) A pivotal question in chemoprevention research is whether the random Fine Needle Aspiration (FNA) mode clinical breast cancer chemoprevention trials being conducted at a single institution can be applied to a multi institutional setting? We will address this question by exporting the methodology developed at the University of Kansas Medical Center (KUMC) to two other sites: PRN Research Inc. at Baylor University Medical Center and Fox Chase Cancer Center. We will validate the FNA model by assess their success with FNA and processing of cytologic samples; and by testing an agent with a different mechanism of action than that currently being studied (DFMO) in the model. LY353381.HCI is a Selective Estrogen Receptor Modulator (SERM) whose efficacy and toxicity profile in preclinical and ongoing Phase I chemoprevention trials compares favorably with tamoxifen and other SERMS. Specifically, we will evaluate the efficacy of LY353381,HCI in reversing/normalizing cytologic abnormalities in cells obtained by FNA of women at high risk off breast cancer development. This is a collaborative efforts between the three sites, Eli Lilly and Company (developer of the SERM), and the National Cancer Institute utilizing the UO1 mechanism for funding. In a Phase II trial, we will determine if a cytological abnormality (specifically epithelial hyperplasia with atypia) previously found to be predictive for subsequent breast cancer detection is reversible by SERM administration. Additional biomarkers include nuclear morphometry, and DNA ploidy, and over-expression of EGFR. A double-blind, placebo controlled, cross-over trial design will be used with SERM/placebo administration for 6 months each. FNA sampling and fixation will be conduct at all three sites, but all biomarker assays will be performed centrally at KUMC. Secondary goals of the trial are to 1) assess toxicity and biomarker change after long-term SERM administration and compare that to effects observed in a trial for SERM for 2-6 weeks duration in women with newly-diagnosed breast cancer; and 2) determine whether cytologic normalization (if obtained) is durable once women discontinue SERM. This project extends and validates random FNA and cytologic characterization as a model for clinical breast cancer chemoprevention trials; and provides much needed information on the chemoprevention efficacy of a novel SERM.
