Estrogen receptor downregulators: New antihormonal therapy for advanced breast cancer

Background: Fulvestrant is the first agent in the new class of estrogen receptor (ER) downregulators to be evaluated in clinical studies. The binding of ER downregulators to ERs inhibits the activation functions of the receptors (AF-1 and AF-2). ER downregulators also disrupt the dimerization and nuclear localization of ERs. In contrast to ER downregulators, when selective estrogen receptor modulators (SERMs) bind to ERs, only AF-2 is inhibited; AF-1 remains active. Therefore, with SERMs, AF-1 can still recruit coactivators, which results in a partially inactivated transcription and a reduced rate of tumor cell division. Consistent with its mechanism of action, animal models have shown that fulvestrant demonstrates a longer suppression of tumor growth than does tamoxifen, and it has antitumor activity in tamoxifen-resistant tumors. Two Phase III trials have been conducted comparing fulvestrant (250 mg IM monthly) with anastrozole (I mg oral tablet daily) in postmenopausal patients with advanced breast cancer progressing after prior endocrine therapy. Objective response in fulvestrant-treated patients in the 2 studies ranged from 17.5% to 20.7% compared with 15.7% to 17.5% for anastrozole-treated patients, and the median duration of response ranged from 14.3 to 19.3 months in the fulvestrant group compared with 10.5 to 14.0 months in the anastrozole group. No statistically significant differences were demonstrated for any of the predefined end points. In both studies, fulvestrant was as well tolerated as anastrozole. Objective: This review describes the pharmacology, clinical activity, safety, dosing, and pharmacokinetic profile of fulvestrant. Conclusions: Based on evidence to date, fulvestrant will likely be an important agent in the treatment of tamoxifen-resistant metastatic breast cancer.