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 receptorp ositive (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 for14 days has no significant effect on tumor cell proliferation.Vasomotor symptoms are a major side effect of adjuvant breast cancer treatment and it has been estimated that up to 96% of women who undergo chemotherapy or endocrine therapy suffer from hot flashes or night sweats (1). Although these symptoms are thought to result from systemic estrogen and progestin deprivation and can effectively be treated by hormone replacement therapy in patients who are not taking tamoxifen, such a therapeutic strategy is contraindicated, mainly because of a fear of the proliferative and tumorpromoting effects attributed to sex steroids (2). Unfortunately, the efficacy and safety of phytoestrogens as alternatives in the treatment of vasomotor symptoms is unproven and nonhormonal therapies with serotonin reuptake inhibitors and gabapentin are, at best, approximately half as effective as estrogen (3, 4). In addition, nonhormonal therapies have no effect on other postmenopausal symptoms such as bone loss or urogenital atrophy (5).Tibolone (Livial) is a selective tissue estrogenic activity regulator, approved for the treatment of climacteric symptoms in postmenopausal women. Following oral administration, it is converted into three primary metabolites, of which the 3a-hydroxymetabolite and the 3h-hydroxymetabolite only bind to the estrogen receptor a, whereas the parent...