We documented 1,345 cases of invasive breast cancer among premenopausal women during 14 years of follow-up. Compared with non-users at baseline in 1989, women who used aspirin, non-aspirin NSAIDs, or acetaminophen were slightly older, were heavier at age 18, had gained more weight since age 18, and consumed more alcohol (). Users also had a higher prevalence of early menarche, current oral contraceptive use, and history of benign breast disease. In a comparison of users and non-users of aspirin and non-aspirin NSAIDs, differences were comparable. Throughout follow-up women were more likely to use non-aspirin NSAIDs (22.2% of person-time) than aspirin (9.5%) or acetaminophen (16.3%).
Age and age-standardized characteristics (mean (SD) or %) of Nurses' Health Study II participants, categorized by any NSAIDs or acetaminophen use in 1989
Compared with non-users, current regular users of aspirin were not at a decreased risk of breast cancer, relative risk (RR)=1.07, 95% CI (0.89−1.29) (). Risk among past users was slightly elevated, RR=1.21, 95% CI (1.03−1.41). Duration of use was not associated with risk among current users (<5 years RR=1.03, 95% CI (0.84−1.26); ≥5 years RR=1.26, 95% CI (0.88−1.80), p-trend=0.55). Frequency of use (days per week) was similarly not associated with breast cancer risk (p-trend=0.39). When we examined regular use of aspirin by estrogen and progesterone receptor (ER/PR) status of the tumor, no associations with current use were apparent among either ER+/PR+ cases (RR=0.97, 95% CI (0.76−1.25)) or ER-/PR- cases (RR=1.21, 95% CI (0.78−1.88)). Though follow-up was limited with our assessment of quantity (tablets per week), which began in 1999, we did not observe any relation with breast cancer risk (p-trend=0.76).
Relative risk (95% confidence interval) of invasive breast cancer among premenopausal women according to aspirin use in the Nurses' Health Study II, 1989−2003
Current regular use of non-aspirin NSAIDs was associated with a modest increased risk of breast cancer compared with non-users, RR=1.16, 95% CI (1.01−1.34), although there was no evidence of a trend in risk with increasing duration of use (<5 years RR=1.18, 95% CI (1.02−1.37); ≥5 years RR=1.11, 95% CI (0.88−1.39)) (). Past use of non-aspirin NSAIDs was not associated with breast cancer risk, RR=1.06, 95% CI (0.91−1.24). Although there was a suggestive inverse trend with frequency of use (p=0.06), this may have been driven by a significant increased risk observed for use 2−3 days per week (RR=1.35, 95% CI (1.09−1.67)) since the only point estimate below one was for NSAIDs use 6+ days per week but this was not statistically significant (RR=0.86, 95% CI (0.60−1.24)). The association between regular use of non-aspirin NSAIDs and breast cancer risk did not differ appreciably by ER/PR status (ER+/PR+ RR=1.08, 95% CI (0.89−1.30) and ER-/PR- RR=1.01, 95% CI (0.72−1.43)). With follow-up from 1999 to 2003, when dose data were available, we observed slightly increased risks for low to moderate quantity of use of non-aspirin NSAIDs (1−2 tablets per week RR=1.47, 95% CI (1.02−2.12); 3−5 tablets per week RR=1.45, 95% CI (1.00−2.09)), but with no significant trend (p=0.64) and no significant associations observed with higher intake (6−14 or ≥15 tablets per week) (data not shown).
Relative risk (95% confidence interval) of invasive breast cancer among premenopausal women according to non-aspirin NSAIDs use in the Nurses' Health Study II, 1989−2003
While acetaminophen is used in similar circumstances as aspirin and other NSAIDs, it is not an anti-inflammatory agent and it does not act on the COX pathway. We investigated the association between acetaminophen use and breast cancer risk as a comparison to ensure that behaviors associated with taking pain-relieving medications did not cause a spurious association between the drugs and breast cancer risk. As expected, acetaminophen was not associated with breast cancer risk by current regular use (RR=0.99, 95% CI (0.84−1.16)), duration (p-trend=0.91), or frequency of use (p-trend=0.60) (). The association did not differ by ER/PR status (ER+/PR+ RR=0.98, 95% CI (0.78−1.22); ER-/PR- RR=1.00, 95% CI (0.67−1.47)). Quantity of use (tablets per week) also was not associated with risk, although follow-up (1999−2003), and hence statistical power, was limited in these analyses (p-trend=0.94).
Relative risk (95% confidence interval) of invasive breast cancer among premenopausal women according to acetaminophen use in the Nurses' Health Study II, 1989−2003
To exclude the possibility that the associations were confounded by other reasons for taking the drugs, we conducted a sensitivity analysis restricted to women who were not diagnosed with inflammatory conditions, such as myocardial infarction, stroke, coronary artery bypass graft, angina, or rheumatoid arthritis; results were unchanged (data not shown). Given that women who used NSAIDs were more likely to report a diagnosis of premenstrual syndrome (e.g., 25.8% among users vs. 14.5% among non-users at baseline), and this syndrome may be associated with hormonal changes that could impact breast cancer risk, we repeated the analyses excluding these women. Again, results were unchanged (data not shown). Further, adjustment for menstrual cycle characteristics, including years from menarche to the onset of regular cycles, cycle pattern between ages 18 and 22 years, and cycle length between ages 18 and 22 years, did not substantially alter results for any of the three drug categories, nor did adjustment for physical activity (data not shown).
Results for all three drug categories did not substantially vary by oral contraceptive use (never users plus short term (<2 years) users vs. ≥2 years users), weight change since age 18 (<10 kg vs. ≥10 kg), family history of breast cancer (yes vs. no), or age (<40 years vs. ≥40 years) (data not shown). Results were also similar when in situ cases were included (data not shown). When aspirin and non-aspirin NSAIDs were included in the same statistical model, results for both were essentially unchanged (current use of aspirin RR=1.05, 95% CI (0.88−1.27) and non-aspirin NSAIDs RR=1.16, 95% CI (1.01−1.34)). Use of any NSAIDs (aspirin or non-aspirin) was not significantly associated with breast cancer risk (current use RR=1.11, 95% CI (0.97−1.28); past use RR=1.05, 95% CI (0.89−1.23)). To examine the importance of the timing of exposure, we conducted a lagged analysis using exposure from 2 years prior to the follow-up period (e.g., 1989 exposure for the 1991−1993 follow-up period). Again, no significant associations were observed.