Use of nonsteroidal anti-inflammatory drugs and breast cancer risk in a prospective cohort of postmenopausal women

Breast cancer is, by far, the most common cancer among women in the world. In France, an estimated 56,162 new cancer cases have been diagnosed in 2018 and 13,353 women died from the disease [1]. Inflammation is recognized as a hallmark of cancer [2], and hence, it has been postulated that nonsteroidal anti-inflammatory drugs (NSAIDs) could have anticancer properties [3]. NSAIDs, including high-dose aspirin (pills of 500 mg or more), ibuprofen, or diclofenac, are commonly used to reduce inflammation associated with conditions such as arthritis, tendonitis, and bursitis, or to alleviate pain from osteoarthritis, headaches, migraine, muscle aches, toothaches, back pain, and menstrual cramps. All NSAIDs inhibit the cyclooxygenase (COX) enzymes 1 and 2 to different extents, leading to a reduction in prostaglandin biosynthesis [4], which could hypothetically promote apoptosis and inhibit mutagenesis [5, 6]. The latest meta-analysis of case-control and cohort studies suggests a slightly protective effect of NSAIDs (especially aspirin and selective COX-2 inhibitors) against invasive breast cancer, which seems to be restricted to hormone receptor-positive tumors [7]. However, authors detected a high degree of heterogeneity among the results from the different studies (especially across cohort studies) and highlighted that studies had limited data on subtypes of breast cancer, types of NSAIDs, and NSAID dose or duration of use. The inconsistencies across studies could be explained by the heterogeneous definitions of exposure (ever use, long-term use), the NSAID subtypes studied (all NSAIDs, all NSAIDs but aspirin, aspirin, ibuprofen, COX-2 inhibitors, etc.), or the exposure assessment period (past, current). In addition, over half of the prospective studies relied on self-reported data on NSAID use, prone to exposure misclassification, while studies exploring the associations between NSAID use and breast cancer risk using medico-administrative healthcare databases [8‐17] had very limited data on potential confounding factors and were not able to evaluate whether the associations differed by specific breast cancer subtypes. Furthermore, there is a lack of epidemiological studies considering the use of other drugs as potential confounders/effect modifiers even though NSAIDs are frequently used concomitantly with other drugs such as proton pump inhibitors (PPIs) [18, 19].

We therefore investigated the association between NSAID use and breast cancer incidence, overall and by breast cancer subtypes, risk factors, and use of other drugs, in the French prospective E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l’Education Nationale) cohort in which there are both self-reported information on lifestyle, medical, and reproductive factors, and drug reimbursement data for the period 2004–2014.

The characteristics of the study population (n = 62,512) are presented in Table 1 and Table S2 (Additional file 1). At the end of follow-up, 56,031 women (90%) had been ever exposed to NSAIDs and 38,493 (62%) had been recurrently exposed. Among the recurrent NSAID users, 7% had been recurrently exposed to aspirin, 21% to ibuprofen, 20% to diclofenac, 17% to ketoprofen, 16% to piroxicam, 13% to selective COX-2 inhibitors, 9% to preferentially COX-2 inhibitors, and 27% to other non-selective NSAIDs during follow-up. A total of 12,897 women (21%) had been recurrently exposed to at least 2 categories of NSAIDs.

During a median follow-up time of 9 years, 2864 incident breast cancer cases were diagnosed (335 in situ and 2353 invasive). Compared to women who were occasionally or never exposed to NSAIDs, recurrent users were more often overweight or obese and had more frequent medical follow-up, exposure to other drugs (paracetamol, anti-arthritics, glucocorticoids, PPI, and MHT), and comorbidities such as migraine and arthrosis. There were no other major differences (Table 1).

The age-adjusted HR of breast cancer associated with having ever been exposed to NSAIDs, compared with having never been exposed, was 1.07 (95% CI, 0.98 to 1.18; Table 2). The multivariable HR was 1.02 (95% CI, 0.93 to 1.12). The multivariable HR of breast cancer associated with having been recurrently exposed to NSAIDs, compared with having been never or occasionally exposed, was 1.00 (95% CI, 0.92 to 1.08). No statistically significant heterogeneity across different types of NSAIDs (P homogeneity = 0.93; Table 2) and across breast cancer subtypes (P homogeneity between 0.14 and 0.98; Fig. 2) was found. Analyses according to characteristics of use yielded no statistically significant trend according to the number of DDDs, duration of use, average daily dose, age at first use, or time since first or last use (P_trend between 0.18 and 0.92; Table 3).

