Abstract
The use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risks of cancers at several sites in some studies; however, we recently reported no association between their use and total cancer risk in women in a prospective study. Here we examine the association between NSAIDs and total and site-specific cancer incidence in the large, prospective Women’s Health Initiative (WHI). 129,013 women were recruited to participate in the WHI at 40 US clinical centers from 1993 to 1998 and followed prospectively. After 9.7 years of follow-up, 12,998 incident, first primary, invasive cancers were diagnosed. NSAID use was systematically collected at study visits. We used Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations between NSAIDs use and total and site-specific cancer risk. Relative to non-use, consistent use (i.e., use at baseline and year 3 of follow-up) of any NSAID was not associated with total cancer risk (HR 1.00, 95% CI: 0.94–1.06). Results for individual NSAIDs were similar to the aggregate measure. In site-specific analyses, NSAIDs were associated with reduced risks of colorectal cancer, ovarian cancer, and melanoma. Our study confirms a chemopreventive benefit for colorectal cancer in women and gives preliminary evidence for a reduction of the risk of some rarer cancers. NSAIDs’ benefit on cancer risk was limited to specific sites and not evident when total cancer risk was examined. This information may be of importance when NSAIDs are considered as chemopreventive agents.
Keywords: Aspirin, cancer, ibuprofen, inflammation, naproxen, non-steroidal anti-inflammatory drug
Introduction
The use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risks of cancers at several sites, most consistently the colon and rectum 1. Overall associations beyond those sites are less clear. A recent series of meta-analyses of randomized trials by Rothwell et al. 2–5, reported that aspirin to reduced cancer risk and mortality. It is noteworthy that women were underrepresented in those analyses and, in most cases, findings were not stratified on sex. Thus associations for women are not well studied. In the only randomized trial of aspirin among women, no overall effect on cancer risk was observed in the Women’s Health Study (WHS) 6, 7, however these findings were based on a single, very low dose (100mg given every second day). In addition, few prospective observational studies of commonly available NSAIDs have examined associations with overall cancer risk in women and among them findings are inconsistent 8–14. In the first study to examine specific non-aspirin formulations, we recently reported that NSAIDs, among participants of the VITamins And Lifestyle (VITAL) cohort study 10, reduced overall cancer incidence in men but not in women.
Given these discrepancies, we took advantage of the large, prospective, Women’s Health Initiative (WHI) to study further the association between NSAIDs and overall as well as site-specific cancer risk in women.
Methods
Women’s Health Initiative
The WHI is a large, prospective study that was designed to examine common causes of morbidity and mortality among postmenopausal women, including cancer, cardiovascular disease, and osteoporosis 15. The study consists of a multifactorial clinical trial (CT) (Trial registration: clinicaltrials.gov identifier, NCT00000611) and an observational study (OS). Detailed methods of the study are given elsewhere 15–17. Briefly, 161,808 women, ages 50–79 years, were recruited at 40 US clinical centers between September 1, 1993 and December 31, 1998. The WHI CT included 3 overlapping components: 2 placebo controlled hormone therapy trials [estrogen-alone (n=10,739) and estrogen plus progestin (n=16,608)]; a dietary modification compared to usual diet trial (n=48,836); and a calcium/vitamin D supplementation placebo controlled trial (n=36,282) 18–20. Participants in the OS were 93,676 women who were screened for participation in the CT but were ineligible or unwilling to participate, or who were directly recruited 21. After the original WHI study ended in 2005, the WHI Extension Study (2005–2010) was carried out to collect an additional five years of follow-up data. Women provided written informed consent for participation in both the original and extension studies. Human Subjects Review Committees at all participating institutions approved the WHI study protocol.
For the present analysis, exclusions were made for women who: reported a positive history of cancer, other than non-melanoma skin cancer, prior to baseline enrollment or who were missing these data (n=16,255); had a cancer diagnosis between baseline and the third year of follow-up (n=3,705); or were missing NSAID exposure data from baseline or year 3 of follow-up (n=12,835) visits. After exclusions, there were 129,013 women available for inclusion in the analysis.
Data collection
WHI participants attended baseline screening visits, during which they completed self-administered questionnaires that collected detailed information on demographics, medical and reproductive history, family history of cancer, physical activity, and other risk factors. Height (cm) and weight (kg) were measured by clinic staff, and used to determine body mass index (BMI; kg/m2).
A computer-driven medication-inventory system was developed to capture usual current medication use 16. Participants were asked to bring prescription and over-the-counter medications used regularly (≥2 times/week) over the previous 2 weeks to their clinic visit to facilitate completion of a computer-assisted interview about current medication use. Women were asked about their current, regular use of NSAIDs, including aspirin, ibuprofen, naproxen, COX-2 inhibitors (e.g., celecoxib), and other NSAID preparations (e.g., indomethacin). Women provided medication data at baseline and year 3 (OS and CT) and additionally years 6 and 9 (CT only).
In an effort to minimize measurement error, use of individual NSAIDs was categorized as none, inconsistent, and consistent, corresponding to non-use at both baseline and the year 3 visits, use at baseline or year 3 only, and use at both baseline and year 3, respectively. Duration of NSAID use was reported at baseline and was dichotomized (<5y and ≥5y). Analyses of NSAID duration were restricted to non- and consistent users. Summary variables were created to account for uses of any NSAID (including prescription and over-the-counter preparations), any aspirin, and any non-aspirin NSAID. We defined low-dose aspirin as ≤100mg.
Follow-up for cancer and censoring
Incident, invasive cancer cases were reported by questionnaire annually in the OS and semi-annually in the CT. Medical records were obtained and reviewed, and cancer diagnoses confirmed by physician adjudicators 22. Only confirmed, invasive cancer diagnoses after year 3, the adjusted “baseline”, were considered cases. After a median of 9.7 years of follow-up, 12,998 invasive cancers were identified. Cancers were additionally grouped by organ system or organ, and those with ≥150 cases were included in site-specific analyses.
Participants were right-censored from the analysis at the earliest date of the following events: end of original follow-up for participants who were not enrolled in the WHI Extension Study (n=24,392), withdrawal from the study (n=1,006), death (n=8,144), in situ diagnosis (n=2,718), loss of contact (n=479), or December 31, 2010, the last date of the WHI Extension study data adjudication (n=81,890). In site-specific analyses an invasive cancer at a given site was considered a “case” if it was the woman’s first primary cancer. Incident cancers which were not the event of interest were censored at their respective times of diagnoses in order to avoid surveillance bias and to be consistent with exclusion criteria.
Statistical analyses
Cox proportional hazards regression models using baseline age as the time metric were used to estimate age- and multivariable-adjusted hazard ratios (HR) and 95% CI for associations between NSAID use and cancer incidence. All multivariable-adjusted regression models were adjusted for randomization/enrollment in the CT. In addition, we selected a priori potential confounders collected at baseline, including known and suspected risk factors of the most common cancers and indications/contraindications for NSAID use for inclusion in regression models (see footnote of Table 2). In order to control for the potential confounding of the association between an individual NSAID and cancer risk by use of another, regression analyses for any one NSAID exposure were further adjusted for the use of other NSAIDs. Tests for linear trend (P trend) across categories of NSAID duration were calculated by including 3-level ordinal variables for NSAID duration (non-use, <5y consistent use, ≥5y consistent use) in regression models.
Table 2.
