Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment
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...
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doaj-ce1bf62793f54429ba102bf9703e4e662021-07-13T15:02:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-07-018210.1136/jitc-2020-001297Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatmentLin Shen0Chan Gao1Yifan Zhou2Jing Gao3Xiaochen Zhao4Jifang Gong5Zhenghang Wang6Xicheng Wang7Zhongwu Li8Dalei Wang9Xiaofang Li10Yuezong Bai11Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, ChinaMedical Affairs, 3D Medicines Inc, Shanghai, ChinaMedical Affairs, 3D Medicines Inc, Shanghai, ChinaDepartment of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, ChinaMedical Affairs, 3D Medicines Inc, Shanghai, ChinaDepartment of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, ChinaDepartment of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, ChinaDepartment of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, ChinaDepartment of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, ChinaClinical Laboratory, 3D Medicines Inc, Shanghai, ChinaResearch & Development, 3D Medicines Inc, Shanghai, ChinaMedical Affairs, 3D Medicines Inc, Shanghai, ChinaBackground 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 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.Results 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.Conclusions 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.https://jitc.bmj.com/content/8/2/e001297.full |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lin Shen Chan Gao Yifan Zhou Jing Gao Xiaochen Zhao Jifang Gong Zhenghang Wang Xicheng Wang Zhongwu Li Dalei Wang Xiaofang Li Yuezong Bai |
spellingShingle |
Lin Shen Chan Gao Yifan Zhou Jing Gao Xiaochen Zhao Jifang Gong Zhenghang Wang Xicheng Wang Zhongwu Li Dalei Wang Xiaofang Li Yuezong Bai Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment Journal for ImmunoTherapy of Cancer |
author_facet |
Lin Shen Chan Gao Yifan Zhou Jing Gao Xiaochen Zhao Jifang Gong Zhenghang Wang Xicheng Wang Zhongwu Li Dalei Wang Xiaofang Li Yuezong Bai |
author_sort |
Lin Shen |
title |
Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment |
title_short |
Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment |
title_full |
Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment |
title_fullStr |
Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment |
title_full_unstemmed |
Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment |
title_sort |
plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2020-07-01 |
description |
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 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.Results 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.Conclusions 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. |
url |
https://jitc.bmj.com/content/8/2/e001297.full |
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