The treatment of advanced colorectal cancer offers an ideal environment for the development and evaluation of pharmacogenetics. The availability of multiple therapeutic options with clear antitumor activity requires clinical decisions to be made for individual patients and these decisions are best made with quantitative information. However, there are currently insufficient tools to guide the selection of therapy for advanced colorectal cancer. The recent FDA approval of irinotecan (CPT-11) and oxaliplatin (OXAL) for advanced colorectal cancer, in addition to the historical standard 5-fluorouracil (5FU), has led to the development of several active combination chemotherapy regimens for this disease. Indeed, the recently completed Gastrointestinal Intergroup study N9741 compared 5FU/CPT-11, 5FU/OXAL, and CPT-11/OXAL, with observed objective response rates of 28-38%. The previous reports of genetic variants associated with toxicity and/or activity from these three agents provides a promising approach for the development of a pharmacogenetic strategy to select therapy for advanced colorectal cancer. Therefore, this project will address the following Specific Aims: 1. Determine the predictive impact of genetic variants in candidate genes on severe toxicity from 5FU, CPT-11, or OXAL therapy in 575 patients from the N9741 study. 2. Define the association of genetic variants in candidate genes with response to therapy, time to progression, overall survival, and quality of life after 5FU, CPT-11, or OXAL regimens for advanced colorectal cancer. 3. Develop methods for incorporating Genetic Polymorphism Profiles into Decision Making.
These aims provide a comprehensive framework for our strategy to provide the first prospective information on the integration of pharmacogenetic information into the selection of therapy for advanced colorectal cancer.
| McLeod, Howard L; Sargent, Daniel J; Marsh, Sharon et al. (2010) Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741. J Clin Oncol 28:3227-33 |
| Thomas, Fabienne; Hoskins, Janelle M; Dvorak, Anne et al. (2010) Detection of the G>C SNP and rare mutations in the 28-bp repeat of TYMS using gel-based capillary electrophoresis. Pharmacogenomics 11:1751-6 |
| McWhinney, Sarah R; Goldberg, Richard M; McLeod, Howard L (2009) Platinum neurotoxicity pharmacogenetics. Mol Cancer Ther 8:10-6 |
| Yu, Jinsheng; Miller, Ryan; Zhang, Wanghai et al. (2008) Copy-number analysis of topoisomerase and thymidylate synthase genes in frozen and FFPE DNAs of colorectal cancers. Pharmacogenomics 9:1459-66 |
| Marsh, Sharon (2007) Pyrosequencing applications. Methods Mol Biol 373:15-24 |
| Marsh, Sharon; McLeod, Howard L (2007) Pharmacogenetics and oncology treatment for breast cancer. Expert Opin Pharmacother 8:119-27 |
| Engen, R M; Marsh, S; Van Booven, D J et al. (2006) Ethnic differences in pharmacogenetically relevant genes. Curr Drug Targets 7:1641-8 |
| Marsh, Sharon; McLeod, Howard L (2006) Pharmacogenomics: from bedside to clinical practice. Hum Mol Genet 15 Spec No 1:R89-93 |
| Marsh, Sharon; Van Booven, Derek J; McLeod, Howard L (2006) Global pharmacogenetics: giving the genome to the masses. Pharmacogenomics 7:625-31 |
| Walgren, Richard A; McLeod, Howard L (2005) Small inhibitory RNA--a tool for credentialing candidate genes. Pharmacogenomics 6:281-92 |
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