Tumor Biomarker Changes Following Pre-Surgical Treatment with 500 mg Fulvestrant Plus Anastrozole Versus 500 mg Fulvestrant Alone and 1 mg Anastrozole Alone.
Authors: Robertson J. , Dixon J. , Sibbering D. , Jahan A. , Ellis I. , Channon E. , Nicholson R. , Gee J. 
Published: December 2010

Background: Fulvestrant (Faslodex™) is an estrogen receptor (ER) antagonist with a distinct mode of action. Previous pre-surgical studies have reported dose-dependent reductions in biological tumor markers (ER, progesterone receptor [PgR], and Ki67 levels) with doses of fulvestrant up to 250 mg (approved dose, AD). The NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors) study was the first to indicate that a higher dose of fulvestrant (500 mg) has significantly greater biological activity than AD in the neoadjuvant setting. A greater ER signaling blockade and subsequent anti-cancer effect might be produced by combining fulvestrant with an estrogen-lowering agent such as the aromatase inhibitor anastrozole (Arimidex™).Objectives: Primary objective: to compare the biological activity of 500 mg fulvestrant plus anastrozole with 500 mg fulvestrant alone and anastrozole alone. Primary endpoints included changes in ER, PgR, and Ki67 index. The secondary objective was to assess tolerability.Methods: This was a Phase II, double-blind, randomized, multicenter trial (9238IL/0057; NCT00259090) in postmenopausal women with ER-positive primary breast cancer. Patients were randomized into one of 3 treatment arms: fulvestrant 500 mg plus anastrozole 1 mg once daily (od) for 14 to 21 days (F+A); fulvestrant 500 mg plus anastrozole placebo 1 mg od for 14 to 21 days (F); fulvestrant placebo plus anastrozole 1 mg od for 14 to 21 days (A). Following randomization, treatment, and curative intent surgery, patients were assessed and reviewed for adverse events. Tumor biopsy samples were taken pre-treatment and at surgery to assess changes in ER, PgR, and Ki67 index. Changes in ER index (evaluated by non-automated H-score assessment) are presented.Results: In total, 121 patients were randomized and, to date, 99 paired samples have been analyzed for ER. Treatment with F, F+A, and A each significantly reduced the mean pre-treatment ER index.Change in ER H-score from baseline FF+AAN352935Mean pre-treatment H-score187.1187.2192.7Mean post-treatment H-score112.1123.1161.3% change (post-treatment)-41%-35%-15% There was a significant overall treatment effect between therapy arms (p=0.0001). Treatment with F showed a significant decrease in ER index compared with A (p=0.0001), as did F+A vs A (p=0.0004). There was no additional reduction in ER by F+A vs F alone (p=0.2). Ki67 and PgR results are being analyzed. Short-term side effects on treatment were similar for F+A compared with F and A alone.Conclusions: This study is the first to investigate treatment with fulvestrant 500 mg combined with anastrozole. The effects on ER confirm the different mechanisms of action reported experimentally for F and A. F or F+A both significantly decreased ER index, but there was no further significant impact on ER changes by combining F+A vs F. Ongoing analysis of PgR and Ki67 will help determine if there is clinical relevance in the decline in ER level associated with both 500 mg F-containing strategies versus A, and help compare the impact of F+A vs F or A alone on ER function.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 24.