Pharmacogenomics of Breast Cancer Adjuvant Chemotherapy

描述(由申请人提供)：本提案是对NIH RFA-HG-08-004《基因组范围协会(GWA)随机临床试验中治疗反应的研究》的回应。我们建议使用Success 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，也是女性癌症死亡的第二大原因，对公共卫生具有重大意义。大多数乳腺癌妇女都接受了联合化疗，并从联合化疗中受益匪浅。然而，乳腺癌患者在对化疗的疗效和药物相关不良事件的发生方面表现出很大的个体差异。Success A试验招募了3754名乳腺癌患者，并有两个手臂。其中一组患者接受由5-氟尿嘧啶-表阿霉素-环磷酰胺(FEC)+多西他赛组成的“标准”化疗，另一组患者接受FECdocetaxel+吉西他滨治疗。因此，这项临床试验提供了一个理想的机会，可以在吉西他滨和不包括吉西他滨的情况下，进行Gwas检查，以确定乳腺癌化疗疗效和毒性变化的基因组标记。这项建议是基于德国的Success A多机构乳腺癌临床试验小组与梅奥诊所NIH药物遗传学研究网络(PGRN)中心之间的持续合作提出的，该中心致力于乳腺癌的药物基因组研究。因此，目前的建议将主要乳腺癌临床试验小组的优势与在临床和实验室乳腺癌药物基因组研究方面拥有丰富经验的小组的优势结合起来。在拟议的GWA研究过程中确定的多态将利用来自其他乳腺癌临床试验的DNA样本进行复制，还将利用Mayo PGRN应用的药物基因组“模型系统”从功能和机械上进行研究，以获得在Success A试验中临床使用的药物的初步全基因组数据。建议的GWASs的目标是提高乳腺癌化疗的疗效并降低其毒性，以便真正实现对女性最常见癌症的“个体化”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都接受了辅助化疗，并且在疗效和毒性方面表现出很大的差异。我们建议对参加Success A乳腺癌临床试验的3754名女性进行全基因组关联研究，以确定使乳腺癌化疗更好地“个体化”成为可能的基因组标记。

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.