Associations between NSAID use and invasive cancer risk in the Women’s Health Initiative observational study and clinical trial, n=129,013.
| NSAID | Cancer cases (n=12,998), n |
Non-cases (n=116,015), n |
Age & NSAID adjusted HR (95% CI)a |
Multivariable- adjusted HR (95% CI)b |
|---|---|---|---|---|
| Any NSAID | ||||
| Non-user | 5,894 | 55,747 | 1.00 reference | 1.00 reference |
| Inconsistent use | 4,436 | 37,903 | 1.11 (1.07–1.15) | 1.07 (1.02–1.13) |
| Consistent usec | 2,668 | 22,365 | 1.02 (0.97–1.07) | 1.00 (0.94–1.06) |
| Duration among consistent usersd | ||||
| <5y | 1,612 | 13,670 | 1.00 (0.95–1.06) | 0.99 (0.93–1.06) |
| ≥5y | 1,056 | 8,695 | 1.02 (0.96–1.09) | 0.99 (0.91–1.08) |
| P trende | 0.822 | |||
| Any aspirin | ||||
| Non-user | 7,858 | 73,399 | 1.00 reference | 1.00 reference |
| Inconsistent use | 3,158 | 26,633 | 0.97 (0.93–1.01) | 0.94 (0.89–0.99) |
| Consistent usec | 1,712 | 13,929 | 0.99 (0.94–1.04) | 0.99 (0.93–1.06) |
| Duration among consistent usersd | ||||
| <5y | 1,045 | 8,655 | 0.98 (0.92–1.05) | 1.00 (0.92–1.08) |
| ≥5y | 667 | 5,274 | 1.00 (0.93–1.09) | 0.98 (0.89–1.08) |
| P trende | 0.712 | |||
| Low-dose aspirin (≤100mg) | ||||
| Non-user | 10,657 | 97,012 | 1.00 reference | 1.00 reference |
| Inconsistent use | 1,278 | 11,146 | 0.93 (0.88–0.99) | 0.92 (0.85–0.99) |
| Consistent usec | 399 | 3,327 | 0.96 (0.87–1.06) | 1.02 (0.90–1.14) |
| Duration among consistent usersd | ||||
| <5y | 321 | 2,604 | 0.99 (0.89–1.11) | 1.05 (0.92–1.20) |
| ≥5y | 78 | 723 | 0.85 (0.68–1.06) | 0.85 (0.65–1.11) |
| P trende | 0.754 | |||
| Regular-strength aspirin (>100mg) | ||||
| Non-user | 9,125 | 84,740 | 1.00 reference | 1.00 reference |
| Inconsistent use | 2,452 | 20,369 | 0.99 (0.95–1.04) | 0.96 (0.90–1.02) |
| Consistent usec | 1,027 | 8,161 | 1.02 (0.95–1.08) | 1.01 (0.93–1.09) |
| Duration among consistent usersd | ||||
| <5y | 531 | 4,418 | 0.99 (0.91–1.08) | 1.00 (0.89–1.11) |
| ≥5y | 496 | 3,743 | 1.06 (0.97–1.17) | 1.05 (0.94–1.18) |
| P trende | 0.453 | |||
| Any non-aspirin NSAID | ||||
| Non-user | 9,814 | 89,287 | 1.00 reference | 1.00 reference |
| Inconsistent use | 2,142 | 18,980 | 1.04 (0.99–1.10) | 1.03 (0.97–1.10) |
| Consistent usec | 524 | 4,581 | 1.06 (0.97–1.16) | 1.04 (0.93–1.16) |
| Duration among consistent usersd | ||||
| <5y | 351 | 2,897 | 1.12 (1.01–1.25) | 1.09 (0.96–1.25) |
| ≥5y | 173 | 1,684 | 0.96 (0.83–1.12) | 0.94 (0.79–1.13) |
| P trende | 0.897 | |||
| Ibuprofen | ||||
| Non-user | 10,236 | 93,714 | 1.00 reference | 1.00 reference |
| Inconsistent use | 1,791 | 15,126 | 1.08 (1.03–1.14) | 1.05 (0.98–1.12) |
| Consistent usec | 424 | 3,646 | 1.08 (0.98–1.19) | 1.07 (0.95–1.20) |
| Duration among consistent usersd | ||||
| <5y | 268 | 2,143 | 1.15 (1.02–1.30) | 1.15 (0.99–1.33) |
| ≥5y | 156 | 1,503 | 0.98 (0.83–1.14) | 0.96 (0.79–1.16) |
| P trende | 0.585 | |||
| Naproxen | ||||
| Non-user | 11,459 | 104,137 | 1.00 reference | 1.00 reference |
| Inconsistent use | 716 | 6,347 | 1.13 (1.01–1.27) | 1.18 (1.03–1.37) |
| Consistent usec | 115 | 955 | 1.09 (0.85–1.41) | 1.22 (0.89–1.65) |
| Duration among consistent usersd | ||||
| <5y | 77 | 699 | 1.00 (0.80–1.25) | 0.98 (0.75–1.27) |
| ≥5y | 38 | 256 | 1.26 (0.91–1.73) | 1.45 (1.02–2.06) |
| P trende | 0.134 | |||
Abbreviations: NSAID, non-steroidal anti-inflammatory drug; HR, hazard ratio; CI, confidence interval
Analyses of individual NSAIDs, low-dose or regular-strength aspirin, ibuprofen, or naproxen are mutually adjusted for in regression models. Total aspirin is adjusted for individual non-aspirin NSAIDs, and total non-aspirin NSAIDs are adjusted for low-dose and regular-strength aspirin. Analyses of ‘any NSAID’ are age-adjusted only
Adjusted for age, observational study enrollment, hormone therapy trial enrollment, diet modification trial enrollment, calcium/vitamin D trial enrollment, US region, education, ethnicity, height, body mass index, physical activity, alcohol consumption, pack-years of smoking, fruit and vegetable consumption, red meat consumption, family histories of: breast cancer, cervical cancer, endometrial cancer, and colorectal cancer (as separate terms); screening for: breast cancer, colon cancer, and cervical cancer (as separate terms); age at menarche, age at menopause, gravidity, age at 1st birth, duration of estrogen therapy, duration of combined postmenopausal hormone therapy, hysterectomy status, multivitamin use, use of anti-hypertensive medication, history of coronary heart disease, use of cholesterol-lowering medication, history of arthritis, history of migraine, history of ulcer, and other NSAID use
Consistent use is defined as NSAID use at baseline and at the third year of follow-up
Duration of use reported at baseline, restricted to analyses of non- and consistent users
P trend is calculated across 3 categories: non-use, <5yrs use among consistent users, and ≥5yrs use among consistent users
We hypothesized a priori that associations between NSAID use and cancer risk would be modified by factors associated with inflammation, including BMI 23, cigarette smoking 24, history of arthritis 25, and use of cholesterol-lowering drugs 26. P values for interaction (P interaction) were calculated by including a cross-product term in regression models. All statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC, USA). All statistical tests are two-sided, and P<0.05 was considered statistically significant.
Results
Age-adjusted associations between characteristics of WHI women and consistent NSAID use are given in Table 1. Increasing age, BMI, smoking, and use of postmenopausal hormones were all positively associated with consistent NSAID use. Women who used multivitamins, had a family history of cancer, were screened for cancer, or had a personal history of hypertension, heart disease, or arthritis were also more likely to use NSAIDs consistently. Non-white women and women who reported gastric ulcers were less likely to use NSAIDs.
Table 1.
Associations between participant characteristics and NSAID use in the Women’s Health Initiative observational study and clinical trial, n=129,013.
