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ABCB1 and ABCC2 genetic polymorphism as risk factors for neutropenia in esophageal cancer patients treated with docetaxel, cisplatin, and 5-fluorouracil chemotherapy

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Abstract

Purpose

The combination of docetaxel, cisplatin and 5-fluorouracil (DCF) is a newly developed chemotherapy regimen for esophageal cancer. Severe neutropenia is dose-limiting toxicity of docetaxel and it is well known to be frequently occurred during DCF chemotherapy. This study aimed to investigate the relationship between severe neutropenia and genetic polymorphisms in patients treated with preoperative DCF chemotherapy.

Methods

A total of 158 patients were investigated for their absolute neutrophil count (ANC) within the first cycle of DCF chemotherapy at the National Cancer Center (NCC) Hospital East. DNA samples obtained from the NCC Biobank Registry were used for the analysis of nine genetic polymorphisms related to docetaxel pharmacokinetics. These genotypes were evaluated for their association with severe neutropenia, and further their risk factors were examined using a multivariate logistic regression.

Results

A total 81 (51.3%) patients developed severe neutropenia. Multivariate analysis revealed that age (OR 1.054; CI 1.008–1.102, P = 0.022), baseline ANC (OR 1.019; CI 1.002–1.037, P = 0.030), ABCB1 3435C>T (OR 2.191; CI 1.087–4.417, P = 0.028) and ABCC2 *+9383C>G (OR 2.342; CI 1.108–4.948, P = 0.026) were significant risk factors for severe neutropenia development. The results from this study showed that age, ANC, ABCB1 3435C>T, and ABCC2 *+9383 G>C increased the incidence of severe neutropenia with the number of identified risk factors.

Conclusions

In addition to age and baseline ANC, ABCB1 3435C>T and ABCC2 *+9383C>G were identified as independent predictors for severe neutropenia in esophageal cancer patients treated with DCF chemotherapy.

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Funding

This work was supported by the University of Shizuoka academic research grant.

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Authors and Affiliations

  1. Department of Innovation and Clinical Research Center, Japan Agency for Medical Research and Development, 21F Yomiuri shinbun Bldg. 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan

    Hisanaga Nomura

  2. Department of Pharmacy, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Hisanaga Nomura, Ken Demachi, Nobuo Mochizuki & Toshikatsu Kawasaki

  3. Department of Clinical Pharmacology & Genetics, University of Shizuoka, Shizuoka, Shizuoka, Japan

    Daiki Tsuji, Haruki Matsuzawa & Kunihiko Itoh

  4. Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Tomonori Yano

  5. Department of Esophageal Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan

    Hiroyuki Daiko

  6. Division of Pathology, Exploratory Oncology Research and Clinical Trial Center National Cancer Center, Kashiwa, Chiba, Japan

    Satoshi Fujii

  7. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Takashi Kojima

  8. Department of Molecular Pathology, Yokohama City University, Graduate School of Medicine, Yokohama, Japan

    Satoshi Fujii

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  1. Hisanaga Nomura
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Contributions

Conception and design were performed by HN, DT, TaKo, TY, HD and SF. Acquisition of data was carried out by HN, KD, DT, HD, and TaKo. The analysis of SNPs was DT, HM and KI. Statistical analysis and interpretation of the data were carried out by NM. Drafting of the article was carried out by NH, DT, TaKo, ToKa, and SF. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hisanaga Nomura.

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Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval

The study protocol was approved by the institutional review board of the NCC, Japan in March 2017 (2016-384). These patients were consented to be used the clinical information and DNA sample in the National Cancer Center (NCC) Biobank Registry. The study design is displayed on the website for the National Cancer Center Hospital East, providing the relatives of deceased patients the opportunity to decline participation in the current study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Nomura, H., Tsuji, D., Demachi, K. et al. ABCB1 and ABCC2 genetic polymorphism as risk factors for neutropenia in esophageal cancer patients treated with docetaxel, cisplatin, and 5-fluorouracil chemotherapy. Cancer Chemother Pharmacol 86, 315–324 (2020). https://doi.org/10.1007/s00280-020-04118-9

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