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CpG island methylator phenotype is associated with the efficacy of sequential oxaliplatin- and irinotecan-based chemotherapy and EGFR-related gene mutation in Japanese patients with metastatic colorectal cancer

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Abstract

Background

The CpG island methylator phenotype (CIMP) with multiple promoter methylated loci has been observed in a subset of human colorectal cancer (CRC) cases. CIMP status, which is closely associated with specific clinicopathological and molecular characteristics, is considered a potential predictive biomarker for efficacy of cancer treatment. However, the relationship between the effect of standard chemotherapy, including cytotoxic drugs and anti-epidermal growth factor receptor (EGFR) antibodies, and CIMP status has not been elucidated.

Methods

In 125 metastatic colorectal cancer (mCRC) patients, we investigated how clinical outcome of chemotherapy was related to CIMP status as detected by methylation-specific PCR (MSP) and to genetic status in five EGFR-related genes (KRAS, BRAF, PIK3CA, NRAS, and AKT1) as detected by direct sequencing.

Results

CIMP-positive status was significantly associated with proximal tumor location and peritoneum metastasis (all P values <0.05). The progression-free survival of patients with CIMP-positive tumors receiving sequential therapy with FOLFOX as the first-line treatment followed by irinotecan-based therapy as the second-line treatment (median = 6.6 months) was inferior to that of such patients receiving the reverse sequence (median = 15.2 months; P = 0.043). Furthermore, CIMP-positive tumors showed higher mutation frequencies for the five EGFR-related genes (74.1 %) than the CIMP-negative tumors did (50.0 %). Among the KRAS wild-type tumors, CIMP-positive tumors were associated with a worse clinical outcome than CIMP-negative tumors following anti-EGFR antibody therapy.

Conclusion

Sequential FOLFOX followed by an irinotecan-based regimen is unfavorable in patients with CIMP-positive tumors. High frequencies of mutation in EGFR-related genes in CIMP-positive tumors may cause the lower response to anti-EGFR antibody therapy seen in patients with wild-type KRAS and CIMP-positive tumors.

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Acknowledgments

This study was supported in part by grants-in-aid from the Ministry of Education, Science, Sports and Culture. We thank Hiromi Nakata for assistance with the mutational analysis as well as Mareyuki Endo at Sendai Kosei Hospital, Hiroyoshi Suzuki at Sendai Medical Center, and Yayoi Takahashi at Tohoku University Hospital for preparing samples.

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Authors and Affiliations

  1. Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aobaku, Sendai, 980-8575, Japan

    Xiaofei Zhang, Hideki Shimodaira, Hiroshi Soeda, Keigo Komine, Hidekazu Takahashi, Kota Ouchi, Masahiro Inoue, Masanobu Takahashi, Shin Takahashi & Chikashi Ishioka

  2. Department of Clinical Oncology, Tohoku University Hospital, Sendai, Japan

    Hideki Shimodaira, Hiroshi Soeda, Keigo Komine, Masahiro Inoue, Masanobu Takahashi, Shin Takahashi & Chikashi Ishioka

Authors
  1. Xiaofei Zhang
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  2. Hideki Shimodaira
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  3. Hiroshi Soeda
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  9. Shin Takahashi
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Correspondence to Chikashi Ishioka.

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Conflict of interest

Chikashi Ishioka has received research funding from Chugai Pharmaceutical Co. Ltd. and Taiho Pharmaceutical Co. Ltd.

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Xiaofei Zhang and Hideki Shimodaira have equally contributed to this work.

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Zhang, X., Shimodaira, H., Soeda, H. et al. CpG island methylator phenotype is associated with the efficacy of sequential oxaliplatin- and irinotecan-based chemotherapy and EGFR-related gene mutation in Japanese patients with metastatic colorectal cancer. Int J Clin Oncol 21, 1091–1101 (2016). https://doi.org/10.1007/s10147-016-1017-6

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  • DOI: https://doi.org/10.1007/s10147-016-1017-6

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