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

Publication ,  Journal Article
Shiovitz, S; Bertagnolli, MM; Renfro, LA; Nam, E; Foster, NR; Dzieciatkowski, S; Luo, Y; Lao, VV; Monnat, RJ; Emond, MJ; Maizels, N; Saltz, LB ...
Published in: Gastroenterology
September 2014

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.

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Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

September 2014

Volume

147

Issue

3

Start / End Page

637 / 645

Location

United States

Related Subject Headings

  • Young Adult
  • Treatment Outcome
  • Time Factors
  • Risk Factors
  • Risk Assessment
  • Proportional Hazards Models
  • Phenotype
  • Neoplasm Staging
  • Middle Aged
  • Male
 

Citation

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Shiovitz, S., Bertagnolli, M. M., Renfro, L. A., Nam, E., Foster, N. R., Dzieciatkowski, S., … Alliance for Clinical Trials in Oncology, . (2014). CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer. Gastroenterology, 147(3), 637–645. https://doi.org/10.1053/j.gastro.2014.05.009
Shiovitz, Stacey, Monica M. Bertagnolli, Lindsay A. Renfro, Eunmi Nam, Nathan R. Foster, Slavomir Dzieciatkowski, Yanxin Luo, et al. “CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer.Gastroenterology 147, no. 3 (September 2014): 637–45. https://doi.org/10.1053/j.gastro.2014.05.009.
Shiovitz S, Bertagnolli MM, Renfro LA, Nam E, Foster NR, Dzieciatkowski S, et al. CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer. Gastroenterology. 2014 Sep;147(3):637–45.
Shiovitz, Stacey, et al. “CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer.Gastroenterology, vol. 147, no. 3, Sept. 2014, pp. 637–45. Pubmed, doi:10.1053/j.gastro.2014.05.009.
Shiovitz S, Bertagnolli MM, Renfro LA, Nam E, Foster NR, Dzieciatkowski S, Luo Y, Lao VV, Monnat RJ, Emond MJ, Maizels N, Niedzwiecki D, Goldberg RM, Saltz LB, Venook A, Warren RS, Grady WM, Alliance for Clinical Trials in Oncology. CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer. Gastroenterology. 2014 Sep;147(3):637–645.
Journal cover image

Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

September 2014

Volume

147

Issue

3

Start / End Page

637 / 645

Location

United States

Related Subject Headings

  • Young Adult
  • Treatment Outcome
  • Time Factors
  • Risk Factors
  • Risk Assessment
  • Proportional Hazards Models
  • Phenotype
  • Neoplasm Staging
  • Middle Aged
  • Male