Prescriptions for selective cyclooxygenase-2 inhibitors, non-selective non-steroidal anti-inflammatory drugs, and risk of breast cancer in a population-based case-control study.

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) prevent the growth of mammary tumours in animal models. Two population-based case-control studies suggest a reduced risk of breast cancer associated with selective cyclooxygenase-2 (sCox-2) inhibitor use, but data regarding the association between breast cancer occurrence and use of non-selective NSAIDs are conflicting.
We conducted a population-based case-control study using Danish healthcare databases to examine if use of NSAIDs, including sCox-2 inhibitors, was associated with a reduced risk of breast cancer. We included 8,195 incident breast cancer cases diagnosed in 1991 through 2006 and 81,950 population controls.
Overall, we found no reduced breast cancer risk in ever users (>2 prescriptions) of sCox-2 inhibitors (odds ratio (OR) = 1.08, 95% confidence interval (95% CI) = 0.99, 1.18), aspirin (OR = 0.98, 95% CI = 0.90-1.07), or non-selective NSAIDs OR = 1.04, (95% CI = 0.98, 1.10)). Recent use (>2 prescriptions within two years of index date) of sCox-2 inhibitors, aspirin, or non-selective NSAIDs was likewise not associated with breast cancer risk (Ors = 1.06 (95% CI = 0.96, 1.18), 0.96 (95% CI = 0.87, 1.06) and 0.99 (95% CI = 0.85, 1.16), respectively). Risk estimates by duration (<10, 10 to 15, 15+ years) or intensity (low/medium/high) of NSAID use were also close to unity. Regardless of intensity, shorter or long-term NSAID use was not significantly associated with breast cancer risk.
Overall, we found no compelling evidence of a reduced risk of breast cancer associated with use of sCox-2 inhibitors, aspirin, or non-selective NSAIDs.

Full text

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RESEARCH ARTICLEOpen Access
Prescriptions for selective cyclooxygenase-2
inhibitors, non-selective non-steroidal anti-
inflammatory drugs, and risk of breast cancer in a
population-based case-control study
Deirdre P Cronin-Fenton1*, Lars Pedersen1, Timothy L Lash1,2, Søren Friis3, John A Baron4, Henrik T Sørensen1,2
Abstract
Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs) prevent the growth of mammary tumours in animal
models. Two population-based case-control studies suggest a reduced risk of breast cancer associated with
selective cyclooxygenase-2 (sCox-2) inhibitor use, but data regarding the association between breast cancer
occurrence and use of non-selective NSAIDs are conflicting.
Methods: We conducted a population-based case-control study using Danish healthcare databases to examine if
use of NSAIDs, including sCox-2 inhibitors, was associated with a reduced risk of breast cancer. We included 8,195
incident breast cancer cases diagnosed in 1991 through 2006 and 81,950 population controls.
Results: Overall, we found no reduced breast cancer risk in ever users (>2 prescriptions) of sCox-2 inhibitors (odds
ratio (OR) = 1.08, 95% confidence interval (95% CI) = 0.99, 1.18), aspirin (OR = 0.98, 95% CI = 0.90-1.07), or non-
selective NSAIDs OR = 1.04, (95% CI = 0.98, 1.10)). Recent use (>2 prescriptions within two years of index date) of
sCox-2 inhibitors, aspirin, or non-selective NSAIDs was likewise not associated with breast cancer risk (Ors = 1.06
(95% CI = 0.96, 1.18), 0.96 (95% CI = 0.87, 1.06) and 0.99 (95% CI = 0.85, 1.16), respectively). Risk estimates by
duration (<10, 10 to 15, 15+ years) or intensity (low/medium/high) of NSAID use were also close to unity.
Regardless of intensity, shorter or long-term NSAID use was not significantly associated with breast cancer risk.
Conclusions: Overall, we found no compelling evidence of a reduced risk of breast cancer associated with use of
sCox-2 inhibitors, aspirin, or non-selective NSAIDs.
