Endocrine therapies of breast cancer.

Endocrine therapies for breast cancer have been used for more than a century. The concept that changing the hormonal balance of the patient with breast cancer could lead to changes in tumor growth and regression of metastatic disease was recognized even before hormones and endocrine agents were available. Ablation of ovaries, adrenals, or hypophysis was used in advanced disease to obtain tumor regression and control of symptoms. Ovarian ablation was also tested for operable breast cancer showing a significant beneficial treatment effect. Several endocrine agents have been developed in recent years: estrogens, androgens, progestins, antiestrogens, aromatase inhibitors, gonadotropin-releasing hormone analogs, antiprogestins, and antiandrogens. The use of some of these agents in advanced disease led to investigations in early breast cancer: tamoxifen was the drug which was most extensively tested, showing a significant long-term benefit for treated patients. Progestins (medroxyprogesterone acetate) and aromatase inhibitors (aminoglutethimide) were also tested in a few clinical trials, but no conclusive recommendations for their use in patients with operable disease may be formulated. The most important current challenges for the appropriate use of endocrine therapies in breast cancer include (1) understanding the effect of endocrine therapies and the mechanisms of resistance associated with their use; (2) developing new agents with novel endocrine antitumor effect; (3) defining the best way to combine endocrine agents with cytotoxics or with other endocrine manipulations; and (4) identifying long-term effects of endocrine agents in terms of disease control and prevention, as well as desirable and undesirable side effects.