Context Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs)
has been associated with a decrease in the risk of several cancers, including
breast cancer. NSAIDs inhibit cyclooxygenase activity and thereby reduce prostaglandin
synthesis; prostaglandins stimulate aromatase gene expression and thereby
stimulate estrogen biosynthesis. Given the importance of estrogen in the pathogenesis
of breast cancer, the ability of aspirin and other NSAIDs to protect against
breast cancer could vary according to hormone receptor status.
Objectives To determine the association between the frequency and duration of use
of aspirin and other NSAIDs and breast cancer risk and to investigate whether
any observed association is more pronounced for women with hormone receptor–positive
breast cancers.
Design, Setting, and Patients Population-based case-control study of women with breast cancer, including
in-person interviews conducted on Long Island, NY, during 1996-1997 (1442
cases and 1420 controls).
Main Outcome Measure Incident invasive and in situ breast cancer by aspirin and NSAID use
and hormone receptor status.
Results Ever use of aspirin or other NSAIDs at least once per week for 6 months
or longer was reported in 301 cases (20.9%) and 345 controls (24.3%) (odds
ratio [OR], 0.80; 95% confidence interval [CI], 0.66-0.97 for ever vs nonusers).
The inverse association was most pronounced among frequent users (≥7 tablets
per week) (OR, 0.72; 95% CI, 0.58-0.90). The results for ibuprofen, which
was used by fewer women on a regular basis, were generally weaker (OR, 0.78;
95% CI, 0.55-1.10 for <3 times per week vs OR, 0.92; 95% CI, 0.70-1.22
for ≥3 times per week). Use of acetaminophen, an analgesic that does not
inhibit prostaglandin synthesis, was not associated with a reduction in the
incidence of breast cancer. The reduction in risk with aspirin use was seen
among those with hormone receptor–positive tumors (OR, 0.74; 95% CI,
0.60-0.93) but not for women with hormone receptor–negative tumors (OR,
0.97; 95% CI, 0.67-1.40).
Conclusion These data add to the growing evidence that supports the regular use
of aspirin and other NSAIDs (which may operate through inhibition of estrogen
biosynthesis) as effective chemopreventive agents for breast cancer.
While cancer epidemiology and prevention have traditionally focused
on the identification and modification of lifestyle factors that may increase
or decrease the risk of various cancers, much recent attention has been centered
on chemoprevention, the use of chemical agents to prevent or inhibit the carcinogenic
process. Significant success has been achieved in this area with the use of
hormonal therapy, with agents such as tamoxifen, to prevent breast cancer
in women at high risk and the use of aspirin and other nonsteroidal anti-inflammatory
drugs (NSAIDs) to prevent colorectal neoplasia.1-5
Over the past decade, numerous studies have suggested that inhibition
of prostaglandin synthesis is a rational approach to cancer prevention. Cyclooxygenase
(COX) catalyzes the synthesis of prostaglandins. NSAIDs inhibit COX and thereby
prostaglandin production, and they have been shown to protect against cancer
in experimental animals.6,7 Organ
site-specific effects, such as modulation of estrogen biosynthesis in breast
tissue, might also be relevant.8 The final
step in estrogen biosynthesis is catalyzed by aromatase cytochrome P450 (aromatase
gene), the product of cytochrome P19 (CYP19). Prostaglandin E2 increases
aromatase gene expression and thereby estrogen production in cultured cells.9 Consistent with this, a positive correlation has been
observed between the level of COX and expression of CYP19 in human breast
cancer.10 Progesterone synthesis can also be
stimulated by PGE2.11 Thus, the
use of NSAIDs to inhibit prostaglandin-driven production of estrogen or progesterone
may be a means to prevent breast cancer. If so, we would predict that the
protective effects of NSAIDs would be greater for hormone receptor–positive
than for hormone receptor–negative breast cancer.
While most of the epidemiologic studies that have examined the association
between aspirin/NSAID use and breast cancer support at least a 20% to 40%
reduction in risk,12-21 prior
studies have not explored whether the protective effect of NSAIDs varies as
a function of estrogen receptor (ER) or progesterone receptor (PR) status.
