Efficacy of neoadjuvant HER-2-targeted therapy in resectable HER-2-positive gastric and esophagogastric junction cancers: A meta-analytic perspective.

422 Background: Gastric, esophageal, and gastroesophageal junction cancers contribute significantly to global morbidity and mortality, with a persistently poor prognosis despite therapeutic advancements. While HER-2-targeted therapies have markedly improved outcomes in HER-2-positive breast cancer, their efficacy in resectable HER-2-positive gastric, esophageal, and gastroesophageal junction cancers remains unclear. This systematic review and meta-analysis aim to evaluate the role of HER-2 inhibition as a neoadjuvant strategy in managing this patient cohort. Methods: This study was conducted following PRISMA guidelines. A comprehensive literature search was performed in PubMed, Embase, and the Cochrane Library to yield a total of 321 articles. After deduplication, 260 articles were screened, and 31 full-text articles were assessed for eligibility. Studies were included if they reported efficacy outcomes of Her-2 directed neoadjuvant therapy in patients with resectable gastric, esophagogastric and gastroesophageal junction cancer. In cases of overlapping trial data across different phases, the most complete report or the one with the longest follow-up as of September 2025 was included. Risk of bias was assessed using the ROB-2 tool. A random-effects meta-analysis using inverse variance weighting was conducted. Pooled proportions were calculated with 95% confidence intervals (CIs), and heterogeneity was assessed using I² and Chi² statistics. Results: The meta-analysis results indicate a pooled overall survival rate of 82.14% (95% CI: 69.47%, 90.29%) across 288 observations, with significant heterogeneity (I² = 78.6%, P < 0.0001), suggesting variability among the eight studies analyzed. Progression-free survival was estimated at 73.81% (95% CI: 53.73%, 87.24%) from 131 observations, showing moderate heterogeneity (I² = 76.3%, P = 0.0148). Additionally, the overall response rate stood at 68.80% (95% CI: 47.65%, 84.23%) across 217 observations, with notable heterogeneity (I² = 84.3%, P < 0.0001). These findings underscore the need for cautious interpretation and personalised treatment strategies, considering the wide confidence intervals and study-specific differences. Conclusions: HER-2-directed therapy offers a promising biomarker-driven approach for treating gastrointestinal malignancies. In the neoadjuvant setting, these therapies demonstrate significant clinical benefits for resectable gastric, esophageal, and gastroesophageal junction cancers, broadening therapeutic options for patients previously excluded from targeted treatments. This meta-analysis reinforces the expanding efficacy of anti-HER2 strategies and advocates for their further integration into multimodal treatment protocols.