Randomised Placebo Controlled Trial Studying Short Term Biological Effects of the Combination of Letrozole and Zoledronic Acid on Invasive Breast Cancer.

Abstract

Abstract To determine whether the addition of Zoledronic Acid to endocrine therapy increases apoptosis or decreases proliferation in early invasive breast cancer, a placebo controlled randomised trial comparing 14 days treatment with Letrozole or Letrozole and Zoledronic Acid pre-operatively was performed.PatientsIn total 109 postmenopausal women with early invasive hormone receptor positive breast cancer were randomised (1:1:1) to either placebo, Letrozole 2.5mg/day or Letrozole with Zoledronic Acid 4mg single dose intravenously 2-4 days before definitive surgical excision. Epithelial proliferation and apoptosis were measured on paired baseline and surgical biopsy specimens (after 14 days of treatment) using Ki67 and Activated Caspase 3 immunohistochemistry. Alterations in angiogenic markers (VCAM/VEGF and CD31) were also studied. The primary endpoint was fall in Ki67 between diagnosis and surgical excision.ResultsOverall 109 women were enrolled but paired biopsies were only available for 101 patients. PlaceboLetrozoleLet + Zoln323435Absolute Ki67 change (median,range)-0.8 (-12,12)8.6 (-14,37)12.9 (-12,29) Caspase 3 change (median,range)0.1 (-3.8, 9.3)0.4 (-2.7, -4.1)0.2 (-10.9, -14.4) Absolute change (Cell turnover index)-0.3 (-142, -59)18.9 (-201, 192)17.7 (-14, 379) Statistically significant reductions in Ki67 and Cell Turnover Index were seen with Letrozole and Let & Zol (p ≤ 0.001) but there was no significant different between Letrozole and Letrozole plus Zoledronic Acid groups (p = 0.26). Apoptosis did not change between the three groups.ConclusionLetrozole reduces proliferation by 70% when used for 14 days prior to surgery. Zoledronic Acid administration prior to surgery is safe but when administered as a single dose at a median of 3 days before surgery did not significantly increase apoptosis or decrease proliferation compared to Letrozole alone. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2009.