CHEMOPREVENTION FOR WOMEN AT HIGH RISK OF BREAST CANCER

描述：（申请人的描述） 化学预防研究是个体是否处于极高风险， 癌症的发展，例如具有易感生殖系突变的那些， 可能受益于化学预防剂的管理，或者他们 对化学预防活性无效吗 这一关键的目标 化学预防试验是评估二氟甲基鸟氨酸的疗效 （DFMO）在一项双盲、安慰剂对照、交叉试验中， 逆转/正常化已知具有以下特征的女性的乳房替代终点生物标志物： BRCA 1、BRCA 2或p53生殖系突变携带者。 这是一 堪萨斯大学医学中心（KUMC）， 克雷顿大学，Ilex（DFMO的当前制造商）， 位于杰克逊维尔的佛罗里达、OncorMed和国家癌症研究所 利用U 01机制筹资。 作为这个独特的 承诺，我们将确定是否获得随机细针穿刺 以前发现的预测乳腺癌（增生）的生物标志物 具有p53和/或EGFR过表达的增生）是 DFMO给药6个月后可逆转。 其次，结果 将与正在进行的DFMO生殖系阴性的IIB期试验进行比较 妇女 次要目标是：1）评估给药后的毒性和生物标志物变化 长期DFMO给药; 2）比较随机FNA细胞学和生物标志物 分析结果与通过芯活检获得的结果;以及3）原位比较mRNA 安慰剂之间关键细胞周期控制基因的杂交试验结果 与对照组 本试验的受试者来自 Creighton遗传性癌症登记处和KUMC高危乳腺癌 诊所 乳腺组织生物标志物采样和测定将在 KUMC。 对尚未被确定为 阴性或阳性将由OnrcorMed进行。 遗传咨询 将由亨利·林奇监管 mRNA原位杂交 试验将由OncorMed进行。 这次审判解决了 乳腺癌发病风险最高的女性， 纳入化学预防临床试验的可能性最大， 对化学预防是顺从的或难治的。 答案影响着 乳腺癌化学预防发展的整个未来的努力。

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.