TY - JOUR
T1 - Effect of DNA methylation status on first-line anti-epidermal growth factor receptor treatment in patients with metastatic colorectal cancer
AU - Osumi, Hiroki
AU - Ouchi, Kota
AU - Shinozaki, Eiji
AU - Takahashi, Shin
AU - Ooki, Akira
AU - Nakayama, Izuma
AU - Wakatsuki, Takeru
AU - Ogura, Mariko
AU - Takahari, Daisuke
AU - Chin, Keisho
AU - Yamaguchi, Kensei
AU - Ishioka, Chikashi
N1 - Funding Information:
This work was supported by a grant from the Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT) (grant number 11110018) and the Project for Cancer Research and Therapeutic Evolution (P-CREATE) by the Japan Agency for Medical Research and Development (grant number 16770660).
Funding Information:
Dr. Takahashi has received honoraria from Taiho, Chugai, Asahikasei, Bayer, Japan Blood Products Organization, Medicon, Termo, Sanofi, Merckbiopharma, Nippon-kayaku, Takeda, Ono, and Yakult and research grant from Merckbiopharma; Ono. Dr. Shinozaki has received honoraria from Taiho, Chugai, Merckbiopharma, Takeda, Sanofi, Eli Lilly, and Daiichi-Sankyo; and Ono. Pr. Ishioka has received honoraria from Chugai, Taiho, Ono, Merckbiopharma, Novartis, Asahi Kasei, Sanofi, Nippon-Kayaku, Daiichi Sankyo, Takeda, Bayer, Eisai, Eli Lilly, Teijin, Hitachi, Bristol-Myers Squibb, Konica Minolta, Pfizer, and Yakult as well as research grant from Hitachi, Riken Genesis, Yakult, Taiho, Ono, Asahi Kasei, Sanofi, Takeda, Eisai, Chugai, Kyowa Kirin, Tsumura, Eli Lilly, Otsuka, Shionogi, Novartis, Daiichi Sankyo, and Nippon-Kayaku. All other authors declared no competing interests.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2022/6
Y1 - 2022/6
N2 - Purpose: The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer (CRC). However, there is a lack of consensus on CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with metastatic CRC (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors. Methods: We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment. We analyzed the incidence and clinicopathological characteristics of highly methylated CRC (HMCC) and associations between genome-wide DNA methylation status and response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: In total, 169 patients were included in the final analyses. The frequency of HMCC was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAF V600E mutation (P < 0.0001). Patients with HMCC showed worse clinical outcomes than those with low-methylated CRC in terms of RR (P = 0.017), PFS (P = 0.004), and OS (P = 0.019). In the multivariate analysis, peritoneal metastasis (P = 0.017), methylation status (P = 0.037), and BRAF V600E mutations (P = 0.0001) were independent factors for shorter PFS. Conclusions: Genome-wide DNA methylation status is an independent factor associated with PFS in patients with mCRC treated with first-line EGFR inhibitors.
AB - Purpose: The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer (CRC). However, there is a lack of consensus on CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with metastatic CRC (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors. Methods: We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment. We analyzed the incidence and clinicopathological characteristics of highly methylated CRC (HMCC) and associations between genome-wide DNA methylation status and response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: In total, 169 patients were included in the final analyses. The frequency of HMCC was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAF V600E mutation (P < 0.0001). Patients with HMCC showed worse clinical outcomes than those with low-methylated CRC in terms of RR (P = 0.017), PFS (P = 0.004), and OS (P = 0.019). In the multivariate analysis, peritoneal metastasis (P = 0.017), methylation status (P = 0.037), and BRAF V600E mutations (P = 0.0001) were independent factors for shorter PFS. Conclusions: Genome-wide DNA methylation status is an independent factor associated with PFS in patients with mCRC treated with first-line EGFR inhibitors.
KW - DNA methylation
KW - Epidermal growth factor receptor inhibitor
KW - Metastatic colorectal cancer
KW - Predictive biomarker
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U2 - 10.1007/s00384-022-04177-9
DO - 10.1007/s00384-022-04177-9
M3 - Article
C2 - 35612620
AN - SCOPUS:85130719531
SN - 0179-1958
VL - 37
SP - 1439
EP - 1447
JO - International Journal of Colorectal Disease
JF - International Journal of Colorectal Disease
IS - 6
ER -
