Cancer Causes Control DOI 10.1007/s10552-015-0578-4
ORIGINAL PAPER
Use of nonsteroidal anti-inflammatory drugs and risk of endometrial cancer: a nationwide case–control study Nanna Brøns1 • Louise Baandrup1 • Christian Dehlendorff2 • Susanne K. Kjaer1,3
Received: 10 November 2014 / Accepted: 7 April 2015 Ó Springer International Publishing Switzerland 2015
Abstract Purpose We examined the association between use of low-dose aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) and endometrial cancer risk in a nationwide case–control study. Methods Cases were all women in Denmark diagnosed with endometrial cancer during 2000–2009. Age-matched female controls were randomly selected by risk-set sampling. Information on NSAID use was collected from the Prescription Registry and classified according to duration and intensity. Conditional logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs), adjusting for potential confounders. Analyses were stratified by endometrial cancer type, and potential effect modification by parity, obesity, and hormone replacement therapy (HRT) use was investigated. Results We identified 5,382 endometrial cancer cases and 72,127 controls. Endometrial cancer was not associated with use of low-dose aspirin (OR 0.97, 95 % CI 0.89–1.05) or non-aspirin NSAIDs (OR 0.96, 95 % CI 0.91–1.02)
Electronic supplementary material The online version of this article (doi:10.1007/s10552-015-0578-4) contains supplementary material, which is available to authorized users. & Susanne K. Kjaer [email protected] 1
Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark
2
Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, Copenhagen, Denmark
3
The Gynecologic Clinic, Juliane Marie Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
compared with nonuse. The ORs did not vary with increasing duration or intensity of NSAID use or with type of endometrial cancer. Interaction analyses showed reduced endometrial cancer risk associated with low-dose aspirin use among nulliparous women (OR 0.82, 95 % CI 0.70–0.95) and with non-aspirin NSAID use among women having used HRT (OR 0.90, 95 % CI 0.82–0.99). Conclusions We found no association between use of NSAIDs and endometrial cancer risk overall, although there were some indications of risk reductions associated with low-dose aspirin use among nulliparous women and with non-aspirin NSAID use among women having used HRT. Keywords Endometrial cancer Nonsteroidal antiinflammatory drugs Aspirin Chemoprevention Case–control study
Introduction Endometrial cancer is the sixth most common cancer in women worldwide, and the incidence is rising [1]. Development of the disease is suggested to be strongly associated with estrogen (endogenous or exogenous), which unopposed by progesterone induces mitotic activity in endometrial cells with subsequent increased risk of malignant transformation [2, 3]. Inflammation, both in itself and through its interaction with estrogen, is also hypothesized to influence endometrial cancer carcinogenesis [4, 5]. The association between inflammation and endometrial cancer has led to the suggestion that aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against endometrial cancer [6]. NSAIDs inhibit the inflammatory cyclooxygenase (COX) enzymes and may
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prevent carcinogenesis through COX-dependent or COXindependent mechanisms [7, 8]. COX-1 is expressed constitutively, whereas COX-2 is an inducible enzyme and has been implicated in the development of cancer [7, 9]. A potential chemopreventive effect of NSAIDs in relation to endometrial cancer is supported by in vitro studies demonstrating a higher COX-2 expression in endometrial cancer cells compared with normal endometrium [9, 10], and inhibition of endometrial cancer cell growth induced by NSAIDs [11, 12]. A recent meta-analysis, pooling the results from nine observational studies, reported that aspirin use may reduce the risk of endometrial cancer [6]. The number of studies reporting on non-aspirin NSAID use and endometrial cancer risk was too limited for evaluation by the metaanalysis [6], and results have been equivocal. All previous studies, except for two [13, 14], were based on self-report with risk of recall bias. Moreover, several of the cohort studies relied solely on baseline information, which was not updated during follow-up [15–20]. Given the inconsistent findings and the limitations in the existing literature, we conducted a nationwide registerbased case–control study nested in the entire Danish female population to explore the association between use of lowdose aspirin and non-aspirin NSAIDs and risk of endometrial cancer.
residence was derived from the Civil Registration System [26], which contains continuously updated information on addresses, dates of birth and death, and migration to and from Denmark. Of 5,751 eligible endometrial cancer cases, we restricted the analysis to include only the 5,382 cases with endometrial cancer classified as type I or II (please see morphology codes in Supplementary Table 1). Type I cancer is of endometrioid morphology and far more common than type II tumors, which comprise a heterogeneous and poorly differentiated group [1]. Selection of population controls For each case, 15 controls were randomly selected from the total Danish female population matched on date of birth (±1 month) using the Civil Registration System and riskset sampling [27]. The controls had to be at risk of a first cancer at the time the matching case was diagnosed (index date) and living in Denmark on 1 January 1995 and on index date. We also required that controls have no previous hysterectomy recorded in the National Patient Register [25], which contains diagnoses and procedures performed during hospital admissions since 1977 and outpatient visits since 1995. A total of 72,127 controls were included in the analysis. Exposure to low-dose aspirin and non-aspirin NSAIDs
Materials and methods The study was based on information from nationwide registries holding information about cancer, prescription use, medical history, reproductive data, and education [21– 25]. Linkage between the registries was performed using the unique civil registration number assigned to all Danish citizens since 1968 by the Civil Registration System [26]. The codes used to identify cases, exposure, and covariates are listed in Supplementary Table 1. Case ascertainment The Danish Cancer Registry comprises data on all incident cancer cases in Denmark since 1943 with a high degree of completeness [22]. Cancer diagnoses are recorded according to the International Classification of Diseases, version 10 (ICD-10), and the ICD for Oncology (ICD-O-3) for topography and morphology codes. All women aged 30–84 years, diagnosed with endometrial cancer during 2000–2009, and with no prior history of cancer (except non-melanoma skin cancer) were eligible as cases. Furthermore, cases had to be living in Denmark on 1 January 1995 (establishment of the Prescription Registry) and on index date (date of diagnosis). Information on
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Information on prescriptions of low-dose aspirin and nonaspirin NSAIDs redeemed by cases and controls from 1995 to 1 year before index date was obtained from the Danish Prescription Registry [24]. We did not include high-dose aspirin in the analyses because it is mainly sold over-thecounter (90 %) and used transiently for acute pains [28]. The Danish Prescription Registry holds information on all prescriptions redeemed at Danish pharmacies since 1995. For each prescription, the Registry records date and a description of the dispensed product, including the anatomical therapeutic code (ATC) [29] and the quantity dispensed, expressed as number of tablets and defined daily doses (DDDs). The DDD represents the typical daily dose required by an adult when the drug is used for its main indication [29]. Study subjects were classified as ever users (C2 prescriptions on separate dates over the entire study period) or nonusers (\2 prescriptions) of low-dose aspirin or non-aspirin NSAIDs, respectively. Ever users were further divided into recent users (C2 prescriptions within 1–3 years before the index date) and former users (C2 prescriptions overall and \2 prescriptions within 1–3 years before the index date). Nonuse (\2 prescriptions over the entire study period) of the drug in question
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served as the reference group in all analyses. Low-dose aspirin is almost exclusively given as one tablet daily, and therefore, the cumulative duration of low-dose aspirin use was based on the dates of prescription and number of days covered by the individual prescriptions. The coverage of each prescription was defined as the number of tablets dispensed plus a 60-day grace period, allowing some degree of non-compliance. The grace periods contributed with exposure time until a new prescription, if any, was redeemed. For study subjects with more than one treatment period, the duration of separate treatment periods was summed. Non-aspirin NSAIDs are given in varying doses, and duration of use was defined as the period between the first and the last prescription plus the duration of the last prescription defined as 60 days. The cumulative duration of both low-dose aspirin and non-aspirin NSAIDs was classified as \5, 5–10, or [10 years. For low-dose aspirin, we estimated the daily dose as the tablet dose prescribed during the exposure period, categorized as 75–100, 150 mg, or mixed strength. For nonaspirin NSAIDs, the intensity of use was defined as the cumulative number of DDDs divided by the duration of use in days and classified into approximate tertiles among controls of low, medium and high intensity. We defined continuous low-dose aspirin use as one treatment period with consecutive prescriptions redeemed within the coverage of the preceding prescription (i.e., without adding separate treatment periods), from the start of treatment until 1 year before the index date. The analysis was performed with 60- and 30-day grace periods. For non-aspirin NSAIDs, continuous use was defined as filling C2 prescriptions each year until 1 year before index date. Potential confounders The Fertility Database [21] provided information on parity and women was classified according to number of births (0, 1, 2, and C3). Information on use of HRT and oral contraceptives (C2 prescriptions on separate dates) was obtained from the Prescription Registry [24]. From the Patient Register [25], we retrieved information on diabetes, obesity, chronic obstructive pulmonary disease, musculoskeletal disorders, and headache including migraine. Diabetes and obesity were assessed as composite measures of the diagnoses in the Patient Register [25] and/or filling prescriptions for anti-diabetics or anti-obesity drugs, respectively. Finally, as a marker for socioeconomic status, we included information on highest educational level from registries in Statistics Denmark [23] and defined three categories (basic/vocational, higher, and unknown).
