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Media type:
E-Article
Title:
Microsatellite instability status determined by next‐generation sequencing and compared with PD‐L1 and tumor mutational burden in 11,348 patients
Description:
<jats:title>Abstract</jats:title><jats:p>Microsatellite instability (<jats:styled-content style="fixed-case">MSI</jats:styled-content>) testing identifies patients who may benefit from immune checkpoint inhibitors. We developed an <jats:styled-content style="fixed-case">MSI</jats:styled-content> assay that uses data from a commercially available next‐generation sequencing (<jats:styled-content style="fixed-case">NGS</jats:styled-content>) panel to determine <jats:styled-content style="fixed-case">MSI</jats:styled-content> status. The assay is applicable across cancer types and does not require matched samples from normal tissue. Here, we describe the <jats:styled-content style="fixed-case">MSI</jats:styled-content>‐<jats:styled-content style="fixed-case">NGS</jats:styled-content> method and explore the relationship of <jats:styled-content style="fixed-case">MSI</jats:styled-content> with tumor mutational burden (<jats:styled-content style="fixed-case">TMB</jats:styled-content>) and <jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1. <jats:styled-content style="fixed-case">MSI</jats:styled-content> examined by <jats:styled-content style="fixed-case">PCR</jats:styled-content> fragment analysis and <jats:styled-content style="fixed-case">NGS</jats:styled-content> was compared for 2189 matched cases. Mismatch repair status by immunohistochemistry was compared to <jats:styled-content style="fixed-case">MSI</jats:styled-content>‐<jats:styled-content style="fixed-case">NGS</jats:styled-content> for 1986 matched cases. <jats:styled-content style="fixed-case">TMB</jats:styled-content> was examined by <jats:styled-content style="fixed-case">NGS</jats:styled-content>, and <jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1 was determined by immunohistochemistry. Among 2189 matched cases that spanned 26 cancer types, <jats:styled-content style="fixed-case">MSI</jats:styled-content>‐<jats:styled-content style="fixed-case">NGS</jats:styled-content>, as compared to <jats:styled-content style="fixed-case">MSI</jats:styled-content> by <jats:styled-content style="fixed-case">PCR</jats:styled-content> fragment analysis, had sensitivity of 95.8% (95% confidence interval [<jats:styled-content style="fixed-case">CI</jats:styled-content>] 92.24, 98.08), specificity of 99.4% (95% <jats:styled-content style="fixed-case">CI</jats:styled-content> 98.94, 99.69), positive predictive value of 94.5% (95% <jats:styled-content style="fixed-case">CI</jats:styled-content> 90.62, 97.14), and negative predictive value of 99.2% (95% <jats:styled-content style="fixed-case">CI</jats:styled-content>, 98.75, 99.57). High <jats:styled-content style="fixed-case">MSI</jats:styled-content> (<jats:styled-content style="fixed-case">MSI</jats:styled-content>‐H) status was identified in 23 of 26 cancer types. Among 11,348 cases examined (including the 2189 matched cases), the overall rates of <jats:styled-content style="fixed-case">MSI</jats:styled-content>‐H, <jats:styled-content style="fixed-case">TMB</jats:styled-content>‐high, and <jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1 positivity were 3.0%, 7.7%, and 25.4%, respectively. Thirty percent of <jats:styled-content style="fixed-case">MSI</jats:styled-content>‐H cases were <jats:styled-content style="fixed-case">TMB</jats:styled-content>‐low, and only 26% of <jats:styled-content style="fixed-case">MSI</jats:styled-content>‐H cases were <jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1 positive. The overlap between <jats:styled-content style="fixed-case">TMB</jats:styled-content>,<jats:styled-content style="fixed-case"> MSI</jats:styled-content>, and <jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1 differed among cancer types. Only 0.6% of the cases were positive for all three markers. <jats:styled-content style="fixed-case">MSI</jats:styled-content>‐H status can be determined by <jats:styled-content style="fixed-case">NGS</jats:styled-content> across cancer types. <jats:styled-content style="fixed-case">MSI</jats:styled-content>‐H offers distinct data for treatment decisions regarding immune checkpoint inhibitors, in addition to the data available from <jats:styled-content style="fixed-case">TMB</jats:styled-content> and <jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1.</jats:p>