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are
inversely associated with the risk of colorectal and other
gastrointestinal cancers (for example, stomach and oeso-
phageal cancer) [1-5]. The protective effect of NSAIDs
against these cancers has prompted studies on breast
cancer prevention by NSAIDs.
Research on human cell lines and animal models indi-
cates a role for cyclooxygenase-2 (Cox-2) in breast carci-
nogenesis [6], which suggests that selective Cox-2
(sCox-2) inhibitors and NSAIDs may prevent the growth
of mammary tumours [7-14]. Some NSAIDs are more
potent against Cox-1 (for example, aspirin), others have
greater affinity for Cox-2 (sCox-2 inhibitors), while
others are relatively non-selective (for example,
naproxen) [15]. Cox-1 is ubiquitously and constitutively
expressed, while Cox-2 is induced in response to stimuli
such as cytokines [16] and is overexpressed in approxi-
mately 40% of human breast tumours [17,18]. NSAIDs
may exert a protective effect against breast cancer by
inhibiting Cox-2 and, in turn, reducing the level of pros-
taglandins, oestrogens and/or prolactin [5,15,19-24].
Results from epidemiological studies of breast cancer,
however, are conflicting [25,26]. To date, five meta-
analyses have indicated chemopreventive effects of aspirin
or NSAIDs against breast cancer [1,27-30]. Some cohort
and case-control studies have reported no reduced risk of
* Correspondence: dc@dce.au.dk
1Department of Clinical Epidemiology, Aarhus University Hospital, Olof
Palmes Alle 43-45, 8200 Aarhus N, Denmark
Cronin-Fenton et al. Breast Cancer Research 2010, 12:R15
http://breast-cancer-research.com/content/12/2/R15
© 2010 Cronin-Fenton 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.

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breast cancer either from use of non-aspirin NSAIDs (NA-
NSAIDs) [31-38] or aspirin [7,26,31,35-45]. Others have
suggested a reduced risk associated with NA-NSAIDs
[8,46-53] and aspirin [8,32,46-52,54-59], albeit less marked
than that observed for colorectal cancer (approximately
30% versus approximately 50% reduction) [58,60,61].
The conflicting evidence may be attributable to a combi-
nation of factors including poor precision and chance
variation [39,43,47,48,58], low response rates with possible
selection bias [7,51], short follow-up time following pre-
scription [36,47,59], limited exposure data [27,57], or fail-
ure to distinguish between different NSAIDs subclasses
[33,34,36,37,53]. Only two, case-control, studies have
investigated the association of newer sCox-2 inhibitors
and breast cancer occurrence; both found decreased breast
cancer risks [47,59], but only one study adjusted for pre-
vious use of NSAIDs in the analyses.
To answer some of the research gaps in the epidemio-
logical literature, we conducted a large population-based
case-control study nested within a source population
with prospectively collected prescription data to exam-
ine the association between use of sCox-2 inhibitors,
aspirin, or non-selective NA-NSAIDs and the risk of
breast cancer occurrence.
Materials and methods
This study was approved by the Danish Registry Board,
reference #2004-41-4693.
Source population
We conducted this nested population-based case-control
study among the residents of North Jutland and Aarhus
counties, Denmark, which together have a total popula-
tion of 1.15 million inhabitants [62]. The Danish
National Health Service provides free tax-supported
healthcare to all residents of the country and refunds
part of patient expenditures on most prescribed drugs,
including aspirin, non-selective NA-NSAIDs, and sCox-
2 inhibitors. Selective Cox-2 inhibitors include the older
sCox-2 inhibitors (for example, meloxicam), and newer
sCox-2 inhibitors (for example, rofecoxib, celecoxib, and
so on), which became available in Denmark in 1999.
Rofecoxib was withdrawn in 2004, and use of the other
newer sCox-2 inhibitors including celecoxib, has
declined (see [63] for types of NSAIDs and sCox-2 inhi-
bitors and package sizes available in Denmark).