| Characteristic | Non-user (n=61,641), n(%) |
Inconsistent NSAID usea (n=42,339), n(%) |
Consistent NSAID use (n=25,033), n (%)b |
|---|---|---|---|
| Demographics and anthropometrics | |||
| Age, years | |||
| 50–54 | 9,794 (15.89) | 5,426 (12.82) | 2,110 (8.43) |
| 55–59 | 13,995 (22.70) | 8,014 (18.93) | 4,006 (16.00) |
| 60–64 | 14,410 (23.38) | 9,877 (23.33) | 5,935 (23.71) |
| 65–69 | 12,556 (20.37) | 9,420 (22.25) | 6,340 (25.33) |
| 70–74 | 7,824 (12.69) | 6,741 (15.92) | 4,707 (18.80) |
| 75–79 | 3,062 (4.97) | 2,861 (6.76) | 1,935 (7.73) |
| Enrolled in WHI observational study | |||
| No | 29,183 (47.34) | 18,619 (43.98) | 10,509 (41.98) |
| Yes | 32,458 (52.66) | 23,720 (56.02) | 14,524 (58.02) |
| Education | |||
| ≤ High school graduate | 13,154 (21.51) | 9,817 (23.34) | 5,547 (22.29) |
| Some college | 22,522 (36.83) | 16,187 (38.48) | 9,505 (38.20) |
| College or advanced degree | 25,477 (41.66) | 16,063 (38.18) | 9,831 (39.51) |
| Ethnicity | |||
| White | 49,275 (79.94) | 35,667 (84.24) | 22,418 (89.55) |
| Black | 5,983 (9.71) | 3,673 (8.68) | 1,477 (5.90) |
| Hispanic | 2,824 (4.58) | 1,524 (3.60) | 457 (1.83) |
| Asian/Pacific Islander | 2,395 (3.89) | 719 (1.70) | 323 (1.29) |
| Other | 1,164 (1.89) | 756 (1.79) | 358 (1.43) |
| Height, inches | |||
| <64 | 33,442 (54.56) | 22,992 (54.65) | 13,724 (55.11) |
| 64–67.9 | 25,167 (41.06) | 17,271 (41.05) | 10,106 (40.58) |
| 68–70.9 | 2,554 (4.17) | 1,697 (4.03) | 1,014 (4.07) |
| ≥71 | 134 (0.22) | 114 (0.27) | 58 (0.23) |
| Body mass index, kg/m2 | |||
| <25 | 23,793 (38.92) | 13,551 (32.30) | 7,852 (31.62) |
| 25–29.9 | 21,361 (34.94) | 14,516 (34.60) | 8,809 (35.47) |
| ≥30 | 15,980 (26.14) | 13,883 (33.09) | 8,175 (32.92) |
| Lifestyle characteristics | |||
| Physical activity, MET-hrs/week | |||
| Inactive | 8,948 (15.29) | 6,642 (16.45) | 3,520 (14.60) |
| >0–6.8 | 16,145 (27.60) | 11,647 (28.85) | 6,832 (28.33) |
| 6.8–16.6 | 16,019 (27.38) | 10,946 (27.11) | 6,964 (28.88) |
| ≥16.7 | 17,394 (29.73) | 11,141 (27.59) | 6,801 (28.20) |
| Alcohol consumption, servings/week | |||
| 0 | 25,565 (41.60) | 18,054 (42.76) | 10,039 (40.18) |
| >0–0.9 | 12,686 (20.64) | 8,488 (20.10) | 4,987 (19.96) |
| 0.9–3.6 | 11,272 (18.34) | 7,472 (17.70) | 4,680 (18.73) |
| ≥3.7 | 11,938 (19.42) | 8,210 (19.44) | 5,280 (21.13) |
| Smoking, pack-years | |||
| Never smoker | 32,443 (54.45) | 21,070 (51.53) | 12,535 (51.65) |
| >0–4.9 | 8,792 (14.75) | 5,940 (14.53) | 3,302 (13.61) |
| 5–19.9 | 8,574 (14.39) | 5,871 (14.36) | 3,478 (14.33) |
| ≥20 | 9,778 (16.41) | 8,005 (19.58) | 4,955 (20.42) |
| Multivitamin use | |||
| No | 39,769 (64.52) | 25,107 (59.30) | 13,447 (53.72) |
| Yes | 21,872 (35.48) | 17,231 (40.70) | 11,586 (46.28) |
| Family medical history | |||
| Family history of breast cancer | |||
| No | 48,233 (82.35) | 32,673 (81.49) | 19,255 (81.24) |
| Yes | 10,335 (17.65) | 7,423 (18.51) | 4,447 (18.76) |
| Family history of cervical cancer | |||
| No | 55,594 (96.13) | 37,786 (95.61) | 22,387 (95.82) |
| Yes | 2,239 (3.87) | 1,736 (4.39) | 976 (4.18) |
| Family history of endometrial cancer | |||
| No | 54,587 (94.51) | 37,160 (94.10) | 21,953 (93.78) |
| Yes | 3,172 (5.49) | 2,331 (5.90) | 1,457 (6.22) |
| Family history of ovarian cancer | |||
| No | 56,131 (97.63) | 38,344 (97.58) | 22,582 (97.25) |
| Yes | 1,362 (2.37) | 952 (2.42) | 638 (2.75) |
| Family history of colorectal cancer | |||
| No | 47,491 (83.83) | 32,318 (83.50) | 19,068 (83.34) |
| Yes | 9,159 (16.17) | 6,387 (16.50) | 3,813 (16.66) |
| Family history of prostate cancer | |||
| No | 52,130 (90.05) | 35,662 (90.16) | 21,011 (89.60) |
| Yes | 5,757 (9.95) | 3,891 (9.84) | 2,438 (10.40) |
| Medications/medical history | |||
| Duration of unopposed estrogen therapy, years | |||
| <4 | 48,476 (78.64) | 31,497 (74.39) | 18,215 (72.76) |
| 4–12 | 7,262 (11.78) | 5,466 (12.91) | 3,352 (13.39) |
| ≥12 | 5,903 (9.58) | 5,375 (12.70) | 3,466 (13.85) |
| Duration of combined hormone therapy, years | |||
| <2.5 | 50,849 (82.49) | 34,758 (82.09) | 20,184 (80.63) |
| 2.5–7 | 5,847 (9.49) | 3,814 (9.01) | 2,331 (9.31) |
| ≥8 | 4,944 (8.02) | 3,767 (8.90) | 2,517 (10.06) |
| Hysterectomy status | |||
| No | 38,348 (62.24) | 24,386 (57.63) | 14,464 (57.81) |
| Yes | 23,267 (37.76) | 17,931 (42.37) | 10,554 (42.19) |
| Breast cancer screening | |||
| No | 2,386 (3.89) | 1,417 (3.36) | 591 (2.37) |
| Yes | 58,910 (96.11) | 40,733 (96.64) | 24,353 (97.63) |
| Cervical cancer screening | |||
| No | 815 (1.43) | 511 (1.30) | 239 (1.02) |
| Yes | 56,043 (98.57) | 38,669 (98.70) | 23,254 (98.98) |
| Colon cancer screening | |||
| No | 30,025 (51.43) | 19,288 (47.90) | 10,571 (43.94) |
| Yes | 28,360 (48.57) | 20,977 (52.10) | 13,487 (56.06) |
| History of hypertension | |||
| No | 44,355 (72.30) | 26,696 (63.43) | 14,600 (58.64) |
| Yes | 16,997 (27.70) | 15,389 (36.57) | 10,297 (41.36) |
| Use of anti-hypertensive medications | |||
| No | 44,443 (72.10) | 26,125 (61.70) | 13,735 (54.87) |
| Yes | 17,198 (27.90) | 16,214 (38.30) | 11,298 (45.13) |
| History of coronary heart disease | |||
| No | 61,021 (99.03) | 41,252 (97.46) | 23,880 (95.47) |
| Yes | 596 (0.97) | 1,075 (2.54) | 1,134 (4.53) |
| Use of cholesterol-lowering medications | |||
| No | 55,127 (89.43) | 35,961 (84.94) | 20,032 (80.02) |
| Yes | 6,514 (10.57) | 6,378 (15.06) | 5,001 (19.98) |
| History of arthritis | |||
| No | 37,311 (62.26) | 20,017 (48.92) | 10,583 (43.52) |
| Rheumatoid | 2,305 (3.85) | 2,306 (5.64) | 1,412 (5.81) |
| Osteoarthritis or other | 20,307 (33.89) | 18,595 (45.44) | 12,324 (50.68) |
| History of migraine headaches | |||
| No | 51,825 (89.75) | 35,186 (88.08) | 21,013 (87.85) |
| Yes | 5,921 (10.25) | 4,760 (11.92) | 2,906 (12.15) |
| History of gastric ulcer | |||
| No | 56,875 (93.50) | 39,214 (93.61) | 23,477 (94.57) |
| Yes | 3,956 (6.50) | 2,676 (6.39) | 1,349 (5.43) |
Abbreviations: NSAID, non-steroidal anti-inflammatory drug
Inconsistent NSAID use is defined as use at baseline or the third year of follow-up.
