微卫星高度不稳定性胃癌及胃食管结合部腺癌的临床病理特征、治疗模式与结局：一项单中心回顾性分析

摘要(中文译文)

※ 中文译文由 AI 辅助生成,仅供学术参考,请以英文原文为准。

微卫星高度不稳定（MSI-H）和错配修复缺陷（dMMR）的胃或胃食管结合部（GEJ）腺癌是生物学上独特的肿瘤，已证实对免疫检查点抑制剂（ICIs）敏感。然而，真实世界治疗模式、疗效异质性及持久获益的预测因素仍定义不清。我们回顾性分析了在单中心接受治疗的活检确诊MSI-H/dMMR胃/GEJ腺癌患者。收集了临床病理、基因组、治疗及结局数据。分子谱分析包括ARID1A、RNF43、TP53、PIK3CA、KRAS、TGFBR2及人表皮生长因子受体2（HER2）。接受ICI治疗的患者根据iRECIST v1.1及临床评估分为获得临床获益（完全缓解、部分缓解或持久疾病稳定≥16周）或无临床获益。采用Kaplan-Meier法估算总生存期（OS）。共纳入34例患者（中位年龄66岁；53%为男性），其中21例为IV期疾病。肿瘤以低分化（65%）和HER2阴性（94%）为主，18%的患者患有Lynch综合征。在22例接受ICI治疗的患者中，55%获得临床获益，这与OS延长显著相关（P < .01）。大多数缓解发生在首次影像学评估时（约12周）。56%的患者存在肿瘤突变负荷升高（TMB；≥20突变/Mb），但与其临床获益无关（P = .40），且无单个基因组改变与治疗结局显著相关。探索性分析提示，肝转移患者较腹膜转移患者OS更长。治疗耐受良好，主要为低级别免疫相关不良事件。基线美国东部肿瘤协作组体能状态（0-1 vs ≥2）与临床获益相关（P = .049）。约半数MSI-H/dMMR胃/GEJ腺癌患者从ICI治疗中获得持久临床获益，且治疗缓解与生存强烈相关。传统基因组特征，包括TMB，未能预测临床获益，凸显了需要额外生物标志物的必要性。

Abstract

Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) gastric or gastroesophageal junction (GEJ) adenocarcinomas are biologically distinct tumors with established sensitivity to immune checkpoint inhibitors (ICIs). However, real-world treatment patterns, response heterogeneity, and predictors of durable benefit remain poorly defined. We retrospectively analyzed patients with biopsy-confirmed MSI-H/dMMR gastric/GEJ adenocarcinoma treated at a single center. Clinicopathologic, genomic, treatment, and outcome data were collected. Molecular profiling included ARID1A, RNF43, TP53, PIK3CA, KRAS, TGFBR2, and human epidermal growth factor 2 (HER2). ICIs-treated patients were classified as achieving clinical benefit (complete response, partial response, or durable stable disease ≥16 weeks) or no clinical benefit using iRECIST v1.1 and clinical assessment. Overall survival (OS) was estimated by using the Kaplan-Meier method. Thirty-four patients were identified (median age, 66 years; 53% male), including 21 with stage IV disease. Tumors were predominantly poorly differentiated (65%) and HER2-negative (94%), and 18% of patients had Lynch syndrome. Among 22 ICI-treated patients, 55% achieved clinical benefit, which was strongly associated with prolonged OS ( < .01). Most responses occurred at the first radiographic assessment (approximately 12 weeks). Elevated tumor mutational burden (TMB; ≥20 mutations/Mb) was present in 56% of patients but was not associated with clinical benefit ( = .40), and no individual genomic alteration significantly correlated with treatment outcome. Exploratory analyses suggested longer OS among patients with liver versus peritoneal metastases. Treatment was well tolerated, with predominantly low-grade immune-related adverse events. Baseline Eastern Cooperative Oncology Group performance status (0-1 ≥ 2) was associated with clinical benefit ( = .049). Approximately half of the patients with MSI-H/dMMR gastric/GEJ adenocarcinoma cancers derived durable clinical benefit from ICIs, and treatment response was strongly associated with survival. Conventional genomic features, including TMB, did not predict clinical benefit, highlighting the need for additional biomarkers.

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