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Soy isoflavone consumption may protect against breast cancer development. We conducted a phase IIB trial of soy isoflavone supplementation to examine its effect on breast epithelial proliferation and other biomarkers in the healthy high-risk breast. One hundred and twenty-six consented women underwent a random fine-needle aspiration (rFNA); those with 4,000 or more epithelial cells were randomized to a double-blind 6-month intervention of mixed soy isoflavones (PTIG-2535) or placebo, followed by repeat rFNA. Cells were examined for Ki-67 labeling index and atypia. Expression of 28 genes related to proliferation, apoptosis, and estrogenic effect was measured using quantitative reverse transcriptase PCR. Hormone and protein levels were measured in nipple aspirate fluid (NAF). All statistical tests were two-sided. Ninety-eight women were evaluable for Ki-67 labeling index. In 49 treated women, the median Ki-67 labeling index was 1.18 at entry and 1.12 post intervention, whereas in 49 placebo subjects, it was 0.97 and 0.92 (P for between-group change: 0.32). Menopausal stratification yielded similar results between groups, but within premenopausal soy-treated women, Ki-67 labeling index increased from 1.71 to 2.18 (P = 0.04). We saw no treatment effect on cytologic atypia or NAF parameters. There were significant increases in the expression of 14 of 28 genes within the soy, but not the control group, without significant between-group differences. Plasma genistein values showed excellent compliance. A 6-month intervention of mixed soy isoflavones in healthy, high-risk adult Western women did not reduce breast epithelial proliferation, suggesting a lack of efficacy for breast cancer prevention and a possible adverse effect in premenopausal women. Cancer Prev Res; 5(2); 309–19. ©2012 AACR.

PDF file - 44K, Hormone and protein concentrations in nipple aspiration fluid (NAF) samples

PDF file - 42K, Changes in cellular parameters for equol producers compared to control women, shown as the differences in post-intervention and baseline values

Background Ductal lavage (DL) allows repeat sampling of breast epithelium for serial observation in a chemoprevention setting; however, the reproducibility of duct cannulation, cell yield and cytology has not been addressed. Methods We conducted a Phase 2 trial, wherein high risk women chose tamoxifen treatment or observation following an entry DL procedure. We present data from the non-intervention arm of our study to assess the reproducibility of cannulation, cell yield, and cytologic diagnosis from DL of the same duct at two time-points. Inter-observer variability was assessed by a blinded review of Papanicoloau-stained slides by two cytopathologists. Results Sixty-five women had a successful lavage of 187 ducts at baseline and chose observation; 63/65 (97%) had a successful lavage 6 months later. Successful recannulation of the same duct was accomplished in 63 women (97%) and162 ducts (87%). Total epithelial cell yields ≥100 were obtained from 57/65 women (88%) and 129/187 ducts (69%) at baseline, and 46/63 women (73%) and 80/162 ducts (49%) at both time-points. Cytologic diagnosis was reproducible in 27/63 (43%) women and 77/162 (48%) ducts. Inter-observer variability for cytologic diagnosis between two observers showed good agreement (κ = 0.62). Conclusions Recannulation and lavage of the same duct after a 6 month interval can be achieved with high frequency; however, reproducibility of cell yield and cytologic findings from the same duct is sub-optimal, leading to significant attrition of evaluable subjects. The utility of DL for the serial monitoring of breast epithelium is therefore limited.

Soy isoflavone consumption may protect against breast cancer development. We conducted a phase IIB trial of soy isoflavone supplementation to examine its effect on breast epithelial proliferation and other biomarkers in the healthy high-risk breast. One hundred and twenty-six consented women underwent a random fine-needle aspiration (rFNA); those with 4,000 or more epithelial cells were randomized to a double-blind 6-month intervention of mixed soy isoflavones (PTIG-2535) or placebo, followed by repeat rFNA. Cells were examined for Ki-67 labeling index and atypia. Expression of 28 genes related to proliferation, apoptosis, and estrogenic effect was measured using quantitative reverse transcriptase PCR. Hormone and protein levels were measured in nipple aspirate fluid (NAF). All statistical tests were two-sided. Ninety-eight women were evaluable for Ki-67 labeling index. In 49 treated women, the median Ki-67 labeling index was 1.18 at entry and 1.12 post intervention, whereas in 49 placebo subjects, it was 0.97 and 0.92 (P for between-group change: 0.32). Menopausal stratification yielded similar results between groups, but within premenopausal soy-treated women, Ki-67 labeling index increased from 1.71 to 2.18 (P = 0.04). We saw no treatment effect on cytologic atypia or NAF parameters. There were significant increases in the expression of 14 of 28 genes within the soy, but not the control group, without significant between-group differences. Plasma genistein values showed excellent compliance. A 6-month intervention of mixed soy isoflavones in healthy, high-risk adult Western women did not reduce breast epithelial proliferation, suggesting a lack of efficacy for breast cancer prevention and a possible adverse effect in premenopausal women. Cancer Prev Res; 5(2); 309–19. ©2012 AACR.

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.

Breast ductal lavage provides a source of both cells and fluid from the breast in a non-invasive manner. The fluid contains freely diffusible steroid hormones and other factors that may be secreted or released from the epithelial cells that line the alveoli and ducts of the breast as well as from myoepithelial cells, stomal cells, and immune cells that populate the breast. The purpose of the present study was to determine how perturbations of the system are reflected in ductal lavage fluid (DLF). We examined changes associated with menopausal status, tamoxifen treatment, and Gail model breast cancer risk scores.