All health-related services are registered to individual
patients by use of their civil personal registration (CPR)
number, assigned to all Danish citizens since 1968 by
the Danish Civil Registration System. This number
encodes gender and date of birth [64] and allows accu-
rate linkage between population-based registries, includ-
ing the National Registry of Patients and the
prescription databases [65].
Breast cancer cases
Healthcare data from the two counties have been
merged into a research database at Aarhus University
[65-67]. This database includes all non-psychiatric hos-
pital admissions since 1977 and out-patient hospital
clinic visits since 1994 among the residents of the coun-
ties. Information is recorded immediately after discharge
or outpatient visit and includes CPR number, dates of
admission and discharge, and up to 20 diagnoses coded
by International Classification of Diseases (ICD) codes
(versions 8th(1977 to 2003) and 10th(1994 on)) [66].
Using these databases, we identified all female patients
who had a first diagnosis of breast cancer (ICD-8 codes
174.01, 174.02, 174.08 and 174.09; ICD-10 codes C50.0-
50.6, C50.8 and C50.9) between 1 January 1991 and 31
December 2006 in North Jutland County and between 1
January 1998 and 31 December 2006 in Aarhus County.
To ensure that we had at least minimal prescription
data for each case (see below), we excluded 127 cases
who had not been resident in the study area for at least
two years, leaving a total of 8,195 breast cancer cases.
Population controls
We used the Civil Registration System [64,68] to select
10 population controls for each case, matched on birth
year and county of residence, using risk-set sampling
(that is, the controls had to be alive and at risk of breast
cancer at the time the corresponding case was diag-
nosed (index date)). We included a total of 81,950 popu-
lation controls, sampling only among individuals who
were resident in the study areas at least two years before
index date.
Data collection
Prescription data
All pharmacies in both counties are equipped with com-
puterised accounting systems that record a customer’s
CPR number, type and quantity of medication (includ-
ing tablet and package sizes), and information on the
drug according to the Anatomical Therapeutic Classifi-
cation (ATC) (World Health Organization Collaborating
Centre for Drug Statistics Methodology, 2001). Health-
care prescription data for refundable drugs have been
transferred electronically to a research database at Aar-
hus University; in North Jutland County since 1989, and
in Aarhus County since 1996. We identified prescrip-
tions for the following sCox-2 inhibitors: newer sCox-2
inhibitors (celecoxib M01AH01, rofecoxib M01AH, val-
decoxib M01AH03, etoricoxib M01AH05), and older
sCox-2 inhibitors (lornoxicam M01AC05, diclofenac
M01AB05, meloxicam M01AC06). We grouped both
newer and older sCox-2 inhibitors together. Aspirin use
was classified as low dose (B01AC06 and N02BA01 in
tablet sizes of 75, 100 or 150 mg) and high dose
(N02BA51 and N02BA01 in tablet size 500 mg).
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We grouped the other non-selective NA-NSAIDs
(remaining codes within M01A) into a separate category.
We also retrieved prescriptions for post-menopausal
hormone replacement therapy (G03C, G03D, G03F,
G03HB01), since use of hormone replacement therapy
increases the risk of breast cancer [69-71] and women
who adhere to one medication may also be more likely
to adhere to other prescription medications, such as
NSAIDs [72]. Although acetaminophen is mainly
obtained over the counter in Denmark, we also investi-
gated the impact of prescribed acetaminophen
(N02BE51) use on breast cancer risk as a comparison
analysis [73].
Comorbidity data
We retrieved information on a hospital history of rheuma-
toid arthritis and migraine from the research database as
proxies for chronic use of over-the-counter NA-NSAIDs
and aspirin. Comorbid diseases before the diagnosis/index
date were identified using the hospital discharge registries
of each county and were summarized using the Charlson
Index [74]. The index comprises 19 conditions, each
weighted according to its potential to influence mortality.
We included both inpatient and outpatient data and used
Deyo’s adaptation of the Charlson comorbidity score for
ICD-9-CM diagnoses [75]. We obtained information on
history of heart disease (myocardial infarction, congestive
heart failure, peripheral vascular disease) from the Danish
National Registry of Patients (DNRP).
