title: Comprehensive analysis of excision repair complementation group 1, glutathione S-transferase, thymidylate synthase and uridine diphosphate glucuronosyl transferase 1A1 polymorphisms predictive for treatment outcome in patients with advanced gastric cancer treated with FOLFOX or FOLFIRI.
abstract: Oxaliplatin and irinotecan have proven effective in the treatment of gastric cancer. We attempted to determine whether single nucleotide polymorphisms in ERCC1, GST, TS and UGT1A1 predicted overall survival in gastric cancer patients receiving FOLFOX and/or FOLFIRI chemotherapy. Total genomic DNA was extracted from the whole blood of patients. The PCR-restriction fragment length polymorphism technique was applied in order to detect the known variant sites of ERCC1, GST, TS and UGT1A1. The response rate of FOLFOX (N=75) was 24%. Grade 3-4 neutropenia and neurotoxicity were observed at frequencies of 34.7 and 16%, respectively. TTP and OS of first-line administration of FOLFOX (N=35) were 3.1 months (95% CI, 0.1-6.1 months) and 13.9 months (95% CI, 12.2-15.6 months), respectively. Only the GSTM1 positive genotype exhibited a significantly better time to progression (P=0.023). However, significant genotypic variation of TS, GST and ERCC1, which was assumed to affect the activity of oxaliplatin, was not observed to affect RR, toxicity and overall survival. The response rate of FOLFIRI (N=74) was 23%. Grade 3-4 neutropenia and diarrhea were observed in 55.4 and 9.5% of cases, respectively. TTP and OS of first-line administration of FOLFIRI (N=33) was 4.9 months (95% CI, 3.5-6.4 months) and 19.0 months (95% CI, 8.5-29.5 months). The low expression type (2R/2R, 2R/3C and 3C/3C) of TS was associated with a high incidence of grade >or=3 neutropenia. However, significant genotypic variation of UGT1A1, which was assumed to affect irinotecan toxicity, was not observed to affect RR, toxicity or survival. In this study, the GSTM1 positive genotype evidenced a significantly better time to progression in cases of advanced gastric cancer being treated with FOLFOX. The low expression type (2R/2R, 2R/3C and 3C/3C) of TS was associated with a high incidence of grade >or=3 neutropenia in cases of advanced gastric cancer treated with FOLFIRI.
authors.affiliation: Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.
authors.forename: Bong-Gun
authors.initials: BG
authors.lastname: Seo
authors.forename: Hyuk-Chan
authors.initials: HC
authors.lastname: Kwon
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Oh
authors.forename: Suee
authors.initials: S
authors.lastname: Lee
authors.forename: Sung-Gun
authors.initials: SG
authors.lastname: Kim
authors.forename: Sung-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Hoon
authors.initials: H
authors.lastname: Han
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D018579:Patient Selection; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D013940:Thymidylate Synthase / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D002955:Leucovorin; D009944:Organoplatinum Compounds; D013940:Thymidylate Synthase; D000099148:UGT1A1 Enzyme; C071447:ERCC1 protein, human