). Results from prospec-
tive studies have been less consistent, with eight reports find-
ing no association [8-15], two studies observing an increased
risk [16,17], one study reporting a U-shaped association [18],
and six studies demonstrating a reduced risk [19-24]. In the
Women's Health Study randomized clinical trial, alternate-day
use of low-dose aspirin for an average of 10 years did not
reduce the incidence of breast cancer [25]. Given the poten-
tial public health impact of NSAIDs as chemopreventive
agents for breast cancer, an increased understanding of the
relationship between NSAIDs and breast cancer is needed.
BMI = body mass index; CI = confidence interval; COX = cyclooxygenase; ER = estrogen receptor; HR = hormone receptor; HT = hormone therapy;
NIH = National Institutes of Health; NSAID = nonsteroidal anti-inflammatory drug; RR = relative risk.
Breast Cancer Research Vol 10 No 2 Gierach et al.
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A protective role of NSAIDs in breast carcinogenesis is biolog-
ically plausible. In vitro and animal studies have consistently
shown that NSAIDs inhibit cyclooxygenase (COX)-1 and
COX-2, which cyclize and oxygenate arachidonic acid, even-
tually producing prostaglandins [26]. While inhibiting COX-1
reduces both platelet aggregation and gastric cytoprotection
[27], inactivating COX-2 may interrupt the carcinogenic proc-
ess in the breast via multiple pathways – including inhibition of
angiogenesis, promotion of apoptosis, and suppression of
estrogen synthesis via decreased aromatase activity [28].
Since aspirin and nonaspirin NSAIDs have different biologic
effects (aspirin permanently inactivates COX-2 [29]), separate
evaluation is needed with respect to breast cancer risk. Inter-
pretation of prior epidemiologic studies is complicated by
incomplete attention to NSAID type [5]. Furthermore, the stud-
ies that have examined the effect of NSAIDs on breast cancer
risk by tumor characteristics, such as hormone receptor (HR)
status [3,13,16-18,23,24,30,31] and stage at diagnosis
[21,30,32], also present conflicting results. The relatively few
studies that have tested for effect modification by participant
characteristics (for example, body mass index, menopausal
hormone therapy use, or smoking status) have produced
inconclusive findings [13,17,18,20,22,24,25,32,33]. The
large cohort of women participating in the prospective
National Institutes of Health (NIH)–AARP Diet and Health
Study allowed us to evaluate these questions.
Materials and methods
Study population
The NIH–AARP Diet and Health Study design and methodol-
ogy have been described in detail [34]. Briefly, the NIH–AARP
Study is a prospective cohort study of diet, health-related
behaviors and cancer.
The study was initiated in 1995 and 1996 when a question-
naire was mailed to 3.5 million members of the AARP (formerly
known as the American Association of Retired Persons) aged
50 to 71 years, who resided in one of six states (California,
Florida, Pennsylvania, New Jersey, North Carolina, and Louisi-
ana) or two metropolitan areas (Atlanta, Georgia and Detroit,
Michigan) that have large AARP membership, large minority
populations, and high-quality cancer registries. The question-
naire captured diet history, demographic characteristics,
reproductive history, menopausal status, and family history of
cancer. Of the 617,119 men and women (17.6%) who
returned the questionnaire, 567,169 satisfactorily completed
it.
In 1996 and 1997 a second questionnaire was sent to collect
additional information on family history of cancer, anthropome-
try, and use of menopausal hormone therapy (HT) and other
medications, including NSAIDs. A total of 337,074 men and
women completed this questionnaire.
After excluding individuals who died or moved out of the can-
cer registry ascertainment area before their second question-
naire was received and scanned (n = 2,166), excluding proxy
respondents to the baseline (n = 6,959) or second (n =
3,424) questionnaires, and excluding 188,117 men, the study
population included 136,408 potentially eligible women
The study was approved by the Special Studies Institutional
Review Board of the US National Cancer Institute.
Assessment of nonsteroidal anti-inflammatory drug
exposure and covariates
The second questionnaire asked whether aspirin products
(generic aspirin, Bayer, Bufferin, Anacin, Ecotrin, or Excedrin)
and nonaspirin NSAIDs (generic ibuprofen, Advil, Nuprin, Mot-
rin, Naprosyn, and so on) had been used in the past 12
months. As acetaminophen is an analgesic with weak anti-
inflammatory activity [35], participants were instructed not to
include 'Tylenol, acetaminophen, or any other pain relievers' in
nonaspirin NSAIDs. Aspirin or nonaspirin NSAID users were
asked to indicate their frequency of usual use: fewer than 2
times per month, 2 to 3 times per month, 1 to 2 times per
week, 3 to 4 times per week, 5 to 6 times per week, 1 time per
day, or 2 or more times per day – which we collapsed to cate-
gories of nonuse, <1/week, 1 to 6/week, and ≥1/day. The
dose, duration, and indication for use were not collected. In
the current report, 'any NSAID' combines the use of aspirin
and nonaspirin NSAIDs.
While the demographic characteristics, lifestyle, and repro-
ductive history were largely obtained through the first ques-
tionnaire, the second questionnaire ascertained a self-
reported history of hypertension, mammogram screening, and
vigorous physical activity. Menopausal hormone therapy use
and history of breast cancer in a first-degree relative were
derived from information collected on both the first and sec-
ond questionnaires.
Cohort follow-up
Cohort members were followed annually for mailing address
changes and vital status. Address changes were identified
through linkage to the US Postal Service's National Change of
Address database, through US Postal Service updates
received with undeliverable mail, through use of other address
change update services, and through participants' notifica-
tions. Vital status was updated through linkage to the Social
Security Administration Death Master File and was verified by
the National Death Index.
Ascertainment of breast cancer
Incident in situ breast cancers and invasive breast cancers
were initially identified through probabilistic linkage to eight
state cancer registries using first and last name, address, sex,
date of birth, and Social Security Number from the baseline
questionnaire. The cancer registry ascertainment area was
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recently expanded to include three additional states (Texas,
Arizona, and Nevada) to capture cancer occurring among par-
ticipants who moved to those states during follow-up. Each
registry has been certified by the North American Association
of Central Cancer Registries for meeting the highest stand-
ards of data quality.
Breast cancer estrogen receptor (ER) status was coded as
described in the American Joint Committee on Cancer's Col-
laborative Staging Site-Specific Factors Manual, with a thresh-
old of >10 fmol cytosol protein per milligram for a positive
tumor; however, the ER status was not reported by the Florida,
Michigan, and Pennsylvania cancer registries. Histology was
defined using the International Classification of Diseases for
Oncology codes, third edition [36]. A previous validation study
in this cohort estimated that registry linkage validly identified
approximately 90% of all incident cancers [37]. The date of
death for fatal cancers was identified through linkage to the
National Death Index.
Analytic sample
Because information regarding NSAID use was not collected
on the baseline questionnaire, we limited analyses to the
136,408 women who completed the second questionnaire.
We excluded 9,022 women who reported a personal cancer
history other than nonmelanoma skin cancer on either ques-
tionnaire (including 942 breast cancers), 1,259 women who
were missing information on NSAID use (including 52 breast
cancers), and three women with no follow-up. Thus, 126,124
women were included in the present analyses.
