Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients

Vanderwalde Ari, David Spetzler, Nianqing Xiao, Zoran Gatalica, John Marshall

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)746-756
Number of pages11
JournalCancer Medicine
Volume7
Issue number3
DOIs
StatePublished - Mar 1 2018

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Microsatellite Instability
Tumor Burden
Confidence Intervals
Neoplasms
Immunohistochemistry
Polymerase Chain Reaction
DNA Mismatch Repair

All Science Journal Classification (ASJC) codes

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. / Ari, Vanderwalde; Spetzler, David; Xiao, Nianqing; Gatalica, Zoran; Marshall, John.

In: Cancer Medicine, Vol. 7, No. 3, 01.03.2018, p. 746-756.

Research output: Contribution to journalArticle

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