title: CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer.
abstract: OBJECTIVE
  The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL).
  
  
  METHODS
  We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated.
  
  
  RESULTS
  Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P = .07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P = .049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P = .01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses.
  
  
  CONCLUSIONS
  Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Stacey
authors.initials: S
authors.lastname: Shiovitz
authors.affiliation: Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
authors.affiliation: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Renfro
authors.affiliation: Division of Hematology/Oncology, Ewha Womans University School of Medicine, Seoul, South Korea.
authors.forename: Eunmi
authors.initials: E
authors.lastname: Nam
authors.affiliation: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Foster
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Slavomir
authors.initials: S
authors.lastname: Dzieciatkowski
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, PR China.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Surgery, University of Washington Medical School, Seattle, Washington.
authors.forename: Victoria Valinluck
authors.initials: VV
authors.lastname: Lao
authors.affiliation: Departments of Pathology and Genome Science, University of Washington Medical School, Seattle, Washington.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Monnat
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Emond
authors.affiliation: Departments of Immunology and Biochemistry, University of Washington, Seattle, Washington.
authors.forename: Nancy
authors.initials: N
authors.lastname: Maizels
authors.affiliation: Alliance Statistics and Data Center, Duke University Medical Center, Durham, North Carolina.
authors.forename: Donna
authors.initials: D
authors.lastname: Niedzwiecki
authors.affiliation: The Ohio State University, Columbus, OH.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Saltz
authors.affiliation: University of California-San Francisco and the Helen Diller Family Comprehensive Cancer Center, San Francisco, CA.
authors.forename: Alan
authors.initials: A
authors.lastname: Venook
authors.affiliation: University of California-San Francisco and the Helen Diller Family Comprehensive Cancer Center, San Francisco, CA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Warren
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Electronic address: wgrady@fhcrc.org.
authors.forename: William M
authors.initials: WM
authors.lastname: Grady
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D017024:Chemotherapy, Adjuvant; D003082:Colectomy; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: CALGB (Alliance) 89803; CRC; Chemotherapy; Epigenetic Factors