Through 31 December 2003, 4,501 women developed breast
cancer (781 in situ, 3,703 invasive, and 17 missing stage).
Among the 2,282 invasive breast cancer cases from states
that collected the ER status, 1,439 were coded as ER-positive
and 280 as ER-negative (the ER status was unavailable for the
remaining 563 invasive cases). There were no substantial risk
factor differences between women from states where ER
information was available and states where it was unavailable.
The majority of invasive breast cancers were ductal carcino-
mas (n = 2,409), followed by lobular (n = 400), mixed (n =
310), and other (n = 584) histologic types.
Statistical analysis
Cox proportional hazards models were used to estimate haz-
ard ratios and 95% confidence intervals (CIs) for breast can-
cer associated with NSAID use; age was the time scale [38],
and ties were handled by enumeration [39]. Follow-up began
at the age at which the second questionnaire was received
and scanned, and continued through the earliest of the follow-
ing dates: participant diagnosed with breast cancer, moved
out of her registry catchment area, died from any cause, or 31
December 2003. To test the proportional hazards assumption,
we generated time-dependent covariates by including interac-
tions of each predictor with the natural log of age (the time
metric); probability values for all time-dependent covariates
were >0.05, consistent with hazards that are proportional.
Multivariate models were used to control for age at entry
(years), race/ethnicity (white versus other/unknown), age at
first birth (nulliparous, <20 years, 20 to 24 years, 25 to 29
years, ≥30 years, or unknown), HT use (never used, estrogen
only, estrogen–progestin, or other/unknown), number of
breast biopsies (0, 1, 2, ≥3, or unknown), alcoholic drinks per
day (0, <1, 1 to 3, ≥3, or unknown), history of hypertension (no,
yes, or unknown), and family history of breast cancer in a first-
degree relative (no, yes, or unknown). Models examining fre-
quency of aspirin use and breast cancer risk also included
terms for frequency of nonaspirin NSAID use and vice versa.
Tests for linear trends across the NSAID exposure categories
were calculated by treating these categorical variables as ordi-
nal variables.
In subsequent models, we adjusted for calendar time and sev-
eral additional factors, including ages at menarche and meno-
pause, mammogram in the past 3 years, self-reported heart
disease, self-rated health quality, physical activity, and body
mass index (BMI). The results were essentially the same and
are not shown here.
We used a likelihood ratio test, comparing models with and
without the interaction terms, to separately examine effect
modification by age at entry (<57 years, 57 to 60 years, 61 to
64 years, 65 to 68 years, or ≥69 years), HT use (never, estro-
gen only, estrogen–progestin, or other/unknown), BMI (<25
kg/m
2
, 25 to 29 kg/m
2
, ≥30 kg/m
2
, or unknown), and smoking
status (never, former, current, or unknown). In addition, we
examined whether the relationship between NSAIDs and
breast cancer incidence differed by ER status (positive or neg-
ative), by stage at diagnosis (in situ or invasive disease), and
by histologic type (ductal, lobular, or mixed).
Probability values <0.05 were considered statistically signifi-
cant. All tests of statistical significance were two-tailed. Anal-
yses were performed using SAS software release 9.1.3 (SAS
Institute Inc., Cary, NC, USA).
Results
Among the 126,124 mostly white, postmenopausal women in
this report, 65.6% reported ever-use of aspirin in the past 12
months. Among all women, 31.8% took aspirin less than once
per week, 16.1% used aspirin one to six times per week, and
17.7% were daily aspirin users. Slightly fewer women reported
ever-use of nonaspirin NSAIDs: 31.5% took nonaspirin
NSAIDs less than once per week, 15.2% used nonaspirin
NSAIDs one to six times per week, and 13.3% were daily non-
aspirin NSAID users. Nearly 85% of women in our study
reported any NSAID use within the past 12 months.
Breast Cancer Research Vol 10 No 2 Gierach et al.
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In general, aspirin and nonaspirin NSAID users shared similar
characteristics (Tables 1 and 2). Compared with women who
did not use aspirin or nonaspirin NSAIDs in the past 12
months, women who had used aspirin or nonaspirin NSAIDs
on a daily basis were more likely to be white, and to reportedly
drink alcohol, smoke, use HT, have fair/poor overall health, and
to report a history of hypertension. Daily aspirin users were
more likely to be older and to report a history of stroke and
heart disease. Daily nonaspirin NSAID users were more likely
to be younger, parous, and obese (BMI ≥30 kg/m
2
), and to
have a history of breast biopsy.
The 126,124 women accrued 836,863 person-years during
an average follow-up of 3.43 years for cases (range, 1 day to
7.13 years) and of 6.75 years for noncases (range, 1 day to
7.17 years). The mean (standard deviation) ages for entry and
exit were 63.1 (5.2) years and 66.5 (5.6) years for cases and
were 62.6 (5.4) years and 69.3 (5.4) years for noncases,
respectively. Breast cancer risk factors in this population were
generally consistent with established associations with age,
BMI, ages at menarche, first birth and menopause, parity,
estrogen–progestin therapy use, number of breast biopsies,
and family history of breast cancer.
Because NSAID exposure was collected on the second ques-
tionnaire, and the response rate for this questionnaire was
~60%, we also examined the association between breast can-
cer risk factors captured on the first questionnaire and breast
cancer risk among the entire cohort. The associations
between risk factors and breast cancer in the entire cohort
were comparable with those observed in the subcohort of
respondents to the second questionnaire (data not shown).
Nonsteroidal anti-inflammatory drug use and breast
cancer
In multivariate proportional hazards models, there was no sta-
tistically significant association between ever-use of NSAIDs
in the past 12 months and total breast cancer (Table 3). Com-
pared with nonusers, the relative risks (RRs) of breast cancer
associated with ever-use of aspirin only, with nonaspirin
NSAIDs only, or with both were 0.97 (95% CI = 0.88 to 1.07),
1.01 (95% CI = 0.92 to 1.12), and 0.95 (95% CI = 0.87 to
1.04), respectively. We tested associations by frequency of
NSAID type. The risk of total breast cancer was slightly
reduced with daily use (versus nonuse) of aspirin (RR = 0.93,
95% CI = 0.85 to 1.01), albeit statistically nonsignificantly (for
trend P = 0.08). Compared with nonuse, daily use of nonaspi-
rin NSAIDs was not associated with breast cancer risk (RR =
0.96, 95% CI = 0.87 to 1.05). The association between
NSAID use and breast cancer risk was not modified by age,
HT use, BMI, or smoking (data not shown).
Several differences emerged in analyses stratified by ER sta-
tus and stage (Tables 4 to 6). The RR of ER-positive breast
cancer was reduced with daily aspirin use (RR = 0.84, 95%
CI = 0.71 to 0.98), and no association was observed with daily
use of nonaspirin NSAIDs (RR = 0.98, 95% CI = 0.83 to 1.16)
(Table 4). In contrast, ER-negative breast cancer was not
associated with daily aspirin or nonaspirin NSAID use. The
inverse relationships with aspirin use were weak for invasive
breast cancer but were stronger for in situ disease (Table 5),
and these differences were not entirely explained by mammo-
graphic screening: in analyses restricted to women who
reported having two or more mammograms in the past three
years, the risks associated with daily aspirin use for invasive
and in situ breast cancers were 0.95 (95% CI = 0.85 to 1.06)
and 0.75 (95% CI = 0.59 to 0.95), respectively (Table 6).
