Abstract
Over one million women in the U.S. receive biopsy diagnoses of benign breast disease (BBD) each year, which confer a 1.5–4.0-fold increase in breast cancer (BC) risk. Studies in the general population suggest that non-steroidal anti-inflammatory agents (NSAIDs) lower BC risk; however, associations among women with BBD are unknown. We assessed whether NSAID use among women diagnosed with BBD is associated with lower BC risk. Participants included 3,080 women (mean age = 50.3 ± 13.5 years) in the Mayo BBD surgical biopsy cohort diagnosed between January 1, 1992 and December 31, 2001 who completed BC risk factor questionnaires that assessed NSAID use, and whose biopsies underwent detailed pathology review, masked to outcome. Women were followed from date of BBD biopsy to BC diagnosis (main outcome) or censoring (death, prophylactic mastectomy, reduction mammoplasty, lobular carcinoma in-situ or last contact). Median follow-up time was 16.4 ± 6.0 years. Incident BC was diagnosed among 312 women over a median follow-up of 9.9 years. Regular non-aspirin NSAID use was associated with lower BC risk (HR=0.63, 95%CI=0.46–0.85; p=0.002) with trends of lower risk (highest tertiles of use versus non-use) for greater number of years used (HR=0.55, 95%CI=0.31–0.97; ptrend=0.003), days used per month (HR=0.51; 95%CI=0.33–0.80;ptrend=0.001) and lifetime number of doses taken (HR=0.53, 95%CI=0.31–0.89; ptrend=0.003). We conclude that non-aspirin NSAID use is associated with statistically significant lower BC risk after a BBD biopsy, including a dose-response effect, suggesting a potential role for NSAIDs in BC prevention among BBD patients.
Keywords: Breast Cancer, Prevention, NSAIDs, Benign Breast Disease
Introduction
Over one million women are diagnosed with benign breast disease (BBD) in the U.S. annually, which defines a large and expanding pool of patients at increased breast cancer (BC) risk (1). Implementing effective BC risk strategies among these women could substantially reduce BC incidence and mortality.
BBD includes morphologically and biologically diverse lesions, several of which may be present concurrently in a single biopsy. To facilitate clinical management, BBD biopsies are classified as non-proliferative, proliferative without atypia or atypical hyperplasia, denoting progressively increasing levels of BC risk. Over 90% of BBD biopsies do not show atypia, and despite conferring only a 1.5–2.0-fold increase in BC risk, non-atypical BBD represents the most frequent diagnosis preceding BC (1,2). Atypical hyperplasia increases BC risk approximately four-fold, but comprises less than 10% of BBD diagnoses (1,2). BBD categories define risk among groups of women, but individual risk varies greatly within BBD categories (3), and we hypothesize that several putative carcinogenic mechanisms underlie risk of developing BBD and its progression to BC.
Increased circulating estrogen levels are associated with proliferative BBD, delayed age-related involution of normal lobules from which BBD arises, and increased BC risk (4–6). Endocrine-based prevention lowers risk of estrogen receptor (ER)-positive BC by approximately 50% (7); however, putative non-hormonal carcinogenic mechanisms, including chronic inflammation and immune responses, are not directly targeted by these agents. Sterile inflammation and aging (“inflammaging”) and other processes such as obesity can contribute to a proposed “inflammogenesis” model of BC (8–10). In this model, cyclooxygenases catalyze prostaglandin production, which drives inflammation and fibrosis, and activates multiple downstream carcinogenic mechanisms. In preclinical BC models, activation of inducible cyclooxygenase-2 (COX-2) increases pro-carcinogenic inflammation; treatment with COX-2 inhibitors, such as non-steroidal anti-inflammatory agents (NSAIDs), reduces inflammation and inhibits BC development (11–15). In human studies, inflammatory mediators have been strongly implicated in breast carcinogenesis (16,17), and elevated COX-2 expression in atypical hyperplasia has been associated with increased BC risk (18). Further, inflammation increases estrogen production via activation of aromatase and regular NSAID use is associated with lower circulating estrogen levels (19). Nonetheless, meta-analyses of studies of average risk women in the general population provide modest evidence that NSAIDs lower BC risk, with significant heterogeneity in results among individual studies and multiple limitations, as noted in these reviews (20–26). However, a notable limitation in nearly all studies of NSAID use and BC risk is a lack of information regarding whether women had pro-carcinogenic inflammation in their breast tissues when medications were used.
Cyst formation and chronic inflammation are integral components of BBD, as reflected in the historical term “chronic cystic mastitis”. Cysts lined by apocrine cells frequently contain fluid with high levels of androgens, inflammatory mediators and enzymes with both prostaglandin synthesizing (COX-2) and degrading functions (15-hydroxy prostaglandin dehydrogenase) (27–29). Cysts are often associated with duct ectasia, consisting of dilated structures containing fluid and macrophages and encircled by mononuclear cells and fibrosis. An analysis of 1,467 BBD patients, including 91 women who developed incident BC, found that aspirin use was associated with significantly reduced BC risk (OR=0.46, 95% CI=0.22–0.98), whereas non-aspirin NSAIDs did not show significant protection (OR=0.82, 95% CI = 0.41–1.62)(30). These data suggest that NSAID use reduces BC risk among BBD patients, but the small sample size and lack of information on medication doses, follow-up time and detailed BBD features limit conclusions. Accordingly, we analyzed associations between NSAID use and BC risk in the Mayo Clinic BBD cohort study, which includes detailed BC risk factor data with pathology review and long-term follow-up (2,31).
Materials and Methods
Study sample
The Mayo BBD Cohort currently includes 13,455 women, ages 18–85 years, who underwent BBD biopsies between 1967 and 2001 at Mayo Clinic (Rochester, MN) (2,31). Women who had not been diagnosed with invasive or in-situ BC prior to or 6 months following BBD biopsy, had not undergone mastectomy or breast reduction and had not used prevention therapy were eligible. This analysis includes 3,080 (69%) of 4,482 potential participants biopsied between January 1, 1992 and December 31, 2001 who completed the study questionnaire that included self-reported NSAID use; prior to 1992 NSAID use was not queried. Mean age at biopsy (S.D.) was 50.3 (13.5) years with mean follow-up of 16.4 (6.0) years. Incident BCs (including ductal carcinoma in-situ) were ascertained from study questionnaires, tumor registry, and review of medical records. The study protocol, including patient contact, written consent in the context of completing questionnaires and patient follow-up, was approved by the Mayo Clinic Institutional Review Board, and in accord with the Common Rule.
Exposure information
Demographic and clinical characteristics and established BC risk factors were collected using study questionnaires and comprehensive medical record review (2). Family history of BC was categorized as strong, weak, or negative. A strong family history was defined as the patient having (1) at least one first degree relative with BC diagnosed before age 50 years or (2) two relatives with BC at any age, with at least one being a first-degree relative. BC risk factors were collected using a baseline study questionnaire and comprehensive medical record review. Participants were asked, “Have you ever regularly take any nonsteroidal anti-inflammatory drugs (see names below), either over-the-counter or by prescription? (Exclude occasional use of less than once per month). Specific drug names were listed, followed by fillable tables, in which the name of each drug was listed over three column headers “Average days per month used”, “On days used, average number of pills taken” and “Total number of years taken”. Each of the three metrics of use was associated with “two-column bubble forms” for entering numerals from 00–99.”
Study coordinators classified agents into the following categories: ibuprofen and other prostaglandin synthesis inhibitors; naproxen, celecoxib, rofecoxib and other COX inhibitors; aspirin; other NSAIDs; and non-NSAIDs. Non-NSAID drugs were excluded from analyses.
Histologic examination
Diagnostic BBD biopsies were reviewed in detail and specific proliferative (e.g. ductal hyperplasia) and non-proliferative lesions (e.g. cysts, apocrine metaplasia, duct ectasia, columnar cell change) were recorded using a standardized form, masked to follow-up (DWV) (2,31,32). An overall BBD classification based on the highest risk category was also assigned: non-proliferative, proliferative without atypia, or atypical hyperplasia. Level of lobular involution (LI), a feature inversely related to BC risk, was assessed as: non-involuted (0 %); partial involution (1–75 %) or complete involution (>75 %)(32).
Statistical Analysis
Associations for different non-aspirin NSAID classes were similar (see below) and these data were combined. We examined ever use overall and by number of years used, average number of days used per month, and total number of doses. Total dose was calculated by multiplying together average number of days used per month, average number of pills taken on days used and total number of years taken. Metrics of NSAID use were stratified as never used, and among users, in tertiles. We compared frequencies of key epidemiological features among NSAID users and non-users using chi-square tests of significance. Among women with BC, we compare NSAID use by BC subtype using chi-square tests.
Women were followed from date of BBD biopsy to either date of BC diagnosis or censoring events, including death, prophylactic mastectomy, reduction mammoplasty, diagnosis of lobular carcinoma in-situ or last contact. Patients with lobular carcinoma in-situ (n=5) were censored because of routine use of mastectomy during the period of the study. We compared BC risk across use of NSAIDs using Kaplan-Meier curves (Supplementary Figure 1) and then in Cox proportional hazards regression models with estimated hazard ratios (HRs) and 95% confidence intervals (CIs). We performed unadjusted analyses and multivariate Cox regression models, adjusted for covariates, including: age at biopsy, BBD classification, level of LI, body mass index (BMI; Kg/m2) and number of years between biopsy and questionnaire. We assessed dose-response effects related to frequency of NSAID use with BC risk using tests for trend, modeling the ordered frequency of use variable as a one degree-of-freedom term in the Cox regression models. Analyses were carried out overall and by subgroups defined by demographic and clinical variables. We confirmed proportional hazards assumptions by fitting time-by-NSAID use interactions. We ran additional Cox regression analyses to assess in turn the potential confounding effects of Breast Imaging, Reporting and Data System (BI-RADs) mammographic density(33) and use of menopausal hormone replacement. We fit Fine and Gray proportional sub-distribution hazards models to determine the potential impact of treating death as a competing risk rather than a censoring variable (34).
To account for the potential for NSAID use recall bias, we ran Cox regression sensitivity analyses that excluded follow-up prior to date of questionnaire, such that individuals with censoring or BC events that preceded date of questionnaire were excluded from these analyses. We ran sensitivity analyses for specific drug classes, adjusted for use of other drug classes. All statistical tests were two-sided, and all analyses were carried out using SAS Studio, Release 3.7 (SAS Institute, Inc., Cary, NC).
Results
NSAID use among women with BBD
Of the 3,080 (69%) women who provided NSAID use data, 312 women were diagnosed with incident BC (230 invasive) over a median of 9.9 (S.D. 5.9) years of follow-up, BC risk was not significantly different among women who provided NSAID data and those who did not and were excluded from the analysis (Cox model p=0.46). Approximately 38% of women reported some level of regular NSAID use with minimal variation by year of BBD biopsy and similar levels of use for specific drug classes (Table 1). Increased total lifetime number of NSAID doses was higher among women 45 years of age and older at biopsy (p<0.001), obese women (p<0.001) and women with proliferative BBD (either with or without atypia) versus non-proliferative BBD (p=0.02). Positive family history was marginally associated with increased NSAID use. Year of biopsy, level of LI and age at first birth were unrelated to NSAID use.
Table 1.
Distributions of demographic and clinical variables by lifetime NSAID doses.
| Attribute | Lifetime NSAID Doses, No. (%) | ||||||
|---|---|---|---|---|---|---|---|
|
| |||||||
| Missing (N=35) | 0 (N=1892) | 1–150 (N=411) | 151–450 (N=372) | 451+ (N=370) | Total (N=3045) | P-value | |
|
| |||||||
| Year of biopsy | 0.87 | ||||||
| <=1993 | 7 | 402 (64.6%) | 78 (12.5%) | 65 (10.5%) | 77 (12.4%) | 622 (20.4%) | |
| 1994–95 | 7 | 359 (60.7%) | 80 (13.5%) | 82 (13.9%) | 70 (11.8%) | 591 (19.4%) | |
| 1996–97 | 5 | 380 (60.9%) | 88 (14.1%) | 79 (12.7%) | 77 (12.3%) | 624 (20.5%) | |
| 1998–99 | 7 | 405 (63.8%) | 79 (12.4%) | 76 (12.0%) | 75 (11.8%) | 635 (20.9%) | |
| 2000–01 | 9 | 346 (60.4%) | 86 (15.0%) | 70 (12.2%) | 71 (12.4%) | 573 (18.8%) | |
| Age at biopsy | <0.001 | ||||||
| <45 | 14 | 710 (65.7%) | 138 (12.8%) | 111 (10.3%) | 122 (11.3%) | 1081 (35.5%) | |
| 45–55 | 11 | 502 (56.0%) | 145 (16.2%) | 130 (14.5%) | 119 (13.3%) | 896 (29.4%) | |
| >55 | 10 | 680 (63.7%) | 128 (12.0%) | 131 (12.3%) | 129 (12.1%) | 1068 (35.1%) | |
| Extent of lobular involution | 0.75 | ||||||
| None | 5 | 339 (63.4%) | 74 (13.8%) | 63 (11.8%) | 59 (11.0%) | 535 (20.5%) | |
| Partial | 16 | 706 (61.2%) | 149 (12.9%) | 153 (13.3%) | 146 (12.7%) | 1154 (44.3%) | |
| Complete | 5 | 561 (61.2%) | 129 (14.1%) | 106 (11.6%) | 120 (13.1%) | 916 (35.2%) | |
| Missing | 9 | 286 | 59 | 50 | 45 | 440 | |
| BBD | 0.02 | ||||||
| NP | 21 | 1091 (64.0%) | 216 (12.7%) | 192 (11.3%) | 207 (12.1%) | 1706 (56.4%) | |
| PDWA | 9 | 640 (60.1%) | 147 (13.8%) | 153 (14.4%) | 125 (11.7%) | 1065 (35.2%) | |
| AH | 5 | 148 (57.8%) | 47 (18.4%) | 25 (9.8%) | 36 (14.1%) | 256 (8.5%) | |
| Missing | 0 | 13 | 1 | 2 | 2 | 18 | |
| Family history of breast cancer | 0.06 | ||||||
| None | 19 | 981 (64.7%) | 189 (12.5%) | 187 (12.3%) | 160 (10.5%) | 1517 (49.9%) | |
| Weak | 7 | 596 (59.5%) | 145 (14.5%) | 122 (12.2%) | 138 (13.8%) | 1001 (32.9%) | |
| Strong | 9 | 312 (59.7%) | 77 (14.7%) | 63 (12.0%) | 71 (13.6%) | 523 (17.2%) | |
| Missing | 0 | 3 | 0 | 0 | 1 | 4 | |
| BMI at biopsy | <0.001 | ||||||
| 0–21 | 6 | 294 (69.2%) | 52 (12.2%) | 48 (11.3%) | 31 (7.3%) | 425 (14.0%) | |
| 22–25 | 7 | 547 (63.4%) | 116 (13.4%) | 102 (11.8%) | 98 (11.4%) | 863 (28.3%) | |
| 26–29 | 8 | 392 (59.7%) | 92 (14.0%) | 87 (13.2%) | 86 (13.1%) | 657 (21.6%) | |
| >=30 | 11 | 472 (56.6%) | 117 (14.0%) | 118 (14.1%) | 127 (15.2%) | 834 (27.4%) | |
| Missing | 3 | 187 (70.3%) | 34 (12.8%) | 17 (6.4%) | 28 (10.5%) | 266 (8.7%) | |
| Age first live birth / No. Children | 0.35 | ||||||
| <21, 1+ | 6 | 392 (58.6%) | 100 (14.9%) | 79 (11.8%) | 98 (14.6%) | 669 (22.1%) | |
| >=21, 3+ | 5 | 540 (64.5%) | 102 (12.2%) | 103 (12.3%) | 92 (11.0%) | 837 (27.6%) | |
| >=21, 1–2 | 15 | 698 (62.9%) | 145 (13.1%) | 137 (12.3%) | 130 (11.7%) | 1110 (36.7%) | |
| Nulliparous | 9 | 249 (60.4%) | 62 (15.0%) | 51 (12.4%) | 50 (12.1%) | 412 (13.6%) | |
| Missing | 0 | 13 | 2 | 2 | 0 | 17 | |
| Number of years between biopsy and questionnaire | 0.56 | ||||||
| <=10 | 19 | 743 (61.0%) | 174 (14.3%) | 158 (13.0%) | 143 (11.7%) | 1218 (40.0%) | |
| 11–15 | 14 | 1055 (62.8%) | 214 (12.7%) | 201 (12.0%) | 211 (12.6%) | 1681 (55.2%) | |
| >=16 | 2 | 94 (64.4%) | 23 (15.8%) | 13 (8.9%) | 16 (11.0%) | 146 (4.8%) | |
Values presented as Number (percent).
Histologic impression: NP, non-proliferative disease; PDWA, proliferative disease without atypia; AH, atypical hyperplasia; BMI, body mass index. P-values calculated using chi-square tests. Strong family history defined as at least one first degree relative diagnosed with breast cancer prior to age 50 years or two or more relatives diagnosed with breast cancer; other reports of a positive family history were defined as weak. Individuals with missing NSAID values provided information on ever NSAID use but not dosage information.
Regular NSAID use and BC risk
Regular NSAID use overall was associated with lower BC risk (HR=0.76, 95%CI=0.59–0.99; p=0.039) with trends suggesting lower risk with increased use (comparing highest tertile for each category of use versus non-use for each metric). Specifically, for number of years used: HR=0.76, 95%CI=0.52–1.10; ptrend=0.058, for days used per month: HR=0.49; 95%CI=0.18–1.33;ptrend=0.015 and for total number of doses taken: HR=0.65, 95%CI=0.43–0.98; ptrend=0.019 (Supplementary Table 1). Specifically, lower risk was associated with regular use of non-aspirin NSAIDs (but not aspirin), yielding HR=0.63 (95%CI=0.46–0.85; p=0.002) (Table 2). Compared with non-use, all metrics of non-aspirin NSAID use showed dose-response effects, including years of use (HR=0.55 (95%CI=0.31–0.97); p-trend =0.003), days used per month (HR=0.51, 95%CI=0.33–0.80); ptrend =0.001) and total lifetime doses (HR=0.53, (95%CI=0.31–0.89), ptrend =0.003). Similar patterns for ever use and increased use were found for Ibuprofen and naproxen and their respective related agents, whereas regular aspirin use was not significantly related to BC risk (Supplementary Table 1).
