) A pivotal question in chemoprevention research is whether individuals at extremely high risk for the development of cancer, e.g. those with predisposing germline mutations, may benefit from administration of chemopreventive agents, or are they refractory to chemopreventive activity? The objective of this pivotal chemoprevention trial is to evaluate the efficacy of difluoromethylomithine (DFMO) in a double-blind, placebo controlled, cross-over trial in reversing/normalizing breast surrogate endpoint biomarkers in women known to be BRCA1, BRCA2, or p53 germline mutational carriers. This is a collaborative effort between the University of Kansas Medical Center (KUMC), Creighton University, Ilex (current manufacturer of DFMO), University of Florida at Jacksonville, OncorMed, and the National Cancer Institute utilizing the U01 mechanism for funding. As part of this unique undertaking, we will determine if random fine needle aspirate obtained biomarkers previously found to be predictive for breast cancer (hyperplasia with atypia, or hyperplasia with overexpression of p53 and/or EGFR) are reversible by DFMO administration for 6 months. Secondarily, the results will be compared to an ongoing phase IIB trial of DFMO in germline negative women. Secondary goals are to 1) assess toxicity and biomarker change after long-term DFMO administration; 2) compare random FNA cytology and biomarker assay results to those obtained by core biopsy; and 3) compare mRNA in situ hybridization assay results for key cell cycle control genes between placebo and control groups. Subjects for this trial will be obtained from Creighton's Hereditary Cancer Registry and from the KUMC High Risk Breast Clinic. Breast tissue biomarker sampling and assays will be performed at KUMC. Genetic testing for those individuals not already identified as negative or positive will be performed by OnrcorMed. Genetic counseling will be overseen by Henry Lynch. Exploratory mRNA in situ hybridization assays will be conducted by OncorMed. This trial addresses the question of whether women with the highest risk of breast cancer development, and thus the greatest probability of inclusion in chemoprevention clinical trials, are amenable or refractory to chemoprevention. The answer impacts on the entire future of breast cancer chemoprevention development efforts.