There was little variation in risks for nonaspirin NSAIDs
according to ER status and stage. Risk relationships for aspirin
and nonaspirin NSAIDs did not vary by histologic subtype for
invasive cancers (data not shown).
Discussion
In the present large prospective study, we found that NSAID
use was unrelated to risk of total breast cancer. Daily aspirin,
but not nonaspirin NSAID, use was associated with a modest
16% reduction in ER-positive breast cancer. We did not
observe an association between NSAID use and ER-negative
breast cancer.
Our null findings for total breast cancer are consistent with
those reported by eight prospective studies [8-15] and one
randomized clinical trial [25] that examined aspirin and/or non-
aspirin NSAID use. Our results differ, however, from those
from seven prospective studies [17,19-24] and 12 case–con-
trol studies [1-3,30-33,40-44], most of which have reported
reduced risks of breast cancer associated with NSAID use.
The reasons for these differing results are unclear, but
associations may be limited to certain subtypes of breast can-
cer. Differences in NSAID exposure assessment across stud-
ies may also account for inconsistent results.
The frequency of aspirin and nonaspirin use in the NIH–AARP
Diet and Health Study is consistent with that reported in other
US cohorts of women [21,45], and the proportion of women
in this study using any NSAID is only slightly higher than that
reported among females ages 45 to 75+ years in the third
National Health and Nutrition Examination Survey – 71.5% to
80.4% of whom reported any nonprescription analgesic in the
past month [46]. Our study lacked information, however, on
the duration, dose, indication, or prescription NSAID use.
Because we only measured recent NSAID use in the year prior
to the 1996 to 1997 questionnaire and followed women
through 2003, the null findings we observed for NSAIDs may
differ from what might be observed with long-term cumulative
exposure. Indeed, several cohort studies have shown that
long-term NSAID use is required for an observed chemopre-
ventive effect on breast cancer [22,23]. Furthermore, if there
were individuals in our referent category who were past users
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Table 1
Distribution of select risk factors across categories of aspirin use among 126,124 women, National Institutes of Health–AARP Study
Frequency of aspirin use in past 12 months
None <weekly 1–6 times/week 1+/day
Characteristic n %
a
n %
a
n %
a
n %
a
Age at second questionnaire
<57 years 8,178 19.0 8,629 21.7 4,029 20.1 2,936 13.3
57–60 years 8,317 19.4 8,211 20.6 4,022 20.1 3,566 16.2
61–64 years 9,750 22.7 9,025 22.7 4,644 23.2 5,132 23.2
65–68 years 11,085 25.8 9,459 23.8 4,881 24.3 6,607 29.9
69+ years 5,630 13.1 4,457 11.2 2,481 12.4 3,839 17.4
Race/ethnicity
Caucasian/non-Hispanic white 38,339 89.2 36,340 91.4 18,561 92.5 20,381 92.3
Other/unknown 4,621 10.8 3,441 8.6 1,496 7.5 1,699 7.7
Education
<High school/high school grad 13,537 32.5 10,675 27.5 5,769 29.6 6,857 32.0
Post-high school+ 28,171 67.5 28,110 72.5 13,696 70.4 14,554 68.0
Body mass index at baseline
<25 kg/m
2
18,461 44.7 18,855 48.9 9,040 46.6 8,718 40.8
25–30 kg/m
2
13,144 31.8 12,331 32.0 6,407 33.0 7,290 34.2
30+ kg/m
2
9,719 23.5 7,342 19.1 3,965 20.4 5,335 25.0
Smoking
Never 19,321 46.3 18,123 47.0 8,996 46.4 8,984 42.1
Former 16,758 40.2 15,314 39.7 7,735 39.9 9,184 43.0
Current 5,630 13.5 5,137 13.3 2,656 13.7 3,193 14.9
Alcoholic drinks
0 drinks per day 14,515 33.8 9,136 23.0 4,784 23.9 7,009 31.7
<1 drink per day 23,322 54.3 24,771 62.3 12,299 61.3 12,111 54.9
1–3 drinks per day 4,037 9.4 4,727 11.9 2,382 11.9 2,297 10.4
3+ drinks per day 1,086 2.5 1,147 2.9 592 3.0 663 3.0
Self-reported general health
Excellent/very good/good 36,189 85.6 36,638 93.3 17,869 90.4 17,868 82.4
Fair/poor 6,094 14.4 2,639 6.7 1,891 9.6 3,814 17.6
Stroke
No 42,293 98.4 39,557 99.4 19,844 98.9 21,112 95.6
Yes 667 1.6 224 0.6 213 1.1 968 4.4
Heart disease
No 39,820 92.7 38,292 96.3 18,924 94.4 17,561 79.5
Yes 3,140 7.3 1,489 3.7 1,133 5.6 4,519 20.5
High blood pressure
No 24,240 60.2 25,179 67.7 11,484 61.5 9,502 46.1
Yes 16,001 39.8 11,997 32.3 7,192 38.5 11,117 53.9
Mammogram in past 3 years
Once or less 13,226 31.0 12,161 30.8 6,043 30.4 6,496 29.8
Yes, more than once 29,408 69.0 27,298 69.2 13,827 69.6 15,327 70.2
Breast Cancer Research Vol 10 No 2 Gierach et al.
