Clinicopathologic features, treatment patterns, and outcomes of microsatellite instability–high (MSI-H) gastric (GC) and gastroesophageal junction adenocarcinoma (GEJ): A single-center retrospective analysis.

Abstract

445 Background: The biologically distinct subtype of MSI-H GC/GEJ has prognostic and therapeutic implications. Immunotherapy (IO) has demonstrated clinical benefit in MSI-H disease; real-world clinical outcomes and treatment patterns are underreported. We performed a retrospective review to characterize clinicopathologic features, treatment patterns, and survival outcomes in locally advanced/metastatic GC/GEJ. Methods: We identified 35 patients (pts) with biopsy-proven MSI-H GC/GEJ treated at City of Hope between 2012 and 2025. Clinical, pathologic, molecular, and treatment data were collected. Pts were categorized as responders/non-responders based on RECIST v1.1 criteria and clinical outcomes. Survival outcomes were estimated using Kaplan–Meier curves and stratified by stage and IO response. Results: Median age was 64 years (SD 14.6); 51.4% were male. Median follow-up was 33 months. At diagnosis, pts had stage I (11.4%), stage II (26.5%), stage III (17.1%), and stage IV (45.7%) disease. Most tumors were poorly differentiated (68.6%) and HER2-negative (91.2%). 17.6% of pts had Lynch Syndrome. Tumor sites included gastric body (40%), pylorus/antrum (28.6%), cardia (20%), and GEJ (11.4%). Surgery was performed on 80% of stage I-III pts and 61.1% of stage IV pts. IO was given to 52.6% of stage II–III pts and 87.5% of stage IV pts. IO response was strongly associated with durable survival. Responders achieved 12-, 24-, and 36-month overall survival (OS) rates of 82%, 82%, and 68%, respectively (median OS not reached). In contrast, non-responders had OS rates of 67%, 33%, and <20%, respectively (median OS 17.8 months) (log-rank p = 0.045). Among IO-treated stage IV pts, early events were observed around 3, 9, and 38 months, with approximately 50% survival probability at 38 months. Of responders, 48% had stage I–III disease, while 52% of non-responders had stage IV disease. No distinct genetic differences were observed between responders vs non-responders. IO-related toxicities included hepatitis, pneumonitis, cytopenia, arthralgia/myositis, and nephritis, each occurring in 14.3% of pts. Notably, 44.1% of pts had no IO-related toxicities. There were no treatment-related deaths. Conclusions: MSI-H GC and GEJ were frequently advanced at presentation, poorly differentiated, and largely HER2-negative. Many pts underwent surgery, including over half with stage IV disease. IO-related toxicities were minimal and aligned with prior reports. IO response was strongly associated with durable survival; non-responders experienced poor outcomes. These findings highlight the urgent need to identify determinants of IO response beyond MSI-H status in non-responders.