We examined these issues using data from a large population-based case-control
study.
A population-based case-control study of breast cancer, the Long Island
Breast Cancer Study Project was conducted on Long Island, NY, in Nassau and
Suffolk counties. Details of the overall study design were published previously
and are summarized briefly here.22 Cases were
English-speaking women with newly diagnosed in situ or invasive breast cancer
diagnosed between August 1, 1996, and July 31, 1997. There were no age or
race restrictions and women ranged in age from 20 to 98 years. The study population
was predominantly white (93.8% of cases and 91.8% of controls identified themselves
as white, 4.6% of cases and 5.5% as black, and 1.7% of cases and 2.7% of controls
as other race).22 In a separate question on
Hispanic ethnicity, 3.8% of cases and 4.0% of controls identified themselves
as Hispanic, regardless of race.22 In-person
interviews were completed for 1508 cases (82.1% of eligible cases). Controls
were randomly selected through random-digit-dialing methods (for women aged
<65 years) and Health Care Financing Administration (HCFA) lists (for women
aged ≥65 years), and frequency-matched to cases in 5-year age groups. In-person
interviews were completed for 1556 controls (62.8% of eligible controls).
Reasons for nonparticipation included subject refusal, 12.4% of cases and
21.6% of controls; too ill, cognitively impaired, or deceased, 4.1% of cases
and 7.8% of controls; unlocatable, moved out of area, or other, 1.4% of cases
and 7.9% of controls.22 Of those who participated,
92.2% of the cases and 80% of the controls reported having a mammogram within
the past 5 years. A summary of the traditional breast cancer risk factors
for this study were published previously and are summarized briefly here.22 Breast cancer risk factors found to be related to
risk in this study population include lower parity, late age at first birth,
little or no breastfeeding, and family history of breast cancer. The institutional
review boards of all the participating institutions approved the study protocol,
and the individual women all signed informed consent forms.
Women were asked to report their intake of aspirin, ibuprofen, and acetaminophen;
1442 cases (96%) and 1420 controls (91%) completed this section of the interviewer-administered,
structured questionnaire. Ever use was defined as taking aspirin, ibuprofen,
and/or acetaminophen at least once a week for 6 months or longer. The questionnaire
also included separate questions on duration and frequency of use. Information
on the calendar years or age at medication use was also collected. We did
not specifically ask about dose. Because the interviews took place after the
breast cancer was diagnosed, we truncated all exposure information to 12 months
prior to the reference age (based on age at diagnosis for the cases and corresponding
age for controls).
In addition to separate measures of duration (measured in years) and
frequency (measured in tablets per week), we derived composite measures based
on duration and frequency to examine the combined effect. We also created
a measure of regularity defined as women who used aspirin at least 4 times
per week for at least 3 months and initiated use at least 1 year prior to
the reference age. This definition was used for comparison with published
studies using this definition of regularity. Finally, we assessed the effects
of cessation by considering the following categories: current users, former
users who stopped using less than 5 years ago, and former users who stopped
using 5 or more years ago.
Acetaminophen use was specifically asked for comparison with the NSAIDs.
We did not expect there to be any biological basis for an association with
acetaminophen use but since other lifestyle factors and also response patterns
may be similar between NSAIDs and acetaminophen use, it would provide a worthwhile
comparison to see if the association was specific to aspirin and other NSAIDs.
We used other data from the main questionnaire including detailed information
on medical history, reproductive history, exogenous hormone use, menopausal
status, body mass index (BMI), cigarette smoking, alcohol intake, family history
of breast cancer, and demographic information (the questionnaire is available
at http://epi.grants.cancer.gov/LIBCSP/projects/Questionnaire.html).
