HER2 expression dynamics and prognostic significance in the treatment of gastric cancer.

4025 Background: The human epidermal growth factor receptor 2 (HER2) expression undergoes changes during the treatment of gastric cancer. This study aims to evaluate post-treatment HER2 expression changes and the impact on survival. Methods: From a prospectively maintained database, we extracted clinical and pathological data, treatment information, and survival outcomes of gastric cancer patients (pts) with paired pre- and post-treatment HER2 immunohistochemistry (IHC) results (2018-2024). Cohen’s Kappa was used to assess HER2 expression concordance. Logistic regression was performed to identify factors associated with HER2 change, while the Kaplan-Meier method and Cox regression were used for survival analysis. Results: 274 gastric cancer pts with paired HER2 IHC results were enrolled, including IHC 0 (67.5%, 185/274), 1+ (14.6%, 40/274), 2+ (13.5%, 37/274), 3+ (4.4%, 12/274) before treatment and IHC 0 (63.8%, 175/274), 1+ (21.9%, 60/274), 2+ (11.7%, 32/274), and 3+ (2.6%, 7/274) after treatment. The overall HER2 change rate was 42.7% (21.5% HER2 expression increased, 21.2% decreased), indicating low concordance (Kappa = 0.179, p < 0.001). Among 7.6% (17/225) of pts with HER2 changes from 0/1+ to 2+/3+, 23.5% (4/17) received anti-HER2 therapy (trastuzumab or anti-HER2 ADCs), achieving a 75.0% response rate. 38.5% (5/13) of initially confirmed HER2-positive pts (IHC 3+/2+ and FISH+) exhibited loss of HER2 positivity after treatment. 3 of 8 initially HER2-negative pts who converted to HER2-positive received trastuzumab for metastatic diseases, achieving a 66.7% response rate. Based on efficacy evaluation on the second HER2 testing, 197 pts were classified into the PR/SD group and 77 into the PD group, with comparable HER2 changes rate (41.6% vs. 45.5%, p = 0.565). Anti-HER2 therapy (n = 28) was associated with a higher HER2 changes rate (67.9% vs. 39.8%, p = 0.005), mainly driven by HER2 reduction (60.7% vs. 16.7%, p < 0.001). Multivariate logistic regression showed that combined immunotherapy (OR [odds ratio] 1.85, p = 0.028) or targeted immunotherapy (OR 4.71, p < 0.001) was associated with a higher HER2 change rate than chemotherapy alone. The median follow-up time was 31.2 months. HER2 expression changes were associated with worse PFS (HR [hazard ratio] 1.52, p = 0.040) and OS (HR 1.51, p = 0.043), with decreased HER2 expression showing the poorest PFS (Log-rank p = 0.030) and OS (Log-rank p = 0.025). Subgroup analysis showed in PR/SD group, HER2 expression changes was associated with significantly worse PFS (HR 2.48, p = 0.003) and OS (HR 2.56, p = 0.002), while no survival differences were observed in PD group. Conclusions: HER2 expression frequently changes during the treatment of gastric cancer, particularly after immunotherapy and targeted therapy, and is associated with worse survival outcomes. Dynamic HER2 testing contributes to guiding precision therapy for gastric cancer.