It is postulated that the inhibition of COX-1 and COX-2 enzymes by nonsteroidal anti-inflammatory drugs (NSAIDs) may play a chemoprophylactic role against oncological diseases by promoting apoptosis and inhibiting mutagenesis. However, the data on the effects of this drug class in breast cancer (BC) prevention have been mixed. These discrepancies have been attributed to heterogeneity among the various study designs.
To help answer the question of whether NSAIDs play a role in BC risk reduction, investigators conducted a prospective cohort analysis. Known as E2N, this French study enrolled over 98,000 women who were born between 1925 and 1950. The intent of this study was to determine whether an association exists between NSAID use and BC incidence, to explore any possible correlation between anti-inflammatory use and BC subtypes, to identify risk factors for BC, and to ascertain whether drugs that are co-administered with NSAIDs (e.g., proton pump inhibitors, PPIs) have any effect on disease expression.
Study participants, who were employees of the national education system, completed a questionnaire that focused on lifestyle and lifetime medical and reproductive history beginning in 1990. Every 2 to 3 years thereafter, survey data was updated with the latest medical information. On January 1, 2004, these data were linked to health insurance information giving researchers information on all outpatient health expenditure reimbursements.
Information on BC diagnoses was obtained from self-reports and, to a lesser extent, from patient clinical records, physician reports, or the national death registry. Pathology reports were obtained for 95% of incident BC cases and were utilized to determine information on tumor characteristics, such as stage, grade, hormone receptor status, and histological type.
Participant follow-up started on July 1, 2004 and continued until the study participants were diagnosed with cancer of any type (except basal cell carcinoma or in situ colorectal cancer), the last questionnaire was completed, or the final mailing of the E3N questionnaire was sent on November 17, 2014.
All NSAID use as of January 1, 2004 was captured. Use of aspirin <325 mg was excluded from analysis, as this was considered an antiplatelet (not anti-inflammatory) dose. NSAID use was divided into three classes: “NSAID ever users” defined as women with at least one NSAID reimbursement since January 1, 2004 or who self-reported NSAID current use in the 2000 or 2002 questionnaire; “NSAID recurrent users” who were women with at least two reimbursements during any previous 3-month period since January 1, 2004 or who self-reported NSAID current use in the 2000 or 2002 questionnaire; and “Occasional NSAID users” who were “ever users” who were not “recurrent users.” Participants were queried whether they had used NSAIDs at least three times per week during 2000 or 2002.
NSAIDs were classified based on either their frequency of use or their COX-selectivity. The most frequently used NSAIDs, which included aspirin >500 mg/day, ibuprofen, ketoprofen, piroxicam, and diclofenac, were individually analyzed. Selective COX-2 inhibitors, which included rofecoxib, etoricoxib, and celecoxib, were grouped, as were the preferential COX-2 inhibitors, meloxicam, etodolac, and nimesulide.
The rest of the NSAIDs fell in the class “non-selective NSAIDs” and included mefenamic acid, indomethacin, tenoxicam, nabumetone, tiaprofenic acid, naproxen, fenoprofen, flurbiprofen, sulindac, phenylbutazone, aceclofenac, alminoprofen, niflumic acid, morniflumate, and floctalenine. It should be noted that many of these NSAIDs are not approved in the U.S.
Information was gathered on time since first or last use of an NSAID, cumulative duration of use, average daily dose, duration of use, and the cumulative number of defined daily doses (DDD), which was the assumed average daily maintenance dose for a molecule used for its main indication in adults as per the World Health Organization. DDD was calculated based on the treatment of pain, osteoarthritis, and rheumatoid arthritis.
Investigators also took into account the presence of covariates such as educational level, breastfeeding, age at menarche, menopause and first full-time pregnancy, physical activity level, family history of breast cancer, lifetime use of oral contraceptives, body mass index, smoking status, lifetime personal history of benign breast disease, mammogram status, lifetime histories of rheumatological diseases or migraines, and concomitant medications, i.e., acetaminophen, corticosteroids, PPIs, lifetime use of menopausal hormone therapy, and symptomatic slow-reacting drugs for osteoarthritis (e.g., glucosamine).
Data were analyzed for 65,512 women who were postmenopausal and cancer-free as of July 1, 2004. At the end of the study period, 90% had been ever exposed to NSAIDs and 62% had been recurrently exposed. When considering individual NSAIDs among recurrent NSAID users, the most frequently used were ibuprofen, diclofenac, ketoprofen, piroxicam, selective COX-2 inhibitors, preferential COX-2 inhibitors, and aspirin in descending order. Twenty-one percent of participants had been recurrently exposed to at least two categories of NSAIDs.
After a median follow-up period of 9 years, there were 2,864 incident breast cancer cases diagnosed among the study population, with 2,353 cases being invasive disease. Recurrent NSAID use was not associated with BC risk among postmenopausal women with up to 10 years of follow-up. However, among recurrent NSAID users, there was a statistically significant 14% decrease in overall BC risk among women who had ever recurrently used PPIs (hazard ratio [HR] = 0.86%, CI: 0.74-0.99). This is the first clinical trial to evaluate the modifying effects of concomitant PPI and NSAID use on BC risks.
Since OTC NSAID use is widespread among postmenopausal women, this study provides reassuring information for pharmacists and patients on the effects of NSAIDs and concomitant medications on BC risk.
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