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Age at menarche
<13 years 21,222 49.8 18,850 47.8 9,679 48.7 11,036 50.4
13–14 years 17,452 41.0 17,101 43.4 8,407 42.3 8,859 40.5
15+ years 3,909 9.2 3,492 8.9 1,792 9.0 1,981 9.1
Parity
Nulliparous 6,253 14.8 5,996 15.3 2,808 14.2 3,089 14.3
One 4,459 10.6 4,056 10.4 2,009 10.2 2,172 10.0
Two 11,052 26.2 10,488 26.8 5,290 26.8 5,406 25.0
Three or more 20,431 48.4 18,578 47.5 9,608 48.7 10,987 50.7
Age at first live birth
Nulliparous 6,253 14.8 5,996 15.3 2,808 14.2 3,089 14.2
<20 years 7,385 17.4 6,016 15.3 3,319 16.8 3,895 17.9
20–24 years 18,472 43.6 17,112 43.6 8,861 44.9 9,800 45.1
25–29 years 7,636 18.0 7,582 19.3 3,632 18.4 3,739 17.2
30+ years 2,575 6.1 2,499 6.4 1,129 5.7 1,191 5.5
Age at menopause
Premenopausal 1,462 3.4 1,738 4.4 742 3.7 445 2.0
<45 years 2,834 6.6 2,429 6.1 1,266 6.3 1,593 7.2
45–49 years 6,543 15.2 6,316 15.9 2,997 14.9 3,358 15.2
50–54 years 11,362 26.4 11,870 29.8 5,415 27.0 5,732 26.0
55+ years 2,650 6.2 2,555 6.4 1,218 6.1 1,284 5.8
Surgical menopause 16,770 39.0 13,577 34.1 7,754 38.7 8,975 40.6
Postmenopausal, age unknown 1,339 3.1 1,296 3.3 665 3.3 693 3.1
Hormone therapy formulation
Never used 17,328 42.4 15,676 41.2 7,201 37.6 8,371 39.8
Estrogen therapy only 11,901 29.1 10,157 26.7 5,844 30.5 6,724 32.0
Estrogen–progestin therapy 11,681 28.6 12,196 32.1 6,100 31.9 5,945 28.3
Moderate/vigorous physical activity during past 10 years
Never 1,801 4.3 1,033 2.6 545 2.8 878 4.0
Rarely 4,911 11.6 4,012 10.2 1,986 10.1 2,539 11.7
<1 hour/week 4,473 10.6 4,102 10.5 2,107 10.7 2,347 10.8
1–3 hours/week 10,495 24.9 10,085 25.7 5,240 26.6 5,457 25.1
4–7 hours/week 10,379 24.6 10,438 26.6 5,311 26.9 5,371 24.7
>7 hours/week 10,100 24.0 9,548 24.3 4,546 23.0 5,122 23.6
Number breast biopsies
None 32,240 75.8 30,183 76.6 14,985 75.4 16,551 75.8
One 6,819 16.0 6,175 15.7 3,217 16.2 3,428 15.7
Two 1,904 4.5 1,666 4.2 926 4.7 997 4.6
Three or more 1,581 3.7 1,360 3.5 737 3.7 863 4.0
Family history of breast cancer in first degree relative (male or female)
No 29,536 83.5 27,782 83.8 13,814 83.6 14,930 83.4
Yes 5,838 16.5 5,356 16.2 2,708 16.4 2,978 16.6
a
Missing values were excluded from percentage calculations.
Table 1 (Continued)
Distribution of select risk factors across categories of aspirin use among 126,124 women, National Institutes of Health–AARP Study
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Table 2
Distribution of select risk factors across categories of nonaspirin nonsteroidal anti-inflammatory drug (NSAID) use among 126,124
women, National Institutes of Health–AARP Study
Frequency of nonaspirin NSAID use in past 12 months
None <weekly 1–6 times/week 1+/day
Characteristic n %
a
n %
a
n %
a
n %
a
Age at second questionnaire
<57 years 7,112 14.3 9,185 23.4 4,563 24.0 2,955 17.9
57–60 years 8,605 17.3 8,288 21.1 4,171 21.9 3,052 18.4
61–64 years 11,482 23.0 8,854 22.5 4,278 22.5 3,876 23.4
65–68 years 14,666 29.4 8,841 22.5 4,039 21.2 4,399 26.6
69+ years 7,962 16.0 4,136 10.5 1,962 10.3 2,263 13.7
Race/ethnicity
Caucasian/non-Hispanic white 44,909 90.1 35,940 91.4 17,537 92.2 15,103 91.3
Other/unknown 4,918 9.9 3,364 8.6 1,476 7.8 1,442 8.7
Education
<High school/high school grad 16,007 33.1 10,402 27.1 5,595 30.3 4,734 29.5
Post-high school+ 32,364 66.9 27,959 72.9 12,851 69.7 11,312 70.5
Body mass index at baseline
<25 kg/m
2
23,279 48.6 18,527 48.6 7,800 42.4 5,418 33.9
25–30 kg/m
2
15,189 31.7 12,423 32.6 6,194 33.7 5,296 33.2
30+ kg/m
2
9,464 19.7 7,193 18.9 4,413 24.0 5,254 32.9
Smoking
Never 22,702 47.0 17,354 45.5 8,254 44.8 7,062 44.0
Former 18,554 38.4 15,751 41.3 7,708 41.9 6,942 43.2
Current 7,025 14.6 5,023 13.2 2,453 13.3 2,050 12.8
Alcoholic drinks
0 drinks per day 16,225 32.6 9,230 23.5 4,728 24.9 5,121 31.0
<1 drink per day 27,087 54.4 24,388 62.0 11,660 61.3 9,312 56.3
1–3 drinks per day 5,108 10.3 4,570 11.6 2,153 11.3 1,616 9.8
3+ drinks per day 1,407 2.8 1,116 2.8 472 2.5 496 3.0
Self-reported general health
Excellent/very good/good 42,891 87.5 35,824 92.4 16,655 88.8 13,073 80.5
Fair/poor 6,142 12.5 2,966 7.6 2,106 11.2 3,176 19.5
Stroke
No 48,762 97.9 38,882 98.9 18,760 98.7 16,223 98.1
Yes 1,065 2.1 422 1.1 253 1.3 322 1.9
Heart disease
No 44,964 90.2 36,916 93.9 17,658 92.9 14,936 90.3
Yes 4,863 9.8 2,388 6.1 1,355 7.1 1,609 9.7
High blood pressure
No 27,666 59.6 23,960 65.1 10,656 60.1 8,036 51.7
Yes 18,783 40.4 12,847 34.9 7,080 39.9 7,508 48.3
Mammogram in past 3 years
Once or less 17,403 35.3 10,768 27.6 5,095 27.0 4,509 27.5
Yes, more than once 31,949 64.7 28,229 72.4 13,749 73.0 11,904 72.5
Breast Cancer Research Vol 10 No 2 Gierach et al.
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Age at menarche
<13 years 23,714 48.1 18,717 48.0 9,436 50.0 8,816 53.7
13–14 years 21,018 42.6 16,749 43.0 7,752 41.1 6,269 38.2
15+ years 4,604 9.3 3,516 9.0 1,685 8.9 1,336 8.1
Parity
Nulliparous 8,010 16.4 5,540 14.3 2,375 12.7 2,212 13.6
One 5,330 10.9 4,022 10.4 1,794 9.6 1,546 9.5
Two 12,441 25.5 10,535 27.2 5,125 27.3 4,095 25.2
Three or more 23,059 47.2 18,566 48.0 9,445 50.4 8,418 51.7
Age at first live birth
Nulliparous 8,010 16.4 5,540 14.3 2,375 12.6 2,212 13.6
<20 years 7,690 15.7 6,056 15.6 3,559 19.0 3,229 19.8
20–24 years 21,059 43.0 17,194 44.4 8,585 45.7 7,350 45.1
25–29 years 9,058 18.5 7,520 19.4 3,310 17.6 2,676 16.4
30+ years 3,153 6.4 2,439 6.3 948 5.0 844 5.2
Age at menopause
Premenopausal 1,145 2.3 1,864 4.7 886 4.7 487 2.9
<45 years 3,654 7.3 2,377 6.0 1,063 5.6 995 6.0
45–49 years 8,216 16.5 5,941 15.1 2,732 14.4 2,288 13.8
50–54 years 14,355 28.8 11,383 29.0 4,705 24.7 3,895 23.5
55+ years 3,209 6.4 2,519 6.4 1,019 5.4 945 5.7
Surgical menopause 17,713 35.5 13,938 35.5 7,962 41.9 7,430 44.9
Postmenopausal, age unknown 1,535 3.1 1,282 3.3 646 3.4 505 3.1
Hormone therapy formulation
Never used 23,083 48.6 14,199 37.8 5,961 32.9 5,179 32.8
Estrogen therapy only 12,664 26.7 10,499 27.9 5,910 32.7 5,522 35.0
Estrogen–progestin therapy 11,762 24.8 12,876 34.3 6,224 34.4 5,072 32.2
Moderate/vigorous physical activity during past 10 years
Never 1,922 3.9 1,004 2.6 551 2.9 749 4.6
Rarely 5,434 11.1 3,953 10.2 1,993 10.6 2,032 12.5
<1 hour/week 5,034 10.3 4,196 10.8 1,980 10.6 1,815 11.2
1–3 hours/week 12,127 24.8 10,252 26.4 4,815 25.7 4,091 25.2
4–7 hours/week 12,378 25.3 10,169 26.2 4,981 26.6 3,924 24.1
>7 hours/week 12,017 24.6 9,234 23.8 4,397 23.5 3,642 22.4
Number breast biopsies
None 37,903 76.9 29,547 75.9 14,113 74.9 12,243 74.7
One 7,549 15.3 6,236 16.0 3,114 16.5 2,727 16.6
Two 2,042 4.1 1,779 4.6 884 4.7 768 4.7
Three or more 1,793 3.6 1,373 3.5 743 3.9 652 4.0
Family history of breast cancer in first degree relative (male or female)
No 33,976 83.6 27,478 83.7 13,197 83.8 11,295 82.8
Yes 6,643 16.4 5,346 16.3 2,554 16.2 2,347 17.2
a
Missing values were excluded from percentage calculations.
