Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
Medical Affairs, 3D Medicines Inc, Shanghai, China.
J Immunother Cancer. 2020 Nov;8(2). doi: 10.1136/jitc-2020-001297.
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.
An algorithm for detecting MSI from peripheral blood was established and validated using clinical plasma samples. Its value for predicting ICB efficacy was evaluated among 60 patients with advanced gastrointestinal cancer. The landscape of MSI in blood was also explored among 5138 advanced solid tumors.
The algorithm included 100 microsatellite markers with high capture efficiency, sensitivity, and specificity. In comparison with orthogonal tissue PCR results, the method displayed a sensitivity of 82.5% (33/40) and a specificity of 96.2% (201/209), for an overall accuracy of 94.0% (234/249). When the clinical validation cohort was dichotomized by pretreatment blood MSI (bMSI), bMSI-high (bMSI-H) predicted both improved progression-free survival and overall survival than the blood microsatellite stable (bMSS) patients (HRs: 0.431 and 0.489, p=0.005 and 0.034, respectively). Four patients with bMSS were identified to have high blood tumor mutational burden (bTMB-H) and trended towards a better survival than the bMSS-bTMB-low (bTMB-L) subset (HR 0.026, 95% CI 0 to 2.635, p=0.011). These four patients with bMSS-bTMB-H plus the bMSI-H group collectively displayed significantly improved survival over the bMSS-bTMB-L patients (HR 0.317, 95% CI 0.157 to 0.640, p<0.001). Pan-cancer prevalence of bMSI-H was largely consistent with that shown for tissue except for much lower rates in endometrial and gastrointestinal cancers, and a remarkably higher prevalence in prostate cancer relative to other cancer types.
We have developed a reliable and robust next generation sequencing-based bMSI detection strategy which, in combination with a panel enabling concurrent profiling of bTMB from a single blood draw, may better inform ICB treatment.
微卫星不稳定性（MSI）代表了首个被批准用于指导免疫检查点阻断（ICB）治疗的泛癌生物标志物。然而，由于组织可用性的限制，其广泛检测，尤其是在胃肠道癌之外，受到了阻碍。
建立并验证了一种从外周血中检测 MSI 的算法，该算法使用临床血浆样本进行。在 60 名晚期胃肠道癌患者中，评估了该方法预测 ICB 疗效的价值。还在 5138 例晚期实体瘤中探索了血液中 MSI 的情况。
该算法包含 100 个具有高捕获效率、灵敏度和特异性的微卫星标记物。与正交组织 PCR 结果相比，该方法显示出 82.5%（33/40）的灵敏度和 96.2%（201/209）的特异性，总准确率为 94.0%（234/249）。当临床验证队列按预处理血 MSI（bMSI）分为两部分时，bMSI-高（bMSI-H）患者的无进展生存期和总生存期均优于血微卫星稳定（bMSS）患者（HR：0.431 和 0.489，p=0.005 和 0.034）。4 例 bMSS 患者的血肿瘤突变负担（bTMB-H）较高，且其生存情况好于 bMSS-bTMB-低（bTMB-L）亚组（HR 0.026，95%CI 0 至 2.635，p=0.011）。这 4 例 bMSS-bTMB-H 加上 bMSI-H 组的总生存情况明显优于 bMSS-bTMB-L 患者（HR 0.317，95%CI 0.157 至 0.640，p<0.001）。除子宫内膜癌和胃肠道癌的发生率明显较低外，bMSI-H 的泛癌发生率与组织基本一致，而前列腺癌的发生率明显高于其他癌症类型。
我们已经开发了一种可靠且强大的基于下一代测序的 bMSI 检测策略，该策略与可同时从单个血样中进行 bTMB 分析的面板相结合，可能更好地指导 ICB 治疗。
