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Gastroenterology. 2014 Sep;147(3):637-45. doi: 10.1053/j.gastro.2014.05.009. Epub 2014 May 21.

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

Author information

1
Department of Medicine, University of Washington, Seattle, Washington; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
2
Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts.
3
Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.
4
Division of Hematology/Oncology, Ewha Womans University School of Medicine, Seoul, South Korea.
5
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
6
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, PR China.
7
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Surgery, University of Washington Medical School, Seattle, Washington.
8
Departments of Pathology and Genome Science, University of Washington Medical School, Seattle, Washington.
9
Department of Biostatistics, University of Washington, Seattle, Washington.
10
Departments of Immunology and Biochemistry, University of Washington, Seattle, Washington.
11
Alliance Statistics and Data Center, Duke University Medical Center, Durham, North Carolina.
12
The Ohio State University, Columbus, OH.
13
Memorial Sloan-Kettering Cancer Center, New York, New York.
14
University of California-San Francisco and the Helen Diller Family Comprehensive Cancer Center, San Francisco, CA.
15
Department of Medicine, University of Washington, Seattle, Washington; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Electronic address: wgrady@fhcrc.org.

Abstract

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.

KEYWORDS:

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

PMID:
24859205
PMCID:
PMC4143495
DOI:
10.1053/j.gastro.2014.05.009
[Indexed for MEDLINE]
Free PMC Article

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