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Effect of DNA methylation status on first-line anti-epidermal growth factor receptor treatment in patients with metastatic colorectal cancer

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Abstract

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.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Ms. Hitomi Hannan, Ms. Yukie Naito, and Ms. Yuki Horiike for data management. We also thank Dr Hiroshi Kawachi for tissue sample preparation.

Funding

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).

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Author notes

  1. Hiroki Osumi and Kota Ouchi contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Hiroki Osumi, Eiji Shinozaki, Akira Ooki, Izuma Nakayama, Takeru Wakatsuki, Mariko Ogura, Daisuke Takahari, Keisho Chin & Kensei Yamaguchi

  2. Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan

    Kota Ouchi, Shin Takahashi & Chikashi Ishioka

  3. Department of Clinical Oncology, Tohoku University Graduate School of Medicine, Miyagi, Japan

    Kota Ouchi, Shin Takahashi & Chikashi Ishioka

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  1. Hiroki Osumi
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Contributions

Conception and design: HO and ES. Development of methodology: KO, ST, and CI. Acquisition of data: HO, KO, ES, ST, and CI. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, and computational analysis): HO and ES. Writing, review, and/or revision of the manuscript: all authors. Administrative, technical, or material support (i.e., reporting or organizing data, and constructing databases): KO, ST, and CI. Study supervision: ES.

Corresponding author

Correspondence to Eiji Shinozaki.

Ethics declarations

Ethics approval

This study was approved by the Institutional Review Board of the Japanese Foundation for Cancer Research (Tokyo, Japan, registry number 2019–1034). The protocol was described on the hospital website, and subjects were provided the opportunity to opt out; therefore, no additional consent was required from patients. All methods were performed in accordance with the Declaration of Helsinki.

Conflict of interest

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.

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Osumi, H., Ouchi, K., Shinozaki, E. et al. Effect of DNA methylation status on first-line anti-epidermal growth factor receptor treatment in patients with metastatic colorectal cancer. Int J Colorectal Dis 37, 1439–1447 (2022). https://doi.org/10.1007/s00384-022-04177-9

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