Statistical analysis Conditional logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between use of low-dose aspirin and non-aspirin NSAIDs and risk of endometrial cancer overall and stratified by type of tumor. In all analyses, nonuse constituted the reference group. Potential confounders were selected a priori based on the literature and availability and included age, parity, HRT use, obesity, diabetes, chronic obstructive pulmonary disease (proxy measure of smoking), education, and mutually adjustment for exposure variables. We examined potential effect measure modification by parity, HRT use, and obesity. We performed several supplementary analyses. The analysis of non-aspirin NSAID use was repeated with additional adjustment for musculoskeletal disorders and headache including migraine (proxy measure of over-thecounter analgesic drug use). In a model restricted to the youngest women in our study population (age \ 50 years), for whom information on oral contraceptives was more complete, we added oral contraceptives to the multivariable model. Potential left truncation of exposure was evaluated by excluding all cases, their corresponding controls, and controls who had redeemed low-dose aspirin or non-aspirin NSAID prescriptions during 1995–1996 (new-user design) [30], and finally, we repeated the overall analyses using nonuse of both study drugs as the reference category. All analyses were performed using R version 3.0.2 [31] with a significance level of 5 %.
Results Characteristics of cases and controls are presented in Table 1. Approximately 75 % of cases were aged 60 years or older, and most were type I endometrial cancer (88.4 %). More cases than controls were nulliparous, users of HRT, obese, and diabetics. The cases and controls were similar regarding the prevalence of low-dose aspirin (cases: 15.2 %; controls: 14.5 %) and non-aspirin NSAID (cases: 48.0 %; controls: 46.8 %) use. Among all low-dose aspirin users, the median number of prescriptions was 3.7 per year and a prescription contained 100 tablets on average. In regard to the non-aspirin NSAID users, the median number of yearly prescriptions was 1.8 and a prescription contained averagely 35 DDDs. Ever versus nonuse of low-dose aspirin was not associated with endometrial cancer risk (OR 0.97, 95 % CI 0.89–1.05), and the OR did not vary with timing of lowdose aspirin use (Table 2). Regarding non-aspirin NSAIDs, ever use and recent use were not associated with
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Cancer Causes Control Table 1 Characteristics of cases and matching controls Characteristics
Cases (n = 5,382) n (%)
Controls (n = 72,127) n (%)
Age at diagnosis/index date 30–39
26 (0.5)
387 (0.5)
40–49
175 (3.3)
2,488 (3.4)
50–59
1,156 (21.5)
15,272 (21.2)
60–69
1,870 (34.7)
24,215 (33.6)
70–85
2,155 (40.0)
29,765 (41.3)
Type of endometrial cancer Type I 4,762 (88.4)
63,833 (88.5)
Type II
620 (11.5)
8,294 (11.5)
0
1,233 (22.9)
13,835 (19.2)
1
1,125 (20.9)
13,875 (19.2)
2
1,915 (35.6)
26,427 (36.6)
C3
1,109 (20.6)
1,799 (24.9)
Obesity
438 (8.1)
2,922 (4.1)
Diabetes
418 (7.8)
3,257 (4.5)
37 (0.7)
792 (1.1)
Parity
COPD Education Basic/vocational
4,217 (78.4)
56,045 (77.7)
Higher
956 (17.8)
12,303 (17.1)
Unknown
209 (3.9)
3,779 (5.2)
2,218 (41.2)
23,402 (32.4)
818 (15.2)
10,481 (14.5)
2,581 (48.0)
33,746 (46.8)
Drug use HRT Low-dose aspirin Non-aspirin NSAIDs
COPD chronic obstructive pulmonary disease, HRT hormone replacement therapy, NSAIDs nonsteroidal anti-inflammatory drugs
(OR 0.88, 95 % CI 0.77–1.01). Risk estimates did not change materially when the analysis on duration and intensity of both study drugs was performed for type I and II tumors separately (data not shown). Compared with nonuse of low-dose aspirin, we observed no association between C5 years of continuous low-dose aspirin use defined by consecutive prescriptions redeemed within the coverage of the preceding prescription (60-day grace: OR 1.07, 95 % CI 0.84–1.36; 30-day grace: OR 0.92, 95 % CI 0.63–1.37). Similarly, continuous use of non-aspirin NSAIDs (C2 prescriptions each year) for C5 years was not associated with endometrial cancer risk (OR 1.10, 95 % CI 0.93–1.31) use (data not shown). The association between ever use of low-dose aspirin and endometrial cancer risk varied between nulliparous (OR 0.82, 95 % CI 0.70–0.95) and parous (OR 1.03, 95 % CI 0.93–1.13) women (p interaction = 0.054) (Table 4). Furthermore, stratification by HRT revealed that nonaspirin NSAID use was associated with decreased endometrial cancer risk solely among ever users of HRT (OR 0.90, 95 % CI 0.82–0.99). No effect measure modification by obesity was found. The four sensitivity analyses, additional adjustment for musculoskeletal disorders and headache in the analysis of non-aspirin NSAIDs, restriction of the study population to women younger than 50 years with additional adjustment for use of oral contraceptives, application of a new-user design, and using nonusers of both study drugs as the reference category, all yielded results similar to those of the main analyses (data not shown).
