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.
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