Pharmacogenomics of Breast Cancer Adjuvant Chemotherapy

描述（由申请人提供）：本提案是对NIH RFA-HG-08-004“随机临床试验中全基因组关联（GWA）治疗反应研究”的回应。我们建议使用成功a乳腺癌辅助化疗试验的DNA样本进行GWA研究。乳腺癌是最常见的癌症，也是妇女癌症死亡的第二大原因，对公共卫生具有重要意义。大多数患有乳腺癌的妇女都接受联合化疗，并从联合化疗中获益良多。然而，乳腺癌患者对化疗的疗效和药物相关不良事件的发生率存在很大的个体差异。成功A试验招募了3754名乳腺癌患者，有两个手臂。一组采用5-氟尿嘧啶-表柔比星-环磷酰胺(FEC) +多西他赛的“标准”化疗，另一组采用FECdocetaxel +吉西他滨。因此，该临床试验提供了一个理想的机会来执行GWAS，以确定有或没有吉西他滨纳入的乳腺癌化疗的疗效和毒性变化的基因组标记。这项提议是基于德国Success A多机构乳腺癌临床试验组和梅奥诊所美国国立卫生研究院药物遗传学研究网络（PGRN）中心之间正在进行的合作，该中心致力于乳腺癌的药物基因组学研究。因此，本提案将主要乳腺癌临床试验小组的优势与在临床和实验室基础的乳腺癌药物基因组学研究方面具有丰富经验的小组的优势结合起来。在拟议的GWA研究过程中发现的多态性将利用来自其他乳腺癌临床试验的DNA样本进行复制，并将利用药物基因组学“模型系统”进行功能和机制上的研究，该系统已被Mayo PGRN应用于获得临床使用药物的初步全基因组数据。拟议的GWAS的目标是提高乳腺癌化疗的疗效并降低其毒性，以便对最常见的女性癌症进行真正的“个体化”治疗。

DESCRIPTION (provided by applicant): This proposal represents a response to NIH RFA-HG-08-004 "Genome-Wide Association (GWA) Studies of Treatment Response in Randomized Clinical Trials". We propose that we perform a GWA study using DNA samples from the Success A breast cancer trial of adjuvant chemotherapy. Breast cancer, the most common cancer, and the second-leading cause of cancer death in women, is of major public health importance. Most women with breast cancer are treated with, and benefit significantly from combination chemotherapy. However, patients with breast cancer display large individual variation in efficacy and the occurrence of drug-related adverse events in response to chemotherapy. The SUCCESS A trial enrolled 3754 breast cancer patients and had two arms. One arm involved treatment with "standard" chemotherapy consisting of 5-flurouracil-epirubicin-cyclophosphamide (FEC) plus docetaxel, and the other involved FECdocetaxel plus gemcitabine. Therefore, this clinical trial provides an ideal opportunity to perform a GWAS to identify genomic markers for variation in efficacy and toxicity of breast cancer chemotherapy, with and without the inclusion of gemcitabine. This proposal is based on an ongoing collaboration between the Success A multi-institutional breast cancer clinical trial group in Germany and the Mayo Clinic NIH Pharmacogenetics Research Network (PGRN) Center-a center with a commitment to pharmacogenomic studies of breast cancer. Therefore, the present proposal unites the strengths of a major breast cancer clinical trials group with those of a group with extensive experience in both clinical and laboratory-based breast cancer pharmacogenomic studies. Polymorphisms identified in the course of the proposed GWA Study will be replicated utilizing DNA samples from other breast cancer clinical trials and will also be pursued functionally and mechanistically with a pharmacogenomic "model system" that has been applied by the Mayo PGRN to obtain preliminary genome-wide data for drugs used clinically in the Success A trial. The goal of the proposed GWAS is to enhance the efficacy and to decrease the toxicity of breast cancer chemotherapy in order to move toward truly "individualized" therapy of the most common cancer of women. Public Health Relevance: Breast cancer is the most common cancer of women. Most of these women are treated with adjuvant chemotherapy, and display large variations in both efficacy and toxicity. We propose a genome-wide association study of the 3754 women who participated in the Success A breast cancer clinical trial to identify genomic markers that will make it possible to better "individualize" breast cancer chemotherapy.