DNA methylation status as a biomarker of anti‐epidermal growth factor receptor treatment for metastatic colorectal cancer

• Published in: Cancer science Vol. 106; no. 12; pp. 1722 - 1729
• Main Authors: Ouchi, Kota, Takahashi, Shin, Yamada, Yasuhide, Tsuji, Shingo, Tatsuno, Kenji, Takahashi, Hidekazu, Takahashi, Naoki, Takahashi, Masanobu, Shimodaira, Hideki, Aburatani, Hiroyuki, Ishioka, Chikashi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2015; John Wiley and Sons Inc
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - mortality; Adult; Aged; Antineoplastic Agents - therapeutic use; Anti‐EGFR treatment; biomarker; Biomarkers; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Cancer; Cancer therapies; Chemotherapy; Cluster Analysis; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Deoxyribonucleic acid; Disease control; Disease-Free Survival; DNA; DNA methylation; DNA Methylation - genetics; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - immunology; Female; Genes; Genomes; Humans; Kaplan-Meier Estimate; Male; Medical prognosis; Medical records; Metastases; Metastasis; Middle Aged; molecular targeted therapy; Mutation; Neoplasm Metastasis; Oligonucleotide Array Sequence Analysis; Original; Patients; Quality control; Retrospective Studies; Studies; Survival; Tumors; Japan; DNA methylation; molecular targeted therapy; colorectal cancer; Anti-EGFR treatment; biomarker
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12827

Anti‐epidermal growth factor receptor (EGFR) treatment is an effective option for metastatic colorectal cancer (CRC) treatment. However, there are few reliable biomarkers to predict the clinical response to anti‐EGFR treatment. We investigated the genome‐wide DNA methylation status in metastatic colorectal cancer to identify associations between the methylation status and clinical response to anti‐EGFR antibody. We retrospectively reviewed the medical records of 97 patients (45 patients for the first cohort and 52 patients for the second cohort) who received anti‐EGFR treatment for KRAS wild‐type metastatic CRC. Then we analyzed the associations between genome‐wide DNA methylation status and clinical response to anti‐EGFR treatment, and evaluated the predictive power and value of the methylation status statistically. As a result, each cohort was classified into highly methylated CRC and low methylated CRC subgroups by unsupervised clustering analyses. In the first cohort, clinical outcomes were significantly better in the low methylated CRC subgroup than in the highly methylated CRC subgroup (response rate, 35.7% vs 6.3%, P = 0.03; disease control rate, 75% vs 31.3%, P = 0.005; hazard ratio for progression‐free survival, 0.27; 95% confidence interval, 0.13–0.57, P < 0.001; overall survival, 0.19; 95% confidence interval, 0.06–0.54, P < 0.001). These results were reproducible in the second cohort. The genome‐wide methylation status was a predictive factor of progression‐free survival and overall survival independently of RAS mutation status. In conclusion, we found that the genome‐wide DNA methylation status is a powerful epigenetic predictor of anti‐EGFR treatment in patients with KRAS wild‐type metastatic colorectal cancer (UMIN000005490). We investigated the genome‐wide DNA methylation status in metastatic colorectal cancer to identify associations between the methylation status and clinical response to anti‐EGFR antibody. We found that the genome‐wide DNA methylation status is a powerful epigenetic predictor of the anti‐EGFR treatment in patients with KRAS wild‐type metastatic colorectal cancer.