DO COX 2 INHIBITORS INCREASE BREAST CANCER SURVIVAL?
Though we’ve been aware of the effects of aspirin for many generations, a critical moment in the history of aspirin is the discovery that it inhibited the prostaglandin forming cyclooxygenase (COX). Cyclooxygenase is the key enzyme in prostaglandin synthesis. Since prostaglandins cause inflammation, fever, and pain as well as gastric protective actions, this discovery provided a unified explanation for the effects of aspirin as well as other NSAIDs. As important, was the discovery that there were 2 cyclooxygenases, COX 1 and COX 2. While COX 1 generated prostaglandins which maintained physiologic functions such as protection of gastric mucosa and platelet aggregation, COX 2 was more relevant in inflammation. Whereas aspirin inhibits both isoforms, a newer drug, celecoxib inhibits only COX 2.
COX 2 has now been found to be overexpressed in many epithelial cancers, including breast cancer. To date, data supporting NSAID use for cancer risk reduction has been most compelling and consistent for colorectal cancer (CRC). Both celecoxib and aspirin have been effective in reducing the incidence of precancerous polyps and reducing CRC mortality. Regrettably, the mechanism of action is not completely understood. The U.S. Preventive Services Task Force now recommends the use of aspirin to reduce the risk of CRC as well as coronary disease in those at increased risk.
When associated with overexpression of COX 2, breast cancers are usually high grade, ER-negative, and Her2 positive. In the animal model, celecoxib, when added to exemestane, increases its duration of benefit. Some data also supports low dose aspirin in cancer survival. Observational data is mixed but do suggest that aspirin may improve breast cancer survival. Unfortunately, data from large randomized controlled trials are lacking for both aspirin and celecoxib. Three trials are currently in progress and will be critical in determining the true effect of celecoxib and aspirin on breast cancer survival: UK REACT TRIAL (NCT02429427), the ABC TRIAL (NCT02927249) and the ADD-ASPIRIN TRIAL (NCT02804815).
Attached is an article examining the effects of celecoxib and low dose aspirin on outcomes in adjuvant aromatase inhibitor-treated patients. (COX 2) The authors concluded that neither celecoxib nor aspirin affected either disease-free or event-free survival. An accompanying editorial noted many limitations of the study (cox2 editorial). The celecoxib arm was much smaller than planned, as the celecoxib arm was discontinued due to NCIs warning about adverse cardiac events. The median duration of exposure was just 4.6 months. There was also a 32% discontinuation rate of the aromatase inhibitor. Because of these issues, the editors concluded that the celecoxib arm was inconclusive.
Surprisingly, the aspirin arm was related to an increase in mortality. The authors concluded that this was due to increase in cardiac disease in this study arm. Moreover, the aspirin arm was a stratification arm as opposed to a randomized variable. Unfortunately, the issues noted, impact the relevance of this study. To decide whether NSAIDs impact survival or incidence of breast cancer, we will continue to have to wait for results of the ongoing randomized controlled trials.