Breast Cancer Research (May 2020)

Antitumor activity of Z-endoxifen in aromatase inhibitor-sensitive and aromatase inhibitor-resistant estrogen receptor-positive breast cancer

  • Swaathi Jayaraman,
  • Xiaonan Hou,
  • Mary J. Kuffel,
  • Vera J. Suman,
  • Tanya L. Hoskin,
  • Kathryn E. Reinicke,
  • David G. Monroe,
  • Krishna R. Kalari,
  • Xiaojia Tang,
  • Megan A. Zeldenrust,
  • Jingfei Cheng,
  • Elizabeth S. Bruinsma,
  • Sarah A. Buhrow,
  • Renee M. McGovern,
  • Stephanie L. Safgren,
  • Chad A. Walden,
  • Jodi M. Carter,
  • Joel M. Reid,
  • James N. Ingle,
  • Matthew M. Ames,
  • John R. Hawse,
  • Matthew P. Goetz

DOI
https://doi.org/10.1186/s13058-020-01286-7
Journal volume & issue
Vol. 22, no. 1
pp. 1 – 12

Abstract

Read online

Abstract Background The tamoxifen metabolite, Z-endoxifen, demonstrated promising antitumor activity in endocrine-resistant estrogen receptor-positive (ER+) breast cancer. We compared the antitumor activity of Z-endoxifen with tamoxifen and letrozole in the letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1), as well as with tamoxifen, fulvestrant, exemestane, and exemestane plus everolimus in a letrozole-resistant MCF7 model (MCF7LR). Methods MCF7AC1 tumor-bearing mice were randomized to control (no drug), letrozole (10 μg/day), tamoxifen (500 μg/day), or Z-endoxifen (25 and 75 mg/kg). Treatment in the letrozole arm was continued until resistance developed. MCF7LR tumor-bearing mice were then randomized to Z-endoxifen (50 mg/kg) or tamoxifen for 4 weeks and tumors harvested for microarray and immunohistochemistry analysis. The antitumor activity of Z-endoxifen in the MCF7LR tumors was further compared in a second in vivo study with exemestane, exemestane plus everolimus, and fulvestrant. Results In the MCF7AC1 tumors, both Z-endoxifen doses were significantly superior to control and tamoxifen in reducing tumor volumes at 4 weeks. Additionally, the 75 mg/kg Z-endoxifen dose was additionally superior to letrozole. Prolonged letrozole exposure resulted in resistance at 25 weeks. In MCF7LR tumor-bearing mice, Z-endoxifen significantly reduced tumor volumes compared to tamoxifen, letrozole, and exemestane, with no significant differences compared to exemestane plus everolimus and fulvestrant. Additionally, compared to tamoxifen, Z-endoxifen markedly inhibited ERα target genes, Ki67 and Akt expression in vivo. Conclusion In endocrine-sensitive and letrozole-resistant breast tumors, Z-endoxifen results in robust antitumor and antiestrogenic activity compared to tamoxifen and aromatase inhibitor monotherapy. These data support the ongoing development of Z-endoxifen.

Keywords