p16 Hypermethylation and KRAS Mutation Are Independent Predictors of Cetuximab Plus FOLFIRI Chemotherapy in Patients with Metastatic Colorectal Cancer.
- Author:
Se Hyun KIM
1
;
Kyu Hyun PARK
;
Sang Joon SHIN
;
Kang Young LEE
;
Tae Il KIM
;
Nam Kyu KIM
;
Sun Young RHA
;
Jae Kyung ROH
;
Joong Bae AHN
Author Information
- Publication Type:Original Article
- Keywords: Colorectal neoplasms; p16; CIMP; Methylation; KRAS
- MeSH: Colorectal Neoplasms*; CpG Islands; Cyclin-Dependent Kinase Inhibitor p16; DNA; Drug Therapy*; Fluorouracil; Genes, p16; Humans; Leucovorin; Logistic Models; Methylation; Multivariate Analysis; Phenotype
- From:Cancer Research and Treatment 2016;48(1):208-215
- CountryRepublic of Korea
- Language:English
- 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.