Table 2.
Associations of regular NSAID use with risk of breast cancer among women diagnosed with BBD.
| No. events | Person-years | HR (95% CI)a | P-valuea | HR (95% CI)b | P-valueb | |
|---|---|---|---|---|---|---|
|
| ||||||
| Non-aspirin NSAIDs (Ibuprofen and other prostaglandin synthesis inhibitors, and naproxen, celecoxib, rofecoxib and other COX inhibitors) | ||||||
| Ever used | 0.002 | 0.002 | ||||
| No | 241 | 35345 | 1.00 (ref) | 1.00 (ref) | ||
| Yes | 65 | 14510 | 0.65 (0.50 to 0.86) | 0.63 (0.46 to 0.85) | ||
| Number of years used | 0.003c | 0.003c | ||||
| 0 | 241 | 35345 | 1.00 (ref) | 1.00 (ref) | ||
| 1–3 | 25 | 4887 | 0.74 (0.49 to 1.12) | 0.70 (0.45 to 1.09) | ||
| 4–10 | 22 | 5455 | 0.59 (0.38 to 0.91) | 0.60 (0.37 to 0.97) | ||
| 11+ | 18 | 4168 | 0.63 (0.39 to 1.01) | 0.55 (0.31 to 0.97) | ||
| Days used per month | <.001c | 0.001c | ||||
| 0 | 241 | 35345 | 1.00 (ref) | 1.00 (ref) | ||
| 1–9 | 24 | 4149 | 0.84 (0.55 to 1.28) | 0.80 (0.49 to 1.32) | ||
| 10–29 | 18 | 4052 | 0.65 (0.40 to 1.04) | 0.67 (0.40 to 1.13) | ||
| 30+ | 23 | 6309 | 0.53 (0.35 to 0.81) | 0.51 (0.33 to 0.80) | ||
| Total number of doses | <.001c | 0.003c | ||||
| 0 | 241 | 35345 | 1.00 (ref) | 1.00 (ref) | ||
| 1–100 | 27 | 4770 | 0.83 (0.55 to 1.23) | 0.69 (0.44 to 1.08) | ||
| 101–360 | 21 | 4928 | 0.62 (0.40 to 0.97) | 0.66 (0.41 to 1.06) | ||
| 361+ | 17 | 4811 | 0.51 (0.31 to 0.84) | 0.53 (0.31 to 0.89) | ||
|
Aspirin | ||||||
| Ever used | 0.564 | 0.426 | ||||
| No | 250 | 41363 | 1.00 (ref) | 1.00 (ref) | ||
| Yes | 56 | 8492 | 1.09 (0.82 to 1.46) | 0.88 (0.64 to 1.21) | ||
| Number of years used | 0.668c | 0.390c | ||||
| 0 | 250 | 41363 | 1.00 (ref) | 1.00 (ref) | ||
| 1–5 | 24 | 3167 | 1.25 (0.82 to 1.90) | 1.04 (0.66 to 1.65) | ||
| 6–14 | 12 | 2561 | 0.77 (0.43 to 1.38) | 0.61 (0.32 to 1.16) | ||
| 15+ | 20 | 2764 | 1.20 (0.76 to 1.89) | 0.94 (0.57 to 1.56) | ||
| Days used per month | 0.671c | 0.468c | ||||
| 0 | 250 | 41363 | 1.00 (ref) | 1.00 (ref) | ||
| 1–29 | 15 | 2040 | 1.22 (0.72 to 2.05) | 0.84 (0.46 to 1.55) | ||
| 30+ | 41 | 6451 | 1.05 (0.75 to 1.46) | 0.89 (0.62 to 1.27) | ||
| Total number of doses | 0.995c | 0.293c | ||||
| 0 | 250 | 41363 | 1.00 (ref) | 1.00 (ref) | ||
| 1–150 | 23 | 2986 | 1.27 (0.83 to 1.95) | 0.95 (0.59 to 1.55) | ||
| 151–360 | 18 | 2581 | 1.15 (0.71 to 1.86) | 0.99 (0.59 to 1.65) | ||
| 361+ | 15 | 2924 | 0.85 (0.50 to 1.42) | 0.70 (0.40 to 1.24) | ||
HR, hazard ratio; CI, confidence interval.
Category-specific numbers of events and person-years may not sum to overall numbers due to missing values for some variables.