Analytic variables
We excluded use of all NSAIDs within a year of diagno-
sis to reduce any potential effect that subclinical disease
could have on NSAIDs and sCox-2 inhibitor use (that
is, reverse causation). We categorised NSAID use
according to the number of prescriptions filled by each
patient. Ever users were defined as women who had
more than two prescriptions and never/rare users were
women who used less than or equal to two prescrip-
tions. Our data showed that the average length of a pre-
scription was 30 days.
We examined temporality of NSAID use by dividing
ever users into recent and former users. Recent users
were those who had three or more prescriptions within
two years of index date (that is, between one and two
years before index date). Former users were those who
had less than three prescriptions within that time period
but more than two prescriptions (as defined by ever use)
during the entire period of observation.
We examined whether breast cancer risk was asso-
ciated with the intensity of NSAID use. The intensity of
use was defined as low (less than 25%), medium (25 to
50%) or high (greater than 50%), according to the num-
ber of days of prescription coverage divided by the total
duration of use in days. The duration was defined as the
number of days from the date of a first prescription to
the date of a last prescription plus the duration of the last
prescription. We divided duration of NSAID use into
long-term (10 to less than or equal to15 years, and
greater than 15 years) and shorter-term (less than 10
years) use. In most analyses, we considered sCox-2 inhi-
bitors and non-selective NSAIDs separately. However, to
examine intensity and duration of NSAID use, we
grouped all NSAIDs together and included only women
with at least 10 years of prescription history, that is, cases
from North Jutland County diagnosed between 1999 and
2006, and from Aarhus County diagnosed in 2006, and
their corresponding controls. This approach ensured that
women who were long-term users were not misclassified
as shorter-term due to a limited prescription history.
The cut points for medication exposures were deter-
mined based on methods developed by Robertson et al.
[76]. Robertson et al used the number of pills of proton
pump inhibitors to assess exposure. We modified the
methods used in the Robertson paper and used prescrip-
tions rather than number of pills to account for the var-
iation in NSAID pill strengths.
Statistical analyses
In all analyses, we used conditional logistic regression to
compute odds ratios (ORs) and their associated 95%
confidence intervals (95% CI) adjusting for a history of
migraine and rheumatoid arthritis, and ever/never hor-
mone replacement therapy use. We completed addi-
tional analyses adjusting for the Charlson comorbidity
index (also as a proxy for chronic NSAID use) and sepa-
rate analyses adjusting for history of heart diseases, but
these had no appreciable effect on the risk estimates
and were therefore dropped from the final models. In
each analysis, we used never or rare use (less than or
equal to two prescriptions in total) as the reference
group. Given the risk set sampling of controls, the ORs
were unbiased estimates of the incidence rate ratios
(IRRs) in the underlying population. Analyses were per-
formed using SAS version 9.13 (SAS Institute Inc., Cary,
North Carolina, USA).
Results
Characteristics of the (8,195) breast cancer cases and
(81,950) population controls are presented in Table 1.
Mean age at index date was 62.1 years. Slightly more
cases than controls had a hospital history of migraine.
As expected, a higher proportion of cases than controls
had ever used hormone replacement therapy (23.8% ver-
sus 19.3%, P <0.001). More cases than controls had ever
used sCox-2 inhibitors (8.6 versus 7.7%, P = 0.007) and/
or NA-NSAIDs (22.4 versus 21.2%, P = 0.02).
