Breast Cancer Chemoprevention Phase I Evaluation of Biomarker Modulation by Arzoxifene, a Third Generation Selective Estrogen Receptor Modulator

• Published in: Clinical cancer research Vol. 10; no. 16; pp. 5403 - 5417
• Main Authors: FABIAN, Carol J, KIMLER, Bruce F, GANZ, Patricia A, SAUTER, Edward R, BEENKEN, Samuel W, GRIZZLE, William E, FRUEHAUF, John P, ARNESON, Dora W, BACUS, James W, LAGIOS, Michael D, JOHNSON, Karen A, BROWNE, Doris, ANDERSON, Julie, TAWFIK, Ossama W, MAYO, Matthew S, BURAK, William E, O'SHAUGHNESSY, Joyce A, ALBAIN, Kathy S, HYAMS, David M, BUDD, G. Thomas
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.2004
• Subjects: Anticarcinogenic Agents - toxicity; Antineoplastic agents; Biological and medical sciences; Biopsy; Breast Neoplasms - prevention & control; Breast Neoplasms - surgery; Dose-Response Relationship, Drug; Estradiol - blood; Estrone - blood; Female; Hormones - blood; Humans; Medical sciences; Middle Aged; Patient Selection; Pharmacology. Drug treatments; Piperidines - toxicity; Postmenopause; Reoperation; Selective Estrogen Receptor Modulators - toxicity; Thiophenes - toxicity; Tumors; Mammary gland diseases; Arzoxifene; Selective estrogen receptor modulator; Modulation; Antiestrogen; Phase I trial; Biological marker; Breast cancer; Antihormone; Mammary gland; Malignant tumor; Anticarcinogen
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-0171

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.