Consistent NSAID use is defined as NSAID use at baseline and at the third year of follow-up.
Age and multivariable-adjusted associations between NSAID use and total cancer incidence are given in Table 2. Results were similar in the OS and CT; therefore, findings are given in the combined cohort, adjusted for CT intervention assignment. Relative to non-use, consistent use of any NSAID (HR 1.00, 95% CI: 0.94–1.06) and increasing baseline duration of use among consistent users (≥5y: HR 0.99, 95% CI: 0.91–1.08) were not associated with total cancer risk. Use of individual NSAIDs, including low-dose and regular-strength aspirin, ibuprofen, and naproxen were also not associated with cancer risk. Although long-term baseline use of naproxen was associated with a 45% increased risk of total cancer (HR 1.45, 95% CI: 1.02–2.06) among consistent users, this result was based on a small number of cases and there was no linear trend for duration of use (P trend=0.14).
We performed several sensitivity analyses in order to evaluate the robustness of our findings. In an analysis where use of individual NSAIDs was compared to a referent of non-users of any NSAID, results were not meaningfully changed (consistent use vs. non-use for any aspirin: HR 1.05, 95% CI: 0.98–1.13; for any non-aspirin NSAID: HR 1.02, 95% CI: 0.92–1.15). We also considered whether our censoring of in situ cancers had an effect on our results. In a separate sensitivity analysis, we examined associations between NSAID use and cancer risk, where a case was defined as incident in situ or invasive cancer. Results were changed only nominally (Supplemental Table 1). Lastly, in an effort to determine whether adjustment for correlates of NSAID use constituted over-adjustment, we examined associations in regression models adjusted only for cancer risk factors (Supplemental Table 2 and footnotes); here again, only very small changes were noticed in the results.
We further examined whether associations between consistent NSAID use and cancer risk were modified by factors known to affect inflammation (Figure 1). There was no effect-modification by BMI, cigarette smoking, history of arthritis, or use of cholesterol-lowering drugs.
Figure 1.
Associations between NSAID use and invasive cancer risk, stratified on characteristics associated with inflammation, in the Women’s Health Initiative observational study and clinical trial, n=129,013. Hazard ratios and 95% confidence intervals estimated using Cox proportional hazards regression models and are adjusted for age, observational study enrollment, hormone therapy trial enrollment, diet modification trial enrollment, calcium/vitamin D trial enrollment, US region, education, ethnicity, height, body mass index, physical activity, alcohol consumption, pack-years of smoking, fruit and vegetable consumption, red meat consumption, family histories of: breast cancer, cervical cancer, endometrial cancer, and colorectal cancer (as separate terms); screening for: breast cancer, colon cancer, and cervical cancer (as separate terms); age at menarche, age at menopause, gravidity, age at 1st birth, duration of estrogen therapy, duration of combined postmenopausal hormone therapy, hysterectomy status, multivitamin use, use of anti-hypertensive medication, history of coronary heart disease, use of cholesterol-lowering medication, history of arthritis, history of migraine, history of ulcer, and other NSAID use. Consistent use is defined as NSAID use at baseline and the third year of follow-up.
Table 3 presents associations between NSAID use and risk of cancers of individual organs or organ systems. In-depth analyses of the associations between NSAIDs and colorectal 27, breast 28, endometrium 29, and skin 30 cancer in the WHI have been published previously. There was strong evidence for a reduction of the risk of GI tract cancers, and colorectal cancer in particular, with use of any NSAID (≥5y among consistent users vs. non-use: HR 0.74, 95% CI: 0.55–0.99). In addition, long-term consistent use of NSAIDs, primarily aspirin, was associated with a reduction of ovarian cancer risk and consistent aspirin use was inversely associated with melanoma incidence. Results were similar by aspirin dose (Supplemental Table 3). NSAID use was not associated with cancers of the urinary tract, lung, breast, endometrium, thyroid, or hematologic malignancies. There were no statistically significant increases in risk for any cancer site.
Table 3.
Associations between NSAID use and risk of individual invasive cancers in the Women’s Health Initiative observational study and clinical trial.
| Non-user | Inconsistent use | Consistent usec,d
|
||||
|---|---|---|---|---|---|---|
| Overall | <5y | ≥5y | P trende | |||
| Gastrointestinal cancers (n=1,876) | ||||||
| Any NSAID | ||||||
| Cases / non-cases | 866 / 60,775 | 676 / 41,663 | 334 / 24,699 | 206 / 1,507 | 128 / 9,623 | |
| HR (95% CI)a | 1.00 reference | 1.13 (1.02–1.24) | 0.83 (0.73–0.94) | 0.84 (0.72–0.97) | 0.80 (0.66–0.96) | 0.003 |
| HR (95% CI)b | 1.00 reference | 1.08 (0.95–1.23) | 0.82 (0.69–0.96) | 0.84 (0.69–1.02) | 0.78 (0.62–0.99) | 0.016 |
| Any aspirin | ||||||
| Cases / non-cases | 1,139 / 80,118 | 463 / 29,328 | 208 / 15,433 | 126 / 9,574 | 82 / 5,859 | |
| HR (95% CI)a | 1.00 reference | 0.90 (0.80–1.01) | 0.77 (0.66–0.89) | 0.76 (0.63–0.91) | 0.79 (0.63–0.99) | 0.002 |
| HR (95% CI)b | 1.00 reference | 0.88 (0.76–1.02) | 0.73 (0.61–0.89) | 0.76 (0.61–0.96) | 0.73 (0.54–0.97) | 0.004 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 1,377 / 97,724 | 351 / 20,771 | 57 / 5,048 | 42 / 3,206 | 15 / 1,842 | |
