Global burden, risk factors, clinicopathological characteristics, molecular biomarkers and outcomes of microsatellite instability-high gastric cancer.

ABSTRACT

Microsatellite instability-high (MSI-H) has gained considerable interests since it was approved as a tumor-agnostic biomarker in immunotherapy. However, the reported characteristics of MSI-H gastric cancer (GC) are inconsistent due to the biological complexity. Here, we aim to clarify the prevalence, risk factors, clinicopathological/molecular features and outcomes of MSI-H GC though a comprehensive review on 43246 patients from 134 cohorts. Overall, the proportion of MSI-H GC was 14.5% (95% CI, 13.3%-15.8%). Patients with MSI-H GC were less likely to have Epstein-Barr virus infection. High incidences of MSI-H GC were associated with female, older age, lower gastric body, Lauren intestinal histology, WHO tubular and mucinous subtypes, and early disease stage. Additionally, patients with MSI-H GC harbored more KRAS mutation, PD-L1 positivity, CD8 overexpression, and higher TMB, but less HER2 positivity and TP53 mutation. When treated with conventional strategy, the 5-year survival rates in MSI-H patients (70.3%) and MSI-L/MSS patients (43.7%) were significantly different (p<0.001). Patients with MSI-H GC derived larger benefit from immunotherapy in term of overall survival (pInteraction<0.001) and objective response (pInteraction=0.02). Since the prevalence of MSI-H GC is relatively high and associated with distinct clinicopathological and molecular characteristics, MSI testing should be conducted during standard diagnostical activity. Moreover, giving MSI-H tumors are often diagnosed at early stage and have favorable outcomes, less aggressive treatment strategies may be considered in clinical practice. In summary, this panoramic review may assist in design and/or interpretation of clinical trials, provide references in drug development, and constitute complementary information in drafting the clinical practice guideline.