The tumour microenvironment score outperforms established molecular classifiers as a prognostic factor for disease-free interval and disease-specific survival in non-metastatic gastric cancer

INTRODUCTION: Molecular classification in gastric cancer has identified relevant disease heterogeneity with prognostic implications.However, limited comparative analysis of molecular classification systems has occurred.We assessed the effect of the Tumour Microenvironment Score (TME), the Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) classification systems on disease-free interval (DFI) and disease-specific survival (DSS) in Stage I-III gastric cancer.METHODS: Previously characterized machine learning models were used to assign TCGA, ACRG and TME molecular classes to stage I-III patients in the ACRG and TCGA datasets (n=523).DFI and DSS was assessed using univariable and multivariable Cox Proportional Hazards models.RESULTS: A multivariable Cox model including TCGA, ACRG and TME subtypes showed that only a high TME score was associated with improved DFI (HR 0.22 [95% CI 0.10, 0.49]; p < 0.001) and DSS (HR 0.2 [95% CI 0.09-0.43];p < 0.001).The significant effect of TME High score was maintained after sensitivity analysis that adjusted for stage, age, sex, chemotherapy, radiation, J o u r n a l P r e -p r o o f tumour location, and study (DFI: TME High HR 0.33 [95% CI 0.15, 0.73)]; p < 0.01 and DSS: TME High HR 0.21 [95% CI 0.08, 0.52)]; p < 0.001).CONCLUSIONS: In an integrated analysis comparing TCGA, ACRG and TME scores, a high TME score is the only independent molecular prognostic factor for DFI and DSS in non-metastatic gastric cancer.Additional investigation into implications of the heterogeneity of the TME score relative to the TCGA and ACRG classifications may yield additional insight into gastric cancer biology and treatment.