Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741

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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Graphical demonstration that overall survival was not different between patients with blood samples for pharmacogenetic study and patients without blood sampling. Blue line, patients who had no blood drawn; gold line, patients who had blood drawn.

Fig 2.

UGT1A1*28 genotype and severe neutropenia (A) or confirmed response (B). IFL, fluorouracil (FU) + irinotecan (IRN); FOLFOX, FU + oxaliplatin; IROX, IRN + oxaliplatin.

Fig 3.

Relationship between GSTM1*0 and grade 4 neutropenia. IFL, fluorouracil (FU) + irinotecan (IRN); FOLFOX, FU + oxaliplatin; IROX, IRN + oxaliplatin.

Fig 4.

Relationship between CYP3A5*3C genotype and confirmed response. IFL, fluorouracil (FU) + irinotecan (IRN); FOLFOX, FU + oxaliplatin; IROX, IRN + oxaliplatin.