Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer

作者：Zhenghang Wang, Qi Zhang, Changsong Qi, Yuezong Bai, Feilong Zhao, Hui Chen, Zhongwu Li, Xicheng Wang, Mifen Chen, Jifang Gong, Zhi Peng, Xiaotian Zhang, Jinping Cai, Shiqing Chen, Xiaochen Zhao, Lin Shen, Jian Li · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2022 · DOI：10.1136/jitc-2022-004703 · 被引用次数：40 · 研究领域：Genetic factors in colorectal cancer、Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis

BACKGROUND: Gastrointestinal (GI) cancer is the second most common cancer type with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) phenotype that is expected to respond to immune-checkpoint inhibitors (ICIs). However, approximately half of the patients with dMMR/MSI-H GI cancer derive no benefit from ICIs. We sought to identify the predictors of primary resistance to ICIs in dMMR/MSI-H GI cancer. METHODS: Three independent cohorts were included: (1) the discovery cohort (65 patients with dMMR/MSI-H GI cancer) with ICI efficacy data and pre-ICIs tissue samples for genomic profile and tumor immune infiltration; (2) the validation cohort (22 patients with dMMR/MSI-H GI cancer) with ICI efficacy data and pre-ICIs plasma samples for genomic profile; and (3) the TCGA (The Cancer Genome Atlas) cohort not receiving ICIs (152 patients with MSI-H GI cancer) with genomic profile and survival data. RESULTS: AKT1 and CDH1 mutations were identified as independent predictors of poor progression-free survival (PFS) and primary resistance to ICIs in dMMR/MSI-H GI cancer. We combined these two genes as an immuno-oncology therapy predictor (IOpred), which could recognize 52.4% (11/21) of dMMR/MSI-H patients with primary resistance to ICIs with a positive predictive value (PPV) of 91.7% (11/12). Receiver operating characteristic analysis demonstrated IOpred with a good performance in predicting primary resistance (area under the curve 0.751). Patients with IOpred-Mut (m...