NEF2L2 rs35652124C>T Polymorphism Predicts Grade 4 Neutropenia in Esophageal Cancer Patients Treated with Docetaxel, Cisplatin, and Fluorouracil Chemotherapy: Results from Exploratory and Validation Cohorts

Background 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 polymorphisms 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 regimen were analyzed: an exploratory cohort (n = 157) and a validation cohort (n = 121). Single nucleotide polymorphisms in genes related to docetaxel pharmacokinetics and the 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, ABCG2 rs2231137G > A and NEF2L2 rs35652124C > T were significant in exploratory cohort, while baseline absolute neutrophil count and NEF2L2 rs35652124C > T were significant in the validation cohort. Conclusions NEF2L2 rs35652124C > T was identified as an independent predictive genetic factor for Grade 4 neutropenia in esophageal cancer patients treated with DCF chemotherapy.