He Mei, Ji Congcong, Li Zhiwei, Chen Shiqing, Gao Jing, Shen Lin, Zhang Cheng
Department of Oncology, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
Gastric Cancer. 2025 May 15. doi: 10.1007/s10120-025-01621-x.
Immune checkpoint inhibitors (ICIs) are becoming more prominent in the treatment of gastric cancer (GC). However, predictive biomarkers of response to ICIs in HER2-negative patients remain incompletely understood.
A total of 47 patients diagnosed with HER2-negative advanced GC who underwent ICI regimens were eligible for this study. Plasma samples with paired white blood cells prior to treatments were collected from these 47 patients. Variations of circulating tumor DNA (ctDNA) was evaluated by next-generation sequencing followed by its significance analysis.
A total of 658 somatic mutations involving 203 genes were identified in all ctDNA. Mutations in MEN1, MLH1, CEBPA, ATR, GNAQ, and FOXL2 genes were more frequent in responders (P < 0.05). Compared with wild-type patients, patients with CEBPA or IRS2 mutations had prolonged median progression-free survival (mPFS, P = 0.0056). Patients with co-occurring mutations in IRS2/CEBPA, IRS2/POLD1, TP53/PIK3CA, or POLD1/CEBPA had longer mPFS compared with others (P = 0.003; 0.006; 0.0166; 0.0315; respectively). Both alteration of CDKN2A alone and co-mutations with MSH6 were significantly associated with superior overall survival (OS, P = 0.0289; 0.0355; respectively). In addition, higher on-treatment ctDNA concentration or variant allele frequency (VAF) were associated with poorer response (P < 0.05). Additionally, the increased molecular alterations of POLE, FGFR2 and MDC1 seemed to indicate the acquired resistance to ICIs.
Variation signatures captured by ctDNA as well as the kinetics of ctDNA could predict the clinical benefits of ICB in HER2-negative GC patients, which was worth further validated in large cohort.
免疫检查点抑制剂（ICIs）在胃癌（GC）治疗中愈发重要。然而，HER2阴性患者对ICIs反应的预测生物标志物仍未完全明确。
本研究纳入47例接受ICI方案治疗的HER2阴性晚期GC患者。从这47例患者中收集治疗前配对的血浆样本及白细胞样本。采用二代测序评估循环肿瘤DNA（ctDNA）的变异情况，并进行显著性分析。
在所有ctDNA中共鉴定出涉及203个基因的658个体细胞突变。MEN1、MLH1、CEBPA、ATR、GNAQ和FOXL2基因的突变在反应者中更为常见（P<0.05）。与野生型患者相比，CEBPA或IRS2突变患者的中位无进展生存期（mPFS）延长（P=0.0056）。IRS2/CEBPA、IRS2/POLD1、TP53/PIK3CA或POLD1/CEBPA同时发生突变的患者与其他患者相比，mPFS更长（分别为P=0.003；0.006；0.0166；0.0315）。单独的CDKN2A改变以及与MSH6的共突变均与较好的总生存期（OS）显著相关（分别为P=0.0289；0.0355）。此外，治疗期间ctDNA浓度或变异等位基因频率（VAF）较高与反应较差相关（P<0.05）。另外，POLE、FGFR2和MDC1分子改变的增加似乎表明对ICIs产生了获得性耐药。
ctDNA捕获的变异特征以及ctDNA的动力学可以预测ICB对HER2阴性GC患者的临床益处，值得在大型队列中进一步验证。
