title: Thymidylate synthase genotype-directed chemotherapy for patients with gastric and gastroesophageal junction cancers.
abstract: BACKGROUND
  Retrospective studies indicate associations between TSER (thymidylate synthase enhancer region) genotypes and clinical outcomes in patients receiving 5-FU based chemotherapy, but well-controlled prospective validation has been lacking.
  
  
  METHODS
  In this phase II study (NCT00515216 registered through ClinicalTrials.gov, http://clinicaltrials.gov/show/NCT00515216), patients with "good risk" TSER genotypes (at least one TSER*2 allele) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates (ORR) in patients with gastric and gastroesophageal junction (GEJ) cancers, compared with historical outcomes in unselected patients (estimated 43%).
  
  
  RESULTS
  The ORR in genotype-selected patients was 39.1% (9 partial responses out of 23 evaluable patients, 95% CI, 22.2 to 59.2), not achieving the primary objective of improving ORR. An encouraging disease control rate (DCR, consisting of partial responses and stable diseases) of 95.7% was noted and patients with homozygous TSER*2 genotype showed better tumor response.
  
  
  CONCLUSIONS
  In this first prospective, multi-institutional study in patients with gastric or GEJ cancers, selecting patients with at least one TSER*2 allele did not improve the ORR but led to an encouraging DCR. Further studies are needed to investigate the utility of selecting patients homozygous for the TSER*2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00515216.
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, United States of America.
authors.forename: Laura W
authors.initials: LW
authors.lastname: Goff
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Nilay
authors.initials: N
authors.lastname: Thakkar
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, United States of America.
authors.forename: Liping
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, United States of America.
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.affiliation: Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Tan
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, United States of America.
authors.forename: Dana B
authors.initials: DB
authors.lastname: Cardin
authors.affiliation: Moffitt Cancer Center, Tampa, Florida, United States of America.
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, United States of America.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Berlin
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Barbara
authors.initials: B
authors.lastname: Zehnbauer
authors.affiliation: Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Chloe
authors.initials: C
authors.lastname: Fournier
authors.affiliation: Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Joel
authors.initials: J
authors.lastname: Picus
authors.affiliation: Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Wooin
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: A Craig
authors.initials: AC
authors.lastname: Lockhart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D002299:Cardia / Q000473:pathology; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D004943:Esophagogastric Junction / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000517:prevention & control; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use; D011446:Prospective Studies; D012306:Risk; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics*; D013940:Thymidylate Synthase / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil