Noninvasive Detection of Microsatellite Instability and High Tumor Mutation Burden in Cancer Patients Treated with PD-1 Blockade
Noninvasive Detection of Microsatellite Instability and High Tumor Mutation Burden in Cancer Patients Treated with PD-1 Blockade
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DOI：
10.1158/1078-0432.ccr-19-1372
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发表时间：
2019-12-01
影响因子：
11.5
通讯作者：
Sausen, Mark
中科院分区：
文献类型：
--
作者：
Georgiadis, Andrew;Durham, Jennifer N.;Sausen, Mark
目的：微卫星不稳定性（MSI）和高肿瘤突变负荷（TMB-高）是有希望的泛肿瘤生物标志物，用于选择接受免疫检查点阻断治疗的患者;然而，不可切除或转移性实体瘤的实时测序通常具有挑战性。我们报告了一种非侵入性的方法检测MSI和TMB-高循环中的patients.Experimental Design：我们开发了一种方法，利用了一个混合捕获为基础的98 kb泛癌基因面板，包括有针对性的微卫星区域。建立了一种多因子误差校正方法和一种新的峰发现算法来鉴定游离DNA（cfDNA）中罕见的MSI移码等位基因。通过分析源自健康供体和转移性癌症患者的组合的cfDNA，误差校正和峰值发现方法产生的特异性>99%（n = 163），灵敏度分别为78%（n = 23）和67%（n = 15），适用于MSI和TMB-High。对于接受PD-1阻断剂治疗的患者，我们证明了治疗前血浆中的MSI和TMB-高水平可预测无进展生存期（风险比：分别为0.21和0.23，P = 0.001和0.003）。此外，我们分析了cfDNA从纵向收集的血浆样本治疗期间获得，以确定谁实现持久响应PD-1 blocked.Conclusions的患者：这些分析证明了无创泛癌筛查和监测的患者谁表现出MSI或TMB-高，并有很高的可能性响应免疫检查点封锁的可行性。
Purpose: Microsatellite instability (MSI) and high tumor mutation burden (TMB-High) are promising pan-tumor biomarkers used to select patients for treatment with immune checkpoint blockade; however, real-time sequencing of unresectable or metastatic solid tumors is often challenging. We report a noninvasive approach for detection of MSI and TMB-High in the circulation of patients.Experimental Design: We developed an approach that utilized a hybrid-capture-based 98-kb pan-cancer gene panel, including targeted microsatellite regions. A multifactorial error correction method and a novel peak-finding algorithm were established to identify rare MSI frameshift alleles in cell-free DNA (cfDNA).Results: Through analysis of cfDNA derived from a combination of healthy donors and patients with metastatic cancer, the error correction and peak-finding approaches produced a specificity of >99% (n = 163) and sensitivities of 78% (n = 23) and 67% (n = 15), respectively, for MSI and TMB-High. For patients treated with PD-1 blockade, we demonstrated that MSI and TMB-High in pretreatment plasma predicted progression-free survival (hazard ratios: 0.21 and 0.23, P = 0.001 and 0.003, respectively). In addition, we analyzed cfDNA from longitudinally collected plasma samples obtained during therapy to identify patients who achieved durable response to PD-1 blockade.Conclusions: These analyses demonstrate the feasibility of noninvasive pan-cancer screening and monitoring of patients who exhibit MSI or TMB-High and have a high likelihood of responding to immune checkpoint blockade.