| HR (95% CI)a | 1.00 reference | 1.11 (0.97–1.26) | 0.79 (0.60–1.03) | 0.93 (0.68–1.27) | 0.57 (0.34–0.95) | 0.044 |
| HR (95% CI)b | 1.00 reference | 1.15 (0.97–1.35) | 0.87 (0.63–1.20) | 1.01 (0.70–1.46) | 0.63 (0.35–1.15) | 0.231 |
| Colorectal cancer (n=1,287) | ||||||
| Any NSAID | ||||||
| Cases / non-cases | 611 / 61,030 | 447 / 41,892 | 229 / 24,804 | 145 / 15,137 | 84 / 9,667 | |
| HR (95% CI)a | 1.00 reference | 1.06 (0.94–1.20) | 0.81 (0.70–0.95) | 0.85 (0.71–1.02) | 0.76 (0.60–0.95) | 0.006 |
| HR (95% CI)b | 1.00 reference | 1.00 (0.86–1.17) | 0.78 (0.64–0.95) | 0.84 (0.67–1.06) | 0.74 (0.55–0.99) | 0.023 |
| Any aspirin | ||||||
| Cases / non-cases | 810 / 80,447 | 299 / 29,492 | 144 / 15,497 | 90 / 9,610 | 54 / 5,887 | |
| HR (95% CI)a | 1.00 reference | 0.85 (0.74–0.99) | 0.76 (0.64–0.91) | 0.78 (0.63–0.97) | 0.75 (0.57–0.99) | 0.006 |
| HR (95% CI)b | 1.00 reference | 0.83 (0.69–0.99) | 0.71 (0.56–0.89) | 0.75 (0.57–1.00) | 0.69 (0.48–0.99) | 0.010 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 959 / 98,142 | 238 / 20,884 | 40 / 5,065 | 31 / 3,217 | 9 / 1,848 | |
| HR (95% CI)a | 1.00 reference | 1.13 (0.97–1.31) | 0.78 (0.57–1.08) | 0.98 (0.69–1.41) | 0.49 (0.25–0.95) | 0.068 |
| HR (95% CI)b | 1.00 reference | 1.19 (0.98–1.44) | 0.79 (0.53–1.19) | 1.00 (0.63–1.56) | 0.51 (0.23–1.14) | 0.169 |
| Pancreatic cancer (n=378) | ||||||
| Any NSAID | ||||||
| Cases / non-cases | 160 / 61,481 | 151 / 42,188 | 67 / 24,966 | 40 / 15,242 | 27 / 9,724 | |
| HR (95% CI)a | 1.00 reference | 1.34 (1.07–1.67) | 0.87 (0.65–1.16) | 0.84 (0.59–1.19) | 0.86 (0.57–1.30) | 0.324 |
| HR (95% CI)b | 1.00 reference | 1.29 (0.97–1.70) | 0.82 (0.57–1.17) | 0.81 (0.53–1.24) | 0.71 (0.42–1.21) | 0.155 |
| Any aspirin | ||||||
| Cases / non-cases | 211 / 81,046 | 108 / 29,683 | 39 / 15,602 | 23 / 9,677 | 16 / 5,925 | |
| HR (95% CI)a | 1.00 reference | 0.97 (0.74–1.25) | 0.74 (0.52–1.04) | 0.71 (0.46–1.09) | 0.78 (0.47–1.29) | 0.114 |
| HR (95% CI)b | 1.00 reference | 0.88 (0.64–1.23) | 0.69 (0.45–1.06) | 0.74 (0.44–1.24) | 0.58 (0.29–1.15) | 0.063 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 259 / 98,842 | 77 / 21,045 | 11 / 5,094 | 7 / 3,241 | 4 / 1,853 | |
| HR (95% CI)a | 1.00 reference | 1.20 (0.90–1.61) | 0.83 (0.45–1.53) | 0.83 (0.39–1.77) | 0.81 (0.30–2.19) | 0.582 |
| HR (95% CI)b | 1.00 reference | 1.20 (0.83–1.72) | 0.92 (0.46–1.83) | 0.93 (0.41–2.12) | 0.80 (0.25–2.53) | 0.686 |
| Urinary tract cancers (n=449) | ||||||
| Any NSAIDs | ||||||
| Cases / non-cases | 204 / 61,437 | 153 / 42,186 | 92 / 24,941 | 54 / 15,228 | 38 / 9,713 | |
| HR (95% CI)a | 1.00 reference | 1.09 (0.88–1.34) | 0.98 (0.76–1.25) | 0.93 (0.69–1.26) | 1.01 (0.71–1.43) | 0.888 |
| HR (95% CI)b | 1.00 reference | 1.10 (0.84–1.43) | 0.91 (0.66–1.25) | 0.75 (0.50–1.12) | 1.07 (0.70–1.63) | 0.853 |
| Any aspirin | ||||||
| Cases / non-cases | 269 / 80,988 | 111 / 29,680 | 62 / 15,579 | 35 / 9,665 | 27 / 5,914 | |
| HR (95% CI)a | 1.00 reference | 1.07 (0.85–1.34) | 0.99 (0.75–1.31) | 0.89 (0.63–1.27) | 1.10 (0.74–1.64) | 0.898 |
| HR (95% CI)b | 1.00 reference | 1.12 (0.85–1.49) | 0.96 (0.68–1.37) | 0.71 (0.44–1.16) | 1.29 (0.82–2.05) | 0.703 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 352 / 98,749 | 74 / 21,048 | 14 / 5,091 | 9 / 3,239 | 5 / 1,852 | |
| HR (95% CI)a | 1.00 reference | 1.07 (0.82–1.39) | 0.80 (0.47–1.38) | 0.81 (0.42–1.58) | 0.78 (0.32–1.89) | 0.455 |
| HR (95% CI)b | 1.00 reference | 0.93 (0.66–1.31) | 0.78 (0.41–1.48) | 0.89 (0.42–1.91) | 0.63 (0.20–1.98) | 0.463 |
| Kidney cancer (n=292) | ||||||
| Any NSAIDs | ||||||
| Cases / non-cases | 134 / 61,507 | 93 / 42,246 | 65 / 24,968 | 38 / 15,244 | 27 / 9,724 | |
| HR (95% CI)a | 1.00 reference | 1.02 (0.78–1.33) | 1.08 (0.80–1.45) | 1.02 (0.71–1.46) | 1.12 (0.74–1.69) | 0.634 |
| HR (95% CI)b | 1.00 reference | 1.03 (0.74–1.44) | 0.86 (0.58–1.29) | 0.62 (0.36–1.06) | 1.15 (0.70–1.89) | 0.942 |
| Any aspirin | ||||||
| Cases / non-cases | 176 / 81,081 | 71 / 29,720 | 41 / 15,600 | 23 / 9,677 | 18 / 5,923 | |
| HR (95% CI)a | 1.00 reference | 1.06 (0.80–1.41) | 1.04 (0.74–1.47) | 0.92 (0.60–1.43) | 1.16 (0.71–1.89) | 0.720 |
| HR (95% CI)b | 1.00 reference | 1.08 (0.76–1.53) | 0.89 (0.57–1.39) | 0.57 (0.29–1.10) | 1.34 (0.77–2.34) | 0.854 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 224 / 98,877 | 54 / 21,068 | 8 / 5,097 | 5 / 3,243 | 3 / 1,854 | |
| HR (95% CI)a | 1.00 reference | 1.26 (0.92–1.72) | 0.72 (0.35–1.47) | 0.70 (0.29–1.71) | 0.73 (0.23–2.29) | 0.407 |
| HR (95% CI)b | 1.00 reference | 1.08 (0.72–1.61) | 0.56 (0.23–1.40) | 0.55 (0.17–1.76) | 0.62 (0.15–2.54) | 0.318 |
| Bladder cancer (n=157) | ||||||
| Any NSAID | ||||||
| Cases / non-cases | 70 / 61,571 | 60 / 42,279 | 27 / 25,006 | 16 / 15,266 | 11 / 9,740 | |
| HR (95% CI)a | 1.00 reference | 1.21 (0.86–1.71) | 0.80 (0.51–1.24) | 0.77 (0.45–1.33) | 0.81 (0.43–1.54) | 0.360 |
| HR (95% CI)b | 1.00 reference | 1.23 (0.79–1.91) | 0.99 (0.58–1.69) | 1.00 (0.53–1.89) | 0.92 (0.42–2.01) | 0.859 |
| Any aspirin | ||||||
| Cases / non-cases | 93 / 81,164 | 40 / 29,751 | 21 / 15,620 | 12 / 9,688 | 9 / 5,932 | |
| HR (95% CI)a | 1.00 reference | 1.08 (0.74–1.58) | 0.91 (0.57–1.47) | 0.84 (0.46–1.53) | 0.99 (0.50–1.97) | 0.788 |
| HR (95% CI)b | 1.00 reference | 1.22 (0.76–1.94) | 1.12 (0.63–1.98) | 1.01 (0.49–2.07) | 1.24 (0.55–2.77) | 0.665 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 128 / 98,973 | 20 / 21,102 | 6 / 5,099 | 4 / 3,244 | 2 / 1,855 | |
| HR (95% CI)a | 1.00 reference | 0.74 (0.44–1.24) | 0.95 (0.41–2.18) | 1.00 (0.37–2.73) | 0.87 (0.21–3.51) | 0.886 |
