Validation of microsatellite instability detection using a comprehensive plasma-based genotyping panel

Jason Willis, Martina I. Lefterova, Alexander Artyomenko, Pashtoon Murtaza Kasi, Yoshiaki Nakamura, Kabir Mody, Daniel V.T. Catenacci, Marwan Fakih, Catalin Barbacioru, Jing Zhao, Marcin Sikora, Stephen R. Fairclough, Hyuk Lee, Kyoung Mee Kim, Seung Tae Kim, Jinchul Kim, Danielle Gavino, Manuel Benavides, Nir Peled, Timmy NguyenMike Cusnir, Ramez N. Eskander, Georges Azzi, Takayuki Yoshino, Kimberly C. Banks, Victoria M. Raymond, Richard B. Lanman, Darya I. Chudova, Amir Ali Talasaz, Scott Kopetz, Jeeyun Lee, Justin I. Odegaard

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


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 Guar-dant360 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.

Original languageEnglish (US)
Pages (from-to)7035-7045
Number of pages11
JournalClinical Cancer Research
Issue number23
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • General Medicine


Dive into the research topics of 'Validation of microsatellite instability detection using a comprehensive plasma-based genotyping panel'. Together they form a unique fingerprint.

Cite this