CHEMOPREVENTION FOR WOMEN AT HIGH RISK OF BREAST CANCER

描述：(申请者的描述)一个关键问题 化学预防研究是指极高风险的个体是否 癌症的发展，例如那些具有易患生殖系突变的癌症， 可能从化学预防药物的管理中受益，或者他们 对化学预防活动无效？这一关键的目标是 化学预防试验是为了评价二氟甲亚胺的疗效 (DFMO)进行双盲、安慰剂对照、交叉试验 逆转/正常化已知的女性乳房替代终点生物标志物 是BRCA1、BRCA2或P53胚系突变携带者。这是一个 堪萨斯大学医学中心(KUMC)、 克雷顿大学，Ilex(目前DFMO的制造商)，华盛顿大学 佛罗里达州杰克逊维尔，OncorMed和国家癌症研究所 利用U01机制进行资金筹措。作为这个独一无二的 承诺，我们将确定是否随机获得细针抽吸物 以前发现的预测乳腺癌(增生)的生物标记物 有不典型，或有P53和/或EGFR过度表达的增生) 可用DFMO治疗6个月。其次，结果是 将与胚系阴性的DFMO正在进行的IIB期试验进行比较 女人。次要目标是1)评估毒性和生物标记物的变化 长期服用DFMO；2)比较随机FNA细胞学和生物标记物 检测结果与岩心活检结果比较；3)原位比较 安慰剂之间关键细胞周期控制基因的杂交检测结果 和对照组。本次试验的受试者将从以下地点获得 Creighton遗传性癌症登记和来自KUMC高危乳房 诊所。乳房组织生物标志物采样和分析将在 KUMC。对那些尚未被确认为 OnrcorMed将执行阴性或阳性检测。遗传咨询 将由亨利·林奇监督。探索性mRNA原位杂交 化验将由OncorMed进行。这项试验解决的问题是 罹患乳腺癌风险最高的女性是否因此 在化学预防临床试验中纳入的可能性最大， 对化学预防是顺从的还是难耐的。答案会影响到 整个未来乳腺癌化学预防的发展努力。

DESCRIPTION: (Applicant's Description) 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.