Table 2 (Continued)
Distribution of select risk factors across categories of nonaspirin nonsteroidal anti-inflammatory drug (NSAID) use among 126,124
women, National Institutes of Health–AARP Study
Available online http://breast-cancer-research.com/content/10/2/R38
Page 9 of 13
(page number not for citation purposes)
or prescription NSAID users, results could be biased toward
the null.
In addition, we were unable to separate low-dose from regular-
dose aspirin use; results from the Women's Health Study ran-
domized trial [25], a study conducted using an insurance data-
base [2], and laboratory evidence [27] suggest that doses
higher than the 80 mg aspirin per day typically recommended
for cardiovascular therapy may be required to permanently
inactivate COX-2. If low-dose aspirin users were included in
our exposed group, thereby diluting any effect associated with
regular-dose aspirin use, the results would be biased toward
the null. Although we did not collect information on indication
for use, it is likely that some daily users were taking aspirin for
heart disease prevention given that daily users more frequently
reported history of heart disease. To address the concern that
women using NSAIDS for cardioprotection may be under
closer medical supervision and/or may be more health con-
scious, we additionally controlled for self-reported heart dis-
ease, self-rated health quality, and mammographic screening
– and the results remained unchanged.
Despite these limitations, the NIH–AARP Diet and Health
Study is the one of largest cohorts to date to have evaluated
the association between NSAID type and breast cancer risk by
tumor characteristics, including ER status. The reduced risk of
ER-positive breast cancer we observed with daily aspirin use
is consistent with the mechanism of action of aspirin (but not
nonaspirin NSAIDs), which permanently inactivates COX-2
[29], potentially reducing breast cancer risk via multiple path-
ways, including suppression of estrogen synthesis by
decreased aromatase activity [28]. In addition, our results are
in agreement with findings from the Long Island Breast Cancer
Prevention Project, a population-based case–control study
that reported in 2004 an inverse association with aspirin that
was significantly greater for HR-positive breast cancer than for
HR-negative breast cancer [30]. Since then, two case–control
studies [3,31] and three prospective cohort studies
[16,17,24] have separately investigated the association for
aspirin, with three of the five studies suggesting some protec-
tion against HR-positive breast cancer with aspirin use
[3,16,31].
A US hospital-based study – the Case–Control Surveillance
Study – reported a 26% nonsignificant reduction (95% CI =
0.44 to 1.26) in HR-positive breast cancer associated with
regular (versus <4 times/week) aspirin use [31]. More
recently, a Canadian population-based case–control study
found a 31% reduction (95% CI = 0.56 to 0.86) in ER-posi-
tive/PR-positive breast cancer associated with daily (versus
<daily) aspirin use [3]. The California Teachers Study followed
114,460 women aged 22 to 85 years for 6 years and found
Table 3
Association between nonsteroidal anti-inflammatory drug (NSAID) use and breast cancer among 126,124 women, National
Institutes of Health–AARP Study
Number of
cancers
Person-years Relative risk
a
95% confidence
interval
P value
for trend
NSAID use
Never 667 124,265 1.00 (referent) n/a
Aspirin only 1,085 203,145 0.97 0.88 to 1.07
Non-aspirin NSAID only 874 157,017 1.01 0.92 to 1.12
Both 1,781 334,792 0.95 0.87 to 1.04
Aspirin use
b
Never 1,556 284,342 1.00 (referent) 0.08
<1/week 1,405 265,676 0.95 0.89 to 1.03
1–6/week 716 133,331 0.95 0.87 to 1.04
1+/day 774 145,317 0.93 0.85 to 1.01
Non-aspirin NSAID use
b
Never 1,764 329,944 1.00 (referent) 0.58
<1/week 1,415 262,000 1.00 0.93 to 1.07
1–6/week 693 126,373 1.02 0.93 to 1.11
1+/day 585 109,098 0.96 0.87 to 1.05
a
Adjusted for age (continuous), race, age at first birth, hormone therapy use, number of breast biopsies, alcohol intake, history of hypertension, and
family history of breast cancer in first-degree relative.
b
These models also include terms for frequency of use of opposite NSAID type.
Breast Cancer Research Vol 10 No 2 Gierach et al.
Page 10 of 13
(page number not for citation purposes)
that long-term daily (versus <once/week) aspirin use was
associated with a statistically nonsignificant decreased risk of
ER-positive/PR-positive breast cancer (RR = 0.80, 95% CI =
0.62 to 1.03) [16]. In contrast, the Multiethnic Cohort Study
and the Danish Diet, Cancer and Health Cohort Study found
no protective effect of aspirin use for HR-positive or HR-nega-
tive breast cancer [17,24]. Finally, the Women's Health Study
randomized clinical trial did not observe any significant pat-
terns of risk by HR status with low-dose aspirin use [25].
