Validation of Microsatellite Instability Detection Using a Comprehensive Plasma-Based Genotyping Panel
Validation of Microsatellite Instability Detection Using a Comprehensive Plasma-Based Genotyping Panel
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DOI：
10.1158/1078-0432.ccr-19-1324
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发表时间：
2019-12-01
影响因子：
11.5
通讯作者：
Odegaard, Justin I.
中科院分区：
文献类型：
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作者：
Willis, Jason;Lefterova, Martina I.;Odegaard, Justin I.
目的：对游离DNA （cfDNA）测序检测微卫星不稳定性（MSI）进行分析和临床验证。实验设计：使用guarant360进行泛癌MSI检测，根据既定指南进行分析验证，并使用1145份cfDNA样本进行临床验证，这些样本的组织MSI状态基于标准护理组织检测。在28,459例临床血浆样本队列中，研究了基于cfdna的MSI在实体肿瘤类型中的分布。对16例cfDNA MSI-H胃癌患者进行免疫治疗的临床结果进行了评价。结果：cfDNA MSI评价具有较高的特异性、精密度和敏感性，检测限为0.1%的肿瘤含量。在可评估的患者中，cfDNA检测准确检测了87%（71/82）的组织MSI-H和99.5%的组织微卫星稳定性（863/867），总体准确率为98.4%(934/949)，阳性预测值为95%（71/75）。cfDNA MSI与组织PCR和下一代测序的一致性显著高于IHC。cfDNA MSI在主要癌症类型中的患病率与组织中报道的一致。最后，在cfDNA MSI阳性的晚期胃癌患者中，免疫治疗的临床活性很强，63%（10/16）的患者获得了完全或部分缓解，并获得了持续的临床获益。结论：guarant360基于cfdna的MSI检测与基于组织的检测高度一致，能够高度准确地检测MSI状态，同时进行全面的基因组分析，并为目前检测方法不足的晚期癌症患者扩大免疫治疗的可及性。
Purpose: To analytically and clinically validate microsatellite instability (MSI) detection using cell-free DNA (cfDNA) sequencing.Experimental Design: Pan-cancer MSI detection using Guardant360 was analytically validated according to established guidelines and clinically validated using 1,145 cfDNA samples for which tissue MSI status based on standard-of-care tissue testing was available. The landscape of cfDNA-based MSI across solid tumor types was investigated in a cohort of 28,459 clinical plasma samples. Clinical outcomes for 16 patients with cfDNA MSI-H gastric cancer treated with immunotherapy were evaluated.Results: cfDNA MSI evaluation was shown to have high specificity, precision, and sensitivity, with a limit of detection of 0.1% tumor content. In evaluable patients, cfDNA testing accurately detected 87% (71/82) of tissue MSI-H and 99.5% of tissue microsatellite stable (863/867) for an overall accuracy of 98.4% (934/949) and a positive predictive value of 95% (71/75). Concordance of cfDNA MSI with tissue PCR and next-generation sequencing was significantly higher than IHC. Prevalence of cfDNA MSI for major cancer types was consistent with those reported for tissue. Finally, robust clinical activity of immunotherapy treatment was seen in patients with advanced gastric cancer positive for MSI by cfDNA, with 63% (10/16) of patients achieving complete or partial remission with sustained clinical benefit.Conclusions: cfDNA-based MSI detection using Guardant360 is highly concordant with tissue-based testing, enabling highly accurate detection of MSI status concurrent with comprehensive genomic profiling and expanding access to immunotherapy for patients with advanced cancer for whom current testing practices are inadequate.