A good drug made better: the fulvestrant dose-response story.

Sequential use of endocrine therapies remains the cornerstone of treatment for hormone receptor-positive advanced breast cancer, before the use of cytotoxic chemotherapy for unresponsive disease. Fulvestrant is an estrogen receptor (ER) antagonist approved for the treatment of postmenopausal women with ER+ advanced breast cancer after failure of prior antiestrogen therapy. Initially approved at a monthly dose of 250 mg, the recommended fulvestrant dose was revised to 500 mg (500 mg/mo plus 500 mg on day 14 of month 1) after demonstration of improved progression-free survival versus fulvestrant 250 mg. We have reviewed the dose-dependent effects of fulvestrant, both from a retrospective combined analysis of dose-dependent reduction of tumor biomarkers in the presurgical setting (3 previously reported studies: Study 18, Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors, and Trial 57) and from a review of clinical studies for advanced breast cancer in postmenopausal women. Analysis of presurgical data revealed a consistent dose-dependent effect for fulvestrant on tumor biomarkers, with increasing fulvestrant dose resulting in greater reductions in ER, progesterone receptor, and Ki67 labeling index. The dose-dependent biological effect corresponds with the dose-dependent clinical efficacy observed in the treatment of advanced breast cancer after failure of prior antiestrogen therapy. Although it remains to be determined in a phase III trial, cross-trial comparisons suggest a dose-dependent relationship for fulvestrant as first-line treatment for advanced breast cancer. Overall, biological and clinical data demonstrate a strong dose-dependent relationship for fulvestrant, supporting the efficacy benefit seen with fulvestrant 500 mg over the 250 mg dose.