Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Carol J Fabian, Bruce F Kimler, Julie Anderson, Ossama W Tawfik, Matthew S Mayo, William E Burak Jr, Joyce A O'Shaughnessy, Kathy S Albain, David M Hyams, G Thomas Budd, Patricia A Ganz, Edward R Sauter, Samuel W Beenken, William E Grizzle, John P Fruehauf, Dora W Arneson, James W Bacus, Michael D Lagios, Karen A Johnson, Doris Browne
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 16 Pg. 5403-17 (Aug 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15328178 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anticarcinogenic Agents
• Hormones
• Piperidines
• Selective Estrogen Receptor Modulators
• Thiophenes
• Estrone
• Estradiol
• LY 353381

Topics

• Anticarcinogenic Agents (toxicity)
• Biopsy
• Breast Neoplasms (prevention & control, surgery)
• Dose-Response Relationship, Drug
• Estradiol (blood)
• Estrone (blood)
• Female
• Hormones (blood)
• Humans
• Middle Aged
• Patient Selection
• Piperidines (toxicity)
• Postmenopause
• Reoperation
• Selective Estrogen Receptor Modulators (toxicity)
• Thiophenes (toxicity)