No effect modification by attained age, BMI, ever use of MHT, comorbidities, recurrent use of anti-arthritics, corticosteroids, and paracetamol was found (P_interaction > 0.14) (Fig. 3). However, there was a statistically significant interaction by PPI use. Recurrent NSAID use was inversely associated with overall breast cancer risk among women who had ever recurrently used PPIs [HR = 0.86 (0.74–0.99)] but not among never/occasional PPI users [HR = 1.07 (0.97–1.18); P_interaction = 0.01]. Associations between recurrent NSAID use and the risk of different breast cancer subtypes in strata of PPI use are shown in Table S3 (Additional file 1). Compared with women never exposed to NSAIDs nor PPIs, concomitant use of NSAIDs and PPIs was not associated with breast cancer risk [HR = 1.00 (0.87–1.14); n exposed cases = 559], NSAID use after PPI use was inversely associated with breast cancer risk [HR = 0.81 (0.69–0.95); n exposed cases = 365], and PPI use after NSAID use was positively associated with breast cancer risk [HR = 1.13 (1.00–1.29); n exposed cases = 607]. Exclusive use of NSAID was not associated with breast cancer risk [HR = 1.05 (0.89–1.09); n exposed cases = 956], and exclusive use of PPI was not associated with breast cancer risk [HR = 0.99 (0.97–1.14); n exposed cases = 773] (P homogeneity = 0.03).

The results remained unchanged after restricting the study sample to women with incident use by excluding women who were using NSAIDs before the beginning of the follow-up, changing the definition of recurrent NSAID use to “at least 2 reimbursements during a 6-month period,” and when we did not consider questionnaire data for NSAID use (data not shown). Results were also the same when the study sample was restricted to women with a recent mammogram (HR = 0.97 (0.90–1.05); n exposed cases = 1264, Additional file 1, Table S4).

Overall, recurrent NSAID use was not associated with breast cancer risk in this large, prospective cohort of 62,512 postmenopausal women with up to 10 years of follow-up. We found no duration- or dose-response relationship or differential effect across types of NSAIDs or breast cancer subtypes. However, we found a statistically significant decreased risk of breast cancer with NSAID use among women who had been previously exposed to PPIs.

Our results are consistent with the majority of results from prospective studies, suggesting no reduced risk of breast cancer with NSAID use whether the exposure considered was any type of NSAIDs [12, 27‐29], high-dose aspirin [17, 27, 30], ibuprofen [27, 31, 32], COX-2 inhibitors [27, 30], or non-aspirin NSAIDs [17, 33‐38]. However, some other studies have reported a reduced risk of breast cancer with NSAIDs (any type) [16, 32, 35, 39], high-dose aspirin [32], ibuprofen [16], COX-2 inhibitors [11, 14, 16, 39], or non-aspirin NSAIDs [29, 30, 40, 41] while a few other studies indicated an increased risk of breast cancer with NSAIDs (any type) [10, 31], high-dose aspirin [10], ibuprofen [10], or COX-2 inhibitors [13, 15].

Among a dozen prospective studies with data on duration or dose of use, a few observed a dose/duration response [16, 28, 32, 40]. In our study, the NSAID-breast cancer association did not differ according to duration or dose of use.

In some previous studies, the NSAID-breast cancer associations were limited to ER+ and/or PR+ breast cancer [33, 42]. In our study, we did not observe any significant heterogeneity according to breast cancer subtypes. The indication for using NSAIDs and the concomitant use of other drugs could also be confounding factors that few studies were able to take into account. Even though we did not know the clinical indications for NSAID use, we were able to adjust or stratify the NSAID-breast cancer associations on several comorbidities that are indications for NSAID use (arthritis, arthrosis, polyarthritis, rheumatism, spondyloarthritis, and migraine), and on use of other drugs (PPI, glucocorticoids, paracetamol, and anti-arthritics). Women exposed to NSAIDs had more comorbidities and were more exposed to other drugs, but we found no confounding or modifying effect of these parameters apart from the statistically significant interaction with recurrent PPI use. A lower risk of breast cancer was found when NSAID use followed PPI dispensation but not when NSAIDs were started at or before PPI dispensation.

