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- Title
p16 Hypermethylation and KRAS Mutation Are Independent Predictors of Cetuximab Plus FOLFIRI Chemotherapy in Patients with Metastatic Colorectal Cancer.
- Authors
Se Hyun Kim; Kyu Hyun Park; Sang Joon Shin; Kang Young Lee; Tae II Kim; Nam Kyu Kim; Sun Young Rha; Jae Kyung Roh; Joong Bae Ahn
- Abstract
Purpose Hypermethylation of the CpG island of p16INK4a 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 KRASmutation 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 KRASmutation (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.
- Subjects
CETUXIMAB; CANCER chemotherapy; COLON cancer patients; FLUOROURACIL; FOLINIC acid; PYROSEQUENCING; LOGISTIC regression analysis
- Publication
Cancer Research & Treatment, 2016, Vol 48, Issue 1, p208
- ISSN
1598-2998
- Publication type
Article
- DOI
10.4143/crt.2014.314