Discussion endometrial cancer risk, whereas former use was associated with a slightly reduced OR for endometrial cancer (OR 0.93, 95 % CI 0.87–1.00). Stratification by type of endometrial cancer revealed no considerable difference in the results for low-dose aspirin use (Table 2). For non-aspirin NSAIDs, we observed a tendency toward lower risk estimates associated with the risk of type II tumors (ever use: OR 0.86, 95 % CI 0.73–1.02; recent use: 0.85, 95 % CI 0.68–1.06) than of type I tumors (ever use: OR 0.98, 95 % CI 0.92–1.04; recent use: OR 1.02, 95 % CI 0.95–1.11). The analyses presented in Table 2 were also applied on endometrioid tumors exclusively, and results were similar to those representing all type I tumors (data not shown). The risk of endometrial cancer did not vary with duration or tablet dose of low-dose aspirin use (Table 3). A more heterogeneous risk pattern was observed for nonaspirin NSAIDs stratified according to intensity and duration of use. Low ORs were observed for \5 years of lowintensity non-aspirin NSAID use (OR 0.88, 95 % CI 0.78–1.00) and for 5–10 years of medium-intensity use
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In this nationwide case–control study, we found no association between use of low-dose aspirin or non-aspirin NSAIDs and risk of endometrial cancer overall or stratified according to tumor type. The findings were consistent across levels of duration and intensity of use. Data suggested a reduced endometrial cancer risk associated with low-dose aspirin use among nulliparous women and with non-aspirin NSAID use among women who had used HRT. The observed null association between use of nonaspirin NSAIDs and endometrial cancer risk is consistent with the results of most previous studies [14–16, 18, 32, 33] including two studies defining NSAIDs as one group comprising aspirin and non-aspirin NSAIDs [19, 34]. Although some studies have reported weak inverse associations between non-aspirin NSAIDs and endometrial cancer risk [6, 20, 35], no dose– or duration–response relations have been found [6, 15, 16, 20, 35]. The literature on the association between aspirin use and endometrial cancer risk is more diverse. Consistent with
Cancer Causes Control Table 2 Risk of endometrial cancer by ever, former, and recent use of low-dose aspirin and non-aspirin nonsteroidal anti-inflammatory drugs Low-dose aspirin Cases
Controls
Non-aspirin NSAIDs Age-adjusted OR (95 % CI)
Multivariable-adjusted ORa (95 % CI)
Cases
Controls
Age-adjusted OR (95 % CI)
Multivariable-adjusted ORa (95 % CI)
Overall endometrial cancer Nonuse
4,564
61,646
Ref
Ref
2,801
38,381
Ref
Ref
Ever use Former use
818 111
10,481 1,579
1.08 (0.99–1.17) 0.97 (0.80–1.19)
0.97 (0.89–1.05) 0.89 (0.73–1.08)
2,581 1,345
33,746 18,540
1.05 (0.99–1.11) 0.99 (0.92–1.06)
0.96 (0.91–1.02) 0.93 (0.87–1.00)
Recent use
707
8,902
1.10 (1.01–1.20)
0.98 (0.90–1.07)
1,236
15,206
1.11 (1.04–1.19)
1.00 (0.93–1.07) Ref
Type I endometrial cancer Nonuse
4,046
54,742
Ref
Ref
2,464
34,085
Ref
716
9,091
1.10 (1.00–1.19)
0.97 (0.89–1.06)
2,298
29,748
1.06 (1.00–1.13)
0.98 (0.92–1.04)
Former use
95
1,375
0.96 (0.78–1.19)
0.87 (0.70–1.08)
1,190
16,359
1.00 (0.93–1.08)
0.94 (0.87–1.01)
Recent use
621
7,716
1.12 (1.02–1.23)
0.99 (0.90–1.09)
1,108
13,389
1.15 (1.06–1.23)
1.02 (0.95–1.11)
Ever use
Type II endometrial cancer Nonuse
518
6,904
Ref
Ref
337
4,296
Ref
Ref
Ever use
102
1,390
0.99 (0.79–1.25)
0.93 (0.74–1.18)
283
3,998
0.89 (0.75–1.05)
0.86 (0.73–1.02)
Former use
16
204
1.06 (0.63–1.78)
1.00 (0.59–1.69)
155
2,181
0.89 (0.73–1.09)
0.87 (0.71–1.07)
Recent use
86
1,186
0.98 (0.77–1.25)
0.92 (0.72–1.18)
128
1,817
0.89 (0.72–1.10)
0.85 (0.68–1.06)
CI confidence interval, NSAIDs non-steroidal anti-inflammatory drugs, OR odds ratio a
Adjusted for age, parity, hormone replacement therapy use, obesity, diabetes, chronic obstructive pulmonary disease, education, and mutually adjustment for exposure variables
our findings, several studies have observed overall risk estimates close to one [13, 17, 20, 32, 34–36]. Among these are some large studies based on prospective data from the Women’s Health Initiative [32], the Multiethnic Cohort [20], and the Nurses’ Health Study [35]. Other studies, including a meta-analysis [6], have reported nonsignificant [15, 16, 33, 37] or significant [6, 18] endometrial cancer risk reductions associated with overall aspirin use. Danforth et al [15] used data from the NIH-AARP Diet and Health Study including 732 endometrial cancer cases and found a significantly reduced risk of endometrial cancer exclusively when aspirin use was taken more than two times daily. The analysis comprised only few cases, and the authors concluded that the single significant association may have been a spurious finding. In contrast, Brasky et al. [18], reporting on the VITamins And Lifestyle cohort, found a 28 % reduced risk of endometrial cancer among users of any aspirin (95 % CI, 0.53–0.98), and similar risk reduction (OR 0.78, 95 % CI 0.63–0.97) was observed by Neill et al. [6] in a population-based case–control study from Australia. In both of these studies, data also indicated further risk reductions with increasing duration [18] or frequency [6] of aspirin use. The remaining studies have not found any dose–response relation [16, 20, 32, 34–37]. Finally, the association between aspirin use and endometrial cancer risk was evaluated by Cook et al. [38, 39] in the Women’s Health Study, where the 39,876 women were randomized to 100 mg of aspirin or placebo every other
day. The authors found no association between aspirin use and endometrial cancer risk during the intervention period of 10 years [39] or after extended post-trial follow-up [38]. Conversely, the study showed that long-term aspirin use reduced the risk of colorectal cancer [38], for which the evidence of a chemopreventive effect of aspirin is convincing [40, 41]. Our results did not seem to differ by type of endometrial cancer, which is consistent with findings reported by Setiawan et al [20] and Neill et al. [6]. It has been suggested that NSAIDs may have a stronger chemopreventive effect on type I endometrial cancer [18]. Most likely because type I endometrial cancer is highly estrogen sensitive, and estrogen and inflammation are hypothesized to be associated [4, 5, 18]. However, only Brasky et al [18] reported results on aspirin use and endometrial cancer compatible with this hypothesis. We observed a reduced risk of endometrial cancer associated with low-dose aspirin use among nulliparous women, who are at greater risk of endometrial cancer than women who have given birth [42]. Our findings, however, are contradictory with the results of the two previous studies, performing analyses stratified according to parity [6, 35]. One of these reported that risk estimates did not differ by parity [35], whereas the other study showed a larger risk reduction associated with aspirin use among women with two or more pregnancies compared with women with less than two pregnancies [6].
