Soy Duct Lavage Pilot Trial: Diet and Hormone Study 2 (DHS2)

Principal Investigator: Peter Gann, MD, ScD

A diverse body of evidence from in vitro, animal model and epidemiological studies suggests that consumption of soy could play a role in reducing the risk of developing breast cancer through antihormonal or antioxidant mechanisms. Clinical studies aimed at delineating the effects of isoflavones and other soy constituents have been conflicting, however, and have thus far failed to provide information about the direct effects of these phytochemicals on breast tissue. Moreover, the effects of isoflavones on DNA oxidation have not been studied in clinical trials. We propose to conduct the pilot phase of a trial in which participants will be randomly assigned to isocaloric diets containing either a) soy protein or b) milk (casein) protein. Soy or milk protein will be integrated into a background diet containing 30% fat calories, and will continue for 6 months or 6 menstrual cycles. Participants will be women between the ages of 30-60 at high risk for developing breast cancer, who will be recruited at the Lynn Sage Breast Cancer Center of Northwestern Memorial Hospital. Before and after intervention, each participant will provide samples of blood, nipple aspirate fluid, and nipple duct lavage (NDL) fluid from one or both breasts. NDL involves cannulation of fluid-yeilding ducts and collection of fluid after saline lavage. Breast epithelial cells obtained by NDL will be assessed for the presence of proliferation and atypia by a cytopathologist, and will be undergo quantitative immunostaining for molecular markers indicating proliferation (Ki67), dysregulation (HER-2/neu, EGFR, ER, p53, TGF-b1) and differentiation (casein, ICAM-1). DNA oxidation damage and lipid peroxidation products in peripheral blood and urine will be measured by 32P postlabeling methods, HPLC and the comet assay. As a secondary aim, serum hormone levels will be measured by immunoassay and both breast fluid and post-soy mammograms will be collected for future, separately-funded analyses. The proposed study represents the first tightly-controlled trial to examine the effects of soy on intermediate biomarkers of breast cancer risk, including effects within breast tissue itself. This pilot phase represents a large step towards the design of definitive Phase 2 trials that could provide the basis for clear public health recommendations regarding the efficacy and safety of soy supplementation for the prevention of breast cancer.