Fulvestrant: an estrogen receptor antagonist that downregulates the estrogen receptor

Fulvestrant, a novel antiestrogen classified as an estrogen receptor antagonist without known agonist effects, was recently approved in the United States for the treatment of postmenopausal, hormone receptor-positive women with progressive metastatic breast cancer after antiestrogen therapy. In a phase II trial, monthly administration of fulvestrant, 250 mg intramuscularly, conferred clinical benefit (partial response or stable disease for ≥ 24 weeks) in 69% of patients with tamoxifen-resistant advanced breast cancer. Furthermore, the median duration of response and survival for this population (26 and 54 months, respectively) was twice as high as those documented for a megestrol acetate-treated historical cohort (14 months and 30 months, respectively). Comparative phase III trials conducted in North America and internationally, which used time to progression as the primary endpoint, demonstrated fulvestrant's tolerability and equivalence to anastrozole in postmenopausal women with tamoxifen-resistant advanced breast cancer, which led to its approval in this setting. Vasodilation and nausea were the principal treatment-related adverse events in the fulvestrant arms, and mild injection-site reactions occurred in 4.6% and 1.1% of monthly fulvestrant courses given in the North American and international trials, respectively. Recent subanalyses of the pivotal phase III data have found that fulvestrant produces a 30% longer mean duration of response compared with anastrozole and that fulvestrant-induced estrogen receptor downregulation does not preclude response to subsequent hormonal therapy. Ongoing trials in patients with advanced breast cancer will provide further insight into the relative merits of fulvestrant versus tamoxifen as first-line therapy for metastatic disease, the use of fulvestrant within combination and sequential regimens, and the efficacy of fulvestrant specifically in premenopausal women. Research efforts focusing on alternate administration schedules for fulvestrant and its potential as an adjuvant hormonal therapy are also anticipated.