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Cancer Causes Control Table 3 Risk of endometrial cancer associated with low-dose aspirin or non-aspirin nonsteroidal anti-inflammatory drugs stratified by duration and intensity of use Cases
Controls
Age-adjusted OR (95 % CI)
Multivariable-adjusted ORa (95 % CI)
281 168
3,565 2,364
1.09 (0.96–1.23) 1.00 (0.84–1.62)
0.97 (0.85–1.10) 0.90 (0.76–1.06)
90
1,340
0.94 (0.75–1.17)
0.84 (0.67–1.04)
75–100 mg
70
774
1.27 (0.98–1.63)
1.11 (0.86–1.44)
150 mg
83
966
1.24 (0.98–1.56)
1.12 (0.89–1.42)
Mixed
84
1,019
1.13 (0.90–1.42)
0.98 (0.78–1.24) 1.26 (0.62–2.58)
Low-dose aspirin \5 years of use 75–100 mg 150 mg Mixed 5–10 years of use
[10 years of use 75–100 mg
9
88
1.43 (0.71–2.90)
150 mg
12
134
1.25 (0.69–2.29)
1.02 (0.56–1.88)
Mixed
21
233
1.24 (0.78–1.96)
1.02 (0.64–1.63)
Low intensity
313
4,598
0.92 (0.81–1.04)
0.88 (0.78–1.00)
Medium intensity
475
6,223
1.05 (0.94–1.16)
0.98 (0.89–1.09)
High intensity 5–10 years of use
513
6,880
1.03 (0.93–1.14)
0.96 (0.87–1.06)
Low intensity
400
5,202
1.03 (0.92–1.16)
0.97 (0.87–1.09)
Medium intensity
271
3,635
0.99 (0.87–1.14)
0.88 (0.77–1.01)
High intensity
274
3,113
1.21 (1.06–1.39)
1.06 (0.92–1.21)
Low intensity
71
1,038
0.95 (0.73–1.23)
0.87 (0.67–1.13)
Medium intensity
86
980
1.27 (1.00–1.62)
1.09 (0.85–1.39)
102
1,173
1.16 (0.93–1.45)
0.94 (0.75–1.18)
Non-aspirin NSAIDs \5 years of use
[10 years of use
High intensity
CI confidence interval, NSAIDs nonsteroidal anti-inflammatory drugs, OR odds ratio a
Adjusted for age, parity, hormone replacement therapy use, obesity, diabetes, chronic obstructive pulmonary disease, education, and mutually adjustment for exposure variables
Estrogen and inflammation may interact [4], and therefore, we investigated potential effect modification by use of HRT. We found an inverse association between use of nonaspirin NSAIDs and endometrial cancer risk among women having used HRT. Only one previous study reported on this potential interaction in regard to endometrial cancer risk [20] finding no effect modification. More studies, however, have reported on the interaction between aspirin and HRT use and endometrial cancer risk [16, 18, 20, 35]. Among these, only Viswanathan et al. [35] observed significant effect modification, suggesting that use of aspirin was associated with reduced endometrial cancer risk among women who never used HRT. Those findings were not replicated in our study. Obesity is associated with a chronic low-grade state of inflammation [43], and therefore, NSAIDs may primarily
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protect against endometrial cancer among obese women as suggested in the meta-analysis on aspirin use and endometrial cancer risk by Neill et al. [6]. In our study, however, we found no effect modification by obesity, and several other studies have also reported similar risk estimates for use of NSAIDs among obese and non-obese women [15, 16, 18, 20, 32–34, 37]. In fact, the differential effect of aspirin according to body mass index observed in the meta-analysis [6] was primarily driven by the results of two studies [35, 36]. Our study has several strengths. It is the largest study conducted on NSAID use and endometrial cancer risk to date, allowing for detailed analysis of duration and intensity of use and effect modification by several factors. The Danish registries, with nearly complete coverage and continuously collected data on all Danish residents,
Cancer Causes Control Table 4 Risk of endometrial cancer associated with use of low-dose aspirin and non-aspirin nonsteroidal anti-inflammatory drugs, stratified by parity, hormone replacement therapy use, and obesity Low-dose aspirin
Non-aspirin NSAIDs Cases
Controls
Multivariable-adjusted ORa (95 % CI)
Cases
Controls
Multivariable-adjusted ORa (95 % CI)
0
213
2,749
0.82 (0.70–0.95)
565
5,925
1.04 (0.92–1.17)
C1
605
7,732
1.03 (0.93–1.13)
2,016
27,821
0.94 (0.88–1.00)
Parity
p interaction
0.054
0.424
HRT use Nonuse
447
6,721
0.95 (0.85–1.06)
1,348
20,286
Ever use
371
3,760
0.99 (0.87–1.11)
1,233
13,460
p interaction
0.649
1.00 (0.93–1.08) 0.90 (0.82–0.99) 0.063
Obesity No
704
9,717
0.90 (0.72–1.14)
2,262
31,638
1.02 (0.81–1.28)
Yes
114
764
0.97 (0.89–1.06)
319
2,108
0.96 (0.90–1.02)
p interaction
0.553
0.611
CI confidence interval, HRT hormone replacement therapy, NSAIDs nonsteroidal anti-inflammatory drugs, OR odds ratio a
Adjusted for age, parity, hormone replacement therapy use, obesity, diabetes, chronic obstructive pulmonary disease, education, and mutually adjustment for exposure variables
minimized selection bias. In particular, the Prescription Registry [24] provided accurate information on redeemed drug prescriptions. Furthermore, by applying a 1-year lag prior to index date, we ensured that we did not include any NSAID use associated with symptoms of a not yet diagnosed endometrial cancer. Finally, our cases were histologically verified, which enhanced case validity and permitted analyses by type of endometrial cancer. Some limitations of our study should also be considered. We had no information on drugs sold over-the-counter. However, during the study period, about 80–90 % of lowdose aspirin and non-aspirin NSAIDs were on prescription [28]. Furthermore, as 50 % of the cost of these drugs is reimbursed when they are prescribed by a physician, chronic use is by prescription in the majority of patients. We added musculoskeletal disorders and headache to the full model, as proxy measures of over-the-counter analgesic use, and this analysis yielded risk estimates on nonaspirin NSAID use similar to the main analysis. In our study, we did not include high-dose aspirin in the analysis since it is mainly sold over-the-counter (90–95 %) [28]. However, in Denmark, high-dose aspirin is primarily used as short-term therapy for acute pains, and therefore, we assume that high-dose aspirin use resulted in only minor misclassification. Finally, over-the-counter use of nonaspirin NSAIDs and high-dose aspirin was most likely similar among cases and controls, thus introducing mainly non-differential exposure misclassification [44].
Non-aspirin NSAIDs may be used sporadically, and one pack of tablets may be shared across family members. Due to the register-based design, we lacked information on the amount of drug, which was actually taken and may therefore have overestimated duration and intensity of nonaspirin NSAID use. However, we assume this limitation to be minimal in analyses of long-term and high-intensity or continuous non-aspirin NSAID use combined. In regard to low-dose aspirin, similar potential limitations are not applicable, because the drug is taken daily for cardiovascular protection. Establishment of the Prescription Registry in 1995 meant that we lacked information on drug use prior to this date. We evaluated the influence of this left truncation of prescription data by applying a new-user design, which yielded results similar to those of the main analysis. Finally, we had no information on body mass index. Obesity is a strong risk factor for endometrial cancer and may also be associated with a higher consumption of NSAIDs. We handled this potential limitation by defining obesity as a composite measure of the diagnosis in the Patient Register and/or redemption of anti-obesity drugs in the Prescription Registry. However, this method captured only a proportion of the obese women in our study population, and residual confounding may have retained. In conclusion, we found no association between lowdose aspirin or non-aspirin NSAIDs and endometrial cancer risk, although there was some indication of a reduced risk of endometrial cancer with use of low-dose aspirin
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among nulliparous women and with non-aspirin NSAID use among women using HRT. Acknowledgments NB was funded by a scholarship from the Lundbeck Foundation. The funding source had no role in the design, analysis, and interpretation of the results. Conflict of interest of interest.
