title: Evaluation of CpG Island Methylator Phenotype as a Biomarker in Colorectal Cancer Treated With Adjuvant Oxaliplatin.
abstract: The CpG island methylator phenotype (CIMP) is a promising biomarker for irinotecan/5-fluorouracil/leucovorin chemotherapy for stage III colon cancer. In the present study, we evaluated whether CIMP is a prognostic biomarker for standard-of-care oxaliplatin-based adjuvant therapy.
  
  
  
  The HE6C/05 trial randomized 441 patients with stage II-III colorectal adenocarcinoma to adjuvant XELOX (capecitabine, oxaliplatin) or modified FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin). The primary and secondary objectives were disease-free and overall survival, respectively. CIMP status was determined using the DNA methylation status of CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Cox models were used to assess the association of CIMP with survival.
  
  
  
  Of the 293 available tumors, 28 (9.6%) were CIMP(+). On univariate Cox regression analysis, no significant differences in survival were observed between individuals with CIMP(+) versus CIMP(-) tumors. CIMP(+) tumors were more likely to be right-sided and BRAF mutant (χ(2), P < .001). In the multivariate model, TNM stage II (vs. stage III) was associated with a reduced risk of relapse (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.11-0.55; Wald's P < .001), and a colon primary located on the left side and earlier TNM stage were associated with a reduced risk of death (HR, 0.48; 95% CI, 0.28-0.81; P = .006; and HR, 0.22; 95% CI, 0.10-0.49; P < .001, respectively).
  
  
  
  In the present exploratory analysis, CIMP did not appear to be a prognostic biomarker in oxaliplatin-treated patients with resected colorectal cancer.
authors.affiliation: Division of Oncology, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. Electronic address: shiovitz@uw.edu.
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Cohen
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; College of Life Sciences, Hebei University, Baoding, Hebei, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wu
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.affiliation: Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Gourgioti
authors.affiliation: Stratifyer Molecular Pathology GmbH, Cologne, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Wirtz
authors.affiliation: Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Raptou
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Chryssa
authors.initials: C
authors.lastname: Gkakou
authors.affiliation: Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kotoula
authors.affiliation: Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Pentheroudakis
authors.affiliation: Oncology Section, Second Department of Internal Medicine, "Hippokration" Hospital, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Papaxoinis
authors.affiliation: Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Karavasilis
authors.affiliation: Oncology Section, Second Department of Internal Medicine, "Hippokration" Hospital, Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pectasides
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece.
authors.forename: Konstantine T
authors.initials: KT
authors.lastname: Kalogeras
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Division of Gastroenterology, University of Washington, Seattle, WA.
authors.forename: William M
authors.initials: WM
authors.lastname: Grady
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D000069287:Capecitabine; D017024:Chemotherapy, Adjuvant / Q000379:methods; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D010071:Oxaloacetates; D010641:Phenotype; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D010071:Oxaloacetates; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D002955:Leucovorin; D005472:Fluorouracil
keywords: CIMP; MSI; Methylation; Prognosis; Survival