Overall, we observed no reduced risk of breast cancer
associated with ever versus never/rare use of sCox-2
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inhibitors (OR = 1.08, 95% CI = 0.99 to 1.18), non-selec-
tive NA-NSAIDs (OR = 1.04, 95% CI = 0.98 to 1.10), or
aspirin (OR = 0.98, 95% CI = 0.90 to 1.07) (Table 2). The
timing of non-selective NA-NSAID or sCox-2 inhibitor
use also did not influence breast cancer risk. Compared
with never/rare use, recent use (OR = 0.98, 95% CI = 0.84
to 1.15) and former use (OR = 1.12, 95% CI = 1.02 to
1.24) of sCox-2 inhibitors were not associated with breast
cancer occurrence. The corresponding risk estimates for
use of non-selective NA-NSAIDs were 1.06 (95% CI =
0.95 to 1.17) and 1.03 (95% CI = 0.97 to 1.10), and for use
of aspirin were 0.96 (95% CI = 0.87 to 1.06) and 1.02 (95%
CI = 0.89 to 1.17). Selective Cox-2 inhibitor use was not
associated with breast cancer occurrence among indivi-
duals with (OR = 1.12, 95% CI = 0.86 to 1.44) or without
(OR = 1.07, 95% CI = 0.98 to 1.17) a history of NSAID use
before beginning sCox-2 inhibitor use. There was no evi-
dence of a reduced risk of breast cancer among women
who used sCox-2 inhibitors only (ever use OR = 1.09, 95%
CI = 0.98 to 1.22; recent use OR = 0.99, 95% CI = 0.80 to
1.23; former use OR = 1.13, 95% CI = 1.00 to 1.29). We
found no association of prescriptions for acetaminophen
with breast cancer occurrence (data not shown).
In analyses that included all NSAID use (selective,
non-selective and aspirin), we found no protective effect
against breast cancer in shorter-term or long-term
users, regardless of the intensity of use (Table 3). We
carried out additional analyses stratifying by drug type
(see Additional file 1).
Discussion
In this population-based case-control study, we found
no substantial association between risk of breast cancer
and use of NSAIDs, whether aspirin, non-selective or
Cox-2 selective NSAIDs.
Our results are inconsistent with those of a case-con-
trol study by Sharpe et al. [53] based on similar pro-
spectively-collected prescription data. Their study
reported a dose-dependent reduced risk of up to 24%
for breast cancer among short-term (two to five years)
users of NSAIDs, an association that is not evident in
our study. The Sharpe study [53] and a study by Zhang
and colleagues [8] investigated the impact of long-term
(over 10 years) use of NSAIDs on breast cancer occur-
rence. Both papers suggested that long-term use of
NSAIDs conferred a modest protective effect. The
Table 1 Frequency distribution of cases and matched population controls (number and percentage)
Characteristic
P-value
Cases* Controls*
N = 8,195% N = 81,950%
Selective Cox-2 Inhibitors
No
Yes
Non-selective Non-aspirin
Non-Steroidal Anti- Inflammatory Drugs
No
Yes
Low Dose Aspirin
No
Yes
High Dose Aspirin
No
Yes
Acetaminophen
No
Yes
Rheumatoid Arthritis
No
Yes
Migraine
No
Yes
Hormone Replacement Therapy
Never
Ever
0.007
7,362
701
89.8
8.6
74,360
6,314
90.7
7.7
0.02
6,361
1,834
77.6
22.4
64,549
17,401
78.8
21.2
0.93
7,414
781
90.5
9.5
74,115
7,835
90.4
9.6
0.28
8,168
27
99.7
0.3
81,733
217
99.7
0.3
0.64
7,317
878
89.3
10.7
73,033
8,917
89.1
10.9
0.70
7,640
555
93.2
6.8
76,490
5,460
93.3
6.7
0.002
7,797
398
95.1
4.9
78,571
3,379
95.9
4.1
<0.001
6,248
1,947
76.2
23.8
66,132
15,818
80.7
19.3
*Matched on county of residence and birth year
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Table 2 Temporality of non-steroidal anti-inflammatory drug use and odds ratio of breast cancer
Characteristics Cases* (N = 8,195)
N
Controls* (N = 81,950)
N
Odds Ratio^ 95% Confidence Interval
%%
Any NSAID use
