Clinical and genomic analysis of a randomised phase II study evaluating anastrozole and fulvestrant in postmenopausal patients treated for large operable or locally-advanced hormone-receptor-positive breast cancer

Background: The aim of this study was to assess the efficacy of neoadjuvant anastrozole and fulvestrant treatment of large operable or locally-advanced hormone- receptor-positive breast cancer not eligible for initial breast-conserving surgery, and to identify genomic changes occurring after treatment. Methods: 120 post-menopausal patients were randomised to receive 1 mg anastrozole (61 patients) or 500 mg fulvestrant (59 patients) for 6 months. Genomic DNA copy number profiles were generated for a subgroup of 20 patients before and after treatment. Results: 108 patients were evaluable for efficacy and 118 for toxicity. The objective response rate determined by clinical palpation was 58.9% (95% CI 45.0-71.9) in the anastrozole arm and 53.8% (95% CI 39.5-67.8) in the fulvestrant arm. The breast- conserving surgery rate was 58.9% (95% CI 45.0-71.9) in the anastrozole arm and 50.0% (95% CI 35.8-64.2) in the fulvestrant arm. Pathological responses >50% occurred in 24 patients (42.9%) in the anastrozole arm and 13 (25.0%) in the fulvestrant arm. The Ki-67 score fell after treatment but there was no significant difference between the reduction in the two arms (anastrozole 16.7% [95%CI 13.3-21.0] before, 3.2% [95%CI 1.9-5.5] after, n=43; fulvestrant 17.1% [95%CI 13.1-22.5] before, 3.2% [95%CI 1.8-5.7] after, n=38) or between the reduction in Ki-67 in clinical responders and non- responders. Genomic analysis appeared to show a reduction of clonal diversity following treatment with selection of some clones with simpler copy number profiles. Conclusion: Both anastrozole and fulvestrant were effective and well-tolerated, enabling breast-conserving surgery in over 50% of patients. Clonal changes consistent with clonal selection by the treatment were seen in a subgroup of patients.