title: A good drug made better: the fulvestrant dose-response story.
abstract: 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.
authors.affiliation: Graduate Entry Medicine and Health School (GEMS), University of Nottingham, Derby, UK. Electronic address: john.robertson@nottingham.ac.uk.
authors.forename: John F R
authors.initials: JF
authors.lastname: Robertson
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Lindemann
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Garnett
authors.affiliation: Formerly AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Anderson
authors.affiliation: Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
authors.affiliation: Massachusetts General Hospital, Boston, MA.
authors.forename: Irene
authors.initials: I
authors.lastname: Kuter
authors.affiliation: Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
authors.forename: Julia M W
authors.initials: JM
authors.lastname: Gee
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy*; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D065171:Estrogen Receptor Antagonists / Q000627:therapeutic use*; D005260:Female; D000077267:Fulvestrant; D006801:Humans
chemical_list: D065171:Estrogen Receptor Antagonists; D000077267:Fulvestrant; D004958:Estradiol
keywords: Advanced breast cancer; Endocrine therapy; Estrogen receptor; Postmenopausal; Tumor biomarkers