Anti-aromatase agents in the treatment and prevention of breast cancer.
Anti-aromatase agents now have a central role in the management of breast cancer in postmenopausal women; they are superior to megestrol acetate as second-line therapy and to tamoxifen for initial therapy of metastatic disease. They also are highly active as neoadjuvant therapy. Two classes of anti-aromatase agents are available: steroidal (eg, exemestane) and nonsteroidal (eg, anastrozole, letrozole). Although both types of agents act on the aromatase enzyme, they do so by different mechanisms and have different effects on cellular aromatase activity. Nonsteroidal agents are associated with increased aromatase enzyme content and steroidal agents are associated with decreased content. The increase in aromatase content seen with the nonsteroidal agents may in part explain the development of resistance with these agents and the ability of the steroidal agent exemestane to induce a response when nonsteroidal agents fail. Because the anti-aromatase agents almost completely eliminate endogenous estrogen production, they not only affect breast cancer tissues, but also may alter the function of other estrogen-responsive tissues. However, preclinical data show that the steroidal agent exemestane may actually improve bone and lipid metabolism. In addition, no increase in clinical fracture rate has been noted in women treated with exemestane in metastatic trials; the fracture risk has not yet been studied following prolonged exposure in healthy women. Exemestane associated beneficial effects on these end organs may be due to the steroidal nature of both the parent compound and its principal metabolite, 17-hydroexemestane. Similar benefits have not been reported with nonsteroidal antiaromatase agents. Based on their excellent activity in the metastatic setting, anti-aromatase agents are now being evaluated in the adjuvant setting and in pilot studies for chemoprevention. These studies will provide long-term data in healthy women and will help to differentiate anti-aromatase agents, in terms of their efficacy in the treatment of breast cancer and their effects on end organs.
Goss
Paul
P
Breast Cancer Prevention Program at the Princess Margaret Hospital, Toronto, Ontario, Canada. pegoss@interlog.com
D000077384:Anastrozole; D000730:Androstadienes / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000517:prevention & control*; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000077289:Letrozole; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000627:therapeutic use; D017698:Postmenopause; D012107:Research Design; D014230:Triazoles / Q000627:therapeutic use
D000730:Androstadienes; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077384:Anastrozole; D000077289:Letrozole; C056516:exemestane