In this large, prospective cohort study of women living in western Washington State, regular, long-term use of aspirin was associated with a reduction in endometrial cancer risk, particularly of endometrioid histology and among non-smokers. Use of ibuprofen and naproxen were not associated with risk.
There is increasing evidence that inflammation and the COX pathway are involved in endometrial carcinogenesis. In response to cytokines, growth factors, and oncogenes, the COX-2 enzyme converts arachidonic acid to prostaglandins, among which several are associated with angiogenesis and tumor growth in endometrial cancers [2
]. In vitro
experimental studies have shown increases in COX expression to result in increases of prostaglandin E2
, aromatase, and estrogen synthesis [9
], which is important because unopposed estrogens are hypothesized to be the primary drivers behind endometrial proliferation [11
]. In vitro
findings are further supported by positive correlations between expressions of COX-2 and aromatase in human endometrial cancer tissue [8
], and a recent finding from the Nurses’ Health Study that use of NSAIDs is associated with reduced blood concentration of estrogen among postmenopausal women [10
]. COX-2 is also strongly expressed in early tumors of in vivo
models of endometrial cancer, suggesting that it plays a role in cancer initiation and progression [2
]. Although the NSAIDs under study are all known to bind to COX-2, we found that only the use of aspirin, and not ibuprofen or naproxen, was associated with reduced risks of endometrial cancer. One possible explanation for this difference in association is that unlike non-aspirin NSAIDs, aspirin binds irreversibly to COX-2 [36
]. It is unclear, however, whether this would translate into greater anti-cancer properties. The stronger, linear reductions in risk observed between aspirin use and endometrial cancer of endometrioid histology, which are highly estrogen-sensitive [32
], support, albeit indirectly, in vitro
findings suggesting an association between inflammation and estrogen synthesis.
Among five case-control studies [13
], four prospective cohort studies [15
], a randomized controlled trial [23
], and a pooled analysis of randomized controlled trials [24
] which have examined the association between aspirin use and endometrial cancer risk, our findings are supported by two case-control studies, one cohort study, and the pooled analysis of trials. In a recent paper, Neill et al. [16
], reported results from a population-based case-control study of Australian women and a meta-analysis of epidemiologic studies. In the case-control analysis, ever use of aspirin (OR 0.78, 95% CI: 0.62–0.97) and increasing frequency of use (≥2/week vs. never use: OR 0.54, 95% CI: 0.38–0.78; P
trend<0.0001) were associated with reductions in endometrial cancer risk. In their meta-analysis, aspirin was found to reduce endometrial cancer risk by 13% (RR 0.87, 95% CI: 0.79–0.96) [16
]. Similarly, Fortuny et al. [14
], found that ever use of aspirin was associated with a 30% reduction (OR 0.7, 95% CI: 0.4–1.0) in endometrial cancer risk in a population-based case-control study of women in New Jersey. In the NIH-AARP Diet and Health cohort, Danforth et al. [19
], observed a strong reduction in endometrial cancer risk among very high users of aspirin (≥2/day vs. non-use: RR 0.55, 95% CI: 0.31–0.95). The remaining observational studies observed no overall reduction in endometrial cancer risk [13
]. Authors of the Multiethnic Cohort study were recently the first to examine the association between NSAIDs and endometrial cancer histologies; they observed no association overall and no differences by histologic subtype [21
]. In contrast, in the Australian case-control study (mentioned above), Neill et al. [16
], reported similar reductions in risk regardless of endometrial cancer histology. Among randomized trials, no effect on uterine cancer was reported in the Women’s Health Study trial of 100mg aspirin given every other day for an average of 10 years (RR 1.22, 95% CI: 0.94–1.58). In contrast to the Women’s Health Study and similar to our finding, Rothwell et al. [24
], recently reported a protective effect of aspirin contrasted against a placebo on uterine cancer incidence (P
=0.003) in a pooled analysis of 51 randomized trials of aspirin and cancer incidence. However, in both cases the uterine cancer endpoints may have included some cervical cancers and cancers of mesenchymal origin.