Information on hormone receptor status (ER and PR) and stage of disease (in
situ vs invasive) was obtained from the pathology reports in the medical records
of the breast cancer cases.22
The potential confounders that we considered fall into 2 groups: those
variables that a priori we thought might be related to the exposure and also
were risk factors for the disease and those variables that previously published
studies had considered as confounders as well as other breast cancer risk
factors. Confounders in these 2 groups were group a: age at diagnosis, race,
education, use of hormone therapy, oral contraceptive use, hypertension, migraine
headache, myocardial infarction, and stroke; group b: age at menarche, menopausal
status, age at first birth, active smoking status, alcohol drinking, family
history of breast cancer, history of breast biopsy, BMI, change in BMI, prior
hysterectomy, lactation history, parity, and incomplete pregnancies.
We assessed confounding by first comparing each potential confounder
with exposure among controls and then with breast cancer status among unexposed.23 Second, we compared the change in estimate for the
exposure coefficient between statistical models with and without the potential
confounder. Unconditional logistic regression was used to estimate odds ratios
(ORs) and 95% confidence intervals (CIs), adjusting for potential confounding
variables.24 Variables were kept in the final
model if they altered the parameter estimates on the exposure by at least
10%. With our sample size, we had power to detect associations of the following
magnitudes for aspirin, ibuprofen, and acetaminophen, respectively: 0.78,
0.73, 0.71.
Effect modification by age, menopausal status, or hormone therapy was
first examined through use of stratified analysis, running separate models
for each subgroup, and then by comparing the log-likelihood statistic for
models that included a multiplicative interaction term in the logistic regression
model to those without.24 Differences in risk
estimates by hormone receptor status and stage of disease were examined using
polytomous logistic regression.24 These models
categorized the dependent variable into 5 groups based on ER positivity (ER+)
or negativity (ER−) and PR positivity (PR+) or negativity (PR−):
ER+PR+, ER+PR−, ER−PR+, ER−PR−, and controls. Finally,
we performed sensitivity analyses to evaluate the impact of missing data on
the overall conclusions from the study. SAS version 8 (SAS Institute Inc,
Cary, NC) was used to analyze the data.
Overall, 301 cases (20.9%) and 345 controls (24.3%) reported ever use
of aspirin, defined as at least once per week for 6 months or longer. Ever
use of aspirin was inversely associated with breast cancer risk (OR, 0.80;
95% CI, 0.66-0.97 for ever vs never use) (Table 1). Associations between ever use of aspirin and in situ and
invasive cancer were of similar magnitude but only statistically significant
among invasive cases (OR, 0.77; 95% CI, 0.63-0.92 for invasive cases vs controls
and OR, 0.83; 95% CI, 0.59-1.18 for in situ cases vs controls). Fewer women
used ibuprofen (176 cases [12.2%] and 202 controls [14.2%]). Ever use of ibuprofen
was not statistically significantly associated with breast cancer risk (OR,
0.91; 95% CI, 0.72-1.16 for ever vs never use). Acetaminophen use was reported
by 172 cases (12%) and 184 controls (13%). As expected, there was no association
with breast cancer risk (OR, 1.02; 95% CI, 0.80-1.31 for ever vs never use).
Table 1 also reports the
overall findings stratified by menopausal status. These results support an
inverse association between ever use of aspirin and breast cancer risk in
both premenopausal and postmenopausal women. The reduced OR is more pronounced
among postmenopausal women (OR, 0.77, 95% CI, 0.62-0.97) than for premenopausal
women (OR, 0.83; 95% CI, 0.56-1.22). There was some suggestion of an inverse
association for ibuprofen use, but only among postmenopausal women (OR, 0.79;
95% CI, 0.58-1.08).
Frequency of aspirin use was associated with breast cancer risk (Table 2). Daily use was inversely associated
with breast cancer, but not less frequent use (OR, 0.72; 95% CI, 0.58-0.90
for ≥7 times per week vs OR, 0.95; 95% CI, 0.72-1.26 for <7 times per
week vs nonusers). Short (<5 years) and long (≥5 years) duration of
use had similar associations with breast cancer risk (OR, 0.81; 95% CI, 0.62-1.08
and OR, 0.81; 95% CI, 0.65-1.02, respectively). Composite measures of duration
and frequency suggested that the effects for frequency were stronger than
they were for duration (OR, 0.74; 95% CI, 0.54-1.01 for frequent but short
duration vs OR, 0.77; 95% CI, 0.57-1.04 for frequent but long duration). The
inverse association was of borderline statistical significance for current
users (OR, 0.81; 95% CI, 0.65-1.00). Regular use (defined as ≥4 times per
week for ≥3 months) was also associated with decreased breast cancer risk
(OR, 0.74; 95% CI, 0.59-0.92). While we had information on frequency and duration
of use as described, dose information (81 mg vs 325 mg) was not collected.