Therefore, while our findings, along with several others, sug-
gest at least some reduction in ER-positive breast cancer
associated with aspirin use, the evidence is not conclusive and
additional prospective studies with detailed exposure data on
Table 4
Association between nonsteroidal anti-inflammatory drug (NSAID) use and breast cancer by estrogen receptor status, National
Institutes of Health–AARP Study
Estrogen receptor-positive Estrogen receptor-negative
NSAID use Number of
cancers
Person-
years
Relative risk
a
95% confidence
interval
P value
for trend
Number
of cancers
Person-
years
Relative risk
a
95% confidence
interval
P value
for trend
Aspirin use
b
Never 493 280,706 1.00 (referent) 0.06 88 279,308 1.00 (referent) 0.54
<1/week 464 262,491 0.98 0.86 to 1.11 93 261,137 1.09 0.81 to 1.47
1–6/week 243 131,724 1.00 0.86 to 1.17 42 131,022 1.01 0.70 to 1.47
1+/day 223 143,476 0.84 0.71 to 0.98 52 142,852 1.14 0.81 to 1.62
Nonaspirin
NSAID use
b
Never 541 325,816 1.00 (referent) 0.86 108 324,250 1.00 (referent) 0.64
<1/week 466 258,767 1.04 0.92 to 1.18 96 257,460 1.08 0.81 to 1.43
1–6/week 230 124,804 1.07 0.92 to 1.26 36 124,115 0.85 0.58 to 1.25
1+/day 186 107,763 0.98 0.83 to 1.16 36 107,241 0.97 0.66 to 1.42
The threshold for a positive estrogen receptor was ≥10 fmol receptor/mg total protein.
a
Adjusted for age (continuous), race, age at first birth, hormone therapy use,
number of breast biopsies, alcohol intake, history of hypertension, and family history of breast cancer in first-degree relative.
b
These models also include terms for
frequency of use of opposite NSAID type.
Table 5
Association between nonsteroidal anti-inflammatory drug (NSAID) use and breast cancer according to stage, National Institutes of
Health–AARP Study
In situ breast cancer Invasive breast cancer
NSAID use Number of
cancers
Person-
years
Relative risk
a
95% confidence
interval
P value
for trend
Number of
cancers
Person-
years
Relative risk
a
95% confidence
interval
P value
for trend
Aspirin use
b
Never 298 280,077 1.00 (referent) 0.02 1,254 283,247 1.00 (referent) 0.37
<1/week 233 261,641 0.80 0.67 to 0.96 1,166 264,821 0.99 0.91 to 1.07
1–6/week 124 131,305 0.85 0.69 to 1.05 589 132,899 0.98 0.88 to 1.08
1+/day 122 143,137 0.78 0.63 to 0.96 648 144,854 0.96 0.87 to 1.06
Non-aspirin
NSAID use
b
Never 292 324,890 1.00 (referent) 0.45 1,463 328,884 1.00 (referent) 0.88
<1/week 269 258,097 1.14 0.96 to 1.35 1,140 261,013 0.97 0.90 to 1.05
1–6/week 122 124,433 1.06 0.85 to 1.31 569 125,934 1.01 0.92 to 1.12
1+/day 91 107,466 0.87 0.69 to 1.10 494 108,757 0.98 0.89 to 1.09
a
Adjusted for age (continuous), race, age at first birth, hormone therapy use, number of breast biopsies, alcohol intake, history of hypertension, and family history of
breast cancer in first-degree relative.
b
These models also include terms for frequency of use of opposite NSAID type.
Available online http://breast-cancer-research.com/content/10/2/R38
Page 11 of 13
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the dose, frequency, duration, and indication are needed.
We found stronger inverse associations with in situ breast
cancer than invasive breast cancer. Among the few prior stud-
ies that have reported results separately for in situ breast can-
cer and invasive breast cancer, two case–control studies
reported decreased risks of both in situ and invasive breast
cancers associated with aspirin [30] and with any NSAID use
[32], but the findings for in situ breast cancer were not statis-
tically significant in either study. The Iowa Women's Health
cohort study reported a reduction in breast cancer risk with
increased frequency of aspirin, but not with nonaspirin
NSAIDs, for both in situ and invasive disease [21]. Both in situ
and invasive breast tumors express COX-2 [47], suggesting
that upregulation of COX-2 may be an early event in carcino-
genesis. Higher rates of COX-2 expression in in situ com-
pared with invasive tumors have led investigators to suggest
that the potential therapeutic impact of COX-2 inhibition may
be more relevant for in situ breast cancer than invasive breast
cancer (reviewed in [48]). The inverse association for in situ
breast cancer associated with aspirin use in the present study
may therefore be biologically plausible and warrants further
investigation.
We observed no variation in risk with HT, smoking status, or
BMI, and our findings are generally consistent with previous
investigations. For the most part, tests for interactions
between HT and NSAID use have been statistically nonsignif-
icant across case–control studies [30,33] and cohort studies
[13,17,22,24,25]; however, two cohort studies have sug-
gested the protective effect of NSAIDs may be attenuated
among HT users [18,20]. In line with data suggesting that
proinflammatory tobacco carcinogens may alter the effective-
ness of chemopreventive agents [49], the Women's Health
Study found that low-dose aspirin use was protective among
former smokers but was associated with an increased risk
among never smokers (for interaction P = 0.09) [25]. We,
along with a Canadian population-based case–control study,
however, did not observe effect modification by smoking [3].
Consistent with our findings, two case–control studies
[32,33] and seven prospective studies
[13,17,18,20,22,24,25] have reported no significant interac-
tions between BMI and NSAID use with respect to breast can-
cer risk.
Conclusion
In summary, our results do not support an important influence
of NSAIDs on total breast cancer risk. Daily aspirin use, how-
ever, appeared to offer some protection for ER-positive breast
cancer in this population. In addition, our findings suggest that
the associations for aspirin use may vary by tumor stage. Our
results provide support for further evaluating relationships in
prospective studies with well-defined measures of NSAID use
by NSAID type, by breast cancer stage, and by ER status.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
AS, ARH, and MFL participated in the acquisition of data.
GLG, LAB, JVL Jr, AS, and MFL were involved with the study
concept and design. GLG, JVL Jr, MFL, DR, and LAB contrib-
Table 6
Association between nonsteroidal anti-inflammatory drug (NSAID) use and breast cancer according to stage among screened
women, National Institutes of Health–AARP Study
In situ breast cancer Invasive breast cancer
NSAID use Number of
cancers
Person-
years
Relative risk
a
95% confidence
interval
P value
for trend
Number of
cancers
Person-
years
Relative risk
a
95% confidence
interval
P value
for trend
Aspirin use
b
Never 241 192,125 1.00 (referent) 0.02 916 194,396 1.00 (referent) 0.15
<1/week 180 179,747 0.77 0.63 to 0.93 847 181,986 0.98 0.89 to 1.07
1–6/week 97 90,680 0.82 0.65 to 1.05 402 91,715 0.90 0.80 to 1.01
1+/day 96 99,793 0.75 0.59 to 0.95 476 101,064 0.95 0.85 to 1.06
Non-aspirin
NSAID use
b
Never 218 209,044 1.00 (referent) 0.50 982 211,655 1.00 (referent) 0.62
<1/week 222 185,624 1.16 0.95 to 1.40 852 187,741 0.98 0.89 to 1.07
1–6/week 97 90,035 1.03 0.81 to 1.31 428 91,161 1.03 0.92 to 1.16
1+/day 76 77,462 0.89 0.69 to 1.16 384 78,439 1.02 0.91 to 1.15
This analysis was restricted to women who reported ≥2 mammograms in the past 3 years.
a
Adjusted for age (continuous), race, age at first birth, hormone therapy use,
number of breast biopsies, alcohol intake, history of hypertension, and family history of breast cancer in first-degree relative.
b
These models also include terms for
frequency of use of opposite NSAID type.
