title: Pharmacogenetic analyses of a phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil and leucovorin plus either oxaliplatin or cisplatin: a study of the arbeitsgemeinschaft internistische onkologie.
abstract: OBJECTIVE
  To evaluate the association of germ-line polymorphisms of genes that may impact treatment outcome of platinum and fluorouracil combination chemotherapy in advanced gastric cancer (AGC).
  
  
  METHODS
  Blood samples of 156 patients enrolled onto a phase III study comparing fluorouracil, leucovorin, and oxaliplatin with fluorouracil, leucovorin, and cisplatin were collected. Polymorphisms within genes of TS, MTHFR, MTR, OPRT, XPD, ERCC1, XRCC1, XPA, GSTP1, GSTT1, and GSTM1 were genotyped using polymerase chain reaction-based techniques.
  
  
  RESULTS
  Median overall survival (OS) was 11.8 months (95% CI, 9.75 to 13.79 months) and median progression-free survival (PFS) was 5.8 months (95% CI, 4.99 to 6.61 months). The TS-3R/+6 haplotype (P = .004), the GSTT1 deletion polymorphism (P = .015), and genotypes of OPRT-Gly213Ala (P = .003) and XRCC1-Arg399Gln (P = .023) could be identified as independent predictors of OS. For PFS analyses, the TS-3R/+6 haplotye (P = .003) and MTR-A2756G (P = .01) were identified as independent positive predictors. The association between the GSTT1 deletion polymorphism and PFS showed only borderline significance (P = .053). Treatment related hematotoxicity in terms of grade 3/4 leukopenia was lowest among TS-3R/+6 haplotype carriers (P = .037). Grade 3/4 neutropenia was directly associated with the MTR-2756G/G genotype (P = .011), GSTP1-105Ile/Ile genotype (P = .02), and with the ERCC1-118T/8092C-haplotype (P = .042). In addition, significant associations between GSTP1-105Ile/Ile genotype and neurotoxicity and between the XPD-Asn312/751Gln haplotype and nephrotoxicity could be identified (P = .028 and P = .005, respectively).
  
  
  CONCLUSIONS
  These findings underline the hypothesis that germ-line polymorphisms may play an important role in individualizing chemotherapy in AGC and deserve further prospective evaluation in AGC patients.
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, University of Dresden, Dresden 01307, Germany.
authors.forename: Eray
authors.initials: E
authors.lastname: Goekkurt
authors.forename: Salah-Eddin
authors.initials: SE
authors.lastname: Al-Batran
authors.forename: Jörg T
authors.initials: JT
authors.lastname: Hartmann
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mogck
authors.forename: Gunter
authors.initials: G
authors.lastname: Schuch
authors.forename: Michael
authors.initials: M
authors.lastname: Kramer
authors.forename: Elke
authors.initials: E
authors.lastname: Jaeger
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.forename: Jan
authors.initials: J
authors.lastname: Stoehlmacher