This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fabian, C. J. Articles by Browne, D. Search for Related Content PubMed PubMed Citation Articles by Fabian, C. J. Articles by Browne, D.

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

¹ University of Kansas Medical Center, Kansas City, Kansas; ² Ohio State University, Columbus, Ohio; ³ US Oncology, Inc., Dallas, Texas; ⁴ Loyola University Medical Center, Maywood, Illinois; ⁵ Desert Comprehensive Cancer Center, Palm Springs, California; ⁶ Cleveland Clinic Foundation, Cleveland, Ohio; ⁷ University of California Los Angeles, Los Angeles, California; ⁸ University of Missouri-Columbia, Columbia, Missouri; ⁹ University of Alabama-Birmingham, Birmingham, Alabama; ¹⁰ Oncotech, Inc., Irvine, California; ¹¹ Midwest Research Institute, Kansas City, Missouri; ¹² Bacus Laboratories, Inc., Elmhurst, Illinois; ¹³ St. Mary’s Hospital, San Francisco, California; and ¹⁴ Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland

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.

This article has been cited by other articles:

				A. Y. Ting, B. F. Kimler, C. J. Fabian, and B. K. Petroff Tamoxifen Prevents Premalignant Changes of Breast, but not Ovarian, Cancer in Rats at High Risk for Both Diseases Cancer Prevention Research, December 1, 2008; 1(7): 546 - 553. [Abstract] [Full Text] [PDF]

				B. Yu, B. M. Dietz, T. Dunlap, I. Kastrati, D. D. Lantvit, C. R. Overk, P. Yao, Z. Qin, J. L. Bolton, and G. R.J. Thatcher Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms Mol. Cancer Ther., September 1, 2007; 6(9): 2418 - 2428. [Abstract] [Full Text] [PDF]

				A. I. Neugut, B. Lebwohl, and D. L. Hershman Cancer Chemoprevention: How Do We Know What Works? J. Clin. Oncol., April 20, 2007; 25(12): 1461 - 1462. [Full Text] [PDF]

				A. Y. Ting, B. F. Kimler, C. J. Fabian, and B. K. Petroff Characterization of a preclinical model of simultaneous breast and ovarian cancer progression Carcinogenesis, January 1, 2007; 28(1): 130 - 135. [Abstract] [Full Text] [PDF]

				K. Liby, M. Rendi, N. Suh, D. B. Royce, R. Risingsong, C. R. Williams, W. Lamph, F. Labrie, S. Krajewski, X. Xu, et al. The Combination of the Rexinoid, LG100268, and a Selective Estrogen Receptor Modulator, Either Arzoxifene or Acolbifene, Synergizes in the Prevention and Treatment of Mammary Tumors in an Estrogen Receptor-Negative Model of Breast Cancer. Clin. Cancer Res., October 1, 2006; 12(19): 5902 - 5909. [Abstract] [Full Text] [PDF]

				G. J. Kelloff, S. M. Lippman, A. J. Dannenberg, C. C. Sigman, H. L. Pearce, B. J. Reid, E. Szabo, V. C. Jordan, M. R. Spitz, G. B. Mills, et al. Progress in Chemoprevention Drug Development: The Promise of Molecular Biomarkers for Prevention of Intraepithelial Neoplasia and Cancer--A Plan to Move Forward Clin. Cancer Res., June 15, 2006; 12(12): 3661 - 3697. [Abstract] [Full Text] [PDF]

				D. Bhandare, S. A. Khan, C. J. Fabian, and Q. J. Khan Ki-67 Expression in Benign Breast Ductal Cells Obtained by Random Periareolar Fine Needle Aspiration Cancer Epidemiol. Biomarkers Prev., September 1, 2005; 14(9): 2278 - 2279. [Full Text] [PDF]

				C J Fabian, B F Kimler, M S Mayo, and S A Khan Breast-tissue sampling for risk assessment and prevention Endocr. Relat. Cancer, June 1, 2005; 12(2): 185 - 213. [Abstract] [Full Text] [PDF]

				P. H. Brown Breast Cancer Chemoprevention: Biomarker End-Point Trials Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 189 - 191. [Full Text] [PDF]

				C. J. Fabian and B. F. Kimler Selective Estrogen-Receptor Modulators for Primary Prevention of Breast Cancer J. Clin. Oncol., March 10, 2005; 23(8): 1644 - 1655. [Full Text] [PDF]

				M. B. Sporn Arzoxifene: A Promising New Selective Estrogen Receptor Modulator for Clinical Chemoprevention of Breast Cancer: Commentary re C. J. Fabian et al., Breast Cancer Chemoprevention Phase I Evaluation of Biomarker Modulation by Arzoxifene, a Third Generation Selective Estrogen Receptor Modulator. Clin Cancer Res 2004;10:5403-17. Clin. Cancer Res., August 15, 2004; 10(16): 5313 - 5315. [Full Text] [PDF]