There were no statistically significant multiplicative interactions
for aspirin use by age, menopausal status, or hormone therapy (data not shown).
However, the magnitude of the effect for ever use of aspirin was more pronounced
among postmenopausal women (OR, 0.73; 95% CI, 0.59-0.90) compared with premenopausal
women (OR, 0.89; 95% CI, 0.62-1.26).
Patterns for duration and frequency of ibuprofen use were less clear
(Table 3). Unlike the findings
with aspirin, increasing frequency of ibuprofen use was not associated with
decreasing risk (OR, 0.78; 95% CI, 0.55-1.10 for <3 times per week vs OR,
0.92; 95% CI, 0.70-1.22 for ≥3 times per week). Measures combining duration
and frequency suggested no clear pattern. A combined analysis considering
any aspirin and/or ibuprofen use resulted in a statistically significant inverse
association for any NSAID use (OR, 0.84; 95% CI, 0.72-0.99) and frequent use
(≥7 times per week) (OR, 0.77; 95% CI, 0.63-0.94).
As expected, there was no association between frequency and duration,
nor any composite measure of frequency and duration, for acetaminophen use.
For example, neither regular use (those who used acetaminophen ≥4 times
per week for ≥3 months) nor nonregular use was associated with breast cancer
risk (OR, 0.95; 95% CI, 0.65-1.39, and OR, 1.12; 95% CI, 0.80-1.57, respectively).
We examined the association between aspirin use and breast cancer risk
by subdividing the cases by hormone receptor status (ER+, ER−, PR+,
and PR−). The inverse association between ever use of aspirin and breast
cancer risk was evident for every subgroup except ER−PR− (OR,
0.75; 95% CI, 0.58-0.97 for ER+PR+; OR, 0.75; 95% CI, 0.47-1.20 for ER+PR−;
OR, 0.36; 95% CI, 0.14-0.90 for ER−PR+; and OR, 0.93, 95% CI, 0.63-1.38
for ER−PR−). Because effect estimates for ever vs never aspirin
use were similar for the 3 subgroups with at least 1 positive hormone receptor,
we combined the first 3 groups for added statistical power (Table 4). The effect of ever use of aspirin and frequency appeared
limited to the hormone receptor–positive subgroup. However, effect sizes
for duration and regular use followed similar patterns for the hormone receptor–positive
and hormone receptor–negative subgroups.
We further examined whether the differences by hormone receptor status
were seen among premenopausal and postmenopausal women separately or if they
were reflecting differences only in menopausal status because premenopausal
women tend to have more hormone receptor–negative tumors. Among postmenopausal
women, the inverse association with aspirin use was seen among women with
hormone receptor–positive tumors (OR, 0.70; 95% CI, 0.54-0.91) and not
among women with hormone receptor–negative tumors (OR, 0.91; 95% CI,
0.58-1.42). Among premenopausal women, there was a more modest inverse association
that was not statistically significant (OR, 0.87; 95% CI, 0.56-1.36 for women
with hormone receptor–positive tumors vs OR, 1.20; 95% CI, 0.63-2.29
for women with hormone receptor–negative tumors). There was a more marked
difference in premenopausal women among regular users (OR, 0.65; 95% CI, 0.35-1.20
for hormone receptor–positive tumors vs OR, 1.33; 95% CI, 0.61-2.89
for hormone receptor–negative tumors). These results suggest that differences
by hormone receptor status are not merely reflecting differences in menopausal
status.
