Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment

• DOI: 10.1136/jitc-2020-001297
• Publication Date: 2020-11-11T08:05:14Z
• Authors: Zhenghang Wang; Xiaochen Zhao; Chan Gao; Jifang Gong; Xicheng Wang; Jing Gao; Zhongwu Li; Jie Wang; Bo Yang; Lei Wang; Bei Zhang; Yifan Zhou; Dalei Wang; Xiaofang Li; Yuezong Bai; Jian Li; Lin Shen
• Keywords: Microsatellite Instability; Immune checkpoint

Background Microsatellite instability (MSI) represents the first pan-cancer biomarker approved to guide immune checkpoint blockade (ICB) treatment. However its widespread testing, especially outside of gastrointestinal cancer, is hampered by tissue availability. Methods An algorithm for detecting MSI from peripheral blood was established and validated using clinical plasma samples. Its value predicting ICB efficacy evaluated among 60 patients with advanced cancer. The landscape in also explored 5138 solid tumors. Results included 100 microsatellite markers high capture efficiency, sensitivity, specificity. In comparison orthogonal PCR results, method displayed a sensitivity 82.5% (33/40) specificity 96.2% (201/209), an overall accuracy 94.0% (234/249). When validation cohort dichotomized pretreatment (bMSI), bMSI-high (bMSI-H) predicted both improved progression-free survival than stable (bMSS) (HRs: 0.431 0.489, p=0.005 0.034, respectively). Four bMSS were identified have tumor mutational burden (bTMB-H) trended towards better bMSS-bTMB-low (bTMB-L) subset (HR 0.026, 95% CI 0 2.635, p=0.011). These four bMSS-bTMB-H plus bMSI-H group collectively significantly over bMSS-bTMB-L 0.317, 0.157 0.640, p<0.001). Pan-cancer prevalence largely consistent that shown except much lower rates endometrial cancers, remarkably higher prostate cancer relative other types. Conclusions We developed reliable robust next generation sequencing-based bMSI detection strategy which, combination panel enabling concurrent profiling bTMB single draw, may inform