Breast cancer chemoprevention trials using the fine-needle aspiration model

Selection of surrogate endpoint biomarkers (SEBs) and appropriate study design are two of the main challenges in evaluating potential chemopreventive agents. In a prospective random fine-needle aspiration (FNA) study of women at high risk of development of breast cancer, we previously demonstrated that cytologic evidence of epithelial hyperplasia with or without atypia, as well as abnormalities of several cellular biomarkers (DNA ploidy; immunocytochemical expression of p53, EGFR, ER, and/or Her-2/neu), were more prevalent in high-risk women than in low-risk controls. We also demonstrated that the subsequent development of breast cancer was best predicted by an initial presentation of hyperplasia with atypia, as well as by multiple biomarker abnormalities. These findings indicate that FNA cytology and biomarkers can be used to identify women who are appropriate subjects for chemoprevention trials, and can then be used as surrogate endpoint biomarkers to monitor efficacy of potential agents. An example of this use in an ongoing single-agent phase II trial is provided. Several options for study design of possible multi-agent breast cancer chemoprevention trials are discussed, depending upon the existing preclinical and clinical data, the questions being asked, and the number of eligible subjects available.