Breast Cancer Research Vol 10 No 2 Gierach et al.
Page 12 of 13
(page number not for citation purposes)
uted to the statistical analyses. GLG, JVL Jr, and LAB partici-
pated in manuscript preparation. All authors participated in the
interpretation of results and critical revision of the manuscript
for important intellectual content. All authors read and
approved the final manuscript.
Acknowledgements
The authors are indebted to the participants in the NIH–AARP Diet and
Health Study for their outstanding cooperation. The authors thank Traci
Mouw, former study coordinator of the NIH–AARP Diet and Health
Study, for research assistance. This research was supported in part by
the Intramural Research Program of the NIH, National Cancer Institute.
Cancer incidence data from the Atlanta metropolitan area were col-
lected by the Georgia Center for Cancer Statistics, Department of Epi-
demiology, Rollins School of Public Health, Emory University. Cancer
incidence data from California were collected by the California Depart-
ment of Health Services, Cancer Surveillance Section. Cancer inci-
dence data from the Detroit metropolitan area were collected by the
Michigan Cancer Surveillance Program, Community Health Administra-
tion, state of Michigan. The Florida cancer incidence data used in this
report were collected by the Florida Cancer Data System under contract
to the Department of Health. The views expressed herein are solely
those of the authors and do not necessarily reflect those of the contrac-
tor or Department of Health. Cancer incidence data from Louisiana were
collected by the Louisiana Tumor Registry, Louisiana State University
Medical Center, New Orleans. Cancer incidence data from New Jersey
were collected by the New Jersey State Cancer Registry, Cancer Epide-
miology Services, New Jersey State Department of Health and Senior
Services. Cancer incidence data from North Carolina were collected by
the North Carolina Central Cancer Registry. Cancer incidence data from
Pennsylvania were supplied by the Division of Health Statistics and
Research, Pennsylvania Department of Health, Harrisburg, Pennsylva-
nia. The Pennsylvania Department of Health specifically disclaims
responsibility for any analyses, interpretations or conclusions.
References
1. Harris RE, Beebe-Donk J, Alshafie GA: Reduction in the risk of
human breast cancer by selective cyclooxygenase-2 (COX-2)
inhibitors. BMC Cancer 2006, 6:27.
2. Rahme E, Ghosn J, Dasgupta K, Rajan R, Hudson M: Association
between frequent use of nonsteroidal anti-inflammatory drugs
and breast cancer. BMC Cancer 2005, 5:159.
3. Kirsh VA, Kreiger N, Cotterchio M, Sloan M, Theis B: Nonsteroidal
antiinflammatory drug use and breast cancer risk: subgroup
findings. Am J Epidemiol 2007, 166:709-716.
4. Khuder SA, Mutgi AB: Breast cancer and NSAID use: a meta-
analysis. Br J Cancer 2001, 84:1188-1192.
5. Harris RE, Beebe-Donk J, Doss H, Burr Doss D: Aspirin, ibupro-
fen, and other non-steroidal anti-inflammatory drugs in cancer
prevention: a critical review of non-selective COX-2 blockade
(review). Oncol Rep 2005, 13:559-583.
6. Bosetti C, Gallus S, La Vecchia C: Aspirin and cancer risk: an
updated quantitative review to 2005. Cancer Causes Control
2006, 17:871-888.
7. Mangiapane S, Blettner M, Schlattmann P: Aspirin use and
breast cancer risk: a meta-analysis and meta-regression of
observational studies from 2001 to 2005. Pharmacoepidemiol
Drug Saf 2008, 17:115-124.
8. Paganini-Hill A, Chao A, Ross RK, Henderson BE: Aspirin use
and chronic diseases: a cohort study of the elderly. BMJ 1989,
299:1247-1250.
9. Egan KM, Stampfer MJ, Giovannucci E, Rosner BA, Colditz GA:
Prospective study of regular aspirin use and the risk of breast
cancer. J Natl Cancer Inst 1996, 88:988-993.
10. Friis S, Sorensen HT, McLaughlin JK, Johnsen SP, Blot WJ, Olsen
JH: A population-based cohort study of the risk of colorectal
and other cancers among users of low-dose aspirin. Br J
Cancer 2003, 88:684-688.
11. Sorensen HT, Friis S, Norgard B, Mellemkjaer L, Blot WJ,
McLaughlin JK, Ekbom A, Baron JA: Risk of cancer in a large
cohort of nonaspirin NSAID users: a population-based study.
Br J Cancer 2003, 88:1687-1692.
12. García Rodríguez LA, González-Pérez A:
Risk of breast cancer
among users of aspirin and other anti-inflammatory drugs. Br
J Cancer 2004, 91:525-529.
13. Jacobs EJ, Thun MJ, Connell CJ, Rodriguez C, Henley SJ, Feigel-
son HS, Patel AV, Flanders WD, Calle EE: Aspirin and other non-
steroidal anti-inflammatory drugs and breast cancer incidence
in a large U.S. cohort. Cancer Epidemiol Biomarkers Prev 2005,
14:261-264.
14. Jacobs EJ, Thun MJ, Bain EB, Rodriguez C, Henley SJ, Calle EE: A
large cohort study of long-term daily use of adult-strength
aspirin and cancer incidence. J Natl Cancer Inst 2007,
99:608-615.
15. Vogel U, Christensen J, Nexo BA, Wallin H, Friis S, Tjonneland A:
Peroxisome profilerator-activated receptorgamma2 Pro12Ala,
interaction with alcohol intake and NSAID use, in relation to
risk of breast cancer in a prospective study of Danes. Carcino-
genesis 2007, 28:427-434.
16. Marshall SF, Bernstein L, Anton-Culver H, Deapen D, Horn-Ross
PL, Mohrenweiser H, Peel D, Pinder R, Purdie DM, Reynolds P,
Stram D, West D, Wright WE, Ziogas A, Ross RK: Nonsteroidal
anti-inflammatory drug use and breast cancer risk by stage
and hormone receptor status. J Natl Cancer Inst 2005,
97:805-812.
17. Friis S, Thomassen L, Sorensen HT, Tjonneland A, Overvad K,
Cronin-Fenton DP, Vogel U, McLaughlin JK, Blot WJ, Olsen JH:
Nonsteroidal anti-inflammatory drug use and breast cancer
risk: a Danish cohort study. Eur J Cancer Prev 2008, 17:88-96.
18. Ready A, Velicer CM, McTiernan A, White E: NSAID use and
breast cancer risk in the VITAL cohort. Breast Cancer Res Treat
2007. DOI 10.1007/s10549-007-9665-x
19. Schreinemachers DM, Everson RB: Aspirin use and lung, colon,
and breast cancer incidence in a prospective study. Epidemi-
ology 1994, 5:138-146.
20. Harris RE, Kasbari S, Farrar WB: Prospective study of nonster-
oidal anti-inflammatory drugs and breast cancer. Oncol Rep
1999, 6:71-73.
21. Johnson TW, Anderson KE, Lazovich D, Folsom AR: Association
of aspirin and nonsteroidal anti-inflammatory drug use with
breast cancer. Cancer Epidemiol Biomarkers Prev 2002,
11:1586-1591.
