In the present large prospective study, we found that NSAID use was unrelated to risk of total breast cancer. Daily aspirin, but not nonaspirin NSAID, use was associated with a modest 16% reduction in ER-positive breast cancer. We did not observe an association between NSAID use and ER-negative breast cancer.
Our null findings for total breast cancer are consistent with those reported by eight prospective studies [8
] and one randomized clinical trial [25
] that examined aspirin and/or nonaspirin NSAID use. Our results differ, however, from those from seven prospective studies [17
] and 12 case–control studies [1
], most of which have reported reduced risks of breast cancer associated with NSAID use. The reasons for these differing results are unclear, but associations may be limited to certain subtypes of breast cancer. Differences in NSAID exposure assessment across studies may also account for inconsistent results.
The frequency of aspirin and nonaspirin use in the NIH–AARP Diet and Health Study is consistent with that reported in other US cohorts of women [21
], and the proportion of women in this study using any NSAID is only slightly higher than that reported among females ages 45 to 75+ years in the third National Health and Nutrition Examination Survey – 71.5% to 80.4% of whom reported any nonprescription analgesic in the past month [46
]. Our study lacked information, however, on the duration, dose, indication, or prescription NSAID use. Because we only measured recent NSAID use in the year prior to the 1996 to 1997 questionnaire and followed women through 2003, the null findings we observed for NSAIDs may differ from what might be observed with long-term cumulative exposure. Indeed, several cohort studies have shown that long-term NSAID use is required for an observed chemopreventive effect on breast cancer [22
]. Furthermore, if there were individuals in our referent category who were past users or prescription NSAID users, results could be biased toward the null.
In addition, we were unable to separate low-dose from regular-dose aspirin use; results from the Women's Health Study randomized trial [25
], a study conducted using an insurance database [2
], and laboratory evidence [27
] suggest that doses higher than the 80 mg aspirin per day typically recommended for cardiovascular therapy may be required to permanently inactivate COX-2. If low-dose aspirin users were included in our exposed group, thereby diluting any effect associated with regular-dose aspirin use, the results would be biased toward the null. Although we did not collect information on indication for use, it is likely that some daily users were taking aspirin for heart disease prevention given that daily users more frequently reported history of heart disease. To address the concern that women using NSAIDS for cardioprotection may be under closer medical supervision and/or may be more health conscious, we additionally controlled for self-reported heart disease, self-rated health quality, and mammographic screening – and the results remained unchanged.
Despite these limitations, the NIH–AARP Diet and Health Study is the one of largest cohorts to date to have evaluated the association between NSAID type and breast cancer risk by tumor characteristics, including ER status. The reduced risk of ER-positive breast cancer we observed with daily aspirin use is consistent with the mechanism of action of aspirin (but not nonaspirin NSAIDs), which permanently inactivates COX-2 [29
], potentially reducing breast cancer risk via multiple pathways, including suppression of estrogen synthesis by decreased aromatase activity [28
]. In addition, our results are in agreement with findings from the Long Island Breast Cancer Prevention Project, a population-based case–control study that reported in 2004 an inverse association with aspirin that was significantly greater for HR-positive breast cancer than for HR-negative breast cancer [30
]. Since then, two case–control studies [3
] and three prospective cohort studies [16
] have separately investigated the association for aspirin, with three of the five studies suggesting some protection against HR-positive breast cancer with aspirin use [3
A US hospital-based study – the Case–Control Surveillance Study – reported a 26% nonsignificant reduction (95% CI = 0.44 to 1.26) in HR-positive breast cancer associated with regular (versus <4 times/week) aspirin use [31
]. More recently, a Canadian population-based case–control study found a 31% reduction (95% CI = 0.56 to 0.86) in ER-positive/PR-positive breast cancer associated with daily (versus <daily) aspirin use [3
]. The California Teachers Study followed 114,460 women aged 22 to 85 years for 6 years and found that long-term daily (versus <once/week) aspirin use was associated with a statistically nonsignificant decreased risk of ER-positive/PR-positive breast cancer (RR = 0.80, 95% CI = 0.62 to 1.03) [16
]. In contrast, the Multiethnic Cohort Study and the Danish Diet, Cancer and Health Cohort Study found no protective effect of aspirin use for HR-positive or HR-negative breast cancer [17
]. Finally, the Women's Health Study randomized clinical trial did not observe any significant patterns of risk by HR status with low-dose aspirin use [25
]. Therefore, while our findings, along with several others, suggest at least some reduction in ER-positive breast cancer associated with aspirin use, the evidence is not conclusive and additional prospective studies with detailed exposure data on the dose, frequency, duration, and indication are needed.
We found stronger inverse associations with in situ
breast cancer than invasive breast cancer. Among the few prior studies that have reported results separately for in situ
breast cancer and invasive breast cancer, two case–control studies reported decreased risks of both in situ
and invasive breast cancers associated with aspirin [30
] and with any NSAID use [32
], but the findings for in situ
breast cancer were not statistically significant in either study. The Iowa Women's Health cohort study reported a reduction in breast cancer risk with increased frequency of aspirin, but not with nonaspirin NSAIDs, for both in situ
and invasive disease [21
]. Both in situ
and invasive breast tumors express COX-2 [47
], suggesting that upregulation of COX-2 may be an early event in carcinogenesis. Higher rates of COX-2 expression in in situ
compared with invasive tumors have led investigators to suggest that the potential therapeutic impact of COX-2 inhibition may be more relevant for in situ
breast cancer than invasive breast cancer (reviewed in [48
]). The inverse association for in situ
breast cancer associated with aspirin use in the present study may therefore be biologically plausible and warrants further investigation.
We observed no variation in risk with HT, smoking status, or BMI, and our findings are generally consistent with previous investigations. For the most part, tests for interactions between HT and NSAID use have been statistically nonsignificant across case–control studies [30
] and cohort studies [13
]; however, two cohort studies have suggested the protective effect of NSAIDs may be attenuated among HT users [18
]. In line with data suggesting that proinflammatory tobacco carcinogens may alter the effectiveness of chemopreventive agents [49
], the Women's Health Study found that low-dose aspirin use was protective among former smokers but was associated with an increased risk among never smokers (for interaction P
= 0.09) [25
]. We, along with a Canadian population-based case–control study, however, did not observe effect modification by smoking [3
]. Consistent with our findings, two case–control studies [32
] and seven prospective studies [13
] have reported no significant interactions between BMI and NSAID use with respect to breast cancer risk.