Regular and Low-dose Aspirin, Other Non-steroidal Anti-inflammatory Medications and Prospective Risk of HER2-defined Breast Cancer

The California Teachers Study

Christina A. Clarke; Alison J. Canchola; Lisa M. Moy; Susan L. Neuhausen; Nadia T. Chung; James V. Lacey Jr; Leslie Bernstein


Breast Cancer Res. 2017;19(52) 

In This Article


The 1457 cases of invasive breast cancer diagnosed during follow up included 998 (68%) HR-positive/HER2-negative, 120 (8%) HR-positive/HER2-positive, 44 (3%) HR-negative/HER2-positive, 138 (9%) HR-negative/HER2-negative breast cancers, and 157 (11%) with missing data on expression status for at least one receptor. The characteristics of cohort participants are shown in Table 1: the majority of participants (88%) were of non-Hispanic, white ethnicity and the median age at the time of the 10-year follow-up survey was 61 years (interquartile range 54–71 years). Participants had a relatively high prevalence of some of the established risk factors for breast cancer, with 20% reporting current use of HT and 15% reporting current consumption of ≥20 g of alcohol per day.

The most common NSAID reported as currently used by participants at the 10-year follow-up was low-dose aspirin (Table 1); 23% of women reported current use of at least three low-dose aspirin tablets per week. Ibuprofen was the second most common pain-relieving medication used, with 18% of participants reporting use of at least three tablets per week. Use of at least three regular-dose (325 mg) aspirin tablets per week was reported by 11% of the CTS participants. Less than 10% of participants reported current use of other NSAIDs or COX-2 inhibitors.

Current use of at least three tablets per week of any NSAID was not statistically significantly associated with any particular subtype of breast cancer or breast cancer overall (Table 2). However, when low-dose aspirin was considered separately, current use of three or more tablets per week of low-dose aspirin was statistically significantly associated with risk of breast cancer overall (HRR = 0.84, 95% CI 0.72–0.98 compared to those not taking any NSAIDS); this association was observed only for the HR-positive/HER2-negative subtype (HRR = 0.80, 95% CI 0.66–0.96). Considering more granular categories of frequency of low-dose aspirin use, relative to women who had not used any NSAID in the past 3 years, an inverse association with breast cancer risk was observed among women using 3–6 tablets per week (HRR = 0.72, 95% CI 0.54–0.96) and a marginal association was observed among those using 7+ tablets per week (HRR = 0.87, 95% CI 0.74–1.02). A similar pattern of inverse association was observed for the HR-positive/HER2-negative breast cancer subtype (for 3–6 tablets/week, HRR = 0.66, 95% CI 0.47–0.94; for 7+ tablets/week, HRR = 0.83, 95% CI 0.68–1.01, data not shown). We also observed a lower risk of breast cancer among women who reported current use of "other" NSAIDs (HRR = 0.79, 95% CI 0.62–1.00). Risk of HR-positive/HER2-positive tumors was increased in those with unknown use of ibuprofen, Cox-2 inhibitors, and "other" NSAIDs, but was based on a small number of cases (n = 13). Significant associations did not appear to differ by overweight status (p interaction = 0.18 for low-dose aspirin and all subtypes of breast cancer.)

To assess associations with risk of breast cancer overall and with risk of one subtype among probable long-term users of NSAIDs, we carried out secondary analyses combining information reported on the baseline and 10-year follow-up questionnaires. Among women currently using 3+ low-dose aspirin tablets per week at the 10-year follow up, risk of breast cancer was comparable between those who reported no NSAID use at baseline (HRR = 0.79, 95% CI 0.66–0.95, 181 cases) and those who reported using aspirin regularly for 4+ days per week at baseline (HRR = 0.79, 95% CI 0.59–1.08, 50 cases) compared to those who reported no NSAID use on both the baseline questionnaire and the 10-year follow-up questionnaire (409 cases). Results were similar for those currently using 3+ tablets per week of regular-dose aspirin at the 10-year follow-up (HRR = 0.92, 95% CI 0.70–1.20 (67 cases) for no NSAID use at baseline; HRR = 0.94, 95% CI 0.67–1.31 (39 cases) for aspirin 4+ days per week at baseline). Similar patterns were observed for the HR-positive/HER2-negative subtype (data not shown).

To assess possible confounding by indication, we also assessed associations between breast cancer and acetaminophen, a pain reliever that is not an NSAID. Current use of at least 3 tablets per week of acetaminophen was not associated with breast cancer or any particular subtype of breast cancer in models adjusted for the five NSAIDS (for breast cancer, HRR = 1.00, 95% CI 0.87–1.15 for current use of 3+ tablets per week of acetaminophen (264 cases) compared to no use of acetaminophen in the last 3 years (1109 cases); for the HR-positive/HER2-negative subtype, HRR = 0.98, 95% CI 0.83–1.16 for current use of 3+ tablets per week (180 cases) compared to no use of acetaminophen in the last 3 years (757 cases); other data not shown).