A Phase IIb Trial of Soy Isoflavone Supplementation To Decrease Breast Cell Proliferation in High Risk Women.

Abstract

Abstract Background: epidemiologic data suggest that consumption of soy isoflavones confers protection against the development of breast cancer. Some recent animal data have conflicted with this. We conducted a Phase IIB trial of soy isoflavone supplementation with the goal of examining the effect of supplementation on breast cell proliferation in healthy women at high risk for breast cancer.Methods: 150 women with an elevated breast cancer risk estimate (Gail or Claus), or a prior history of completely treated unilateral breast cancer, were randomly assigned to a mixed soy isoflavone supplement (PTIG-2535, Unconjugated Isoflavones-70, containing genistein 150mg, daidzein 74 mg, glycitein 11 mg) or placebo, stratified by menopausal status, and by ER status of prior breast cancer if present. A random fine needle aspiration (rFNA) of a previously unaffected breast/s was performed at study entry and repeated after six months of study intervention. Women were excluded if estimated epithelial cell yield was ≤ 4000 cells. Cells were immunostained for Ki-67 (primary endpoint), examined for cytomorphology, and by spectral imaging. Plasma samples were obtained for determination of genistein and equol concentrations, for compliance monitoring. Sex hormone-binding globulin (SHBG) and follicle-stimulating hormone (FSH) assays were included to monitor the presence of a systemic estrogenic effect of soy isoflavones. The trial was powered to detect a 50% decrease in Ki-67 labeling, from 2% at baseline to 1% following active intervention.Results: A total of 99 randomized women were evaluable for the primary endpoint of Ki-67 labeling index (LI). Fifty were in the treatment group and 49 in the placebo group; 57 were premenopausal, 42 were postmenopausal. Twelve postmenopausal and 13 premenopausal women had a prior history of breast cancer (10 ER neg, 15 ER pos). The overall median Ki-67 LI at study entry was 1.08, and following intervention was 1.04. In the treated women, the entry and post-intervention Ki-67 LI was 1.18 and 1.12 respectively, whereas in the placebo group it was 0.97 and 0.92 (between group 2-sided Wilcoxon rank-sum p=0.32). There was no significant difference in the change in Ki-67 LI when menopausal strata were examined separately (Wilcoxon rank-sum p=0.33 for premenopausal and 0.42 for postmenopausal groups). The median Masood scores for cytomorphologic features pre- and post-intervention were 14 vs. 14 in the soy and 13 vs. 14 in the placebo groups. There was no significant change in SHBG (p=.347) or FSH values (p=.465 for premenopausal and .297 for postmenopausal women). Compliance assessment is ongoing and will be completed shortly. Spectral imaging analysis of cellular material is also underway.Conclusions: A six-month intervention of mixed soy isoflavones does not appear to cause a significant change in breast epithelial cell proliferation in healthy high risk women. These results argue against the efficacy of soy isoflavone supplementation of the adult western diet for purposes of breast cancer prevention, but also do not suggest an adverse effect on the breast. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1049.