Unadjusted Cox proportional hazards analysis
Cox proportional hazard analyses adjusted for age at biopsy, histologic impression, extent of lobular involution, BMI and number of years between biopsy and completion of questionnaire
Test for trend
Non-aspirin NSAID use and BC risk by selected patient and biopsy characteristics
Reduced BC risk with regular non-aspirin NSAID use was found among women with non-proliferative BBD (HR=0.52, 95%CI=0.31–0.87; p=0.013); associations for proliferative BBD with or without atypia were similar in direction, but failed to reach significance (Table 3). Similarly, significantly decreased risk with regular non-aspirin NSAID use was found among women ≤50 years of age (HR=0.56, 95%CI=0.36–0.87, p=0.010), parous women (HR=0.64, 95%CI=0.46–0.89; p=0.007) and obese women (HR=0.45, 95%CI=0.0.25–0.80; p=0.007), whereas risks were non-significantly reduced among women who were >50 years of age, nulliparous or non-obese, albeit in some analyses that included few events. Lower BC risk was associated with several features included in the spectrum of non-proliferative BBD (cysts, apocrine metaplasia, duct ectasia and columnar cell change) and were markedly lower for women with ≥3 such lesions (HR=0.33, 95%CI=0.17–0.65; p=0.001). Among BBD patients who later developed BC, risks for NSAID use did not vary by estrogen receptor, progesterone receptor or nodal status of the BC (Supplementary Table 2).
Table 3.
Associations of regular non-aspirin NSAID use with BC risk in relation to demographic and clinical variables
| Stratification Variable | Ever Use | Person Years | No. Censored | No. Events | HR (95% CI)a | p-valuea |
|---|---|---|---|---|---|---|
|
| ||||||
| Non-proliferative | No | 20397 | 1130 | 111 | 1.00 (ref) | 0.013 |
| Disease | Yes | 8263 | 441 | 24 | 0.52 (0.31 to 0.87) | |
| Proliferative Disease | No | 14736 | 828 | 128 | 1.00 (ref) | 0.083 |
| Yes | 6178 | 324 | 41 | 0.72 (0.49 to 1.04) | ||
| Proliferative Disease | No | 12158 | 686 | 86 | 1.00 (ref) | 0.126 |
| without Atypia | Yes | 5039 | 266 | 27 | 0.69 (0.43 to 1.11) | |
| Atypical Hyperplasia | No | 2578 | 142 | 42 | 1.00 (ref) | 0.425 |
| Yes | 1139 | 58 | 14 | 0.76 (0.39 to 1.49) | ||
| Age ≤ 50 | No | 19048 | 1008 | 106 | 1.00 (ref) | 0.010 |
| Yes | 9029 | 471 | 33 | 0.56 (0.36 to 0.87) | ||
| Age > 50 | No | 16297 | 961 | 135 | 1.00 (ref) | 0.135 |
| Yes | 5481 | 299 | 32 | 0.73 (0.48 to 1.10) | ||
| Parous | No | 30883 | 1714 | 206 | 1.00 (ref) | 0.007 |
| Yes | 12444 | 656 | 57 | 0.64 (0.46 to 0.89) | ||
| Nulliparous | No | 4463 | 255 | 35 | 1.00 (ref) | 0.288 |
| Yes | 2066 | 114 | 8 | 0.63 (0.26 to 1.49) | ||
| BMI < 30 | No | 23179 | 1283 | 162 | 1.00 (ref) | 0.120 |
| Yes | 8664 | 453 | 47 | 0.75 (0.53 to 1.08) | ||
| BMI ≥ 30 | No | 8960 | 486 | 75 | 1.00 (ref) | 0.007 |
| Yes | 4766 | 254 | 17 | 0.45 (0.25 to 0.80) | ||
| Time between biopsy and | No | 17020 | 1028 | 124 | 1.00 (ref) | 0.141 |
| survey < 12 years | Yes | 7247 | 420 | 40 | 0.74 (0.49 to 1.11) | |
| Time between biopsy | No | 18325 | 941 | 117 | 1.00 (ref) | 0.013 |
| And survey ≥ 12 years | Yes | 7263 | 350 | 25 | 0.56 (0.35 to 0.89) | |
| Cyst - Present | No | 13810 | 749 | 114 | 1.00 (ref) | 0.008 |
| Yes | 6168 | 325 | 29 | 0.56 (0.36 to 0.86) | ||
| Cyst - Absent | No | 21428 | 1215 | 125 | 1.00 (ref) | 0.146 |
| Yes | 8287 | 441 | 36 | 0.73 (0.48 to 1.12) | ||
| Duct ectasia | No | 3748 | 204 | 32 | 1.00 (ref) | 0.038 |
| - Present | Yes | 1601 | 84 | 5 | 0.36 (0.13 to 0.95) | |
| Duct ectasia | No | 31466 | 1758 | 207 | 1.00 (ref) | 0.028 |
