Impact of HER2 and microsatellite instability status on response to neoadjuvant/conversion therapy and survival in patients with gastric cancer

Objectives: The prognostic significance of microsatellite instability (MSI) and HER2 status in advanced gastric cancer (AGC) treated with neoadjuvant or conversion chemotherapy (NAC) remains unclear. This study aimed to evaluate their impact on pathological response and survival outcomes in AGC patients undergoing NAC followed by surgery. Methods: This single-center, retrospective observational study included 121 patients with gastric adenocarcinoma at clinical stage >cT2N0, defined as tumor invasion beyond the muscularis propria, nodal involvement, or both. Eligible patients received at least two cycles of NAC and underwent surgical resection. Adults without other malignancies and with biopsy samples available for molecular analysis were included. Data were obtained from a prospectively maintained surgical database. Imaging studies were reviewed by expert radiologists, and molecular analyses were performed in the pathology department. Results: Among the 121 patients, MSI was identified in 6.6% and HER2 positivity in 9.9%. All MSI tumors were HER2 negative (P < 0.001). HER2 positivity was more frequent in intestinal-type tumors (P = 0.034) and was associated with better pathological response (P = 0.048). The 5-year overall survival (OS) rate was 44.7%, with a median OS of 42.6 months. Multivariate Cox regression identified tumor location in the upper third, residual tumor, nodal stage, Lauren diffuse-mixed histotype, and negative HER2 status as independent prognostic factors (P < 0.05). MSI status was not significantly associated with OS (P = 0.786), although a trend toward improved survival was observed in MSI-H patients. Conclusions: HER2 overexpression correlated with better pathological response and independently predicted improved OS. MSI and HER2 status may serve as biomarkers to guide preoperative treatment strategies in AGC.