GENETIC STAGING OF BREAST CANCERS FOR ADJUVANT THERAPY

描述：(申请人摘要)本项目的总体目标 是开发一种早期乳腺癌的基因分期系统，该系统将 允许识别处于高危状态的早期疾病患者 复发风险，以及谁最有可能从标准 辅助治疗或强化治疗。基本原则是 这一应用的基础是，在每个乳腺癌中，肿瘤细胞 当它们进化成更具侵袭性的 恶性，在他们基因进化的某个时刻，一些细胞 积累关键的基因异常，使他们能够 转移瘤。如果人们能对肿瘤细胞进行适当的测量 在手术时从特定患者的乳腺癌中获得，以及 确定肿瘤中是否含有具有必要基因的细胞 对于获得转移能力的变化，人们可以使用 这些信息直接为制定个性化的临床治疗提供了依据 为那个病人做计划。申请人的学业和其他人的学业 表明人类至少有三条主要的遗传进化途径 人类实体肿瘤，包括乳腺癌。这些是微卫星 不稳定途径，以及依赖于遗传不稳定的两条途径 这是由于野生型P53的丢失，即腺鳞癌 遗传进化途径与神经内分泌遗传进化 路径。到目前为止，申请人的工作重点是阐明 腺鳞片途径的遗传序列。使用多参数流 细胞学和多参数FISH技术，他已经建立了 序列，P53丢失后HER-2/neu过表达EGF受体 在ras过度表达之后，在大多数 人类乳腺癌。他现在提议，a)阐明基因 乳房中ras过度表达下游的进化变化 癌症，b)阐明神经内分泌遗传进化途径 乳腺癌，c)优化多参数流组合策略 细胞学测量和FISH研究在表征人卵巢癌中的作用 临床乳腺肿瘤样本的遗传进化途径，d)至 开发和测试新的流式细胞仪测量方法和新的组合 用于描述遗传进化的多参数测量 临床乳腺癌样本的变化，以及e)开发统计 提取遗传进化测序信息的建模方法 从HIS收集的越来越复杂的数据集 多参数研究。

DESCRIPTION: (Applicant's Abstract) The overall objective of this project is to develop a genetic staging system for early breast cancer that will permit the identification of patients with early disease who are at high risk for recurrence, and who are most likely to benefit from standard adjuvant therapy or from intensive treatment. The basic principles that underlie this application are that within each breast cancer, tumor cells accumulate genetic abnormalities as they evolve to a more aggressive malignancy, and that at some point in their genetic evolution some cells accumulate the critical genetic abnormalities that enable them to metastasize. If one could perform appropriate measurements on tumor cells obtained from a given patient's breast cancer at the time of surgery, and determine if the tumor contained cells that had the requisite genetic changes for the acquisition of the capacity to metastasize, one could use this information directly to develop an individualized clinical treatment plan for that patient. The applicant's studies and those of others have suggested that there at least three major genetic evolutionary pathways in human solid tumors, including breast cancer. These are the microsatellite instability pathway, and two pathways that depend on the genetic instability that results from the loss of wild type p53, namely, the adenosquamous genetic evolutionary pathway and the neuroendocrine genetic evolutionary pathway. The applicant's work to date has focused on the elucidation of the genetic sequences of the adenosquamous pathway. Using multiparameter flow cytometric and multiparameter FISH techniques, he has established that the sequence, p53 loss followed by Her-2/neu overexpression + EGF receptor overexpression followed by ras overexpression, occurs in the majority of human breast cancers. He now proposes, a) to elucidate the genetic evolutionary changes that lie downstream of ras overexpression in breast cancer, b) to elucidate the neuroendocrine genetic evolutionary pathway in breast cancer, c) to optimize the strategy for combining multiparameter flow cytometric measurements and FISH studies in the characterization of the genetic evolutionary pathways in clinical breast tumor samples, d) to develop and test new flow cytometric measurements and new combinations of multiparameter measurements for the characterization of genetic evolutionary changes in clinical breast cancer samples, and e) to develop statistical modeling approaches to extract genetic evolutionary sequencing information from the increasingly more complex data sets being collected in his multiparameter studies.