de la Fouchardière Christelle, Cammarota Antonella, Svrcek Magali, Alsina Maria, Fleitas-Kanonnikoff Tania, Lordick Obermannová Radka, Wagner Anna Dorothea, Yap Wei Ting Dominic, Enea Diana, Petrillo Angelica, Smyth Elizabeth C
Institut PAOLI-CALMETTES, 232 Boulevard Sainte-Marguerite 13009, Marseille, France; Unicancer GI (UCGI) Group, Paris, France; EORTC-GITC Group, Brussels, Belgium.
EORTC-GITC Group, Brussels, Belgium; Hepatobiliary Immunopathology Lab, Humanitas University, Pieve Emanuele, Milan, Italy.
Cancer Treat Rev. 2025 Mar;134:102890. doi: 10.1016/j.ctrv.2025.102890. Epub 2025 Feb 1.
In less than a decade, immune checkpoint inhibitors (ICIs) have transformed the management of mismatch repair-deficient (dMMR) and microsatellite instability-high (MSI) cancers. However, beyond colorectal cancer (CRC), much of the evidence is mostly derived from non-randomized phase II studies or post-hoc analyses of broader clinical trials. dMMR/MSI tumours represent a specific subgroup of gastro-esophageal adenocarcinomas (GEA), accounting for approximately 9 % of cases, with a higher prevalence in early-stage compared to advanced-stage disease and older female patients. These tumours are predominantly sporadic, often linked to MLH1 promoter methylation, and rarely exhibit HER2 overexpression/ERBB2 amplification or other oncogenic drivers. The treatment landscape for early stage dMMR/MSI GEA is likely to change substantially soon, as ICIs have shown high pathological complete response (pCR) rates in small phase II trials, raising questions on optimisation of neoadjuvant therapy, and paving the way for organ preservation. The standard of treatment for untreated patients with advanced dMMR/MSI GEA is chemotherapy + ICI irrespectively of PDL-1 status. However, the role of chemotherapy-free regimen consisting of CTLA-4 plus PD-1 inhibitors remains undetermined. This review addresses these and other emerging questions, offering expert opinions and insights into the future therapeutic landscape for dMMR/MSI GEA.
在不到十年的时间里，免疫检查点抑制剂（ICIs）已经改变了错配修复缺陷（dMMR）和微卫星高度不稳定（MSI）癌症的治疗方式。然而，除了结直肠癌（CRC）之外，大部分证据大多来自非随机的II期研究或更广泛临床试验的事后分析。dMMR/MSI肿瘤是胃食管腺癌（GEA）的一个特定亚组，约占病例的9%，与晚期疾病和老年女性患者相比，在早期阶段的患病率更高。这些肿瘤主要是散发性的，通常与MLH1启动子甲基化有关，很少表现出HER2过表达/ERBB2扩增或其他致癌驱动因素。早期dMMR/MSI GEA的治疗格局可能很快会发生重大变化，因为ICIs在小型II期试验中显示出较高的病理完全缓解（pCR）率，这引发了关于新辅助治疗优化的问题，并为器官保留铺平了道路。无论PDL-1状态如何，晚期dMMR/MSI GEA未治疗患者的标准治疗方法是化疗+ICI。然而，由CTLA-4加PD-1抑制剂组成的无化疗方案的作用仍未确定。本综述探讨了这些以及其他新出现的问题，提供了专家意见，并对dMMR/MSI GEA未来的治疗格局进行了深入分析。
