Ko Josephine Mun-Yee, Guo Chen, Leung Alvin Ka-Kiu, Chan Steve Chun-Yin, Lo Anthony Wing-Ip, Tao Lihua, Ng Hoi-Yan, Wong Carissa Wing-Yan, Law Simon, Wong Ian Yu-Hong, Wong Claudia Lai-Yin, Chan Fion Siu-Yin, Chan Kwan Kit, Law Tsz Ting, Lam Ka-On, Kwong Dora Lai-Wan, Dai Wei, Lam Alfred King-Yin, Lung Maria Li
Department of Clinical Oncology, Centre of Cancer Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), Hong Kong, People's Republic of China.
Division of Anatomical Pathology, Queen Mary Hospital, Hong Kong (Special Administrative Region), Hong Kong, People's Republic of China.
Br J Cancer. 2025 Aug 8. doi: 10.1038/s41416-025-03113-2.
BACKGROUND: The poor prognosis of resectable esophageal squamous cell carcinoma (ESCC) poses an unmet need to identify early predictive and prognostic genomic biomarkers to improve treatment outcome and risk stratification. METHODS: Mutational profiling was performed for 171 ESCC patients receiving curative neoadjuvant chemoradiation treatment (nCRT). The discovery cohort included 100 ESCC formalin-fixed paraffin-embedded (FFPE) tumor specimens; the validation FFPE cohort consisted of serial ctDNA samples from 71 patients. RESULTS: The discovery cohort identified hot-spot oncogenic NFE2L2 mutations exclusively localized at DLG and ETGE KEAP1-binding motifs in poor responders associated with incomplete pathological response (P = 0.004). Patients with NFE2L2 mutations in two independent FFPE cohorts had about 2-fold higher risk of death and recurrence. Serial ctDNA analysis further demonstrated oncogenic NFE2L2 mutations detected at post-nCRT were independent prognosticators for recurrence (HR = 5.90; P = 0.005) and survival (HR = 4.75; P = 0.013). Risk stratification based on pathological T and N stages, positive FFPE (HR = 4.50) and ctDNA NFE2L2 mutations (HR = 8.50) identified high-risk groups for recurrence (P = 0.001). Combined FFPE and ctDNA NFE2L2 mutation status predicted nCRT responses (P = 0.05) by ROC analysis. CONCLUSIONS: Tracking oncogenic NFE2L2 mutations at pre-treatment and post-surgery or serial ctDNA monitoring during treatment are useful nCRT predictors and independent prognosticators of survival for locally advanced ESCC.
背景：可切除食管鳞状细胞癌（ESCC）预后较差，因此迫切需要识别早期预测和预后基因组生物标志物，以改善治疗效果和风险分层。 方法：对171例接受根治性新辅助放化疗（nCRT）的ESCC患者进行突变分析。发现队列包括100例ESCC福尔马林固定石蜡包埋（FFPE）肿瘤标本；验证FFPE队列由71例患者的系列循环肿瘤DNA（ctDNA）样本组成。 结果：发现队列中，在与不完全病理反应相关的低反应者中，发现热点致癌NFE2L2突变仅位于DLG和ETGE KEAP1结合基序处（P = 0.004）。在两个独立的FFPE队列中，NFE2L2突变患者的死亡和复发风险高出约2倍。系列ctDNA分析进一步表明，nCRT后检测到的致癌NFE2L2突变是复发（风险比[HR]=5.90；P = 0.005）和生存（HR = 4.75；P = 0.013）的独立预后因素。基于病理T和N分期、FFPE阳性（HR = 4.50）和ctDNA NFE2L2突变（HR = 8.50）的风险分层确定了复发高危组（P = 0.001）。通过受试者工作特征（ROC）分析，联合FFPE和ctDNA NFE2L2突变状态可预测nCRT反应（P = 0.05）。 结论：治疗前和手术后追踪致癌NFE2L2突变或治疗期间进行系列ctDNA监测，是局部晚期ESCC有用的nCRT预测指标和生存独立预后因素。
Gastroenterology. 2018-9-19
World J Surg Oncol. 2025-6-20
Zotero 插件