title: Pharmacogenetic profiling and clinical outcome of patients with advanced gastric cancer treated with palliative chemotherapy.
abstract: OBJECTIVE
  To investigate whether polymorphisms with putative influence on fluorouracil/cisplatin activity are associated with clinical outcomes of patients with advanced gastric cancer (AGC).
  
  
  METHODS
  Peripheral blood samples from 175 prospectively enrolled AGC patients treated with fluorouracil/cisplatin palliative chemotherapy were used for genotyping 13 polymorphisms in nine genes (TS, MTHFR, XPD, ERCC1, XRCC1, XRCC3, GSTPI, GSTTI, GSTMI). Genotypes were correlated to response and survival.
  
  
  RESULTS
  The overall response rate was 41%, the median progression-free survival (PFS) was 24 weeks (range, 4 to 50 weeks), and the median overall survival (OS) was 39 weeks (range, 8 to 72+ weeks). Chemoresistance and poor survival were significantly associated with TS 5'-UTR 3G-genotype (2R/3G, 3C/3G, 3G/3G) and GSTP1 105 A/A homozygous genotype. Sixty-one patients (35%) did not show any of these risk genotypes (group 0), 57 patients (32.5%) showed one of the two risk genotypes (group 1), and 57 patients (32.5%) showed both risk genotypes (group 2). Median PFS and OS in group 0 patients were 32 weeks (range, 8 to 50 weeks) and 49 weeks (range, 18 to 72+ weeks), respectively. Group 1 and group 2 patients showed significantly worse PFS (median, 26 weeks [range, 6 to 44 weeks] and 14 weeks [range, 4 to 38 weeks], respectively) and worse OS (median, 39 weeks [range, 10 to 58 weeks] and 28 weeks [range, 8 to 56 weeks]), respectively, than group 0 patients. This adverse effect was retained in multivariate analysis.
  
  
  CONCLUSIONS
  Specific polymorphisms may influence clinical outcomes of AGC patients. Selecting palliative chemotherapy on the basis of pretreatment genotyping may represent an innovative strategy that warrants prospective studies.
authors.affiliation: Medical Oncology Unit, Hospital of Urbino, Urbino, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Ruzzo
authors.forename: Francesco
authors.initials: F
authors.lastname: Graziano
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kawakami
authors.forename: Go
authors.initials: G
authors.lastname: Watanabe
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Catalano
authors.forename: Renato
authors.initials: R
authors.lastname: Bisonni
authors.forename: Emanuele
authors.initials: E
authors.lastname: Canestrari
authors.forename: Rita
authors.initials: R
authors.lastname: Ficarelli
authors.forename: Ettore Tito
authors.initials: ET
authors.lastname: Menichetti
authors.forename: Davide
authors.initials: D
authors.lastname: Mari
authors.forename: Enrica
authors.initials: E
authors.lastname: Testa
authors.forename: Rosarita
authors.initials: R
authors.lastname: Silva
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincenzi
authors.forename: Paolo
authors.initials: P
authors.lastname: Giordani
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
authors.forename: Lucio
authors.initials: L
authors.lastname: Giustini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D016022:Case-Control Studies; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D018579:Patient Selection; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011379:Prognosis; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016019:Survival Analysis
chemical_list: D002945:Cisplatin; D005472:Fluorouracil