| HR (95% CI)b | 1.00 reference | 0.61 (0.30–1.23) | 1.20 (0.47–3.06) | 1.55 (0.56–4.34) | 0.63 (0.09–4.56) | 0.318 |
| Lung cancer (n=1,417) | ||||||
| Any NSAID | ||||||
| Cases / non-cases | 569 / 61,072 | 553 / 41,786 | 295 / 24,738 | 185 / 15,097 | 110 / 9,641 | |
| HR (95% CI)a | 1.00 reference | 1.40 (1.25–1.58) | 1.12 (0.97–1.28) | 1.14 (0.97–1.35) | 1.05 (0.85–1.29) | 0.324 |
| HR (95% CI)b | 1.00 reference | 1.27 (1.09–1.48) | 1.02 (0.85–1.22) | 1.13 (0.92–1.40) | 0.91 (0.70–1.18) | 0.822 |
| Any aspirin | ||||||
| Cases / non-cases | 777 / 80,480 | 407 / 29,384 | 199 / 15,422 | 127 / 9,573 | 72 / 5,869 | |
| HR (95% CI)a | 1.00 reference | 1.09 (0.95–1.24) | 1.09 (0.93–1.27) | 1.14 (0.94–1.37) | 1.03 (0.81–1.31) | 0.430 |
| HR (95% CI)b | 1.00 reference | 0.97 (0.82–1.16) | 1.05 (0.86–1.28) | 1.19 (0.94–1.50) | 0.89 (0.65–1.22) | 0.995 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 1,030 / 9,807 | 234 / 20,888 | 52 / 5,053 | 37 / 3,211 | 15 / 1,842 | |
| HR (95% CI)a | 1.00 reference | 1.10 (0.94–1.28) | 1.07 (0.81–1.42) | 1.19 (0.85–1.65) | 0.83 (0.50–1.39) | 0.940 |
| HR (95% CI)b | 1.00 reference | 1.07 (0.88–1.30) | 1.01 (0.70–1.45) | 1.20 (0.79–1.82) | 0.68 (0.35–1.33) | 0.536 |
| Breast and reproductive cancers (n=6,020) | ||||||
| Any NSAID | ||||||
| Cases / non-cases | 2,796 / 58,845 | 1,973 / 40,366 | 1,251 / 23,782 | 764 / 14,518 | 487 / 9,264 | |
| HR (95% CI)a | 1.00 reference | 1.06 (1.00–1.12) | 1.05 (0.98–1.12) | 1.04 (0.96–1.13) | 1.03 (0.94–1.14) | 0.324 |
| HR (95% CI)b | 1.00 reference | 1.05 (0.97–1.12) | 1.05 (0.97–1.14) | 1.03 (0.93–1.14) | 1.04 (0.92–1.17) | 0.445 |
| Any aspirin | ||||||
| Cases / non-cases | 3,723 / 77,534 | 1,403 / 28,388 | 802 / 14,839 | 505 / 9,195 | 297 / 5,644 | |
| HR (95% CI)a | 1.00 reference | 0.98 (0.92–1.05) | 1.04 (0.96–1.12) | 1.06 (0.97–1.16) | 1.01 (0.89–1.13) | 0.509 |
| HR (95% CI)b | 1.00 reference | 0.97 (0.89–1.05) | 1.07 (0.97–1.17) | 1.10 (0.98–1.23) | 1.01 (0.87–1.16) | 0.448 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 4,632 / 94,469 | 964 / 20,158 | 252 / 4,853 | 168 / 3,080 | 84 / 1,773 | |
| HR (95% CI)a | 1.00 reference | 1.02 (0.95–1.10) | 1.07 (0.94–1.22) | 1.13 (0.97–1.32) | 0.98 (0.79–1.22) | 0.544 |
| HR (95% CI)b | 1.00 reference | 1.02 (0.93–1.11) | 1.03 (0.88–1.20) | 1.06 (0.87–1.28) | 0.94 (0.73–1.23) | 0.901 |
| Breast cancer (n=4,815) | ||||||
| Any NSAID | ||||||
| Cases / non-cases | 2,231 / 59,410 | 1,577 / 40,762 | 1,007 / 24,026 | 610 / 14,672 | 397 / 9,354 | |
| HR (95% CI)a | 1.00 reference | 1.06 (1.00–1.13) | 1.06 (0.98–1.14) | 1.04 (0.95–1.14) | 1.06 (0.95–1.18) | 0.203 |
| HR (95% CI)b | 1.00 reference | 1.07 (0.99–1.16) | 1.07 (0.98–1.18) | 1.06 (0.95–1.19) | 1.07 (0.94–1.22) | 0.213 |
| Any aspirin | ||||||
| Cases / non-cases | 2,969 / 78,288 | 1,118 / 28,673 | 657 / 14,984 | 413 / 9,287 | 244 / 5,697 | |
| HR (95% CI)a | 1.00 reference | 1.00 (0.93–1.07) | 1.07 (0.98–1.16) | 1.09 (0.98–1.21) | 1.04 (0.91–1.18) | 0.230 |
| HR (95% CI)b | 1.00 reference | 0.99 (0.91–1.09) | 1.11 (1.00–1.24) | 1.15 (1.01–1.30) | 1.05 (0.89–1.23) | 0.162 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 3,721 / 95,380 | 779 / 20,343 | 190 / 4,915 | 124 / 3,124 | 66 / 1,791 | |
| HR (95% CI)a | 1.00 reference | 1.03 (0.95–1.12) | 1.02 (0.88–1.18) | 1.04 (0.87–1.25) | 0.96 (0.75–1.23) | 0.940 |
| HR (95% CI)b | 1.00 reference | 1.05 (0.94–1.16) | 0.97 (0.81–1.17) | 0.99 (0.79–1.24) | 0.89 (0.66–1.21) | 0.466 |
| Ovarian cancer (n=414) | ||||||
| Any NSAID | ||||||
| Cases / non-cases | 191 / 50,797 | 152 / 33,998 | 71 / 20,150 | 53 / 12,283 | 18 / 7,867 | |
| HR (95% CI)a | 1.00 reference | 1.22 (0.98–1.51) | 0.88 (0.67–1.15) | 1.07 (0.79–1.46) | 0.57 (0.35–0.92) | 0.082 |
| HR (95% CI)b | 1.00 reference | 1.13 (0.87–1.46) | 0.80 (0.57–1.12) | 0.90 (0.62–1.32) | 0.54 (0.32–0.94) | 0.038 |
| Any aspirin | ||||||
| Cases / non-cases | 251 / 66,438 | 108 / 24,015 | 43 / 12,675 | 35 / 7,851 | 8 / 4,824 | |
| HR (95% CI)a | 1.00 reference | 0.94 (0.73–1.21) | 0.80 (0.58–1.11) | 1.08 (0.76–1.54) | 0.40 (0.20–0.81) | 0.047 |
| HR (95% CI)b | 1.00 reference | 0.92 (0.68–1.24) | 0.74 (0.50–1.10) | 0.99 (0.64–1.54) | 0.37 (0.16–0.84) | 0.038 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 304 / 81,164 | 66 / 16,879 | 17 / 4,027 | 12 / 2,562 | 5 / 1,465 | |
| HR (95% CI)a | 1.00 reference | 0.96 (0.71–1.28) | 1.09 (0.67–1.79) | 1.27 (0.71–2.27) | 0.93 (0.38–2.25) | 0.797 |
| HR (95% CI)b | 1.00 reference | 0.88 (0.62–1.26) | 0.99 (0.56–1.76) | 1.03 (0.50–2.10) | 1.05 (0.43–2.57) | 0.950 |
| Endometrial cancer (n=774) | ||||||
| Any NSAID | ||||||
| Cases / non-cases | 362 / 38,012 | 243 / 24,165 | 169 / 14,310 | 97 / 8,790 | 72 / 5,520 | |
| HR (95% CI)a | 1.00 reference | 1.08 (0.92–1.28) | 1.18 (0.98–1.41) | 1.08 (0.86–1.35) | 1.27 (0.99–1.64) | 0.067 |
| HR (95% CI)b | 1.00 reference | 0.90 (0.73–1.11) | 1.08 (0.86–1.35) | 0.92 (0.69–1.22) | 1.19 (0.88–1.61) | 0.449 |
| Any aspirin | ||||||
| Cases / non-cases | 488 / 48,788 | 177 / 17,232 | 100 / 9,233 | 55 / 5,784 | 45 / 3,449 | |
| HR (95% CI)a | 1.00 reference | 0.98 (0.82–1.18) | 1.01 (0.81–1.25) | 0.89 (0.68–1.18) | 1.20 (0.89–1.64) | 0.533 |
| HR (95% CI)b | 1.00 reference | 0.90 (0.71–1.13) | 1.01 (0.77–1.31) | 0.86 (0.61–1.21) | 1.17 (0.81–1.69) | 0.727 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 593 / 60,104 | 118 / 11,679 | 43 / 2,704 | 30 / 1,716 | 13 / 988 | |
| HR (95% CI)a | 1.00 reference | 1.09 (0.89–1.34) | 1.62 (1.19–2.23) | 1.77 (1.23–2.57) | 1.32 (0.76–2.29) | 0.014 |
| HR (95% CI)b | 1.00 reference | 0.94 (0.72–1.22) | 1.32 (0.89–1.96) | 1.36 (0.85–2.18) | 1.21 (0.64–2.29) | 0.228 |
| Thyroid (n=208) | ||||||
| Any NSAID | ||||||
| Cases / non-cases | 105 / 61,536 | 62 / 42,277 | 41 / 24,992 | 20 / 15,262 | 21 / 9,730 | |
| HR (95% CI)a | 1.00 reference | 0.89 (0.65–1.23) | 0.93 (0.65–1.34) | 0.75 (0.46–1.21) | 1.23 (0.77–1.97) | 0.774 |
| HR (95% CI)b | 1.00 reference | 1.01 (0.69–1.47) | 1.03 (0.66–1.61) | 0.81 (0.45–1.46) | 1.45 (0.81–2.59) | 0.413 |
| Any aspirin | ||||||
| Cases / non-cases | 134 / 81,123 | 43 / 29,748 | 26 / 15,615 | 15 / 9,685 | 11 / 5,930 | |
| HR (95% CI)a | 1.00 reference | 0.89 (0.62–1.27) | 0.96 (0.63–1.47) | 0.90 (0.52–1.53) | 1.06 (0.57–1.96) | 0.968 |
| HR (95% CI)b | 1.00 reference | 0.92 (0.60–1.41) | 0.90 (0.53–1.53) | 0.76 (0.38–1.53) | 1.20 (0.58–2.51) | 0.956 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 166 / 98,935 | 27 / 21,095 | 11 / 5,094 | 5 / 3,243 | 6 / 1,851 | |
| HR (95% CI)a | 1.00 reference | 0.70 (0.44–1.09) | 1.25 (0.67–2.32) | 0.90 (0.37–2.19) | 1.87 (0.83–4.25) | 0.245 |
| HR (95% CI)b | 1.00 reference | 0.86 (0.51–1.45) | 1.61 (0.79–3.26) | 1.32 (0.53–3.29) | 1.96 (0.71–5.40) | 0.149 |
| Melanoma (n=531) | ||||||
| Any NSAID | ||||||
| Cases / non-cases | 248 / 61,393 | 176 / 42,163 | 107 / 24,926 | 66 / 15,216 | 41 / 9,710 | |
| HR (95% CI)a | 1.00 reference | 1.06 (0.87–1.29) | 0.99 (0.79–1.25) | 0.99 (0.76–1.31) | 0.96 (0.69–1.34) | 0.835 |
| HR (95% CI)b | 1.00 reference | 0.96 (0.75–1.22) | 0.83 (0.62–1.12) | 0.86 (0.61–1.23) | 0.76 (0.49–1.18) | 0.173 |
| Any aspirin | ||||||
| Cases / non-cases | 347 / 80,910 | 116 / 29,675 | 61 / 15,580 | 37 / 9,663 | 24 / 5,917 | |
| HR (95% CI)a | 1.00 reference | 0.84 (0.67–1.05) | 0.83 (0.63–1.09) | 0.81 (0.58–1.14) | 0.84 (0.55–1.27) | 0.197 |
| HR (95% CI)b | 1.00 reference | 0.71 (0.53–0.95) | 0.66 (0.46–0.95) | 0.63 (0.40–1.00) | 0.69 (0.40–1.20) | 0.043 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 387 / 98,714 | 104 / 21,018 | 24 / 5,081 | 16 / 3,232 | 8 / 1,849 | |
| HR (95% CI)a | 1.00 reference | 1.34 (1.07–1.68) | 1.16 (0.76–1.76) | 1.24 (0.75–2.05) | 1.98 (0.53–2.18) | 0.524 |
| HR (95% CI)b | 1.00 reference | 1.24 (0.92–1.67) | 1.18 (0.71–1.96) | 1.28 (0.69–2.38) | 1.15 (0.51–2.60) | 0.492 |
| Hematologic malignancies (n=1,354) | ||||||
| Any NSAID | ||||||
| Cases / non-cases | 602 / 61,039 | 449 / 41,890 | 303 / 24,730 | 179 / 15,103 | 124 / 9,627 | |
| HR (95% CI)a | 1.00 reference | 1.08 (0.96–1.22) | 1.09 (0.95–1.25) | 1.05 (0.89–1.25) | 1.13 (0.93–1.37) | 0.204 |
| HR (95% CI)b | 1.00 reference | 1.04 (0.89–1.20) | 1.03 (0.86–1.22) | 1.02 (0.83–1.25) | 0.99 (0.78–1.27) | 0.997 |
| Any aspirin | ||||||
| Cases / non-cases | 799 / 80,458 | 345 / 29,446 | 187 / 15,454 | 109 / 9,591 | 78 / 5,863 | |
| HR (95% CI)a | 1.00 reference | 1.01 (0.88–1.16) | 1.01 (0.86–1.19) | 0.95 (0.78–1.16) | 1.08 (0.86–1.37) | 0.723 |
| HR (95% CI)b | 1.00 reference | 0.99 (0.84–1.17) | 1.00 (0.82–1.22) | 0.97 (0.76–1.23) | 1.00 (0.75–1.34) | 0.918 |
| Any non-aspirin NSAIDs | ||||||
| Cases / non-cases | 1,027 / 98,074 | 206 / 20,916 | 65 / 5,040 | 45 / 3,203 | 20 / 1,837 | |
| HR (95% CI)a | 1.00 reference | 1.00 (0.85–1.17) | 1.29 (1.00–1.66) | 1.43 (1.06–1.93) | 1.10 (0.70–1.71) | 0.109 |
| HR (95% CI)b | 1.00 reference | 0.94 (0.77–1.14) | 1.17 (0.86–1.60) | 1.24 (0.85–1.80) | 1.11 (0.66–1.90) | 0.426 |
Adjusted for age and other NSAID use
Adjusted for age, observational study enrollment, hormone therapy trial enrollment, diet modification trial enrollment, calcium/vitamin D trial enrollment, US region, education, ethnicity, height, body mass index, physical activity, alcohol consumption, pack-years of smoking, fruit and vegetable consumption, red meat consumption, family histories of: breast cancer, cervical cancer, endometrial cancer, and colorectal cancer (as separate terms); screening for: breast cancer, colon cancer, and cervical cancer (as separate terms); age at menarche, age at menopause, gravidity, age at 1st birth, duration of estrogen therapy, duration of combined postmenopausal hormone therapy, hysterectomy status, multivitamin use, use of anti-hypertensive medication, history of coronary heart disease, use of cholesterol-lowering medication, history of arthritis, history of migraine, history of ulcer, and other NSAID use
Consistent use is defined as NSAID use at baseline and at the third year of follow-up
Duration of use reported at baseline, restricted to analyses of non- and consistent users
P trend is calculated across 3 categories: non-use, <5yrs use among consistent users, and ≥5yrs use among consistent users
Discussion
In this large prospective study, we found little evidence to support the use of NSAIDs, in sum or individually, for cancer chemoprevention in postmenopausal women, beyond their suggested role in reducing colorectal cancer incidence. There was preliminary evidence for inverse associations with melanoma and ovarian cancers. Consistent NSAID use did not reduce the risks of breast, lung, endometrial, or thyroid cancers, the most common cancers in women aside from colorectal cancer 31.
NSAIDs are thought to reduce cancer risk through the inhibition of the cyclooxygenase (COX) enzymes, particularly the inducible isoform, COX-2. Inhibition of COX-2 reduces the downstream synthesis of pro-inflammatory prostaglandins (PG), particularly PGE2, a potent mitogen which has been considered a target for cancer prevention and therapy 32. COX-2 and PGE2 are also correlated with aromatase expression in vitro 33 and there is human evidence that their inhibition is associated with reduced estrogen metabolism 34.
