Prevention strategies with aromatase inhibitors

Aromatase (estrogen synthetase) inhibitors are superior to tamoxifen in terms of both efficacy and toxicity in the treatment of advanced breast cancer and also in the neoadjuvant setting. Recent results from the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial showed a marked reduction in contralateral primary breast cancer with anastrozole, an apparent prevention effect. A similar effect was seen in the MA.17 adjuvant trial comparing letrozole with placebo after 5 years of adjuvant tamoxifen. This has accelerated interest in aromatase inhibitors as primary preventive therapy. Two studies being conducted by the National Cancer Institute of Canada's Clinical Trials Group select women by virtue of mammographic breast density. The International Breast Cancer Intervention Study 2 trial randomizes women at elevated risk to anastrozole or placebo. Because of its steroidal structure, exemestane may be more effective than the nonsteroidal aromatase inhibitors and may protect bone and lipid metabolism from the effects of estrogen ablation. Elevated prostaglandin E2 levels from cyclooxygenase-2 induction by preinvasive and invasive breast lesions increase a number of tumor-promoting pathways, including aromatase, as well as angiogenetic, antiapoptotic, and others. Additive or synergistic effects between celecoxib, a cyclooxygenase-2 inhibitor, and exemestane have been demonstrated and have led to the National Cancer Institute of Canada's Clinical Trials Group MAP.3 trial, which will randomize women at elevated risk to placebo or to exemestane with or without celecoxib. The efficacy and long-term toxicity data from the aromatase inhibitor prevention trials, and the identification of risk profiles from trial results, are awaited with interest.