NFE2L2 rs35652124C>T polymorphism predicts Grade 4 neutropenia in esophageal cancer patients treated with DCF chemotherapy - Original Article

Sep 23, 2026

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Chemotherapy-induced neutropenia is a serious adverse event, and DCF (docetaxel, cisplatin, 5-fluorouracil) is an effective neoadjuvant therapy for esophageal cancer but often leads to high rates of Grade 4 neutropenia. This study retrospectively examined pharmacogenetic and endogenous antioxidant defense factors using two independent cohorts from the National Cancer Center Biobank in Japan. Multivariate analyses assessed SNPs linked to docetaxel pharmacokinetics and the Keap1-Nrf2 antioxidant system.

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Cancer Chemotherapy and Pharmacology (2026) 96:23 [https://doi.org/10.1007/s00280-026-04866-0](https://doi.org/10.1007/s00280-026-04866-0) ORIGINAL ARTICLE NFE2L2 rs35652124C>T polymorphism predicts Grade 4 neutropeniain esophageal cancer patients treated with docetaxel, cisplatin, and fluorouracil chemotherapy: results from exploratory and validation cohorts Hisanaga Nomura1,2 · Takaya Suzuki3 · Takashi Kojima4 · Kunihiko Itoh3 · Daiki Tsuji5 Received: 8 October 2025 / Accepted: 22 January 2026 © The Author(s) 2026 Abstract Purpose Chemotherapy-induced neutropenia is a serious adverse event. Combination chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) is an effective neoadjuvant therapy for esophageal cancer, but it is associated with a high incidence of Grade 4 neutropenia. In previous study, we identified associations between genetic variants and severe neutropenia. The aim of this study was to explore genetic factors related to pharmacokinetics and endogenous antioxidant defense mechanisms that may be associated with the development of Grade 4 neutropenia in esophageal cancer patients treated with DCF chemotherapy using two independent cohorts. Methods We conducted a retrospective pharmacogenetic analysis using DNA samples from the National Cancer Center Biobank in Japan. Two independent cohorts of esophageal cancer patients treated with the DCF chemotherapy were analyzed: an exploratory cohort (n = 157) and a validation cohort (n = 121) . Single nucleotide polymorphisms (SNPs) in genes related todocetaxel pharmacokinetics and the Keich-like ECH-associated protein 1-Nuclear factor erythroid2-related factor 2 (Keap1-Nrf2) antioxidant system were examined. Results A total 53 (33.8%) and 62 (51.2%) patients developed Grade 4 neutropenia in exploratory and validation cohort, respectively. Multivariate analysis revealed that age, Adenosine triphosphate-binding cassette (ABC) G2 rs2231137G >A and Nuclear factor, erythroid 2 like 2 (NFE2L2) rs35652124C >T were significant in exploratory cohort, while baseline absolute neutrophil count and NFE2L2 rs35652124C >T were significant in the validation cohort. Conclusions NFE2L2 rs35652124C >T was identified as an independent predictive genetic factor for Grade 4 neutropeniain esophageal cancer patients treated with DCF chemotherapy. Keywords Esophageal cancer · DCF chemotherapy · NFE2L2 · Variants 􀀍 Hisanaga Nomura [hisanaga0726@kuhp.kyoto-u.ac.jp](hisanaga0726@kuhp.kyoto-u.ac.jp) 1 Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan 2 Department of Pharmacy, National Cancer Center Hospital East, Kashiwa, Chiba, Japan 3 Department of Clinical Pharmacology & Genetics, University of Shizuoka, Shizuoka, Shizuoka, Japan 4 Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, Chiba, Japan 5 Department of Clinical Pharmaceutics, University of Shizuoka, Shizuoka, Shizuoka, Japan Introduction Esophageal cancer is a malignancy with a relatively poor prognosis, as evidenced by an annual incidence of 25,920 cases and a 5-year relative survival rate of 42% . This contrasts with the more favorable prognoses observed in other gastrointestinal cancers, such as gastric and colorectal cancers. A phase III trial demonstrated a significant improvement in overall survival with preoperative chemotherapy compared to postoperative chemotherapy in patients with clinical stage II/III esophageal cancer [1] . Furthermore, the docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy, a modification of the standard 5-fluorouracil and cisplatin (FP) chemotherapy, has shown superior efficacy in 1 3 preoperative chemotherapy, resulting in a significant overall survival benefit [2]. While a phase II study in Japan reported a high response rate with the DCF chemotherapy, it also revealed a significant incidence of adverse events,

FAQs

What is the main goal of this study?

To identify genetic factors associated with the development of Grade 4 neutropenia in esophageal cancer patients treated with DCF chemotherapy, using two independent cohorts.

How were the two cohorts and genetic analyses conducted?

A retrospective pharmacogenetic analysis used DNA from the National Cancer Center Biobank. An exploratory cohort (n=157) and a validation cohort (n=121) were analyzed for SNPs related to docetaxel pharmacokinetics and the Keap1-Nrf2 antioxidant system.

Which genetic variant was found to predict Grade 4 neutropenia?

NFE2L2 rs35652124C>T was identified as an independent predictive genetic factor for Grade 4 neutropenia in patients treated with DCF chemotherapy.

Sep 23, 2026

Uploaded by Riley