Our study was the first one to evaluate the NSAID-breast cancer associations according to PPI use. PPIs, inhibitors of gastric acid secretion, are approved for the treatment or prevention of a broad range of related gastric conditions such as gastroesophageal reflux, gastric and duodenal ulcers, or NSAID-induced gastrointestinal complications [18, 43]. PPIs alter (increase or decrease depending on the molecule) the absorption of other drugs by increasing the intragastric pH and interfering with the metabolism of other drugs [44, 45]. Surprisingly, several reviews concluded that few studies were published about potential drug interactions between PPIs and NSAIDs [45, 46]. These studies focused on the concomitant use of these two drugs and showed no influence of PPIs on the pharmacokinetics of NSAIDs [45, 46]. However, PPI use might increase the risk of an imbalance in gut microbiota composition, even 8 weeks after PPI treatment [47, 48]. This change in microbiota composition has been shown to exacerbate NSAID side effects [49].

The main strengths of this study included its prospective design and the use of information from a drug reimbursement database to identify NSAID exposure, which avoids differential recall bias between cases and non-cases and minimizes exposure misclassification. Indeed, a French survey showed that among 250 French pregnant women, around 70% thought that high-dose aspirin and ibuprofen were not NSAIDs [50], and prescription analyses noted that among 184 prescriptions which contained at least one NSAID, 98% were obtained for acute symptoms and consequently for a short duration, contributing to recall bias [51]. In addition, the detailed NSAID reimbursement data allowed us to consider precise information on NSAID exposure (including molecules, duration, dose, time since last and time since first use). In our cohort, we found that exposure to NSAIDs was associated with a decreased risk of colorectal cancer (HR = 0.67 (0.54–0.82) for ever versus never exposed women; Additional file 1, Table S5), in close agreement with estimates from meta-analyses [52, 53], which provides support for the accuracy of our assessment of NSAID exposure. However, because NSAID is mostly used sporadically (as noted in a study from the French National Health Insurance Claims [54]), our statistical power remained limited to evaluate the NSAID-breast cancer associations for a long duration of use. In addition, the period of follow-up was inadequate to examine the NSAID-breast cancer associations in different windows of susceptibility such as postpartum or perimenopause [55, 56]. Since data on NSAID reimbursements were combined with self-reported data on lifestyle, reproductive, and medical factors, we were able to take into consideration potential confounders and to examine interactions of NSAID use with breast cancer risk factors, comorbidities, and other drugs. However, although we adjusted for many potential confounders, we cannot exclude residual confounding. For example, we could not take into account the severity of rheumatoid polyarthritis or other comorbidities. In addition, a high number of comparisons were evaluated and the significant interaction with recurrent PPI use may be a chance finding.

Drug reimbursement data combined with information on lifestyle, reproductive factors, and medical events are a great asset, but these data have some limitations. Exposure assessment based on reimbursements rather than intake leads to an obvious misclassification of NSAID use since, in France, NSAIDs can also be obtained over-the-counter. Indeed, several surveys in France noted that between 70 and 80% interviewed persons had already used NSAIDs by self-medication [57, 58]. Furthermore, we had no data regarding the compliance/adherence to the purchased treatment. However, we assumed that women who need NSAIDs chronically will go to the doctor to get reimbursed. We defined recurrent users as women with at least 2 reimbursements during any 3-month period which would suggest that they took the drug. Self-reported data on NSAID use, which therefore included NSAIDs purchased over-the-counter and captured only taken medications, were only available before year 2004 and consequently were used to assess prevalent use of NSAIDs.

To conclude, in this large, prospective cohort of postmenopausal women with up to 10 years of follow-up, we observed a decreased risk of breast cancer with NSAID use only among women who previously used PPI. Our study is the first one to evaluate the modifying effect of PPI on the NSAID-breast cancer associations. Therefore, our finding of an interaction between NSAID and PPI use regarding the risk of breast cancer deserves replication in other settings.