title: Thymidylate synthase genotype-directed neoadjuvant chemoradiation for patients with rectal adenocarcinoma.
abstract: OBJECTIVE
  Downstaging (DS) of rectal cancers is achieved in approximately 45% of patients with neoadjuvant fluorouracil (FU) -based chemoradiotherapy (CRT). Polymorphisms in the thymidylate synthase gene (TYMS) had previously defined two risk groups associated with disparate tumor DS rates (60% v 22%). We conducted a prospective single-institution phase II study using TYMS genotyping to direct neoadjuvant CRT for patients with rectal cancer.
  
  
  METHODS
  Patients with T3/T4, N0-2, M0-1 rectal adenocarcinoma were evaluated for germline TYMS genotyping. Patients with TYMS *2/*2, *2/*3, or *2/*4 (good risk) were treated with standard chemoradiotherapy using infusional FU at 225 mg/m²/d. Patients with TYMS *3/*3 or *3/*4 (poor risk) were treated with FU/RT plus weekly intravenous irinotecan at 50 mg/m². The primary end point was pathologic DS. Secondary end points included complete tumor response (ypT0), toxicity, recurrence rates, and overall survival.
  
  
  RESULTS
  Overall, 135 patients were enrolled, of whom 27.4% (37 of 135) were considered poor risk. The prespecified statistical goals were achieved, with DS and ypT0 rates reaching 64.4% and 20% for good-risk and 64.5% and 42% for poor-risk patients, respectively.
  
  
  CONCLUSIONS
  To our knowledge, this is the first study to prospectively use TYMS genotyping to direct neoadjuvant CRT in patients with rectal cancer. High rates of DS and ypT0 were achieved among both risk groups when personalized treatment was based on TYMS genotype. These results are encouraging, and further evaluation of this genotype-based strategy using a randomized study design for locally advanced rectal cancer is warranted.
authors.affiliation: Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Tan
authors.forename: Fabienne
authors.initials: F
authors.lastname: Thomas
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Myerson
authors.forename: Barbara
authors.initials: B
authors.lastname: Zehnbauer
authors.forename: Kathryn
authors.initials: K
authors.lastname: Trinkaus
authors.forename: Robert S
authors.initials: RS
authors.lastname: Malyapa
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Mutch
authors.forename: Elliot E
authors.initials: EE
authors.lastname: Abbey
authors.forename: Amer
authors.initials: A
authors.lastname: Alyasiry
authors.forename: James W
authors.initials: JW
authors.lastname: Fleshman
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D020360:Neoadjuvant Therapy / Q000379:methods*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D018579:Patient Selection; D011379:Prognosis; D011446:Prospective Studies; D018714:Radiotherapy, Adjuvant; D012004:Rectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018570:Risk Assessment; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000187:drug effects / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D013940:Thymidylate Synthase