Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 26, No 15S (May 20 Supplement), 2008: 4132
© 2008 American Society of Clinical Oncology

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Abstract

Pharmacogenetic approach for capecitabine or 5-fluorouracil (5FU) selection to be combined with oxaliplatin as first-line chemotherapy in advanced colorectal cancer

Hospital Germans Trias i Pujol-ICO Badalona, Badalona, Spain; Hospital Reina Sofía, Córdoba, Spain; Hospital Clínico San Carlos, Madrid, Spain; Hospital Universitari la Fe, Valencia, Spain; Hospital Morales Meseguer, Murcia, Spain; Hospital Virgen de los Lirios, Alicancte, Spain; Institut Català d’Oncologia-IDIBELL, L’Hospitalet de Llobregat, Spain

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Background: The possible replacement of continuous infusion 5FU by the oral pro-drug capecitabine is controversial. The aim of this work was to study genetic polymorphisms and their role in tailoring fluroropyrimidine/oxaliplatin treatment in metastatic colorectal cancer (mCRC). Methods: A total of 110 patients participating in the clinical phase III trial done by the Spanish TTD group comparing the efficacy and safety of capecitabine plus oxaliplatin (XELOX) versus Spanish-based continuous-infusion high-dose 5FU plus oxaliplatin (FUOX) regimens as first-line therapy for mCRC, were selected prospectively for TS (5’VNTR, 5’SNP and 3’UTR), XRCC1–399, XPD-751, ERCC1–118 and XRCC3–241 genotyping. Genotypes were analyzed as codominant, dominant and recessive models. Contingency tables, Chi-square and Fisher’s exact test were used to evaluate the association of polymorphisms with categorical variables. The association of genetic variants and clinical parameters with progression free survival (PFS) was estimated by calculating HR and their 95% CI from univariate and multivariate Cox proportional hazards regression models. The differences were considered statistically significant when two- sided p-values were less than 0.05. Results: In the FUOX group, TS-3’UTR +6bp/+6bp and ERCC1–118 C/T or C/C genotypes correlated with a shorter PFS (HR = 2.62, 95% CI (1.3 - 5.3) p = 0.007 and, HR =1.96, 95% CI (0.99 - 3.92) p = 0.050). When analyzed jointly, the higher the number of favorable genotypes (FG) the longer the PFS (6.8 m for 0 FG (group 3), 9.6 m for 1 FG (group 2) and 25.8 m for 2 FG (group 1); p = 0.005, group 2 HR = 2.57, 95% CI 0.94–7; group 3 HR = 5.63, 95% CI 1.92–16.53). Disease-control rate was higher in group 1 (100% vs. 87% group 2 and 38.5% group 3; p = 0.001). In the multivariate analysis, ERCC1–118 C/T or C/C (p = 0.0037) and TS-3’UTR +6bp/+6bp (p = 0.006) were strong independent prognostic factors. No differences were found in the XELOX group in which median PFS for the equivalent group 3 was 10.2 months. Conclusions: According to this, mCRC patients harboring TS- 3’UTR +6bp/+6bp and ERCC1–118 C/T or C/C genotypes may better receive capecitabine instead of 5FU in an oxaliplatin-based first line treatment.

No significant financial relationships to disclose.

Abstract presentation from the 2008 ASCO Annual Meeting