Effect of Raloxifene on Breast Cancer Cell Ki67 and Apoptosis

Effect of Raloxifene on Breast Cancer Cell Ki67 and Apoptosis

A Double-Blind, Placebo-controlled, Randomized Clinical Trial in Postmenopausal Patients1

Royal Marsden NHS Trust, London, England SM2 5PT [M. D., M. J. H.]; University Hospital South, Manchester, England M20 2LR [N. J. B.]; European Institute of Oncology, Milan, Italy 20141 [A. D., P. V.]; Huddersfield Royal Infirmary, Huddersfield, England HD3 3EA [R. C. S.]; Eli Lilly and Company, Indianapolis, Indiana 46285 [Y. L., F. J. C., T. S., D. B. M.]; and Kent Cancer Centre, Maidstone, Kent, England ME16 9QQ [M. E. R. O.]

Abstract

Purpose: Raloxifene is a selective estrogen receptor (ER) modulator approved for prevention and treatment of postmenopausal osteoporosis. This is an exploratory study of raloxifene in primary breast cancer patients.

Experimental Design: Postmenopausal women (50–80 years of age), with histological or cytological diagnosis of stage I or II primary breast cancer, were randomly assigned to 14 days of placebo, 60 mg/day raloxifene, or 300 mg twice daily (600 mg/day) of raloxifene. A core biopsy of the primary tumor was obtained before therapy, and a representative sample of the excised tumor was obtained from the operative specimen after treatment. Paired baseline and endpoint biopsies from each patient were analyzed for Ki67, apoptosis, and estrogen and progesterone receptors. Treatment group differences in efficacy measurements were primarily evaluated for baseline-to-endpoint change and percentage change using a one-way ANOVA with treatment as the fixed effect.

Results: Of 167 enrolled patients, 143 had evaluable efficacy data. Most breast cancer cases were invasive (98.6%), stage I (76.6%), and ER-positive (83.2%). In patients with ER-positive tumors, Ki67 increased 7% from baseline on placebo and decreased by 21% on 60 mg/day raloxifene (P = 0.015 versus placebo) and by 14% on 600 mg/day raloxifene (P = 0.064 versus placebo). Raloxifene did not affect apoptosis. ER decreased significantly with 60 mg/day or 600 mg/day raloxifene compared with placebo (P < 0.01 for each comparison). Raloxifene had no statistically significant effects on Ki67 among patients with ER-negative tumors. There were no treatment differences in adverse events.

Conclusion: In this exploratory trial, 60 mg/day raloxifene showed a significant antiproliferative effect in ER-positive breast cancer, demonstrated by the decrease in Ki67, with no effect in ER-negative cancer. This provides support for raloxifene having a breast cancer preventive effect in postmenopausal women.

Footnotes

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵1 Eli Lilly provided funding for the trial.
↵2 Y. Lu, F. J. Cohen, D. B. Muchmore, and T. Scott are employees of Eli Lilly, and the trial was conducted by Eli Lilly and Company.
↵3 To whom requests for reprints should addressed, at Department of Biochemistry, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, United Kingdom. Phone: 44-207-808-2885; Fax: 44-207-376-3918; E-mail: mitch{at}icr.ac.uk
↵4 Present address: R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869-0602.
↵5 The abbreviations used are: SERM, selective estrogen receptor modulator; ER, estrogen receptor; PR, progesterone receptor.
- Accepted June 8, 1901.
- Received December 31, 1900.
- Revision received June 1, 1901.