Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 genetic variation, and breast cancer risk
Brasky, Theodore Michael
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Chronic inflammation has been consistently associated with cancers of several sites, including the breast. While non-steroidal anti-inflammatory drugs (NSAIDs) have been hypothesized to reduce breast cancer risk, results of studies of this association have been inconsistent. It may be that different tumor types may have different etiology, and that molecular characterizations of breast tumors, such as estrogen and progesterone receptor status (ER and PR), HER2, and p53, need to be taken into account. As NSAIDs are thought to exert their antiinflammatory properties through binding with cyclooxygenase-2 (COX-2), genetic variation in COX-2 may also affect breast cancer risk by affecting inflammatory response and response to NSAID use. Lifetime aspirin and recent use of NSAIDs was examined in a population-based case-control study in western New York State. We identified eight tag SNPs for the COX-2 gene. Cases had incident, primary, histologically confirmed breast cancer (n=1170). Controls (n=2115) were randomly selected from NY Department of Motor Vehicles records (<65yrs) or Medicare rolls (≥65yrs). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). Recent ibuprofen use was not associated with decreased risk and there was a suggestion that it was associated with increased risk of ER+/PR+ tumors (OR 1.33, 95% CI: 1.09-1.62); no significant differences were observed for tumors stratified by HER2 or p53. Recent aspirin use was inversely associated with breast cancer risk (OR 0.81, 95% CI: 0.70-0.94); associations were not different by molecular subtype. Lifetime aspirin use per decade of life was inversely associated with risk but not different by ER/PR status. The COX-2 SNP, rs2745559, was associated with an increased risk of breast cancer (OR 1.23, 95% CI: 1.03-1.46). Other variants were associated with small, non-significant decreased risks. We observed significant interaction between recent aspirin use and rs4648261 ( p =0.04). No significant interactions were observed with recent ibuprofen or lifetime aspirin use for any of the SNPs. Our findings support existing evidence that aspirin use is inversely associated with risk; however, they do not support the hypothesis that this association differs by tumor subtype. Our finding of an increased risk of ER+/PR+ but not ER-/PR-tumors in association with ibuprofen use may suggest departures in mechanisms of action between aspirin and ibuprofen. Though variation in COX-2 did not substantially affect breast cancer risk, small associations, particularly with rs2745559, were observed.