Induction Chemotherapy Followed by Immunotherapy Increases Pathological Complete Response Rate in dMMR/MSI-H Gastric Cancer: A Retrospective Cohort Study

Hong Zeng,1,* Yingying Wu,1,* Ziwei Zhang,1 Jingdong Liu,1 Jie Sun,1 Xinyou Liu,1,2 Yuan Gu,1 Mengxin Tian,1 Weidong Chen,1 Zhenbin Shen,1 Kuntang Shen,1 Chen Xu,3 Xuefei Wang,1,2,4 Zhaoqing Tang,1,2,4 Yihong Sun1,4,5 1Department of Gastrointestinal Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of General Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, People’s Republic of China; 3Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 4Gastric Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 5Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yihong Sun, Department of Gastrointestinal Surgery, Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China, Email sun.yihong@zs-hospital.sh.cn Zhaoqing Tang, Department of Gastrointestinal Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China, Email tang.zhaoqing@zs-hospital.sh.cnBackground: Immune checkpoint inhibitor (ICI)-based strategies have become a consensus in the preoperative treatment of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) gastric cancer (GC). However, the necessity and optimal strategy of combining ICIs with chemotherapy remain uncertain.Methods: This retrospective study aimed to evaluate the efficacy of different preoperative chemo-immunotherapy combinations in patients with dMMR/MSI-H GC. According to their therapeutic regimens, patients were divided into three cohorts: ICI-alone cohort; immunotherapy with induction chemotherapy (IC) cohort (ICI + IC): 1– 2 cycles of IC followed by ICI; concurrent chemo-immunotherapy cohort (ICI + chemo): ICI combined with chemotherapy throughout the entire preoperative treatment. The pathological complete response (pCR) rate and major pathological response (MPR) rate were analyzed. Peripheral blood parameters before and after preoperative treatment were analyzed.Results: A total of 45 patients with locally advanced or oligometastatic dMMR/MSI-H GC were included. Baseline characteristics were well balanced among the three cohorts. The pCR rates were 18.2% (95% CI, 2.3– 51.8%) in the ICI-alone cohort, 85.7% (95% CI, 42.1– 99.6%) in the ICI + IC cohort, and 37.0% (95% CI, 19.4– 57.6%) in the ICI + chemo cohort. Notably, the ICI + IC cohort showed a significantly higher pCR rate than the other two cohorts (p=0.015). The MPR rates were 54.5%, 85.7%, and 48.1% in the three cohorts, respectively, with no statistical significance. After preoperative treatment, monocyte-to-lymphocyte ratio exhibited an upward trend in the ICI + IC (p=0.100) and ICI + chemo (p=0.058) cohorts, indicating enhanced antigen presentation activity and immune activation.Conclusion: A preoperative strategy of IC followed by ICIs significantly increased pCR rate compared to ICI monotherapy or concurrent chemo-immunotherapy, suggesting a more effective strategy for patients with resectable dMMR/MSI-H GC. Given its retrospective design, small sample size, and lack of safety data, this study warrants validation in prospective clinical trials.Keywords: dMMR/MSI-H gastric cancer, preoperative treatment, induction therapy, immunotherapy, chemotherapy, pathological complete response