22. Harris RE, Chlebowski RT, Jackson RD, Frid DJ, Ascenseo JL,
Anderson G, Loar A, Rodabough RJ, White E, McTiernan A,
Women's Health Initiative: Breast cancer and nonsteroidal anti-
inflammatory drugs: prospective results from the Women's
Health Initiative. Cancer Res 2003, 63:6096-6101.
23. Gallicchio L, Visvanathan K, Burke A, Hoffman SC, Helzlsouer KJ:
Nonsteroidal anti-inflammatory drugs and the risk of develop-
ing breast cancer in a population-based prospective cohort
study in Washington County, MD. Int J Cancer 2007,
121:211-215.
24. Gill JK, Maskarinec G, Wilkens LR, Pike MC, Henderson BE, Kolo-
nel LN: Nonsteroidal antiinflammatory drugs and breast cancer
risk: the multiethnic cohort. Am J Epidemiol 2007,
166:1150-1158.
25. Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, Manson JE,
Hennekens CH, Buring JE: Low-dose aspirin in the primary pre-
vention of cancer: the Women's Health Study: a randomized
controlled trial. JAMA 2005, 294:47-55.
26. Thun MJ, Henley SJ, Patrono C: Nonsteroidal anti-inflammatory
drugs as anticancer agents: mechanistic, pharmacologic, and
clinical issues. J Natl Cancer Inst 2002, 94:252-266.
27. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G: Platelet-
active drugs: the relationships among dose, effectiveness, and
side effects: the Seventh ACCP Conference on Antithrombotic
and Thrombolytic Therapy. Chest 2004, 126:234S-264S.
28. Singh-Ranger G, Salhab M, Mokbel K: The role of cyclooxygen-
ase-2 in breast cancer: review. Breast Cancer Res Treat 2007.
DOI 10.1007/s10549-007-9641-5
29. Kadar D: Anti-inflammatory analgesics. In Principles of Medical
Pharmacology Edited by: Kalant H, Roschlau WHE. New York:
Oxford University Press; 1998:410-430.
Available online http://breast-cancer-research.com/content/10/2/R38
Page 13 of 13
(page number not for citation purposes)
30. Terry MB, Gammon MD, Zhang FF, Tawfik H, Teitelbaum SL, Brit-
ton JA, Subbaramaiah K, Dannenberg AJ, Neugut AI: association
of frequency and duration of aspirin use and hormone recep-
tor status with breast cancer risk. JAMA 2004,
291:2433-2440.
31. Zhang Y, Coogan PF, Palmer JR, Strom BL, Rosenberg L: Use of
nonsteroidal antiinflammatory drugs and risk of breast cancer:
the Case–Control Surveillance Study revisited. Am J Epidemiol
2005, 162:165-170.
32. Moorman P, Grubber J, Millikan R, Newman B: Association
between non-steroidal anti-inflammatory drugs (NSAIDs) and
invasive breast cancer and carcinoma in situ of the breast.
Cancer Causes Control 2003, 14:915-922.
33. Cotterchio M, Kreiger N, Sloan M, Steingart A: Nonsteroidal anti-
inflammatory drug use and breast cancer risk. Cancer Epide-
miol Biomarkers Prev 2001, 10:1213-1217.
34. Schatzkin A, Subar AF, Thompson FE, Harlan LC, Tangrea J, Hol-
lenbeck AR, Hurwitz PE, Coyle L, Schussler N, Michaud DS,
Freedman LS, Brown CC, Midthune D, Kipnis V: Design and ser-
endipity in establishing a large cohort with wide dietary intake
distributions: the National Institutes of Health-American Asso-
ciation of Retired Persons Diet and Health Study. Am J
Epidemiol 2001, 154:1119-1125.
35. Chandrasekharan NV, Dai H, Roos KLT, Evanson NK, Tomsik J,
Elton TS, Simmons DL: COX-3, a cyclooxygenase-1 variant
inhibited by acetaminophen and other analgesic/antipyretic
drugs: cloning, structure, and expression. Proc Natl Acad Sci
USA 2002, 99:13926-13931.
36. ICD-O-3 Coding Materials [http://seer.cancer.gov/icd-o-3/
]
37. Michaud DS, Midthune D, Hermansen S, Leitzmann M, Harlan LC,
Kipnis V, Schatzkin A: Comparison of cancer registry case
ascertainment with SEER estimates and self-reporting in a
subset of the NIH-AARP Diet and Health Study. J Registry
Manage 2005, 32:70-75.
38. Thiébaut AC, Bénichou J: Choice of time-scale in Cox's model
analysis of epidemiologic cohort data: a simulation study. Stat
Med 2004, 23:3803-3820.
39. Gail MH, Lubin JH, Rubinstein LV: Likelihood calculations for
matched case–control studies and survival studies with tied
death times. Biometrika 1981, 68:703-707.
40. Coogan PF, Rao SR, Rosenberg L, Palmer JR, Strom BL, Zauber
AG, Stolley PD, Shapiro S: The relationship of nonsteroidal
anti-inflammatory drug use to the risk of breast cancer. Prev
Med 1999, 29:72-76.
41. Harris RE, Namboodiri K, Stellman SD, Wynder EL: Breast cancer
and NSAID use: heterogeneity of effect in a case–control
study. Prev Med 1995, 24:119-120.
42. Harris RE, Namboodiri KK, Farrar WB: Nonsteroidal antiinflam-
matory drugs and breast cancer. Epidemiology 1996,
7:203-205.
43. Sharpe CR, Collet JP, McNutt M, Belzile E, Boivin JF, Hanley JA:
Nested case–control study of the effects of non-steroidal anti-
inflammatory drugs on breast cancer risk and stage. Br J
Cancer 2000, 83:112-120.
44. Swede H, Mirand AL, Menezes RJ, Moysich KB: Association of
regular aspirin use and breast cancer risk. Oncology 2005,
68:40-47.
45. Curhan GC, Bullock AJ, Hankinson SE, Willett WC, Speizer FE,
Stampfer MJ: Frequency of use of acetaminophen, nonsteroi-
dal anti-inflammatory drugs, and aspirin in US women. Phar-
macoepidemiol Drug Saf 2002, 11:687-693.
46. Paulose-Ram R, Hirsch R, Dillon C, Losonczy K, Cooper M, Ostch-
ega Y: Prescription and non-prescription analgesic use among
the US adult population: results from the third National Health
and Nutrition Examination Survey (NHANES III). Pharmacoep-
idemiol Drug Saf
2003, 12:315-326.
47. Leo C, Faber S, Hentschel B, Höckel M, Horn LC: The status of
cyclooxygenase-2 expression in ductal carcinoma in situ
lesions and invasive breast cancer correlates to cyclooxygen-
ase-2 expression in normal breast tissue. Ann Diagn Pathol
2006, 10:327-332.
48. Howe LR: Inflammation and breast cancer. Cyclooxygenase/
prostaglandin signaling and breast cancer. Breast Cancer Res
2007, 9:210.
49. Mayne ST, Lippman SM: Cigarettes: a smoking gun in cancer
chemoprevention. J Natl Cancer Inst 2005, 97:1319-1321.
