Abstract
BackgroundThe 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).MethodsMCF7AC1 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.ResultsIn 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.ConclusionIn 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.
Highlights
The tamoxifen metabolite, Z-endoxifen, demonstrated promising antitumor activity in endocrineresistant estrogen receptor-positive (ER+) breast cancer
In endocrine-sensitive and letrozole-resistant breast tumors, Z-endoxifen results in robust antitumor and antiestrogenic activity compared to tamoxifen and aromatase inhibitor monotherapy
The effect of Z-endoxifen on the growth of aromatase inhibitor (AI)-sensitive and AI-resistant Estrogen receptor (ER)+ breast cancer in vivo Assessment of the tumor volume at 4 weeks in the AIsensitive MCF7AC1 xenografted mice treated with control (n = 28), letrozole (n = 29), tamoxifen (n = 30), or Zendoxifen [25 mg/kg (n = 27) or 75 mg/kg (n = 26)] revealed that the 75 mg/kg Z-endoxifen treatment was superior in reducing tumor volume, analyzed using the area under the curve, compared to control (p < 0.0001), tamoxifen (p < 0.0001), and letrozole (p = 0.0005) treatments while the 25 mg/kg Z-endoxifen treatment was superior to control (p < 0.0001) and tamoxifen (p = 0.002) with a trend towards greater benefit compared to letrozole (p = 0.10) (Fig. 1a and b)
Summary
The tamoxifen metabolite, Z-endoxifen, demonstrated promising antitumor activity in endocrineresistant estrogen receptor-positive (ER+) breast cancer. Pharmacokinetics studies have shown that direct oral administration of endoxifen yields substantially higher concentrations compared to endoxifen levels achieved via tamoxifen [7, 8] Based on these data, prospective clinical trials of oral Z-endoxifen (synthesized at the National Cancer Institute, Bethesda, MD) were initiated with initial observations demonstrating substantial Z-endoxifen plasma concentrations (2–6 μM), manageable side effects, and promising antitumor activity in aromatase inhibitor (AI)- and tamoxifen-resistant patients [9]. Prospective clinical trials of oral Z-endoxifen (synthesized at the National Cancer Institute, Bethesda, MD) were initiated with initial observations demonstrating substantial Z-endoxifen plasma concentrations (2–6 μM), manageable side effects, and promising antitumor activity in aromatase inhibitor (AI)- and tamoxifen-resistant patients [9] Given these data, we further characterized the in vivo activity of Z-endoxifen using the aromatase expressing MCF7 cell line model (MCF7AC1). We assessed the antitumor activity of Z-endoxifen across a broad panel of ER+, ER-negative (ER−), and human epidermal growth factor receptor 2positive (HER2+) cell lines
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