Dihydropyrimidine dehydrogenases (DPYD), and cytidine-deaminase (CDA) gene polymorphisms as genomic predictors of clinical outcome in resected gastric cancer patients (GCP) treated with fluoropyrimidine-based adjuvant chemotherapy

Abstract

4052 Background: Single nucleotide polymorphisms (SNPs) of DPYD gene induces DPD deficiency resulting in decreased activity of 5-fluorouracil derivatives in treatment of colorectal cancer patients (pts). In GCP has not been previously analysed. Methods: We analysed paraffin-embedded biopsies from 50 consecutive resected GCP who received adjuvant chemotherapy with four cycles of Mitomycin C (MMC), 20 mg/m2 iv day 1 plus oral Tegafur (TG), 500 mg/m2 day 1 to day 45 every six weeks, for SNPs of genes DPYD1 (A/G; Ile/Val), DPYD2 (C/T; Arg/Cys) and CDA (A/C; Lys/Gin). The status of alleles (wild type or at least 1 polymorphism) was correlated with outcome, overall survival (OS) and toxicity. Results: The status of SNPs frequencies according to the classification between wild type/non-wild type, were 36/14 in DPYD1; 26/24 in DPYD2; and 17/23 in CDA or between homozygous/heterozygous were 39/11 in DPYD1; 33/17 in DPYD2 and 26/24 in CDA respectively. After 77 months of median follow-up, 18 pts died of tumor relapse, (7 in peritoneum and 11 in distant organs). Difference in survival was observed in DPYD1 pts only, for non wild-type over wild-type (p = 0.0283) and in any of the 3 genes tested heterozygous over homozygous pts (p = 0.0463). In 10 pts (20%) total dose was reduced by toxicity (5 diarrhea, 2 neutropenia, 2 hepatotoxicity, 1 vomiting), only 3 of them were homozygous. Conclusions: SNPs of DPYD1, DPYD2 and CDA predict outcome, survival and toxicity of GCP treated with 5-FU-based adjuvant chemotherapy. No significant financial relationships to disclose.