Pharmacogenetic profiling for oxaliplatin-based adjuvant chemotherapy (CT) benefit in stage II-III colon cancer (CC) patients: A GEMCAD study.

Abstract

3618 Background: Identifying molecular biomarkers for tumour recurrence is critical in successfully selecting early-stage CC patients who are more likely to benefit from adjuvant CT. We tested whether single nucleotide polymorphisms (SNP) within genes involved in biological pathways of interest for CC progression and treatment resistance would predict the risk of recurrence in stage II-III CC patients treated with oxaliplatin and fluoropyrimidines-based adjuvant CT. Methods: Genomic DNA was extracted from formalin-fixed paraffin-embedded samples from 202 surgically treated high-risk stage II (29.7%) and stage III (70.29%) CC patients receiving adjuvant CT (25.24% FOLFOX, 74.75% XELOX) from January 2004 to December 2008. Minimum follow-up was 36 months. Genotyping was performed for 62 SNPs in 31 genes using the MassARRAY (SEQUENOM) technology. Our results were validated in an independent cohort of 177 stage II-III CC. Results: After a median follow-up of 51.4 months (7-96), 63 patients (31.18%) had experienced a relapse and 31 (15.34%) had died. Three-year disease-free survival (DFS) and overall survival (OS) were 72.2% (+/-0.032) and 89.1% (+/-0.022), respectively. Multivariate analysis showed that the risk of recurrence for patients with the E-selectine rs3917412 G>A G/G genotype was higher than for those with any A allele genotype [relative risk (RR): 2.02, 95% confidence interval (CI): 1.09-3.73, p=0.024]. In haplotype analysis, patients harboring the E-selectine rs3917412 G>A G/G and methylentetrahydrofolate reductase (MTHFR) rs1801133 C>T T/T haplotype had a higher risk of developing tumor recurrence compared to the E-selectine rs3917412 G>A any A and/or MTHFR rs1801133 C>T any C haplotype (RR: 3.39, 95% CI, 1.51-7.62, p=0.003). The ability to predict recurrence of this combined analysis was independently validated in the second cohort (RR: 3.75, 95% CI, 1.32-10.68, p=0.013). Conclusions: E-selectine and MTHFR SNPs were found to be independent prognostic markers for stage II-III CC patients, suggesting that this combined analysis provides additional prognostic information to that offered by clinicopathologic variables.