Cox-2 Hormonal Approaches for the Treatment and Prevention of Breast Cancer
Faculty Disclosure: Paul E. Goss, MD, PhD
In this presentation by Dr. Goss there is discussion of celecoxib for the treatment and prevention of breast cancer which is not approved by the FDA.
Presenter: Paul E. Goss, MD, PhD
Affiliation: Princess Margaret Hospital
The advent of hormonal and chemotherapeutic agents has been a significant advance in the treatment of breast cancer. Further studies have investigated newer agents to inhibit breast tumor growth and to inhibit estrogen's tumorigenic effect on both normal breast tissue and breast tumor cells. Recently, it has been shown that Cox-2 is induced by both in-situ and invasive breast cancers. Cox-2 catalyzes the conversion of arachidonic acid to prostaglandin E2 (PGE2). PGE2, in turn, upregulates a number of intracellular growth pathways. Therefore, blocking Cox-2 with a specific inhibitor, such as celecoxib, would inhibit these pathways. To this effect, celecoxib has been shown to inhibit angiogenesis, inhibit cell growth and division, and also cause a pro-apoptotic effect. In keeping with these tumor preventative properties, recent studies have suggested a reduction (by 50%) in the occurrence of breast cancers in women who chronically ingest anti-inflammatories (which would inhibit Cox-2). In preclinical models, celecoxib reduces the incidence of ER positive tumors and reduces the growth of ER positive tumors already present. As one of the pathways it blocks is the production of aromatase, celecoxib also has an additive effect with aromatase inhibitors in preventing ER positive tumor growth.
Aromatase inhibitors, which work by inhibiting estrogen synthetase and hence estrogen, are an alternative to treatment with tamoxifen. In the ATAC trial, aromatase inhibitors were shown to be at least of equal efficacy and in some groups, superior to tamoxifen. In addition, anastrazole was shown to reduce the occurrence of contralateral ER positive breast cancers more so than did tamoxifen. This raises the hope that aromatase inhibitors may have a preventative role as well as a role in treatment in breast cancer. Hence, aromatase inhibitors are also a new and exciting group of agents that could be efficacious in the treatment and possibly prevention of breast cancer.
The biggest toxicity concern with aromatase inhibitors is increased bone resorption, which was noted in both the ATAC and the MA17 trial, though in the MA17 trial there was no increased incidence of fractures. There is also still a question as to whether the first generation aromatase inhibitors truly represent an advantage over tamoxifen. Newer agents may assist in addressing both concerns about aromatase inhibitors. Exemestane is a newer steroidal aromatase inhibitor which has an additional androgenic anti-tumor effect, but with anabolic effects on bone and lipid metabolism. In rats, it has been shown to preserve bone. Therefore, it is an aromatase inhibitor that deserves further investigation, and is currently being tested in many studies.
With these characteristics, newer aromatase inhibitors and Cox-2 inhibitors may represent an advance in both breast cancer treatment and prevention. There are open studies investigating these very questions. In a 2x2 design, postmenopausal women with ER positive tumors are randomized both between exemestane vs. anastrazole for five years as well as between celecoxib vs. placebo for 3 years. Designed accrual for this study is 6800 patients. The NCIC is also investigating these two agents in breast cancer prevention. In high-risk, premenopausal women, randomization is to one of three arms: exemestane, exemestane + celecoxib, or placebo. The hope is that there will not only be a preventative effect but that there will be a decrease in ER negative tumors as well. With their common pathways and synergistic effect, celecoxib and exemestane are both intriguing agents in both the treatment and prevention of breast cancer. However, whether these truly represent an advantage over tamoxifen and whether they will incur an actual survival advantage remains to be seen and will likely not be definitively proven for quite some time.