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.

Abstract

10547 Background: Although the benefit of oxaliplatin-based adjuvant CT has been demonstrated in patients with resected stage II-III CC, the recommendation to administer postoperative treatment must consider its potential adverse events. Predicting individual patients’risk of severe toxicity could potentially improve the quality of care by allowing individualization of treatment. We investigate the utility of determining single nucleotide polymorphisms (SNPs) in genes involved in oxaliplatin and fluoropyrimidines metabolisms to predict the toxicity of adjuvant CT in stage II-III CC patients. Methods: DNA was extracted from formalin-fixed paraffin-embedded samples from 379 surgically treated high-risk stage II (27.71%) and stage III (72.29%) CC patients receiving adjuvant CT (54.35% FOLFOX, 45.65% XELOX) from January 2004 to December 2008. Genotyping was performed for 35 SNP in 18 genes using the MassARRAY (SEQUENOM) technology. Results: A total of 89 (23.4%) patients 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%). The MTHFR rs1801133 C>T C/C (30.1% C/C, 17.5% C/T, 21.7% T/T; p=0.043) and XRCC2 rs3218408 T>G T/T (28.3% T/T, 16.2% G/T and 10% G/G; p=0.007) genotypes were associated with higher risk of any grade 3-4 toxicities, whereas the incidence of severe toxicity was lower in patients with the UMPS rs3772807 G>C C/C (14% C/C, 21% C/G, 28.9% G/G; p=0.021) and DPYD rs970337 G>A A/A (16.7% A/A, 21.1% A/G, 30.1% G/G; p=0.028) genotypes. In addition, the DPYD rs970337 G>A A/A genotype was associated with a lower rate of grade 3-4 diarrhea (5% A/A, 9.4% A/G, 8.1% G/G; p=0.030), the ABCG2 rs3114018 A>C C/C genotype with an increased rate of grade 3-4 neutropenia (15.2% C/C, 6.3% A/C, 4.5% A/A; p=0.034) and the ERCC1 rs11615 T>C T/T genotype with a lower rate of grade 3-4 neurotoxicity (5.4% T/T, 9.1% C/T, 10.2% C/C; p=0.032). Conclusions: Our data suggest that SNPs in genes involved in oxaliplatin and fluoropyrimidines metabolisms can potentially predict severe toxicity in stage II-III CC patients treated with adjuvant CT.