CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer

Stacey Shiovitz, Monica M. Bertagnolli, Lindsay A. Renfro, Eunmi Nam, Nathan R. Foster, Slavomir Dzieciatkowski, Yanxin Luo, Victoria Valinluck Lao, Raymond J. Monnat, Mary J. Emond, Nancy Maizels, Donna Niedzwiecki, Richard M. Goldberg, Leonard B. Saltz, Alan Venook, Robert S. Warren, William M. Grady

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103 Scopus citations


Background & Aims 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.

Original languageEnglish
Pages (from-to)637-645
Number of pages9
Issue number3
StatePublished - Sep 2014

Bibliographical note

Funding Information:
Funding The research reported in this article was supported by National Institutes of Health (NIH) National Cancer Institute (NCI) Program award P01CA77852 (RJM); NIH awards 5T32-CA009515-28/29 (SS), RO1CA115513, P30CA15704, UO1CA152756, U54CA143862, and P01CA077852 (WMG); Burroughs Wellcome Fund Translational Research Award for Clinician Scientist (WMG); ACS fellowship PF-11-086-01-TBG, NIH 2T32DK007742-16, ASCRS GSRRIG, and NIH NCI F32CA1591555-01 (VVL); CA32291 (MMB); CA77658 (RMG); CA77651 (LBS); CA60138 (AV, RSW). CALGB 89803 (Alliance) was supported partly by grants from the NCI (CA31946) to the Alliance for Clinical Trials in Oncology (MMB, Chair) and to the Alliance Statistics and Data Center (Daniel J. Sargent, PhD, CA33601) (LAR, NRF, DN). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.


  • CALGB (Alliance) 89803
  • CRC
  • Chemotherapy
  • Epigenetic Factors


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