The authors declare that they have no conflict
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17. Schreinemachers DM, Everson RB (1994) Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 5:138–146 18. Brasky TM, Moysich KB, Cohn DE, White E (2013) Non-steroidal anti-inflammatory drugs and endometrial cancer risk in the VITamins And Lifestyle (VITAL) cohort. Gynecol Oncol 128:113–119 19. Phipps AI, Anderson GL, Cochrane BB et al (2012) Migraine history, nonsteroidal anti-inflammatory drug use, and risk of postmenopausal endometrial cancer. Horm Cancer 3:240–248 20. Setiawan VW, Matsuno RK, Lurie G et al (2012) Use of nonsteroidal anti-inflammatory drugs and risk of ovarian and endometrial cancer: the Multiethnic Cohort. Cancer Epidemiol Biomarkers Prev 21:1441–1449 21. Blenstrup LT, Knudsen LB (2011) Danish registers on aspects of reproduction. Scand J Public Health 39:79–82 22. Gjerstorff ML (2011) The Danish Cancer Registry. Scand J Public Health 39:42–45 23. Jensen VM, Rasmussen AW (2011) Danish education registers. Scand J Public Health 39:91–94 24. Kildemoes HW, Sorensen HT, Hallas J (2011) The Danish National Prescription Registry. Scand J Public Health 39:38–41 25. Lynge E, Sandegaard JL, Rebolj M (2011) The Danish National Patient Register. Scand J Public Health 39:30–33 26. Pedersen CB (2011) The Danish Civil Registration System. Scand J Public Health 39:22–25 27. Rothman K, Greenland S, Lash TL, Rothman K, Greenland S, Lash TL (2008) Case-control studies. Modern epidemiology, 3rd edn. Lippincott Williams & Wilkins, Philadelphia, pp 111–127 28. Schmidt M, Hallas J, Friis S (2014) Potential of prescription registries to capture individual-level use of aspirin and other nonsteroidal anti-inflammatory drugs in Denmark: trends in utilization 1999–2012. Clin Epidemiol 6:155–168 29. ATC Classification Index with DDDs. World Health Organization Collaborating Centre for Drug Statistics Methodology.http:// www.whocc.no/atc_ddd_index/. Accessed 16 Oct 2014 30. Ray WA (2003) Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 158:915–920 31. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.http://www.R-project.org/. Accessed 2 Nov 2014 32. Brasky TM, Liu J, White E et al (2014) Non-steroidal anti-inflammatory drugs and cancer risk in women: results from the Women’s Health Initiative. Int J Cancer 135:1869–1883 33. Fortuny J, Sima C, Bayuga S et al (2009) Risk of endometrial cancer in relation to medical conditions and medication use. Cancer Epidemiol Biomarkers Prev 18:1448–1456 34. Bodelon C, Doherty JA, Chen C, Rossing MA, Weiss NS (2009) Use of nonsteroidal antiinflammatory drugs and risk of endometrial cancer. Am J Epidemiol 170:1512–1517 35. Viswanathan AN, Feskanich D, Schernhammer ES, Hankinson SE (2008) Aspirin, NSAID, and acetaminophen use and the risk of endometrial cancer. Cancer Res 68:2507–2513 36. Moysich KB, Baker JA, Rodabaugh KJ, Villella JA (2005) Regular analgesic use and risk of endometrial cancer. Cancer Epidemiol Biomarkers Prev 14:2923–2928 37. Bosetti C, Bravi F, Talamini R, Montella M, Negri E, La VC (2010) Aspirin and risk of endometrial cancer: a case-control study from Italy. Eur J Cancer Prev 19:401–403 38. Cook NR, Lee IM, Zhang SM (2013) Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial. Ann Intern Med 159:77–85 39. Cook NR, Lee IM, Gaziano JM et al (2005) Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial. JAMA 294:47–55
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ORIGINAL PAPER
Use of nonsteroidal anti-inflammatory drugs and risk of endometrial cancer: a nationwide case–control study Nanna Brøns1 • Louise Baandrup1 • Christian Dehlendorff2 • Susanne K. Kjaer1,3
Received: 10 November 2014 / Accepted: 7 April 2015 Ó Springer International Publishing Switzerland 2015
Abstract Purpose We examined the association between use of low-dose aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) and endometrial cancer risk in a nationwide case–control study. Methods Cases were all women in Denmark diagnosed with endometrial cancer during 2000–2009. Age-matched female controls were randomly selected by risk-set sampling. Information on NSAID use was collected from the Prescription Registry and classified according to duration and intensity. Conditional logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs), adjusting for potential confounders. Analyses were stratified by endometrial cancer type, and potential effect modification by parity, obesity, and hormone replacement therapy (HRT) use was investigated. Results We identified 5,382 endometrial cancer cases and 72,127 controls. Endometrial cancer was not associated with use of low-dose aspirin (OR 0.97, 95 % CI 0.89–1.05) or non-aspirin NSAIDs (OR 0.96, 95 % CI 0.91–1.02)
Electronic supplementary material The online version of this article (doi:10.1007/s10552-015-0578-4) contains supplementary material, which is available to authorized users. & Susanne K. Kjaer [email protected] 1
Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark
2
Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, Copenhagen, Denmark
3
The Gynecologic Clinic, Juliane Marie Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
compared with nonuse. The ORs did not vary with increasing duration or intensity of NSAID use or with type of endometrial cancer. Interaction analyses showed reduced endometrial cancer risk associated with low-dose aspirin use among nulliparous women (OR 0.82, 95 % CI 0.70–0.95) and with non-aspirin NSAID use among women having used HRT (OR 0.90, 95 % CI 0.82–0.99). Conclusions We found no association between use of NSAIDs and endometrial cancer risk overall, although there were some indications of risk reductions associated with low-dose aspirin use among nulliparous women and with non-aspirin NSAID use among women having used HRT. Keywords Endometrial cancer Nonsteroidal antiinflammatory drugs Aspirin Chemoprevention Case–control study
Introduction Endometrial cancer is the sixth most common cancer in women worldwide, and the incidence is rising [1]. Development of the disease is suggested to be strongly associated with estrogen (endogenous or exogenous), which unopposed by progesterone induces mitotic activity in endometrial cells with subsequent increased risk of malignant transformation [2, 3]. Inflammation, both in itself and through its interaction with estrogen, is also hypothesized to influence endometrial cancer carcinogenesis [4, 5]. The association between inflammation and endometrial cancer has led to the suggestion that aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against endometrial cancer [6]. NSAIDs inhibit the inflammatory cyclooxygenase (COX) enzymes and may
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prevent carcinogenesis through COX-dependent or COXindependent mechanisms [7, 8]. COX-1 is expressed constitutively, whereas COX-2 is an inducible enzyme and has been implicated in the development of cancer [7, 9]. A potential chemopreventive effect of NSAIDs in relation to endometrial cancer is supported by in vitro studies demonstrating a higher COX-2 expression in endometrial cancer cells compared with normal endometrium [9, 10], and inhibition of endometrial cancer cell growth induced by NSAIDs [11, 12]. A recent meta-analysis, pooling the results from nine observational studies, reported that aspirin use may reduce the risk of endometrial cancer [6]. The number of studies reporting on non-aspirin NSAID use and endometrial cancer risk was too limited for evaluation by the metaanalysis [6], and results have been equivocal. All previous studies, except for two [13, 14], were based on self-report with risk of recall bias. Moreover, several of the cohort studies relied solely on baseline information, which was not updated during follow-up [15–20]. Given the inconsistent findings and the limitations in the existing literature, we conducted a nationwide registerbased case–control study nested in the entire Danish female population to explore the association between use of lowdose aspirin and non-aspirin NSAIDs and risk of endometrial cancer.
residence was derived from the Civil Registration System [26], which contains continuously updated information on addresses, dates of birth and death, and migration to and from Denmark. Of 5,751 eligible endometrial cancer cases, we restricted the analysis to include only the 5,382 cases with endometrial cancer classified as type I or II (please see morphology codes in Supplementary Table 1). Type I cancer is of endometrioid morphology and far more common than type II tumors, which comprise a heterogeneous and poorly differentiated group [1]. Selection of population controls For each case, 15 controls were randomly selected from the total Danish female population matched on date of birth (±1 month) using the Civil Registration System and riskset sampling [27]. The controls had to be at risk of a first cancer at the time the matching case was diagnosed (index date) and living in Denmark on 1 January 1995 and on index date. We also required that controls have no previous hysterectomy recorded in the National Patient Register [25], which contains diagnoses and procedures performed during hospital admissions since 1977 and outpatient visits since 1995. A total of 72,127 controls were included in the analysis. Exposure to low-dose aspirin and non-aspirin NSAIDs
Materials and methods The study was based on information from nationwide registries holding information about cancer, prescription use, medical history, reproductive data, and education [21– 25]. Linkage between the registries was performed using the unique civil registration number assigned to all Danish citizens since 1968 by the Civil Registration System [26]. The codes used to identify cases, exposure, and covariates are listed in Supplementary Table 1. Case ascertainment The Danish Cancer Registry comprises data on all incident cancer cases in Denmark since 1943 with a high degree of completeness [22]. Cancer diagnoses are recorded according to the International Classification of Diseases, version 10 (ICD-10), and the ICD for Oncology (ICD-O-3) for topography and morphology codes. All women aged 30–84 years, diagnosed with endometrial cancer during 2000–2009, and with no prior history of cancer (except non-melanoma skin cancer) were eligible as cases. Furthermore, cases had to be living in Denmark on 1 January 1995 (establishment of the Prescription Registry) and on index date (date of diagnosis). Information on
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Information on prescriptions of low-dose aspirin and nonaspirin NSAIDs redeemed by cases and controls from 1995 to 1 year before index date was obtained from the Danish Prescription Registry [24]. We did not include high-dose aspirin in the analyses because it is mainly sold over-thecounter (90 %) and used transiently for acute pains [28]. The Danish Prescription Registry holds information on all prescriptions redeemed at Danish pharmacies since 1995. For each prescription, the Registry records date and a description of the dispensed product, including the anatomical therapeutic code (ATC) [29] and the quantity dispensed, expressed as number of tablets and defined daily doses (DDDs). The DDD represents the typical daily dose required by an adult when the drug is used for its main indication [29]. Study subjects were classified as ever users (C2 prescriptions on separate dates over the entire study period) or nonusers (\2 prescriptions) of low-dose aspirin or non-aspirin NSAIDs, respectively. Ever users were further divided into recent users (C2 prescriptions within 1–3 years before the index date) and former users (C2 prescriptions overall and \2 prescriptions within 1–3 years before the index date). Nonuse (\2 prescriptions over the entire study period) of the drug in question
Cancer Causes Control
served as the reference group in all analyses. Low-dose aspirin is almost exclusively given as one tablet daily, and therefore, the cumulative duration of low-dose aspirin use was based on the dates of prescription and number of days covered by the individual prescriptions. The coverage of each prescription was defined as the number of tablets dispensed plus a 60-day grace period, allowing some degree of non-compliance. The grace periods contributed with exposure time until a new prescription, if any, was redeemed. For study subjects with more than one treatment period, the duration of separate treatment periods was summed. Non-aspirin NSAIDs are given in varying doses, and duration of use was defined as the period between the first and the last prescription plus the duration of the last prescription defined as 60 days. The cumulative duration of both low-dose aspirin and non-aspirin NSAIDs was classified as \5, 5–10, or [10 years. For low-dose aspirin, we estimated the daily dose as the tablet dose prescribed during the exposure period, categorized as 75–100, 150 mg, or mixed strength. For nonaspirin NSAIDs, the intensity of use was defined as the cumulative number of DDDs divided by the duration of use in days and classified into approximate tertiles among controls of low, medium and high intensity. We defined continuous low-dose aspirin use as one treatment period with consecutive prescriptions redeemed within the coverage of the preceding prescription (i.e., without adding separate treatment periods), from the start of treatment until 1 year before the index date. The analysis was performed with 60- and 30-day grace periods. For non-aspirin NSAIDs, continuous use was defined as filling C2 prescriptions each year until 1 year before index date. Potential confounders The Fertility Database [21] provided information on parity and women was classified according to number of births (0, 1, 2, and C3). Information on use of HRT and oral contraceptives (C2 prescriptions on separate dates) was obtained from the Prescription Registry [24]. From the Patient Register [25], we retrieved information on diabetes, obesity, chronic obstructive pulmonary disease, musculoskeletal disorders, and headache including migraine. Diabetes and obesity were assessed as composite measures of the diagnoses in the Patient Register [25] and/or filling prescriptions for anti-diabetics or anti-obesity drugs, respectively. Finally, as a marker for socioeconomic status, we included information on highest educational level from registries in Statistics Denmark [23] and defined three categories (basic/vocational, higher, and unknown).
Statistical analysis Conditional logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between use of low-dose aspirin and non-aspirin NSAIDs and risk of endometrial cancer overall and stratified by type of tumor. In all analyses, nonuse constituted the reference group. Potential confounders were selected a priori based on the literature and availability and included age, parity, HRT use, obesity, diabetes, chronic obstructive pulmonary disease (proxy measure of smoking), education, and mutually adjustment for exposure variables. We examined potential effect measure modification by parity, HRT use, and obesity. We performed several supplementary analyses. The analysis of non-aspirin NSAID use was repeated with additional adjustment for musculoskeletal disorders and headache including migraine (proxy measure of over-thecounter analgesic drug use). In a model restricted to the youngest women in our study population (age \ 50 years), for whom information on oral contraceptives was more complete, we added oral contraceptives to the multivariable model. Potential left truncation of exposure was evaluated by excluding all cases, their corresponding controls, and controls who had redeemed low-dose aspirin or non-aspirin NSAID prescriptions during 1995–1996 (new-user design) [30], and finally, we repeated the overall analyses using nonuse of both study drugs as the reference category. All analyses were performed using R version 3.0.2 [31] with a significance level of 5 %.
Results Characteristics of cases and controls are presented in Table 1. Approximately 75 % of cases were aged 60 years or older, and most were type I endometrial cancer (88.4 %). More cases than controls were nulliparous, users of HRT, obese, and diabetics. The cases and controls were similar regarding the prevalence of low-dose aspirin (cases: 15.2 %; controls: 14.5 %) and non-aspirin NSAID (cases: 48.0 %; controls: 46.8 %) use. Among all low-dose aspirin users, the median number of prescriptions was 3.7 per year and a prescription contained 100 tablets on average. In regard to the non-aspirin NSAID users, the median number of yearly prescriptions was 1.8 and a prescription contained averagely 35 DDDs. Ever versus nonuse of low-dose aspirin was not associated with endometrial cancer risk (OR 0.97, 95 % CI 0.89–1.05), and the OR did not vary with timing of lowdose aspirin use (Table 2). Regarding non-aspirin NSAIDs, ever use and recent use were not associated with
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Cancer Causes Control Table 1 Characteristics of cases and matching controls Characteristics
Cases (n = 5,382) n (%)
Controls (n = 72,127) n (%)
Age at diagnosis/index date 30–39
26 (0.5)
387 (0.5)
40–49
175 (3.3)
2,488 (3.4)
50–59
1,156 (21.5)
15,272 (21.2)
60–69
1,870 (34.7)
24,215 (33.6)
70–85
2,155 (40.0)
29,765 (41.3)
Type of endometrial cancer Type I 4,762 (88.4)
63,833 (88.5)
Type II
620 (11.5)
8,294 (11.5)
0
1,233 (22.9)
13,835 (19.2)
1
1,125 (20.9)
13,875 (19.2)
2
1,915 (35.6)
26,427 (36.6)
C3
1,109 (20.6)
1,799 (24.9)
Obesity
438 (8.1)
2,922 (4.1)
Diabetes
418 (7.8)
3,257 (4.5)
37 (0.7)
792 (1.1)
Parity
COPD Education Basic/vocational
4,217 (78.4)
56,045 (77.7)
Higher
956 (17.8)
12,303 (17.1)
Unknown
209 (3.9)
3,779 (5.2)
2,218 (41.2)
23,402 (32.4)
818 (15.2)
10,481 (14.5)
2,581 (48.0)
33,746 (46.8)
Drug use HRT Low-dose aspirin Non-aspirin NSAIDs
COPD chronic obstructive pulmonary disease, HRT hormone replacement therapy, NSAIDs nonsteroidal anti-inflammatory drugs
(OR 0.88, 95 % CI 0.77–1.01). Risk estimates did not change materially when the analysis on duration and intensity of both study drugs was performed for type I and II tumors separately (data not shown). Compared with nonuse of low-dose aspirin, we observed no association between C5 years of continuous low-dose aspirin use defined by consecutive prescriptions redeemed within the coverage of the preceding prescription (60-day grace: OR 1.07, 95 % CI 0.84–1.36; 30-day grace: OR 0.92, 95 % CI 0.63–1.37). Similarly, continuous use of non-aspirin NSAIDs (C2 prescriptions each year) for C5 years was not associated with endometrial cancer risk (OR 1.10, 95 % CI 0.93–1.31) use (data not shown). The association between ever use of low-dose aspirin and endometrial cancer risk varied between nulliparous (OR 0.82, 95 % CI 0.70–0.95) and parous (OR 1.03, 95 % CI 0.93–1.13) women (p interaction = 0.054) (Table 4). Furthermore, stratification by HRT revealed that nonaspirin NSAID use was associated with decreased endometrial cancer risk solely among ever users of HRT (OR 0.90, 95 % CI 0.82–0.99). No effect measure modification by obesity was found. The four sensitivity analyses, additional adjustment for musculoskeletal disorders and headache in the analysis of non-aspirin NSAIDs, restriction of the study population to women younger than 50 years with additional adjustment for use of oral contraceptives, application of a new-user design, and using nonusers of both study drugs as the reference category, all yielded results similar to those of the main analyses (data not shown).
Discussion endometrial cancer risk, whereas former use was associated with a slightly reduced OR for endometrial cancer (OR 0.93, 95 % CI 0.87–1.00). Stratification by type of endometrial cancer revealed no considerable difference in the results for low-dose aspirin use (Table 2). For non-aspirin NSAIDs, we observed a tendency toward lower risk estimates associated with the risk of type II tumors (ever use: OR 0.86, 95 % CI 0.73–1.02; recent use: 0.85, 95 % CI 0.68–1.06) than of type I tumors (ever use: OR 0.98, 95 % CI 0.92–1.04; recent use: OR 1.02, 95 % CI 0.95–1.11). The analyses presented in Table 2 were also applied on endometrioid tumors exclusively, and results were similar to those representing all type I tumors (data not shown). The risk of endometrial cancer did not vary with duration or tablet dose of low-dose aspirin use (Table 3). A more heterogeneous risk pattern was observed for nonaspirin NSAIDs stratified according to intensity and duration of use. Low ORs were observed for \5 years of lowintensity non-aspirin NSAID use (OR 0.88, 95 % CI 0.78–1.00) and for 5–10 years of medium-intensity use
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In this nationwide case–control study, we found no association between use of low-dose aspirin or non-aspirin NSAIDs and risk of endometrial cancer overall or stratified according to tumor type. The findings were consistent across levels of duration and intensity of use. Data suggested a reduced endometrial cancer risk associated with low-dose aspirin use among nulliparous women and with non-aspirin NSAID use among women who had used HRT. The observed null association between use of nonaspirin NSAIDs and endometrial cancer risk is consistent with the results of most previous studies [14–16, 18, 32, 33] including two studies defining NSAIDs as one group comprising aspirin and non-aspirin NSAIDs [19, 34]. Although some studies have reported weak inverse associations between non-aspirin NSAIDs and endometrial cancer risk [6, 20, 35], no dose– or duration–response relations have been found [6, 15, 16, 20, 35]. The literature on the association between aspirin use and endometrial cancer risk is more diverse. Consistent with
Cancer Causes Control Table 2 Risk of endometrial cancer by ever, former, and recent use of low-dose aspirin and non-aspirin nonsteroidal anti-inflammatory drugs Low-dose aspirin Cases
Controls
Non-aspirin NSAIDs Age-adjusted OR (95 % CI)
Multivariable-adjusted ORa (95 % CI)
Cases
Controls
Age-adjusted OR (95 % CI)
Multivariable-adjusted ORa (95 % CI)
Overall endometrial cancer Nonuse
4,564
61,646
Ref
Ref
2,801
38,381
Ref
Ref
Ever use Former use
818 111
10,481 1,579
1.08 (0.99–1.17) 0.97 (0.80–1.19)
0.97 (0.89–1.05) 0.89 (0.73–1.08)
2,581 1,345
33,746 18,540
1.05 (0.99–1.11) 0.99 (0.92–1.06)
0.96 (0.91–1.02) 0.93 (0.87–1.00)
Recent use
707
8,902
1.10 (1.01–1.20)
0.98 (0.90–1.07)
1,236
15,206
1.11 (1.04–1.19)
1.00 (0.93–1.07) Ref
Type I endometrial cancer Nonuse
4,046
54,742
Ref
Ref
2,464
34,085
Ref
716
9,091
1.10 (1.00–1.19)
0.97 (0.89–1.06)
2,298
29,748
1.06 (1.00–1.13)
0.98 (0.92–1.04)
Former use
95
1,375
0.96 (0.78–1.19)
0.87 (0.70–1.08)
1,190
16,359
1.00 (0.93–1.08)
0.94 (0.87–1.01)
Recent use
621
7,716
1.12 (1.02–1.23)
0.99 (0.90–1.09)
1,108
13,389
1.15 (1.06–1.23)
1.02 (0.95–1.11)
Ever use
Type II endometrial cancer Nonuse
518
6,904
Ref
Ref
337
4,296
Ref
Ref
Ever use
102
1,390
0.99 (0.79–1.25)
0.93 (0.74–1.18)
283
3,998
0.89 (0.75–1.05)
0.86 (0.73–1.02)
Former use
16
204
1.06 (0.63–1.78)
1.00 (0.59–1.69)
155
2,181
0.89 (0.73–1.09)
0.87 (0.71–1.07)
Recent use
86
1,186
0.98 (0.77–1.25)
0.92 (0.72–1.18)
128
1,817
0.89 (0.72–1.10)
0.85 (0.68–1.06)
CI confidence interval, NSAIDs non-steroidal anti-inflammatory drugs, OR odds ratio a
Adjusted for age, parity, hormone replacement therapy use, obesity, diabetes, chronic obstructive pulmonary disease, education, and mutually adjustment for exposure variables
our findings, several studies have observed overall risk estimates close to one [13, 17, 20, 32, 34–36]. Among these are some large studies based on prospective data from the Women’s Health Initiative [32], the Multiethnic Cohort [20], and the Nurses’ Health Study [35]. Other studies, including a meta-analysis [6], have reported nonsignificant [15, 16, 33, 37] or significant [6, 18] endometrial cancer risk reductions associated with overall aspirin use. Danforth et al [15] used data from the NIH-AARP Diet and Health Study including 732 endometrial cancer cases and found a significantly reduced risk of endometrial cancer exclusively when aspirin use was taken more than two times daily. The analysis comprised only few cases, and the authors concluded that the single significant association may have been a spurious finding. In contrast, Brasky et al. [18], reporting on the VITamins And Lifestyle cohort, found a 28 % reduced risk of endometrial cancer among users of any aspirin (95 % CI, 0.53–0.98), and similar risk reduction (OR 0.78, 95 % CI 0.63–0.97) was observed by Neill et al. [6] in a population-based case–control study from Australia. In both of these studies, data also indicated further risk reductions with increasing duration [18] or frequency [6] of aspirin use. The remaining studies have not found any dose–response relation [16, 20, 32, 34–37]. Finally, the association between aspirin use and endometrial cancer risk was evaluated by Cook et al. [38, 39] in the Women’s Health Study, where the 39,876 women were randomized to 100 mg of aspirin or placebo every other
day. The authors found no association between aspirin use and endometrial cancer risk during the intervention period of 10 years [39] or after extended post-trial follow-up [38]. Conversely, the study showed that long-term aspirin use reduced the risk of colorectal cancer [38], for which the evidence of a chemopreventive effect of aspirin is convincing [40, 41]. Our results did not seem to differ by type of endometrial cancer, which is consistent with findings reported by Setiawan et al [20] and Neill et al. [6]. It has been suggested that NSAIDs may have a stronger chemopreventive effect on type I endometrial cancer [18]. Most likely because type I endometrial cancer is highly estrogen sensitive, and estrogen and inflammation are hypothesized to be associated [4, 5, 18]. However, only Brasky et al [18] reported results on aspirin use and endometrial cancer compatible with this hypothesis. We observed a reduced risk of endometrial cancer associated with low-dose aspirin use among nulliparous women, who are at greater risk of endometrial cancer than women who have given birth [42]. Our findings, however, are contradictory with the results of the two previous studies, performing analyses stratified according to parity [6, 35]. One of these reported that risk estimates did not differ by parity [35], whereas the other study showed a larger risk reduction associated with aspirin use among women with two or more pregnancies compared with women with less than two pregnancies [6].
