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Effect of Tibolone on Breast Cancer Cell Proliferation in Postmenopausal ER+ Patients: Results from STEM Trial

Authors' Affiliations: ¹ Division of Special Gynecology, Medical University of Vienna, Vienna, Austria; ² Global Clinical Development, NV Organon, Oss, the Netherlands; ³ Department of Academic Biochemistry, Royal Marsden Hospital, London, United Kingdom; ⁴ Department of Obstetrics and Gynecology, University of Liège, Liege, Belgium; ⁵ Department of Obstetrics and Gynecology II, Comenius University School of Medicine, Bratislava, Slovak Republic; ⁶ Department of Gynecology, University of Ghent, Ghent, Belgium; ⁷ Cancer Research Center, Moscow, Russia; and ⁸ St. Petersburg City Clinical Oncology Dispensary and ⁹ St. Petersburg Research Institute of Oncology, St. Petersburg, Russia

Requests for reprints: Christian F. Singer, Division of Special Gynecology, Vienna Medical University, Vienna, Austria. Phone: 43-1-40400-2801; Fax: 43-1-406-6749; E-mail: Christian.singer{at}meduniwien.ac.at.

Purpose: Tibolone is a selective tissue estrogenic activity regulator, approved for the treatment of vasomotor symptoms in postmenopausal women. We have done an exploratory, double-blind, randomized, placebo-controlled pilot trial to investigate the tissue-specific effects of 2.5 mg tibolone on breast cancer in postmenopausal women, in particular on tissue proliferation (STEM, Study of Tibolone Effects on Mamma carcinoma tissue).

Experimental Design: Postmenopausal women with initially stage I/II, estrogen receptor–positive (ER+) primary breast cancer, were randomly assigned to 14 days of placebo or 2.5 mg/d tibolone. Core biopsies of the primary tumor were obtained before and after treatment. Ki-67 and apoptosis index were analyzed in baseline and corresponding posttreatment specimen.

Results: Of 102 enrolled patients, 95 had evaluable data. Baseline characteristics were comparable between both treatment groups. Breast cancer cases are mainly invasive (99%), stage I or II (42% and 50% respectively), and ER+ (99%). Median intratumoral Ki-67 expression at baseline was 13.0% in the tibolone group and 17.8% in the placebo group, and decreased to 12.0% after 14 days of tibolone while increasing to 19.0% in the placebo group. This change from baseline was not significantly different between tibolone and placebo (Wilcoxon test; P = 0.17). A significant difference was observed between the treatment groups when the median change from baseline apoptosis index was compared between the treatment groups (tibolone, 0.0%; placebo, +0.3%; Wilcoxon test; P = 0.031). The incidence of adverse effects was comparable.

Conclusions: In ER+ breast tumors, 2.5 mg/d tibolone given for 14 days has no significant effect on tumor cell proliferation.