Ever versus never
Never/rare1
Recent use2
Former use3
1.04
1.00
1.00
1.02
0.99 to 1.10
5,353
1,147
1,695
65
14
21
54,742
11,236
15,972
67
14
20
0.93 to 1.08
0.96 to 1.09
Selective Cox-2 Inhibitors
Ever versus never
Never/rare1
Recent use2
Former use3
1.08
1.00
0.98
1.12
0.99 to 1.18
6,361
442
1,392
78
5
17
64,549
4,105
13,296
79
5
16
0.84 to 1.15
1.02 to 1.24
Non-selective Non-aspirin
Non-Steroidal Anti-Inflammatory Drugs
Ever versus never
Never/rare1
Recent use2
Former use3
1.04
1.00
1.06
1.03
0.98 to 1.10
7,494
184
517
91
2
6
75,636
1,812
4,502
92
2
6
0.95 to 1.17
0.97 to 1.10
Aspirin
Ever versus never
Never/rare1
Recent use2
Former use3
7,396
548
251
90
7
3
73,947
5,596
2,407
90
7
3
0.98
0.96
1.02
0.90 to 1.07
0.87 to 1.06
0.89 to 1.17
* Matched on county of residence and birth year. ^Analyses adjusted for use of hormone replacement therapy, rheumatoid arthritis and migraine.1Never/rare
use: <3 prescriptions in total.2Recent use: >2 prescriptions within two years of diagnosis.3Former use, </= 2 prescriptions within two years of diagnosis.
NSAIDs, non-steroidal anti-inflammatory drugs.
Table 3 Duration and intensity of NSAID¤ use among women with ≥ 10 years of prescription history
Characteristics Cases*
N%
Controls*Odds Ratio95% Confidence Interval
N%
Never/rare1,188 5012,714 53 1.00
Shorter-term <10 years:
Low Intensity†
Medium Intensity‡
High Intensity+
317
210
332
13
9
14
2,997
2,078
2,961
13
9
12
1.09
1.03
1.16
0.96 to 1.25
0.88 to 1.20
1.01 to 1.33
Long-term 10 to </= 15 years:
Low Intensity†
Medium Intensity‡
High Intensity+
151
81
88
6
3
4
1,301
773
971
5
3
4
1.18
1.06
0.90
0.98 to 1.42
0.83 to 1.35
0.71 to 1.13
Long-term >15 years:
Low Intensity†
Medium Intensity‡
High Intensity+
6
16
10
0.3
0.7
0.4
76
74
96
0.3
0.3
0.4
0.80
2.30
1.01
0.35 to 1.85
1.30 to 4.06
0.52 to 1.97
¤(sCox-2 inhibitors, aspirin, and non-aspirin non-selective NSAID). * Matched on county of residence and birth year. ^Analyses adjusted for use of hormone
replacement therapy, history of rheumatoid arthritis and migraine. † Low intensity was prescription use <25% of duration. ‡ Medium intensity was prescription
use >25% but <50% of duration.+High intensity was prescription use >50% of duration.
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Zhang study also examined very long-term (over 20
years) use of NSAIDs and found a 38% reduction in
risk, but this was not statistically significantly different
from estimates for shorter-term use [8]. Our study
shows no evidence of a reduced risk of breast cancer
associated with either shorter-term or long-term use of
NSAIDs.
The only two previous studies to examine the impact
of sCox-2 inhibitors on breast cancer risk reported a
risk reduction of at least 20% [47,77]. Both studies,
however, had important limitations, which should be
considered when interpreting their findings. One, a hos-
pital-based case-control study, sampled cases and con-
trols from different base populations; all cases in the
cancer hospital were eligible, however controls were
selected among women attending the hospital’s mam-
mography service, so may not have been representative
of the population that gave rise to the cases [47]. The
other, a Canadian registry-based study, had accurate
exposure data sourced from an insurance database, how-
ever it only had a maximum exposure period of three
years [59]. As women who were long-term users of
NSAIDs may have switched to sCox-2 inhibitors when
they became available to avoid any adverse side-effects,
a reduced risk of breast cancer in such women could
have been attributable to long-term use of NSAIDs
rather than sCox-2 inhibitors.
