Antitumor Activity of Z-endoxifen in Aromatase Inhibitor-Sensitive and Resistant Estrogen Receptor-Positive Breast Cancer

The overarching goal of this study was to explore the antitumor activity of Z-endoxifen, a tamoxifen metabolite, with first-line endocrine therapies tamoxifen and letrozole in the letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1), and with second-line endocrine therapies including tamoxifen, fulvestrant, exemestane, and exemestane plus everolimus, in letrozole-resistant MCF7 model (MCF7LR) in vivo. We used microarray to identify genes that are commonly and differently reguated by Z-endoxifen and tamoxifen treatments in the letrozole-resistant MCF7LR tumors. In the first study MCF7AC1 tumors-bearing mice were randomized to control (no drug), letrozole (10μg/day), tamoxifen (500 µg/day) or Z-endoxifen (25 and 75 mg/kg) and the efficacy of Z-endoxifen compared to first-line endocrine therapies were studied. Treatment in the letrozole arm was continued for an extended period of time until resistance developed in vivo. Owing to mouse body weight loss observed with the 75 mg/kg dose of Z-endoxifen, the MCF7LR tumor-bearing mice were randomized to 50 mg/kg dose of Z-endoxifen or tamoxifen for four weeks and Z-endoxifen efficacy was compared to tamoxifen in the resistant setting. At the end of four weeks, tumors were harvested for microarray and immunohistochemistry analysis. In the second in vivo study, the efficacy of Z-endoxifen in the second-line setting was compared with FDA approved endocrine therapies (exemestane, exemestane+everolimus and fulvestrant) for the treatment of AI-resistant breast tumors.