Single Nucleotide Polymorphisms Predict Severe Toxicity of Adjuvant Therapy in Colorectal Cancer


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Oxaliplatin/fluoropyrimidine–based adjuvant therapy is of benefit in patients with resected stage II/III colon cancer, but the ability to predict risk of toxicity could improve care by permitting individualization of treatment. Ana Custodio, MD, and colleagues from GEMCAD (Grupo Español Multidisciplinario del Cancer Digestivo) recently identified several single nucleotide polymorphisms that appear to predict risk of severe toxicity in patients receiving such adjuvant therapy.1

In this study, DNA was extracted from formalin-fixed paraffin-embedded tumor samples from 379 patients with surgically treated high-risk stage II (28%) and stage III (72%) colon cancer receiving oxaliplatin and fluoropyrimidine-based adjuvant therapy (54% FOLFOX, 46% XELOX) from January 2004 to December 2008. Genotyping was performed for 35 single nucleotide polymorphisms in 18 genes known to be involved in oxaliplatin and fluoropyrimidine metabolism using MassARRAY (Sequenom, Inc) technology.

Variations in Several Genes Alter Risk

A total of 89 patients (23.4%) experienced at least one grade 3/4 adverse event. The most common grade 3/4 toxicities were neutropenia (15.3%), diarrhea (8.17%), and neurotoxicity (7.65%). Genotypes associated with higher risk of any grade 3/4 toxicity were MTHFR rs1801133 C>T C/C and XRCC2 rs3218408 T>G T/T.

Genotypes associated with a reduced incidence of severe toxicity were UMPS rs3772807 G>C C/C and DPYD rs970337 G>A A/A.

In addition, the DPYD rs970337 G>A A/A genotype was associated with a lower rate of grade 3/4 diarrhea, the ABCG2 rs3114018 A>C C/C genotype was associated with an increased rate of grade 3/4 neutropenia, and the ERCC1 rs11615 T>C T/T genotype was associated with a lower rate of grade 3/4 neurotoxicity.

Further study is warranted to determine if the identification of the single nucleotide polymorphisms that increase risk of severe toxicity with oxaliplatin/fluoropyrimidine adjuvant treatment can be translated into modification of adjuvant regimens.■

Disclosure: The investigators reported no potential conflicts of interest.

Reference

1. Custodio A, Moreno J, Aparicio J, et al: Pharmacogenetic predictors of adverse events in stage II-III colon cancer (CC) patients treated with oxaliplatin and fluoropyrimidines-based adjuvant chemotherapy (CT): A GEMCAD study. 2012 ASCO Annual Meeting. Abstract 10547. Presented June 4, 2012.10547. Presented June 4, 2012.



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