Cancer Res Treat.  2016 Jan;48(1):208-215. 10.4143/crt.2014.314.

p16 Hypermethylation and KRAS Mutation Are Independent Predictors of Cetuximab Plus FOLFIRI Chemotherapy in Patients with Metastatic Colorectal Cancer

Affiliations
  • 1Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
  • 2Institute for Cancer Research, College of Medicine, Yonsei University, Seoul, Korea. vvswm513@yuhs.ac
  • 3Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
  • 4Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.

Abstract

PURPOSE
Hypermethylation of the CpG island of p16(INK4a) occurs in a significant proportion of colorectal cancer (CRC). We aimed to investigate its predictive role in CRC patients treated with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), and cetuximab.
MATERIALS AND METHODS
Pyrosequencing was used to identify KRAS mutation and hypermethylation of 6 CpG island loci (p16, p14, MINT1, MINT2, MINT31, and hMLH1) in DNA extracted from formalin-fixed paraffin-embedded specimens. Logistic regression and Cox regression were performed for analysis of the relation between methylation status of CpG island methylator phenotype (CIMP) markers including p16 and clinical outcome.
RESULTS
Hypermethylation of the p16 gene was detected in 14 of 49 patients (28.6%) and showed significant association with KRAS mutation (Fisher exact, p=0.01) and CIMP positivity (Fisher exact, p=0.002). Patients with p16-unmethylated tumors had significantly longer time to progression (TTP; median, 9.0 months vs. 3.5 months; log-rank, p=0.001) and overall survival (median, 44.9 months vs. 16.4 months; log-rank, p=0.008) than those with p16-methylated tumors. Patients with both KRAS and p16 aberrancy (n=6) had markedly shortened TTP (median, 2.8 months) compared to those with either KRAS or p16 aberrancy (n=11; median, 8.6 months; p=0.021) or those with neither (n=32; median, 9.0 months; p < 0.0001). In multivariate analysis, KRAS mutation and p16 methylation showed independent association with shorter TTP (KRAS mutation: hazard ratio [HR], 3.21; p=0.017; p16 methylation: HR, 2.97; p=0.027).
CONCLUSION
Hypermethylation of p16 was predictive of clinical outcome in metastatic CRC patients treated with cetuximab and FOLFIRI, irrespective of KRAS mutation.

Keyword

Colorectal neoplasms; p16; CIMP; Methylation; KRAS

MeSH Terms

Colorectal Neoplasms*
CpG Islands
Cyclin-Dependent Kinase Inhibitor p16
DNA
Drug Therapy*
Fluorouracil
Genes, p16
Humans
Leucovorin
Logistic Models
Methylation
Multivariate Analysis
Phenotype
Cyclin-Dependent Kinase Inhibitor p16
DNA
Fluorouracil
Leucovorin

Figure

  • Fig. 1. Kaplan-Meier plots for time to progression (A, C) and overall survival (B, D) according to p16 methylation status and CpG island methylator phenotype (CIMP) status. CIMP positive denotes tumors with two or more methylation sites in six CpG islands. All p-values correspond to the log-rank test.

  • Fig. 2. Response rates according to number of aberrancies (KRAS mutation or p16 methylation). p-value corresponds to the linear-by-linear association test for trend.

  • Fig. 3. Kaplan-Meier plot for time to progression according to number of aberrancies (KRAS mutation or p16 methylation). p-value corresponds to the log-rank test.


Reference

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