FAT4 mutation as a potential predictive biomarker for immunotherapy combined with anti-angiogenic therapy in MSS metastatic colorectal cancer.

e15504 Background: Microsatellite stable (MSS) metastatic colorectal cancer (CRC) lacks effective treatments and has a poor prognosis. The aim of this study was to identify patients who could benefit from immunotherapy combined with anti-angiogenic therapy. Exploration of predictive biomarkers could help to maximize the clinical benefits. Methods: In total, FFPE tissues samples before immunotherapy combined with anti-angiogenic therapy of 21 patients were successfully tested for tumor microenvironments (TMEs) by multiple immunofluorescence, of which 11 of them were successfully detected by 733-gene NGS panel in a CLIA-certified laboratory. The correlation between gene variations and clinical durable benefit (DCB: PR, or SD≥6 months), PFS and TMEs were analyzed by Fisher's test, K-M survival curve analysis and Mann Whitney analysis respectively. Results: Significant difference was detected between FAT4 mutation (FAT4-MUT) and FAT4 wildtype (FAT4-WT) regarding DCB (100%, 4/4 vs 17%, 1/7, P = 0.0152) and progress-free survival (median PFS, 13.8 months vs 2.8 months, LogRank P = 0.003). There was no significant difference in TMB level between DCB and NDB (SD＜6 months, or PD) groups (12 mut/Mb vs 6 mut/Mb, P = 0.0823) or between FAT4-MUT and FAT4-WT (11 mut/Mb vs 6 mut/Mb, P = 0.3697). TMEs analyses revealed that the CD3+CD4+ T cell proportion was tended to be higher in FAT4-MUT (0.7% vs 0.3%, P = 0.054). Further TIMER2.0 data showed FAT4-MUT was significantly associated with higher Immune infiltration of four immune cells, including CD4+ T cell in both colon and rectal adenocarcinoma, CD8+ central memory T cell, B cell, and Macrophage in colon adenocarcinoma. Conclusions: Our findings indicated that FAT4 mutation serves as a potential novel biomarker correlated with a better response to immunotherapy combined with anti-angiogenic therapy in MSS metastatic CRC, which may be related to the activation of CD4 T cell infiltration. However, these need to be validated by further cohort expansion.