To overcome potential limitations, we included all
available data on use of newer sCox-2 inhibitors, the
entire period for which they were available on the Dan-
ish market [78,79], and longer than in the previous stu-
dies [47,59]. We examined the associations of sCox-2
inhibitors with and without consideration of earlier
NSAID use, and the risk of breast cancer among women
who used sCox-2 inhibitors only, but these additional
analyses did not alter the estimates of association. Over-
all, our findings on ever/never use and recent versus for-
mer use of sCox-2 inhibitors do not support a protective
effect of sCox-2 inhibitors on breast cancer risk.
Between 5% and 56% of breast cancer patients are
estimated to harbour mammogram-detectable carcino-
mas two to five years before clinical diagnosis [80].
Mammographic screening was not widespread in Den-
mark during our study period, so it is not clear whether
the limited availability of newer sCox-2 inhibitors
(approval in 1999 and withdrawal in 2004 due to con-
cern for their cardiovascular toxicity [81-83] enabled
sufficient time to intercept the pathway from tumour
initiation to detectable disease. Moreover, data from a
post-hoc analysis of British aspirin trials reported that
five years of aspirin use was associated with a reduced
risk of colorectal cancer, but the protective effect
required a latent period and first emerged 10 years after
treatment initiation [84]. Subjects included in our study
may therefore have had insufficient exposure time to
enable protection against breast cancer, even if they
were diagnosed late in the study period.
The validity of our estimates depends on several fac-
tors. First, the use of population-based prescription
registries, with a completeness approaching 100% [65],
ensured unbiased assessment of exposure data before
breast cancer diagnosis and the registry source elimi-
nated potential recall bias. Furthermore, for hormone
replacement therapy use, the prescription data are in
very good agreement with self-reported use [85]. The
use of prescription records may be more accurate than
self-reported or in-person interview questionnaire data,
particularly when capturing intermittent NSAID use.
Second, we had complete follow-up. Using the Danish
Cancer Registry as a reference standard, the sensitivity
and positive predictive value of a cancer diagnosis in the
hospital registry is high [86]. Any misclassification of
cases would bias our results to the null because it is
unlikely to be associated with NSAID use. In our ana-
lyses of duration and intensity of NSAID use, we
included only patients with at least 10 years of prescrip-
tion history, thus bias due to left-censoring of exposure
was reduced. Furthermore, we examined the duration
and regularity of NSAID use, which are important fac-
tors in reducing the risk of colorectal cancer by NSAIDs
[7]. The number of cases of breast cancer in the study
area determined the sample size of our study and 10
controls were matched for each case. The large size of
our study ensured almost 100% power to detect inverse
associations with NSAIDs of the size reported earlier
[27,59]. Finally, the positive association between hor-
mone replacement therapy use and breast cancer risk
observed in our study is consistent with previous
research and lends face validity to the null NSAID
results.
Our study also had limitations. We were unable to
examine the impact of NSAID use on breast cancer risk
by specific breast cancer characteristics such as hormone
receptor status. Earlier studies suggest that NSAID use
can decrease the risk of oestrogen receptor positive
tumours in post-menopausal women [87]. However, such
a protective effect would have to be counterbalanced by a
causal effect in the hormone receptor negative group in
order to obtain a null result. As there is no evidence in
the literature of such a causal effect in oestrogen receptor
negative disease, and given our null result, it is unlikely
that our inability to segregate our analyses by hormone
receptor status masked any association. We did stratify
our analyses by menopausal status but found little change
in the risk estimates. We had no data regarding adher-
ence with prescriptions or the use of non-prescription
NSAIDs (a consideration likely to be relevant primarily
for short-term use). However, our drug exposure
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assessment was based on redeemed prescriptions, and
because patients had to pay a proportion of the drug
cost, our estimates are likely to reflect actual use.