| - Absent | Yes | 12820 | 680 | 60 | 0.70 (0.51 to 0.96) | |
| Apocrine Metaplasia | No | 10477 | 567 | 80 | 1.00 (ref) | 0.002 |
| - Present | Yes | 4428 | 235 | 16 | 0.41 (0.23 to 0.73) | |
| Apocrine Metaplasia | No | 24761 | 1397 | 159 | 1.00 (ref) | 0.165 |
| - Absent | Yes | 10027 | 531 | 49 | 0.78 (0.54 to 1.11) | |
| Columnar cell alteration | No | 13272 | 735 | 115 | 1.00 (ref) | 0.040 |
| - Present | Yes | 6033 | 312 | 37 | 0.66 (0.45 to 0.98) | |
| Columnar cell alteration | No | 21966 | 1229 | 124 | 1.00 (ref) | 0.028 |
| - Absent | Yes | 8422 | 454 | 28 | 0.58 (0.36 to 0.94) | |
| No inflammatory lesionsb | No | 15430 | 868 | 83 | 1.00 (ref) | 0.263 |
| Yes | 5895 | 315 | 23 | 0.73 (0.43 to 1.26) | ||
| At least one inflammatory | No | 19809 | 1096 | 156 | 1.00 (ref) | 0.006 |
| Lesionb | Yes | 8542 | 450 | 42 | 0.60 (0.42 to 0.87) | |
| Number inflammatory | No | 7045 | 405 | 45 | 1.00 (ref) | 0.250 |
| lesions=1b | Yes | 2862 | 151 | 13 | 0.67 (0.34 to 1.33) | |
| Number inflammatory | No | 5661 | 310 | 52 | 1.00 (ref) | 0.959 |
| lesions=2b | Yes | 2427 | 129 | 18 | 1.02 (0.57 to 1.81) | |
| Number inflammatory | No | 7103 | 381 | 59 | 1.00 (ref) | 0.001 |
| lesions=3 or moreb | Yes | 3252 | 170 | 11 | 0.33 (0.17 to 0.65) | |
HR, hazard ratio; CI, confidence interval; BMI, body mass index.
Category-specific numbers of events and person-years may not sum to overall numbers due to missing values for some variables.
Cox proportional hazard analyses adjusted for age, histologic impression, extent of lobular involution, BMI and number of years between biopsy and completion of questionnaire.
Non-proliferative BBD lesions include: cyst, duct ectasia, apocrine metaplasia and columnar cell alteration.
Sensitivity Analyses
Associations of ever vs. never regular non-aspirin NSAID use with risk of BC were similar when subsetting to proliferative BBD and atypical hyperplasia (see Table 3) and in analyses adjusted additionally for breast density (HR=0.62, 95% CI 0.46–0.84) and menopausal hormone use (HR=0.61, 95% CI 0.45–0.83). Accounting for death as a competing risk did not substantively change results (HR=0.65, 95% CI 0.48–0.88). Analyses that excluded follow-up prior to date of completion of the questionnaire (which effectively removed 197 participants who were diagnosed with BC prior to completing the questionnaire and 604 participants right-censored prior to completion) yielded similar results (HR 0.57, 95% CI 0.35–0.93). See Supplementary Table 3 for full results. Associations persisted when BC risk related to a specific agent was adjusted for use of other agents.
Discussion
Well-tolerated targeted BC prevention strategies could offer great benefits for individual women diagnosed with BBD and reduce the burden of BC in the population. We report that women in the Mayo BBD cohort who regularly used non-aspirin NSAIDs experienced significantly lower BC risk, with suggestively greater effects among subsets of patients.
Regular use of non-aspirin NSAIDs was associated with 37% lower BC risk in our analysis, with greater effects in relation to increased years or frequency of use and greater number of lifetime doses consumed. Sensitivity analyses that excluded women who were diagnosed with BC prior to reporting NSAID use or for whom data were provided by next-of-kin yielded similar results, limiting concerns of bias. Adjusting for mammographic density, use of menopausal hormone therapy or use of multiple different NSAIDs did not alter these conclusions. Risk associations did not vary by estrogen receptor or nodal status of BCs.
