title: Evaluation of 5-fluorouracil metabolic enzymes as predictors of response to adjuvant chemotherapy outcomes in patients with stage II/III colorectal cancer: a decision-curve analysis.
abstract: BACKGROUND
  The effectiveness of 5-fluorouracil (5-FU)-based adjuvant chemotherapy is reported in patients with colorectal cancer (CRC), but the usefulness of 5-FU metabolic enzymes as predictive biomarkers of the efficacy of this chemotherapy remains unclear.
  
  
  OBJECTIVE
  This study aims to verify whether 5-FU metabolic enzymes are predictive biomarkers in the clinical setting of adjuvant chemotherapy for stage II/III CRC.
  
  
  METHODS
  In total, 179 patients with stage II/III CRC who were treated at our institute between 2000 and 2010 were enrolled. Messenger RNA (mRNA) expression of major 5-FU metabolic enzymes, namely thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase (TP), orotate phosphoribosyl transferase, and β-actin (control) was evaluated using the Danenberg Tumor Profile method. mRNA expression and other clinicopathological data were investigated with regard to CRC relapse.
  
  
  RESULTS
  A total of 78 patients underwent surgery alone, while 101 underwent adjuvant chemotherapy (5-FU plus leucovorin [LV] or tegafur plus uracil /LV) following surgery. Relapse-free survival was longer and risk of recurrence was lower in association with high TP mRNA expression than in association with low TP mRNA expression in the adjuvant chemotherapy group (hazard ratio 0.66; 95 % confidence interval 0.47-0.92; p = 0.016), but not in the surgery alone group. mRNA expression of no other enzymes was associated with relapse in both groups. In decision-curve analyses, the predictive efficiency of TP mRNA expression plus clinicopathological factors was slightly better than that of clinicopathological factors only.
  
  
  CONCLUSIONS
  TP mRNA expression in tumors predicted the effects of adjuvant chemotherapy for stage II/III CRC, although the beneficial effects were marginal.
authors.affiliation: Department of Surgery, Keio University School of Medicine, Tokyo, Japan, ohlkoh@gmail.com.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shigeta
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ishii
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Koji
authors.initials: K
authors.lastname: Okabayashi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D003661:Decision Support Techniques; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009962:Orotate Phosphoribosyltransferase / Q000235:genetics; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000032:analysis*; D005641:Tegafur / Q000008:administration & dosage; D013939:Thymidine Phosphorylase / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D005641:Tegafur; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D013939:Thymidine Phosphorylase; D002955:Leucovorin; D005472:Fluorouracil