There are relatively few observational studies with the capacity to adjust for potential confounding factors aside from age that have examined associations between NSAID use and total cancer risk in women 8–10. Recently, we published findings from the VITAL cohort, which included 2,534 cases among 31,580 women followed for 7 years 10. Similar to the current findings, use of NSAIDs was not associated with total cancer risk in women (≥4 days/week for ≥4 years vs. non-use: HR 1.10, 95% CI: 0.96–1.25) 10. Reports from the Iowa Women’s Health Study [(IWHS); n cases=3,487; 10y follow-up] 8 and the Cancer Prevention Study II Nutrition Cohort [(CPS); n female cases=7,196; 8y follow-up] 9 were suggestive of reduced risks of total cancer. In the IWHS, a prospective cohort of postmenopausal women, Bardia et al. 8, reported that current use of aspirin ≥6 days/week at baseline was associated with a 19% reduction in total cancer risk [Relative Risk (RR) 0.81, 95% CI: 0.73–0.90; P trend<0.001]. Use of non-aspirin NSAIDs was not associated with total cancer risk (RR 0.94, 95% CI: 0.83–1.06). To our knowledge, long-term NSAID exposure was not assessed. In the Cancer Prevention Study (CPS), current daily use of regular or extra-strength aspirin for ≥5 years was associated with a statistically non-significant 14% reduction in total cancer risk in women (RR 0.86, 95% CI: 0.73–1.03) 9. In that study, use of non-aspirin NSAIDs was not assessed. Three earlier studies 11–13 reported only age-adjusted relative risks. Among them, findings were null for aspirin in the NHANES I cohort 12, and 8–10% increases in risk were reported for low-dose aspirin 11 or non-aspirin NSAIDs 13 in a cohort linked to the Danish Cancer Registry.
This study is only the second to examine associations of ibuprofen and naproxen with total cancer risk. Our current findings are consistent with our previous report among women in the VITAL cohort 10. In it, we found no evidence of a reduction in cancer risk for long-term regular use of ibuprofen (≥4 days/week for ≥4 years vs. non-use: HR 1.05, 95% CI: 0.88–1.27) or naproxen (≥4 days/week for ≥4 years vs. non-use: HR 1.05, 95% CI: 0.77–1.44) relative to non-use 10.
Results from randomized trials are limited to aspirin, predominately conducted among men, and are conflicting. Recently, Rothwell et al. published a series of pooled analyses of randomized trials of aspirin on the short-term risk of cancer 4 and long-term risk of metastatic cancer 5. In six trials of daily low-dose aspirin tested against a placebo, which included 642 incident cancers in approximately 16,400 women, aspirin was protective in women for total cancer after 3 years of follow-up (OR 0.75, 95% CI: 0.59–0.94) but not earlier (OR 1.13, 95% CI: 0.91–1.40) 4. Aspirin (≥75mg/day) reduced the risk of distant metastasis in five trials (HR 0.64, 95% CI: 0.48–0.84) 5; however less than a third of participants were women and findings were not stratified on sex. The WHS is the only randomized controlled trial of an NSAID, low-dose aspirin (100mg given every second day), for cancer prevention in women 6, 7. The study included 39,876 women and 2,865 incident cancers after 10 years of follow-up 6. Similar to our findings, no effect of low-dose aspirin on overall cancer risk was reported (HR 1.01, 95% CI: 0.94–1.08) 6, 7.
Only VITAL 10, IWHS 8, and the WHS 6 have examined whether associations between NSAIDs and cancer risk are modified by factors known to influence inflammation. Similar to this study, none has reported effect-modification.
Our site-specific findings are largely consistent with previous reports from the WHI in which the use of NSAIDs and risks of cancers of the breast 28, colon and rectum 27, skin 30, and endometrium 29, were examined. Our results differ with 2 prior publications 27, 28 among the WHI OS. Whereas we observed no reduction in breast cancer risk, Harris et al. 28, reported that long-term use of NSAIDs was associated with a linear reduction in breast cancer risk (RR 0.72, 95% CI: 0.56–0.91) after 3.6 years of follow-up. Conversely, whereas we found a strong reduction in colorectal cancer risk, Allison et al. 27, reported no association between aspirin use and colorectal cancer risk (HR 0.95, 95% CI: 0.69–1.31) after 6.4 years of follow-up. In an effort to explain these differences, we examined site-specific associations in the OS alone. The subgroup findings for breast and colorectal cancer did not differ from the combined OS + CT estimates (data not shown). Accrual of additional cases over a longer follow-up period may explain these differences in findings.
Our findings for a reduction in colorectal cancer risk are consistent with randomized trials and observational studies of NSAIDs, which have shown these medications to be chemoprotective for colorectal cancer risk 7, 35–37 and mortality 3, 38. Evidence for the remaining cancer sites remains inconsistent and in the case of cancers shared between the sexes, few meta-analyses have stratified findings on sex. Nevertheless, our findings for lung cancer agree with those from a recent meta-analyses 39, 40 which reported reductions in lung cancer risk for men but not women. Our finding of a possible reduction of ovarian cancer risk and no association with endometrial cancer risk is also consistent with recent meta-analyses 41, 42. Contrary to the current findings, meta-analyses have reported that use of NSAIDs are associated with small reductions in breast cancer risk 1, 43. Our reported inverse association between aspirin use and melanoma risk, in conjunction with a recent report from the WHI-OS 30, is inconsistent with a recent meta-analysis of aspirin use among women 44, which found no association (RR 0.94, 95% CI: 0.72–1.22); however findings for women were not restricted to prospective studies, among which there are few.
This study has several strengths. It is by far the largest to prospectively examine the association between NSAID use and overall cancer risk in women. Follow-up of participants was nearly complete, thereby reducing the likelihood of attrition bias. Unlike most other studies, we were able to examine associations for specific, commonly available NSAID formulations. Lastly, we were able to adjust for a large number of potential confounding factors including correlates of NSAID use. The primary limitations of this study center on the measurement of NSAIDs. In addition to a long follow-up period which allows for participants to begin or cease NSAID use, we had limited data on non-aspirin NSAID dose and no data on the frequency of NSAID use or the number of pills taken per pill-taking event; each contributes to measurement error and may have contributed to the observed null results. Similarly, daily users may have been more likely to recall their use in the prior 2 weeks as compared to transient users, further contributing to error. Nevertheless, we attempted to create a more reliable measure of NSAIDs by combining baseline and year 3 data. The consistency of our findings measured against our previous report 10 and the inverse associations observed for specific organ sites (e.g., colorectal cancer) provides evidence that our NSAID measurement was valid. Another limitation is that we included a large number of potential confounders for adjustment in multivariable regression models. For rarer cancers, this adjustment may have resulted in less precise estimates of hazard. Lastly, and in light of the reanalysis of the WHS trial data, which reported a protective effect for low-dose aspirin on colorectal cancer risk only after 10 years of follow-up 7, it is possible that the 10-year follow-up period in WHI was too short to observe an association overall or for other specific sites.
Our study confirms a chemopreventive benefit of NSAID use for colorectal cancer in women and gives preliminary evidence for a reduction in the risk of ovarian cancer and melanoma. NSAIDs’ benefit on cancer risk was limited to specific sites in women and not evident when total cancer risk was examined. Use of NSAIDs for chemoprevention of colorectal cancer and perhaps other cancers in postmenopausal women warrants further consideration; however this research does not support the use of NSAIDs for overall cancer chemoprevention in postmenopausal women.
Supplementary Material
Impact.
The current report confirms that NSAIDs reduce colorectal cancer incidence in postmenopausal women but, importantly, they may not confer an overall cancer chemopreventive benefit. These findings challenge an unsubstantiated belief that NSAID use reduces cancer risk for women.
Acknowledgments
The WHI programs are funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C. This work is additionally supported by the National Institutes of Health grant K05-CA154337 (National Cancer Institute and Office of Dietary Supplements).
Footnotes
Conflict of interest statement
The authors have no competing conflicts of interest to declare.
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