In a prior report, with limited dosing information, aspirin use among women with BBD showed a significant reduction in BC risk, whereas non-aspirin NSAID use was associated with non-significantly lower risk (30). We did not identify significant risk associations for aspirin use; however, 54.1% of aspirin users in our analysis were 55 years of age or older compared with 21.4% of non-aspirin users, and we did not collect data on dosage of the tablets consumed; thus, if risk reduction with aspirin use is greatest among younger women or only realized with high dose formulations, a protective effect may not have been found. Consistent with this view, risk associations were greatest among non-aspirin NSAID users who were less than 50 years of age. Several features of the premenopausal period are associated with inflammation, including menses, which is associated with increased circulating inflammatory cytokines (35), and post-partum involution, in which breast tissue undergoes dramatic remodeling. In preclinical models, post-partum involution drives the development of aggressive BC and this effect can be mitigated with NSAIDs (14). In humans, dysregulated post-partum inflammation may contribute to transiently elevated BC risk after childbirth (36). Effects of non-aspirin NSAID use on BC risk were also greater among obese versus non-obese women. Obesity is associated with low-grade chronic inflammation, which may manifest in adipose rich tissues, such as the breast, and increase BC risk through hormonal and non-hormonal pathways (37). Mechanistic studies show that sera from obese patients induce dramatic increases in macrophage production of COX-2, which can be linked to increased aromatase expression in pre-adipocytes, and can be inhibited with the NSAID celecoxib (38).
Meta-analyses among average risk women have generally found that aspirin and non-aspirin NSAID use are associated with lower BC risk; however, results are variable (20–25) and magnitudes of effects are generally modest. Misclassification of drug use is an important concern in observational epidemiological studies evaluating BC risk; however, random misclassification would generally result in under-estimation of true relationships and over-reporting among cases (recall bias) would likely produce a similar effect. Further, NSAID use in large epidemiological studies cannot be temporally related to inflammation in the breast, which would be anticipated to dilute protective effects. Previously, we reported that immune cells are increased in BBD biopsies versus normal tissues donated for research, and that specific immune responses may predict BC risk among women with BBD (18,39,40), suggesting that targeting inflammation may have potential utility for prevention among women with BBD.
Our data suggest that lower BC risk with NSAID use was more evident for non-proliferative BBD, which is the most common category of BBD diagnosis. Non-proliferative BBD frequently accompanies proliferative BBD or atypical hyperplasia, although pathology reports may only report the highest risk lesion. Apocrine cysts are among the most frequent manifestations of non-proliferative BBD, and while cysts are not BC precursors, cyst fluid is rich in hormones and inflammatory mediators, which may create a microenvironment conducive to BC development (27–29,41). Further, cysts may form and collapse, resulting in inflammation and scarring, even when no longer recognizable microscopically. Women with ≥3 non-proliferative histopathologic BBD lesions in BBD biopsies, a potential marker of diffuse bilateral disease, showed markedly lower BC risk with non-aspirin NSAID use (HR=0.33, 95%CI=0.17–0.65; p=0.001).
Our study leverages strengths of the Mayo BBD cohort, which includes collection of BC risk factors, tissues and follow-up. Our ability to demonstrate a dose-response relationship between non-aspirin NSAID use and lower BC risk among women with BBD is an additional strength. However, this population is comprised almost exclusively of white women, which limits generalizability. Further, medication use was self-reported at a single time point and did not distinguish use of low-dose aspirin from higher doses, which may have limited our ability to identify a significant association for use of this drug. In addition, stratified analyses assessing NSAID associations in certain subsets of women resulted in modest sample sizes and decreased statistical power. We did not collect information about use of statins or bisphosphonates, which are frequently used at older ages, and could affect BC risk. Results of multivariable analyses adjusted for potential confounders, produced only modest effects on risk estimates. Although anti-inflammatory agents are used sporadically for acute illnesses or injuries, our analysis focused on regular use and found strongest effects for higher cumulative doses.
In summary, our analysis of women with BBD demonstrates that regular use of non-aspirin NSAIDs is associated with an approximately 37% reduction in BC risk. Given that BBD is associated with increased BC risk, and frequently includes inflammatory lesions in breast tissues, our findings suggest that NSAIDs may represent an important prevention strategy, and therefore merits further clinical and mechanistic investigation. We propose that clinical prevention trials evaluating the efficacy of NSAIDs for BC prevention among women with BBD that incorporate correlative studies to examine interactions between inflammation and estrogen pathways in breast tissues are warranted. A recently completed phase II trial of celecoxib 400 mg twice daily for 6 months, demonstrated good tolerance with favorably modulation of selected biomarkers (42).
Supplementary Material
Acknowledgments
Financial Support: This work was supported by the National Cancer Institute of the National Institutes of Health (CA229811 to M.E.S and A.C.D. and CA1187112 to A.C.D).
Footnotes
Conflict of Interests: None
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