Our finding of no associations between long-term use of non-aspirin NSAIDs, individually or in sum, are consistent with the literature. Although none have examined the use of these medications individually, authors of one case-control [14
] and four prospective cohort studies [15
] have investigated the use of non-aspirin NSAIDs as a group with endometrial cancer. Similar to our findings, none reported an association. Lastly, a recent report from the Women’s Health Initiative examining NSAID use as a group found no association with endometrial cancer [22
]. In that study, only current use was assessed.
In subgroup analyses, we observed effect-modification by smoking status, and no statistically significant interaction by BMI or HRT use. To our knowledge, this is the first study to examine effect-modification by smoking. Because aspirin is metabolized by some of the same enzymes which are responsible for the metabolism of polycyclic aromatic hydrocarbons (PAH) found in cigarette smoke, it is possible that our finding represents a biological phenomenon [37
]. However, our finding that the inverse association between aspirin and endometrial cancer risk was restricted to never smokers is complicated by the well-established risk reduction for endometrial cancer among smokers. Thus, these findings clearly warrant replication in larger samples that will allow for a more detailed analysis of this initially detected interaction.
Whereas we observed an inverse association between aspirin and endometrial cancer risk overall, two studies [13
] and a meta-analysis [16
] reported inverse associations between aspirin use and endometrial cancer risk restricted to obese women only. Moysich et al. [13
], reported that use of aspirin ≥1 day/week for ≥6 months was associated with a 50% reduction in endometrial cancer risk (OR 0.50, 95% CI: 0.27–0.92) among obese women (BMI>30) and no association among overweight (25≤BMI≤30; OR 1.21, 95% CI: 0.65–2.23) or normal-weight (18.5 ≤BMI<25; OR 1.61, 95% CI: 0.71–1.90) women. In an analysis of the prospective Nurses’ Health Study, including 82,971 women and 747 incident cases identified over >24 years of follow-up, Viswanathan et al. [15
], reported that relative to non-use, current use of aspirin was associated with a 44% reduction (RR 0.66, 95% CI: 0.36–0.95) in endometrial cancer risk among obese (BMI≥30) women, and a statistically significant increase in risk among non-obese women (1.41, 95% CI: 1.05–1.89; P
interaction=0.009). In their meta-analysis, Neill et al. [16
], found that aspirin was inversely associated with endometrial cancer only among obese women (BMI≥30, RR 0.72, 95% CI: 0.58–0.90; BMI<30, RR 1.08, 95% CI: 0.82–1.43). Similar to our findings, several others observed no differences by BMI [14
]. Authors of the Nurses’ Health Study additionally reported a reduction in endometrial cancer among never users of post-menopausal hormones (RR 0.64, 95% CI: 0.45–0.91) and increases in risk among ever users (RR 1.34, 95% CI: 0.94–1.89; P
]. No study, including this one, has replicated the latter finding.
The major strengths of the VITAL study include: 1) its prospective nature and near-complete follow-up of participants; 2) collection of long-term use of individual NSAIDs; and 3) our strong ability to statistically control for the potential confounding effects of indications/contraindications of NSAID use. The chief limitation of this study is that we did not collect data on the number of NSAID pills taken per day, or dose of individual non-aspirin NSAIDs. Such measurement error could potentially explain a null finding for non-aspirin NSAIDs, but findings for aspirin would be in spite of such error. An additional limitation is that we did not prospectively update participants’ post-baseline NSAID exposures, further contributing to measurement error. Lastly, a relatively small percentage of women were high users of non-aspirin NSAIDs. It is therefore possible that analyses of the uses of these medications lacked statistical power.
In this large, prospective study of women living in western Washington State, we provide added evidence that long-term, regular use of aspirin is associated with reductions in endometrial cancer risk; particularly for endometrioid tumors and among non-smokers. Given the inconsistent nature of studies which have examined NSAIDs and endometrial cancer thus far, additional prospective studies with high-quality measurement of NSAID use are needed before a public health recommendation could be made. Nevertheless, given the evidence that aspirin reduces the risk of colorectal cancer [40
] and possibly other cancers [24
], our findings add support of aspirin for cancer chemoprevention.