Pharmacogenomics of Breast Cancer Adjuvant Chemotherapy

描述（由申请方提供）：本提案是对NIH RFA-HG-08-004“随机临床试验中治疗反应的全基因组关联（GWA）研究”的回应。 我们建议我们进行一项GWA研究，使用来自成功A乳腺癌辅助化疗试验的DNA样本。 乳腺癌是最常见的癌症，也是妇女癌症死亡的第二大原因，具有重大的公共卫生意义。 大多数患有乳腺癌的女性接受联合化疗治疗，并从中获益匪浅。 然而，乳腺癌患者在疗效和对化疗反应的药物相关不良事件的发生方面显示出很大的个体差异。 SUCCESS A试验招募了3754名乳腺癌患者，分为两组。 一组采用5-氟尿嘧啶-表阿霉素-环磷酰胺（FEC）加多西他赛的“标准”化疗，另一组采用FEC多西他赛加吉西他滨。 因此，这项临床试验提供了一个理想的机会，进行GWAS，以确定乳腺癌化疗的疗效和毒性变化的基因组标志物，包括和不包括吉西他滨。 该提案基于德国Success A多机构乳腺癌临床试验组和马约诊所NIH药物遗传学研究网络（PGRN）中心（致力于乳腺癌药物基因组学研究的中心）之间的持续合作。 因此，本提案将主要乳腺癌临床试验组的优势与在临床和实验室乳腺癌药物基因组学研究方面具有丰富经验的组的优势结合起来。 将利用来自其他乳腺癌临床试验的DNA样本复制在拟定的GWA研究过程中鉴定的多态性，并且还将利用药物基因组学“模型系统”在功能和机制上进行追踪，该模型系统已由马约PGRN应用以获得Success A试验中临床使用的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，以实现对最常见的女性癌症的真正“个性化”治疗。 公共卫生相关性：乳腺癌是女性最常见的癌症。 这些妇女中的大多数接受辅助化疗，并在疗效和毒性方面表现出很大的差异。 我们提出了一个全基因组关联研究的3754名妇女参加了成功的乳腺癌临床试验，以确定基因组标记，这将使人们有可能更好地“个性化”乳腺癌化疗。

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.