Furthermore, only low-dose ibuprofen and aspirin were
available without prescription in Denmark, the former
accounting for approximately 14% of total NSAID use
[88]. Although we lacked information on clinical indica-
tion for NSAID use, we included an adjustment for
migraine and rheumatoid arthritis in our analyses to cap-
ture some chronic use of over-the-counter NSAIDs and
observed little difference in the risk estimates for history
of migraines and/or rheumatoid arthritis between cases
and controls. In addition, we evaluated potential con-
founding by heart disease and the Charlson comorbidity
index but found no difference in the risk estimates (see
Additional file 1). Finally, due to low numbers it is diffi-
cult to draw any conclusions from our analyses on the
risk of breast cancer according to duration and intensity
of aspirin use (see Additional file 1).
We had no information on family history of breast
cancer, body mass index, use of oral contraceptives and
life-style factors such as alcohol consumption and diet-
ary fat intake [87]. While these factors may impact on
breast cancer risk, it is not clear what association, if any,
they would have with NSAIDs or sCox-2 inhibitor use.
Furthermore, any confounding by these variables would
have to occur even after the adjustments we did make.
Therefore, we expect these factors to have little impact
on our study findings.
Conclusions
Our findings in this large population-based setting do
not support an association of prescription NSAID use
with the risk of breast cancer.
Additional file 1: Tables S1-S3. Table S1: Duration and intensity of non-
steroidal anti-inflammatory drug use (sCox-2 inhibitors and non-selective
non-aspirin non-steroidal anti-inflammatory drugs) among women with
at least 10 years of prescription history and odds ratio of breast cancer.
Table S2: Duration and intensity of non-steroidal anti-inflammatory drug
use (aspirin and non-selective non-aspirin non-steroidal anti-inflammatory
drugs) among women with at least 10 years of prescription history and
odds ratio of breast cancer. Table S3: Duration and intensity of aspirin
use among women with at least 10 years of prescription history and
odds ratio of breast cancer.
Abbreviations
95% CI: 95% Confidence Interval; ATC: Anatomical Therapeutic Classification;
Cox-2: cyclooxygenase-2; CPR number: civil personal registration number;
ICD: International Classification of Diseases; IRRs: incidence rate ratios;
NSAIDs: non-steroidal anti-inflammatory drugs; NA-NSAID: non-aspirin NSAID;
OR: odds ratio; sCox-2: selective cyclooxygenase-2.
Acknowledgements
This work was funded by the Karen Elise Jensen Foundation. The funding
sources had no role in the design, conduct, analysis or reporting of the
study.
Author details
1Department of Clinical Epidemiology, Aarhus University Hospital, Olof
Palmes Alle 43-45, 8200 Aarhus N, Denmark.2Department of Epidemiology,
School of Public Health, Boston University, 715 Albany Street, TE3, Boston,
MA 02118, USA.3Institute of Cancer Epidemiology, The Danish Cancer
Society, Strandboulevarden 49, 2100 Copenhagen Ø, Denmark.
4Departments of Community and Family Medicine and Medicine and the
Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon,
NH, USA.
Authors’ contributions
HTS, DCF, SF and LAP conceived the study idea and designed the study.
HTS and LAP collected the data. LAP, DCF, JAB, TLL and HTS planned and
performed the analyses. DCF reviewed the literature and drafted the
manuscript. DCF, TLL, SF, JAB and HTS edited the manuscript.
Competing interests
JAB is a consultant to Bayer Pharmaceuticals, Merck Pharmaceuticals and
Pozen Incorporated and holds a US patent regarding the chemopreventive
efficacy of aspirin in the large bowel. HTS did not report receiving fees,
honoraria, grants or consultancies. The Department of Clinical Epidemiology
is, however, involved in studies with funding from various companies as
research grants to (and administered by) Aarhus University. None of these
studies are related to the present study. All other authors declare no
competing interests.
Received: 21 August 2009 Revised: 14 January 2010
Accepted: 1 March 2010 Published: 1 March 2010
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doi:10.1186/bcr2482
Cite this article as: Cronin-Fenton et al.: Prescriptions for selective
cyclooxygenase-2 inhibitors, non-selective non-steroidal anti-
inflammatory drugs, and risk of breast cancer in a population-based
case-control study. Breast Cancer Research 2010 12:R15.
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