Pharmacogenetic profiling and clinical outcome of patients (pts) with advanced gastric cancer (AGC) treated with S-1 monotherapy

Abstract

4600 Background: Intra-tumor gene expressions of thymidylate synthase (TS) and orotate phosphoribosyltranseferase (OPRT) have been indicated to be positive predictive markers for the clinical outcome of pts treated by S-1 monotherapy for AGC (Int J Cancer 119:1245,2006). The aim of this study is to investigate whether polymorphisms with putative influence on S-1 activity are associated with clinical outcomes of pts with AGC. Patients and Methods: The study population consisted of consecutive 55 pts with AGC from 01/1999 to 03/2002 in our institute. All patients homogenously received the S-1 monotherapy (80mg/sqm/day, 4 wks with 2-wks drug holiday) as a first line treatment. The overall response rate was 40% and the median overall survival (OS) was 8.0 months (range, 2.1 to 23.0 months). Genomic DNA obtained before starting chemotherapy was used for genotyping 8 polymorphisms in 5 genes (DPD, TS, OPRT, MTHFR, CYP2A6). Results: No alleles of DPYD*2 were found in this Japanese cohort. There were no association among the clinical outcome, such as tumor response and OS, and genotypes including tandem repeat (VNTR) in TS 5’UTR, G/C polymorphism with in the 3R VNTR, OPRT G638C, MTHFR C677T, CYP2A6*4, and CYP2A6*9. Even if TS 5’UTR and G/C polymorphism were combined, TS 5’UTR 3G genotype (2R/3G, 3C/3G, 3G/3G) was not associated with the clinical outcome. Only 6-bp insertion/deletion (ins/del) in the TS 3’UTR was closely related to both tumor response and OS. The response rates were 23% and 55% in pts with del/del genotype and pts with ins/ins or ins/del, respectively, with a statistical significance (P=0.015). The median OS was 9.5 months in pts with the ins allele versus 6.2 months in pts with del homozygote (P=0.0345). Conclusion: This exploratory study shows that polymorphism in TS 3’UTR may influence clinical outcomes of AGC pts treated by S-1. No significant financial relationships to disclose.