Kanesada Gen, Tsunedomi Ryouichi, Nakagami Yuki, Matsui Hiroto, Shindo Yoshitaro, Tomochika Shinobu, Akita Hirofumi, Ioka Tatsuya, Takahashi Hidenori, Nagano Hiroaki
Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
Research Institute for Cell Design Medical Science, Yamaguchi University, Ube, Yamaguchi, Japan.
Cancer Sci. 2025 Jul;116(7):2008-2019. doi: 10.1111/cas.70087. Epub 2025 Apr 26.
Pancreatic cancer (PC) is an aggressive and lethal tumor with a poor prognosis. FOLFIRINOX improves the prognosis of patients with PC; however, despite UGT1A1 screening, adverse events, such as severe neutropenia, occur frequently. This study aimed to identify the novel biomarkers of severe neutropenia in patients treated with modified FOLFIRINOX (mFFX) for PC. In this study, patients with PC treated with mFFX (n = 71) and gemcitabine plus nab-paclitaxel (GnP) (n = 92) and patients with colorectal cancer treated with FOLFOXIRI (n = 50) were included. Genome-wide screening using whole-exome sequencing was performed during the screening phase. Validation analysis was performed using polymerase chain reaction genotyping, the Cochran-Armitage trend test, and multivariate analysis. The diagnostic performance of combined risk factors for severe neutropenia was examined using logistic regression with leave-one-out cross-validation. Three gene polymorphisms were selected from the screening phase and subjected to the validation phase. In the validation phase, a single nucleotide polymorphism in C11orf24 (c.448C>T, rs901827) was significantly correlated with ≥ Grade 3 neutropenia in mFFX and FOLFOXIRI but not in GnP. Multivariate analysis showed C11orf24 and baseline neutrophil count as independent risk factors for ≥ Grade 3 neutropenia. The diagnostic performance of the neutropenia prediction model showed areas under the curve of 0.754 (sensitivity = 0.605, specificity = 0.848) and 0.856 (sensitivity = 0.800, specificity = 0.893) for ≥ Grade 3 and 4 neutropenia, respectively. The C11orf24 gene and baseline neutrophil count may be useful biomarkers for predicting severe neutropenia following irinotecan-containing triplet chemotherapy.
胰腺癌（PC）是一种侵袭性强且致命的肿瘤，预后较差。FOLFIRINOX方案可改善PC患者的预后；然而，尽管进行了UGT1A1筛查，但严重中性粒细胞减少等不良事件仍频繁发生。本研究旨在确定接受改良FOLFIRINOX（mFFX）治疗PC患者发生严重中性粒细胞减少的新型生物标志物。本研究纳入了接受mFFX治疗的PC患者（n = 71）、吉西他滨联合纳米白蛋白结合型紫杉醇（GnP）治疗的PC患者（n = 92）以及接受FOLFOXIRI治疗的结直肠癌患者（n = 50）。在筛查阶段进行了全外显子测序的全基因组筛查。使用聚合酶链反应基因分型、 Cochr an-Armitage趋势检验和多变量分析进行验证分析。使用留一法交叉验证的逻辑回归检验严重中性粒细胞减少联合危险因素的诊断性能。从筛查阶段选择了三个基因多态性并进入验证阶段。在验证阶段，C11orf24基因的一个单核苷酸多态性（c.448C>T，rs901827）与接受mFFX和FOLFOXIRI治疗的≥3级中性粒细胞减少显著相关，但与接受GnP治疗的患者无关。多变量分析显示C11orf24和基线中性粒细胞计数是≥3级中性粒细胞减少的独立危险因素。中性粒细胞减少预测模型的诊断性能显示，≥3级和4级中性粒细胞减少的曲线下面积分别为0.754（敏感性 = 0.605，特异性 = 0.848）和0.856（敏感性 = 0.800，特异性 = 0.893）。C11orf24基因和基线中性粒细胞计数可能是预测含伊立替康三联化疗后严重中性粒细胞减少的有用生物标志物。