Because 4% of cases and 9% of controls were missing information on aspirin
use, we examined characteristics of those missing data and used this information
in sensitivity analyses. Cases with missing aspirin data were younger, less
likely to use hormone therapy, less likely to have hypertension, less likely
to report migraine, and less likely to have had a myocardial infarction than
were cases with aspirin data available (data not shown). Because all of these
factors were inversely associated with aspirin use, the cases with missing
data were less likely to have taken aspirin. In contrast, controls with missing
aspirin data were older and more likely to have reported hypertension and
migraine. Thus, these controls are more likely to have been aspirin users.
Sensitivity analyses resulted in statistically significant estimates of ORs
ranging from 0.5 to 0.8 for the association between ever aspirin use and breast
cancer risk if complete data were available (data not shown). These estimates
are consistent with the overall finding of a protective effect, which demonstrates
that our results are unlikely to be substantially biased by the missing information.
All use of aspirin, NSAIDs, and acetaminophen was truncated to 1 year
prior to diagnosis (or corresponding reference age for controls) to be consistent
with other published studies and also to ensure that medication use started
at the time of diagnosis was not counted as contributing to the etiology of
the disease. Current use was also defined as use 1 year prior to diagnosis
(or corresponding reference age for controls). Although very few cases started
aspirin, ibuprofen, and/or acetaminophen use within the same year as diagnosis
or corresponding reference age, we performed additional analyses to see how
sensitive our results were to the decision we made to truncate all exposure
information, and the overall conclusions do not change. The associations with
all reported use, regardless of when it was started, are OR, 0.76 (95% CI,
0.64-0.91) for aspirin; OR, 0.85 (95% CI, 0.69-1.05) for ibuprofen, and OR,
0.97 (95% CI, 0.78-1.19) for acetaminophen. Associations with duration and
frequency were also similar whether or not we truncated the exposure information.
We found an overall inverse association of 0.8 between ever use of aspirin
and breast cancer risk relative to nonusers, consistent with most of the epidemiologic
literature that suggests associations in the range of 0.6 to 0.8.12-21 Notably,
we found the inverse association with aspirin alone or with aspirin and other
NSAIDs. We found the association to be strongest among frequent users (≥7
tablets per week) and among current and recent users (<5 years). These
findings on the importance of frequency over duration agree with most,15,16,19,20 but
not all,14,21 studies. Our data
support those of Sharpe and colleagues18 who
conclude that the period within 2 to 5 years of diagnosis is the critical
period for an effect. These findings help explain the discrepancy between
the few studies25-27 that
reported no association between aspirin use and breast cancer risk, which
used different measures of aspirin use.28 The
association between ibuprofen use and breast cancer risk was less clear, but
fewer women regularly used ibuprofen than used aspirin in our study. Consistent
with the specific pharmacologic effects of NSAIDs, acetaminophen, a non-NSAID
analgesic, was not associated with breast cancer risk.
We found that the inverse association with ever aspirin use and with
frequent aspirin use was more pronounced for those with hormone receptor–positive
cancers. However, analyses of duration and regular use showed similar effect
estimates between the hormone receptor subgroups. The participant numbers
were small for these analyses of duration and frequency by hormone receptor
status, limiting the statistical power even in this large study. Our study
results also suggest that differences by hormone receptor status are not merely
reflecting differences in menopausal status. Since this is the first study,
to our knowledge, that examined whether the protective effect of aspirin may
be limited to hormone receptor–positive breast cancer, our findings
need to be replicated before drawing definitive conclusions. The analyses
for the 4 hormone receptor groups were preplanned. However, the inverse association
between ever use of aspirin and breast cancer risk was evident for every subgroup
except ER−PR−. Because effect estimates for ever/never aspirin
use were similar for the 3 subgroups with at least 1 positive hormone receptor,
we combined the first 3 groups for added statistical power. Furthermore, the
idea for carrying out this type of analysis was driven by the extensive preclinical
evidence that prostaglandins can regulate the production of both estrogen
and progesterone and therefore should have an impact among women with at least
estrogen- or progesterone-positive receptors.9,11
The inductive effect of COX-derived prostaglandins on aromatase activity
occurs rapidly due to enhanced transcription.9 Because
COX is constantly synthesized, frequent use of aspirin should protect against
breakthrough synthesis of prostaglandins and thereby suppress aromatase activity.