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Cancer Causes Control Table 3 Risk of endometrial cancer associated with low-dose aspirin or non-aspirin nonsteroidal anti-inflammatory drugs stratified by duration and intensity of use Cases
Controls
Age-adjusted OR (95 % CI)
Multivariable-adjusted ORa (95 % CI)
281 168
3,565 2,364
1.09 (0.96–1.23) 1.00 (0.84–1.62)
0.97 (0.85–1.10) 0.90 (0.76–1.06)
90
1,340
0.94 (0.75–1.17)
0.84 (0.67–1.04)
75–100 mg
70
774
1.27 (0.98–1.63)
1.11 (0.86–1.44)
150 mg
83
966
1.24 (0.98–1.56)
1.12 (0.89–1.42)
Mixed
84
1,019
1.13 (0.90–1.42)
0.98 (0.78–1.24) 1.26 (0.62–2.58)
Low-dose aspirin \5 years of use 75–100 mg 150 mg Mixed 5–10 years of use
[10 years of use 75–100 mg
9
88
1.43 (0.71–2.90)
150 mg
12
134
1.25 (0.69–2.29)
1.02 (0.56–1.88)
Mixed
21
233
1.24 (0.78–1.96)
1.02 (0.64–1.63)
Low intensity
313
4,598
0.92 (0.81–1.04)
0.88 (0.78–1.00)
Medium intensity
475
6,223
1.05 (0.94–1.16)
0.98 (0.89–1.09)
High intensity 5–10 years of use
513
6,880
1.03 (0.93–1.14)
0.96 (0.87–1.06)
Low intensity
400
5,202
1.03 (0.92–1.16)
0.97 (0.87–1.09)
Medium intensity
271
3,635
0.99 (0.87–1.14)
0.88 (0.77–1.01)
High intensity
274
3,113
1.21 (1.06–1.39)
1.06 (0.92–1.21)
Low intensity
71
1,038
0.95 (0.73–1.23)
0.87 (0.67–1.13)
Medium intensity
86
980
1.27 (1.00–1.62)
1.09 (0.85–1.39)
102
1,173
1.16 (0.93–1.45)
0.94 (0.75–1.18)
Non-aspirin NSAIDs \5 years of use
[10 years of use
High intensity
CI confidence interval, NSAIDs nonsteroidal anti-inflammatory drugs, OR odds ratio a
Adjusted for age, parity, hormone replacement therapy use, obesity, diabetes, chronic obstructive pulmonary disease, education, and mutually adjustment for exposure variables
Estrogen and inflammation may interact [4], and therefore, we investigated potential effect modification by use of HRT. We found an inverse association between use of nonaspirin NSAIDs and endometrial cancer risk among women having used HRT. Only one previous study reported on this potential interaction in regard to endometrial cancer risk [20] finding no effect modification. More studies, however, have reported on the interaction between aspirin and HRT use and endometrial cancer risk [16, 18, 20, 35]. Among these, only Viswanathan et al. [35] observed significant effect modification, suggesting that use of aspirin was associated with reduced endometrial cancer risk among women who never used HRT. Those findings were not replicated in our study. Obesity is associated with a chronic low-grade state of inflammation [43], and therefore, NSAIDs may primarily
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protect against endometrial cancer among obese women as suggested in the meta-analysis on aspirin use and endometrial cancer risk by Neill et al. [6]. In our study, however, we found no effect modification by obesity, and several other studies have also reported similar risk estimates for use of NSAIDs among obese and non-obese women [15, 16, 18, 20, 32–34, 37]. In fact, the differential effect of aspirin according to body mass index observed in the meta-analysis [6] was primarily driven by the results of two studies [35, 36]. Our study has several strengths. It is the largest study conducted on NSAID use and endometrial cancer risk to date, allowing for detailed analysis of duration and intensity of use and effect modification by several factors. The Danish registries, with nearly complete coverage and continuously collected data on all Danish residents,
Cancer Causes Control Table 4 Risk of endometrial cancer associated with use of low-dose aspirin and non-aspirin nonsteroidal anti-inflammatory drugs, stratified by parity, hormone replacement therapy use, and obesity Low-dose aspirin
Non-aspirin NSAIDs Cases
Controls
Multivariable-adjusted ORa (95 % CI)
Cases
Controls
Multivariable-adjusted ORa (95 % CI)
0
213
2,749
0.82 (0.70–0.95)
565
5,925
1.04 (0.92–1.17)
C1
605
7,732
1.03 (0.93–1.13)
2,016
27,821
0.94 (0.88–1.00)
Parity
p interaction
0.054
0.424
HRT use Nonuse
447
6,721
0.95 (0.85–1.06)
1,348
20,286
Ever use
371
3,760
0.99 (0.87–1.11)
1,233
13,460
p interaction
0.649
1.00 (0.93–1.08) 0.90 (0.82–0.99) 0.063
Obesity No
704
9,717
0.90 (0.72–1.14)
2,262
31,638
1.02 (0.81–1.28)
Yes
114
764
0.97 (0.89–1.06)
319
2,108
0.96 (0.90–1.02)
p interaction
0.553
0.611
CI confidence interval, HRT hormone replacement therapy, NSAIDs nonsteroidal anti-inflammatory drugs, OR odds ratio a
Adjusted for age, parity, hormone replacement therapy use, obesity, diabetes, chronic obstructive pulmonary disease, education, and mutually adjustment for exposure variables
minimized selection bias. In particular, the Prescription Registry [24] provided accurate information on redeemed drug prescriptions. Furthermore, by applying a 1-year lag prior to index date, we ensured that we did not include any NSAID use associated with symptoms of a not yet diagnosed endometrial cancer. Finally, our cases were histologically verified, which enhanced case validity and permitted analyses by type of endometrial cancer. Some limitations of our study should also be considered. We had no information on drugs sold over-the-counter. However, during the study period, about 80–90 % of lowdose aspirin and non-aspirin NSAIDs were on prescription [28]. Furthermore, as 50 % of the cost of these drugs is reimbursed when they are prescribed by a physician, chronic use is by prescription in the majority of patients. We added musculoskeletal disorders and headache to the full model, as proxy measures of over-the-counter analgesic use, and this analysis yielded risk estimates on nonaspirin NSAID use similar to the main analysis. In our study, we did not include high-dose aspirin in the analysis since it is mainly sold over-the-counter (90–95 %) [28]. However, in Denmark, high-dose aspirin is primarily used as short-term therapy for acute pains, and therefore, we assume that high-dose aspirin use resulted in only minor misclassification. Finally, over-the-counter use of nonaspirin NSAIDs and high-dose aspirin was most likely similar among cases and controls, thus introducing mainly non-differential exposure misclassification [44].
Non-aspirin NSAIDs may be used sporadically, and one pack of tablets may be shared across family members. Due to the register-based design, we lacked information on the amount of drug, which was actually taken and may therefore have overestimated duration and intensity of nonaspirin NSAID use. However, we assume this limitation to be minimal in analyses of long-term and high-intensity or continuous non-aspirin NSAID use combined. In regard to low-dose aspirin, similar potential limitations are not applicable, because the drug is taken daily for cardiovascular protection. Establishment of the Prescription Registry in 1995 meant that we lacked information on drug use prior to this date. We evaluated the influence of this left truncation of prescription data by applying a new-user design, which yielded results similar to those of the main analysis. Finally, we had no information on body mass index. Obesity is a strong risk factor for endometrial cancer and may also be associated with a higher consumption of NSAIDs. We handled this potential limitation by defining obesity as a composite measure of the diagnosis in the Patient Register and/or redemption of anti-obesity drugs in the Prescription Registry. However, this method captured only a proportion of the obese women in our study population, and residual confounding may have retained. In conclusion, we found no association between lowdose aspirin or non-aspirin NSAIDs and endometrial cancer risk, although there was some indication of a reduced risk of endometrial cancer with use of low-dose aspirin
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Cancer Causes Control
among nulliparous women and with non-aspirin NSAID use among women using HRT. Acknowledgments NB was funded by a scholarship from the Lundbeck Foundation. The funding source had no role in the design, analysis, and interpretation of the results. Conflict of interest of interest.
The authors declare that they have no conflict
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