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.