Reduction in Ki-67 in benign breast tissue of high-risk premenopausal women with the SERM acolbifene.

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520 Background: Selective Estrogen Receptor Modulators (SERMs) are approved for reduction of risk for breast cancer; however, uptake and use is limited. We conducted a pilot study of a 4th generation SERM to determine tolerability and effect on tissue biomarkers in healthy women at high risk for development of breast cancer. Methods: Premenopausal women at elevated risk for breast cancer were screened by random periareolar fine needle aspiration (RPFNA) performed during the follicular phase of the menstrual cycle. Women were eligible if breast epithelial cells exhibited evidence of cytologic hyperplasia with or without atypia, as well as Ki-67 ≥2% by immunocytochemistry. Following 6-8 months of open-label acolbifene (20 mg/d), the RPFNA was repeated. The primary endpoint was modulation of the proportion of cells that expressed Ki-67. Body composition (DEXA), pelvic sonography, mammographic breast density, and serum levels of IGF-1/IGFBP3 and several bioavailable hormones were assessed pre and post intervention. Results: 76 women were screened by RPFNA, with 25 eligible and enrolled in the intervention over a 9 month period. All 25 (7 on oral contraceptives) subjects completed the study, had a second RPFNA, and were evaluable. Median Ki-67 at baseline was 4.6% (range 2.4 – 21.9%) and off study 1.4% (range 0 – 6.6%); median change was a reduction of 3.0% (range -20.2% to +2.8%; decreased in 23, increased in 2) or a relative reduction of 77%. The end-of-study Ki-67 was significantly less than baseline (p<0.001, 2-tailed Wilcoxon test). There were no statistically significant changes in cytomorphology over this short intervention period. There was a marginal effect on breast density (16 decreased; 8 increased; p=0.067). Adverse events were minimal with greatest grade of 3 reported by 2 subjects, grade 2 by 7 subjects, and grade 1 by 11 subjects. No serious adverse event was reported and no subject discontinued the study due to an AE. Conclusions: Based on preliminary evaluation showing favorable modulation of proliferation and minimal adverse events, further investigation of acolbifene, a fourth generation SERM, as a breast cancer chemoprevention agent for premenopausal women appears warranted. Supported by NO1-CN-35135.