Use of Nonsteroidal Anti-inflammatory Drugs and Survival Following Breast Cancer Diagnosis

Identification of potential factors affecting breast cancer survival is of great public health importance, as approximately 2.6 million women previously diagnosed with breast cancer are alive in the United States today (1). Relatively consistent evidence suggests that nonsteroidal anti-inflammatory drugs (NSAID) reduce breast cancer risk (2). Emerging evidence suggests that NSAIDs might influence cancer prognosis by inducing apoptosis and inhibiting angiogenesis (3). In the present study, we assessed associations of breast cancer survival with NSAID use in the period prior to breast cancer diagnosis and for aspirin use throughout the lifetime up to the time of diagnosis.

A total of 1,024 women with incident, primary, histologically confirmed, invasive breast cancer were identified as part of the Western New York Exposures and Breast Cancer (WEB) study, a population-based case–control study conducted between 1996 and 2001 in Western New York, as described in Brasky and colleagues (4).

Information on demographics, medication use, and breast cancer risk factors was collected through in-person interviews and self-administered questionnaires. Included were questions about the use of aspirin, ibuprofen, and the analgesic acetaminophen in the 12 to 24 months prior to interview. For the analysis of recent NSAID use, frequency of use was categorized as nonusers (0 d/mo), infrequent users (≤14 d/mo), and regular users (>14 d/mo). Intensity of use was categorized as nonusers (0 pills/d), low intensity (<2 pills/d), and high intensity (≥2 pills/d). In addition, participants were asked about their average monthly frequency of aspirin use for each decade of adult life starting at age 21. Cumulative adult lifetime aspirin usage was estimated as the sum of average annual aspirin frequency for each decade of life. These data were categorized into lifetime nonusers (0 d/mo), irregular users (≤10 d/mo), and regular users (>10 d/mo; ref. 4).

Vital status of the women with breast cancer was determined through a National Death Index search through December 31, 2006. Survival time was calculated as the number of months from the date of diagnosis until the date of death or December 31, 2006. All-cause mortality was defined as death from any cause, and underlying cause of death was broadly classified as breast cancer, other cancers, cardiovascular diseases, and others.

Cox proportional hazards regression models, adjusted for age at diagnosis, race, education, body mass index (kg/m²), menopausal status, stage of breast cancer at diagnosis, estrogen receptor/progesterone receptor status, and use of other NSAIDs, were used to estimate HRs and 95% confidence intervals (95% CI) for all-cause and breast cancer–specific mortality. The proportional hazards assumption was tested and found to hold in all analyses. All statistical tests were two-sided and considered statistically significant at P < 0.05.

Descriptive characteristics of participants at the time of questionnaire completion are shown in Table 1. Up to censoring date, 160 deaths occurred with a mean survival time of 7.32 ± 1.74 years. The most frequent cause of death was breast cancer (n = 95), followed by cardiovascular disease (n = 22) and other cancers (n = 11).

Associations between NSAID use and overall and breast cancer survival are shown in Table 2. Recent use of ibuprofen was associated with reduced all-cause mortality in univariate analysis (HR, 0.65; 95% CI, 0.48–0.89) and borderline significance after adjustment for potential confounders (HR, 0.71; 95% CI, 0.50–1.00). None of the NSAIDs was associated with a reduction in breast cancer mortality (Table 2). Increasing frequency or intensity of use were also not associated with mortality when stratified by menopausal status (data not shown).

Epidemiologic evidence about NSAID use and breast cancer survival is inconsistent. Most studies have focused on postdiagnostic use. In the Iowa Women's Health Study, ever use of any NSAID after diagnosis was associated with a statistically significant reduction in all-cause mortality and a nonsignificant reduction for breast cancer mortality among 591 postmenopausal women with invasive breast cancer (5). Data from the Nurses' Health Study suggested a reduced risk of breast cancer mortality and all-cause mortality for women reporting aspirin use after breast cancer (6). In contrast, postdiagnosis NSAID use was not associated with all-cause or breast cancer mortality in 3,058 breast cancer cases in Wisconsin (7).

Our study was limited to an examination of prediagnostic NSAID use. However, examination of the association of prediagnosis NSAID use and survival after breast cancer diagnosis is also of importance due to the uncertainty about the appropriate timing of NSAIDs use to improve cancer survival (8). Information on both pre- and postdiagnostic NSAID use is needed to address whether there is a window of time when use is effective, if at all. Another limitation of this study is potential misclassification due to dependence on self-report to assess NSAID use. However, error in report would not be correlated with outcome in that the assessment was done prospectively. In addition, we did not have information on postdiagnosis treatment.

In conclusion, our findings do not support an association between prediagnostic NSAID use and breast cancer–specific mortality or all-cause mortality.

No potential conflicts of interest were disclosed.

This work was supported in part by grants DAMD-17-03-1-0446 and DAMD-17-96-1-6202 from the U.S. Department of Defense, and NCI RO1CA92040 and P50-AA09802 from the NIH, National Cancer Institute.