2. Academic Validation
  3. Antitumor activity of Z-endoxifen in aromatase inhibitor-sensitive and aromatase inhibitor-resistant estrogen receptor-positive breast cancer

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

  • Breast Cancer Res. 2020 May 19;22(1):51. doi: 10.1186/s13058-020-01286-7.
Swaathi Jayaraman 1,  Xiaonan Hou 1,  Mary J Kuffel 1,  Vera J Suman 2,  Tanya L Hoskin 2,  Kathryn E Reinicke 1,  David G Monroe 3,  Krishna R Kalari 2,  Xiaojia Tang 2,  Megan A Zeldenrust 1,  Jingfei Cheng 1,  Elizabeth S Bruinsma 3,  Sarah A Buhrow 1,  Renee M McGovern 1,  Stephanie L Safgren 1,  Chad A Walden 1,  Jodi M Carter 4,  Joel M Reid 1,  James N Ingle 1,  Matthew M Ames 1,  John R Hawse 3,  Matthew P Goetz 5 6
Affiliations

Affiliations

  • 1 Department of Oncology, Mayo Clinic, Rochester, MN, USA.
  • 2 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
  • 3 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
  • 4 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • 5 Department of Oncology, Mayo Clinic, Rochester, MN, USA. Goetz.Matthew@mayo.edu.
  • 6 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. Goetz.Matthew@mayo.edu.
PMID: 32430040 DOI: 10.1186/s13058-020-01286-7
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

AI-resistant and AI-sensitive ER+ breast cancer; Estrogen-regulated genes; Signaling kinase; Tamoxifen; Tumor growth in vivo; Z-endoxifen.

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