Kimler B F, Fabian C J, Wallace D D
Department of Radiation Oncology, University of Kansas Medical Center, Kansas City 66160-7321, USA.
J Cell Biochem Suppl. 2000;34:7-12.
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.
选择替代终点生物标志物（SEB）和合适的研究设计是评估潜在化学预防剂的两个主要挑战。在一项针对乳腺癌高危女性的前瞻性随机细针穿刺（FNA）研究中，我们先前证明，有或无异型性的上皮增生的细胞学证据，以及几种细胞生物标志物（DNA倍体；p53、表皮生长因子受体（EGFR）、雌激素受体（ER）和/或人表皮生长因子受体2（Her-2/neu）的免疫细胞化学表达）的异常，在高危女性中比在低危对照组中更为普遍。我们还证明，随后发生乳腺癌的最佳预测指标是最初出现的异型增生，以及多种生物标志物异常。这些发现表明，FNA细胞学和生物标志物可用于识别适合进行化学预防试验的女性，然后可作为替代终点生物标志物来监测潜在药物的疗效。本文提供了在一项正在进行的单药II期试验中这种应用的一个例子。根据现有的临床前和临床数据、所提出的问题以及可用的合格受试者数量，讨论了可能的多药乳腺癌化学预防试验的几种研究设计选择。