In other words, frequent use would be predicted to lead to a steady-state
reduction in intramammary estrogen and thereby reduce the risk of breast cancer.
Thus, both our findings on frequent use and on hormone receptor status lend
support for this proposed underlying biological mechanism. We did not have
data available concerning the dosage of the aspirin tablets. Differences in
dose could impact the magnitude of reduction in intramammary prostaglandin
production and thereby estrogen synthesis. Whether the dose of aspirin required
for cardiovascular protection will prove to be sufficient for optimal protection
against breast cancer remains uncertain.
Our study relied on retrospective reporting of medication use, which
is subject to error, particularly underreporting. For recall bias to explain
our findings, however, cases would have to underreport more than controls.
Our findings, however, agree in magnitude with most of the other observational
epidemiologic studies of both cohort12,16,18,20,21,25,26 and
case-control designs.13-15,17,19,27 Because
recall bias is not seen in cohort studies and because effect sizes are similar
between the 2 types of studies, it is unlikely that recall bias played a large
role in explaining the findings from the case-control studies. However, it
is possible that retrospective reporting of medication use may have led to
similar estimates by years of duration if women had difficulty assessing when
they actually started using medication. This possibility may explain differences
with recent large cohort studies like the Women's Health Initiative, which
found duration to be important.21 It is unlikely
that missing data could explain our overall findings because our sensitivity
analyses indicated that the missing data would not have altered the overall
conclusion of a protective effect between aspirin use and breast cancer.
We considered potential confounding by a number of variables, including
some medical conditions not considered in other studies, including history
of hypertension, migraine headache, and myocardial infarction. Nevertheless,
there was little confounding, as the age-adjusted results were very similar
to the multivariate-adjusted results. While it is possible that we have not
included all of the potential confounders or that our confounders were measured
with error, for incomplete adjustment to explain our findings, the unmeasured
confounders would have to mimic the patterns we observed between frequency
of aspirin use and breast cancer risk. Furthermore, given that the inverse
associations were specific to aspirin and ibuprofen and not to acetaminophen,
the likelihood that unmeasured confounding can explain our findings is reduced.
If the association were merely reflecting other "lifestyle" factors, we would
also expect to see an inverse association between acetaminophen intake and
breast cancer risk.
Based on these findings, further studies are warranted to elucidate
the mechanisms underlying the protective effect of NSAIDs. It will be important,
for example, to determine whether NSAIDs suppress aromatase activity or levels
of progesterone in breast tissue. Currently, selective estrogen receptor modifiers
(SERMs), such as tamoxifen, are being used to prevent breast cancer. Recently,
an aromatase inhibitor was reported to substantially reduce the recurrence
of hormone receptor–positive breast cancer.29 Adverse
effects such as osteoporosis sometimes occur in patients treated with aromatase
inhibitors. Our results raise the possibility that combining an NSAID with
an aromatase inhibitor might permit lower doses of aromatase inhibitor to
be used without a loss of efficacy. Because NSAIDs modulate apoptosis, cell
proliferation, angiogenesis, and immune surveillance30 in
addition to inhibiting aromatase activity, a combination regimen might result
in an overall increase in therapeutic efficacy.
Our data, supported by other epidemiologic and laboratory evidence,
bolster the case for the use of aspirin and NSAIDs as chemopreventive agents
against breast cancer, particularly among postmenopausal women. The mechanisms
are probably distinct from those that are protective against gastrointestinal
tract cancers. There are many attractive features to such a chemopreventive
agent, including its ease of use and association with reducing risk of other
health outcomes. The potential benefits need to be balanced against potential
harmful effects of long-term aspirin use such as peptic ulcer disease and
gastrointestinal bleeding.31,32 It
is also important to study whether these findings are supported in more racially
and ethnically diverse populations. Finally, the results of this study support
the need for prospective clinical trials to confirm the value of using NSAIDs
to prevent breast cancer.
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