Fabian CJ, Kimler BF, Anderson J, et al. Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator

The Ohio State University, Columbus, Ohio, United States
Clinical Cancer Research (Impact Factor: 8.72). 08/2004; 10(16):5403-17. DOI: 10.1158/1078-0432.CCR-04-0171
Source: PubMed


Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer.
In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers.
In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry.
Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.

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    • "A phase 1 clinical trial of arzoxifene determined that daily oral dosing was safe and well tolerated; and combined with all previous studies, this suggests that arzoxifene may be useful in the treatment of metastatic breast cancer (Munster et al., 2001; Fabian et al., 2004). A phase 2 clinical trial determined that arzoxifene is effective in treating tamoxifen-sensitive and tamoxifen-refractory patients with advanced or metastatic breast cancer (Chan, 2002; Baselga et al., 2003; Buzdar et al., 2003). "
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    • "However, it increased the risk of endometrial cancer and venous thrombo-embolism in these patients (Nelson et al., 2009). Another clinical trial with arzoxifene, a potent antiestrogenic agent, showed decreased expression of estrogen receptor, although no significant reduction of proliferation was observed (Fabian et al., 2004). Administration of a-difluoromethylornithine, an irreversible inhibitor of polyamine synthesis, among high-risk women in a randomized phase II trial showed no difference in cytology results, expression of proliferation and transcription markers, and the study concluded that the dose of adifluoromethylornithine was too low to affect polyamine synthesis (Fabian et al., 2002). "
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