title: 5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer.
abstract: OBJECTIVE
  5-Fluorouracil (5-FU)-based adjuvant chemotherapy does not increase survival times of patients with colorectal tumors with microsatellite instability. We determined the response of patients with colorectal tumors with the CpG island methylator phenotype (CIMP) to 5-FU-based therapy.
  
  
  METHODS
  We analyzed a population-based cohort of 302 patients with colorectal cancer (CRC) for a median follow-up time of 50.7 months. CIMP status was determined by analysis of the CACNAG1, SOCS1, RUNX3, NEUROG1, and MLH1 promoters; tumors were considered to be CIMP positive if at least 3 promoters were methylated.
  
  
  RESULTS
  Tumors from 29.5% of patients (89/302) were CIMP positive; CIMP status did not influence disease-free survival (DFS; log-rank = 0.3). Of tumors of TNM stages II-III (n = 196), 32.7% were CIMP positive. Among patients with stages II-III CRC who did not receive adjuvant 5-FU chemotherapy, those with CIMP-positive tumors had longest times of DFS (log-rank = 0.04); In patients who received chemotherapy, those with CIMP-positive tumors had shorter times of DFS (log-rank = 0.02). In patients with CIMP-negative tumors, adjuvant 5-FU chemotherapy significantly increased time of DFS (log-rank = 0.00001). However, in patients with CIMP-positive tumors, adjuvant 5-FU chemotherapy did not affect time of DFS (log-rank = 0.7). Multivariate analysis showed a significant, independent interaction between 5-FU treatment and CIMP status (hazard ratio [HR], 0.6; 95% confidence interval [CI], 0.5-0.8). Among patients with CIMP-positive tumors, adjuvant chemotherapy was not an independent predictor of outcome (HR, 0.8; 95% CI, 0.3-2.0). In patients who did not receive adjuvant 5-FU chemotherapy, CIMP status was the only independent predictor of survival (HR, 2.0; 95% CI, 1.1-3.8).
  
  
  CONCLUSIONS
  Patients with CIMP-positive colorectal tumors do not benefit from 5-FU-based adjuvant chemotherapy.
authors.affiliation: Unidad de Gastroenterología, Hospital General Universitario de Alicante, Alicante, Spain. jover_rod@gva.es
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jover
authors.forename: Thuy-Phuong
authors.initials: TP
authors.lastname: Nguyen
authors.forename: Lucía
authors.initials: L
authors.lastname: Pérez-Carbonell
authors.forename: Pedro
authors.initials: P
authors.lastname: Zapater
authors.forename: Artemio
authors.initials: A
authors.lastname: Payá
authors.forename: Cristina
authors.initials: C
authors.lastname: Alenda
authors.forename: Estefanía
authors.initials: E
authors.lastname: Rojas
authors.forename: Joaquín
authors.initials: J
authors.lastname: Cubiella
authors.forename: Francesc
authors.initials: F
authors.lastname: Balaguer
authors.forename: Juan D
authors.initials: JD
authors.lastname: Morillas
authors.forename: Juan
authors.initials: J
authors.lastname: Clofent
authors.forename: Luis
authors.initials: L
authors.lastname: Bujanda
authors.forename: Josep M
authors.initials: JM
authors.lastname: Reñé
authors.forename: Xavier
authors.initials: X
authors.lastname: Bessa
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Xicola
authors.forename: David
authors.initials: D
authors.lastname: Nicolás-Pérez
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.forename: Montserrat
authors.initials: M
authors.lastname: Andreu
authors.forename: Xavier
authors.initials: X
authors.lastname: Llor
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D018899:CpG Islands / Q000502:physiology*; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil