Pharmacogenetic Predictors of Adverse Events and Response to Chemotherapy in Metastatic Colorectal Cancer: Results From North American Gastrointestinal Intergroup Trial N9741
- 10 July 2010
- journal article
- research article
- Published by American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology
- Vol. 28 (20), 3227-3233
- https://doi.org/10.1200/jco.2009.21.7943
Abstract
Purpose With three available chemotherapy drugs for advanced colorectal cancer (CRC), response rate (RR) and survival outcomes have improved with associated morbidity, accentuating the need for tools to select optimal individualized treatment. Pharmacogenetics identifies the likelihood of adverse events or response based on variants in genes involved in drug transport, metabolism, and cellular targets. Patients and Methods Germline DNA was extracted from 520 patients on the North American Gastrointestinal Intergroup N9741 study. Three study arms were evaluated: IFL (fluorouracil [FU] + irinotecan [IRN]), FOLFOX (FU + oxaliplatin), and IROX (IRN + oxaliplatin). Information on adverse events, response, and disease-free survival was available. Thirty-four variants in 15 candidate genes for analysis based on previous associations with adverse events or outcome were assessed. Genotyping was performed using pyrosequencing. Results All variants were polymorphic. The homozygous UGT1A1*28 allele observed in 9% of patients was associated with risk of grade 4 neutropenia in patients on IROX (55% v 15%; P = .002). Deletion in GSTM1 was associated with grade 4 neutropenia after FOLFOX (28% v 16%; P = .02). Patients with a homozygous variant genotype for GSTP1 were more likely to discontinue FOLFOX because of neurotoxicity (24% v 10%; P = .01). The presence of a CYP3A5 variant was significantly associated with RR on IFL (29% v 60%; P = .0074). Most previously published genotype-toxicity or -efficacy relationships were not validated in this study. Conclusion This study provides a platform to evaluate pharmacogenetic predictors of response or severe adverse events in advanced CRC. Pharmacogenetic studies can be conducted in multicenter trials, and our findings demonstrate that with continued research, clinical application is practical.Keywords
This publication has 26 references indexed in Scilit:
- KRAS Mutation Signature in Colorectal Tumors Significantly Overlaps With the Cetuximab Response SignatureJournal of Clinical Oncology, 2008
- Interpreting P Values in Pharmacogenetic Studies: A Call for Process and PerspectiveJournal of Clinical Oncology, 2007
- UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Dose MattersJNCI Journal of the National Cancer Institute, 2007
- Cost-effectiveness analysis of oxaliplatin compared with 5-fluorouracil/leucovorin in adjuvant treatment of stage III colon cancer in the USCancer, 2007
- Randomized Controlled Trial of Reduced-Dose Bolus Fluorouracil Plus Leucovorin and Irinotecan or Infused Fluorouracil Plus Leucovorin and Oxaliplatin in Patients With Previously Untreated Metastatic Colorectal Cancer: A North American Intergroup TrialJournal of Clinical Oncology, 2006
- Individualizing cancer chemotherapy.2006
- Pharmacogenomics — Drug Disposition, Drug Targets, and Side EffectsThe New England Journal of Medicine, 2003
- Thymidylate Synthase Pharmacogenetics in Colorectal CancerClinical Colorectal Cancer, 2001
- Recommendation for Caution with Irinotecan, Fluorouracil, and Leucovorin for Colorectal CancerThe New England Journal of Medicine, 2001
- Polymorphisms of the Repeated Sequences in the Enhancer Region of the Thymidylate Synthase Gene Promoter May Predict Downstaging After Preoperative Chemoradiation in Rectal CancerJournal of Clinical Oncology, 2001