Bridging Tumor Biology and Clinical Outcomes in Locally Advanced and Oligometastatic Gastric Cancer: Molecular and Histopathological Biomarkers in the Multimodal Treatment Setting

Background: Gastric cancer is a heterogeneous disease, and outcomes after preoperative chemotherapy and surgery remain variable. Molecular and histopathological biomarkers may help refine prognostic stratification in locally advanced and selected oligometastatic disease. Aim: This study evaluated the association of HER2, MSI/MMR status, E-cadherin, and Claudin 18.2 with pathological response and survival in patients with gastric adenocarcinoma treated with preoperative chemotherapy followed by surgery. Methods: This retrospective single-center study included 121 patients treated between January 2010 and April 2023. All patients received at least two cycles of neoadjuvant or conversion chemotherapy followed by gastrectomy. HER2 and MSI/MMR status were assessed in the whole cohort, while E-cadherin and Claudin 18.2 were evaluated in a subgroup of poorly cohesive carcinomas with available surgical tissue. Results: HER2 positivity was found in 12 patients (9.9%) and MSI in 8 patients (6.6%). HER2-positive tumors were more frequently intestinal-type and showed better pathological regression. Five-year overall survival was 44.7%, with a median OS of 42.6 months. At multivariate analysis, proximal tumor location, non-radical resection, ypN3 stage, diffuse/mixed Lauren histotype, and HER2-negative status were independently associated with worse OS. E-cadherin and Claudin 18.2 showed no significant association with OS or DFS in the exploratory subgroup. Conclusion: In this cohort, pathological stage, radicality of resection, tumor location, and Lauren histotype remained the main prognostic factors. HER2 positivity was associated with better pathological response and more favorable survival, while MSI, E-cadherin, and Claudin 18.2 had limited prognostic impact. Larger multicenter studies are needed to validate these findings and better define the role of molecular and histopathological biomarkers in the multimodal treatment of gastric cancer.