Noninvasive detection of microsatellite instabilit and high tumor mutation burden in cancer patients treated with PD-1 blockade

Andrew Georgiadis, Jennifer N. Durham, Laurel A. Keefer, Bjarne R. Bartlett, Magdalena Zielonka, Derek Murphy, James R. White, Steve Lu, Ellen L. Verner, Finey Ruan, David Riley, Robert A. Anders, Erika Gedvilaite, Sam Angiuoli, Siân Jones, Victor E. Velculescu, Dung T. Le, Luis A. Diaz, Mark Sausen

Research output: Contribution to journalArticlepeer-review


Purpose: Microsatellite instability (MSI) and high tumor mutation burden (TMB-High) are promising pan-tumor biomarkers used to select patients for treatment with immune checkpoint blockade; however, real-time sequencing of unresectable or metastatic solid tumors is often challenging. We report a noninvasive approach for detection of MSI and TMB-High in the circulation of patients. Experimental Design: We developed an approach that utilized a hybrid-capture–based 98-kb pan-cancer gene panel, including targeted microsatellite regions. A multifactorial error correction method and a novel peak-finding algorithm were established to identify rare MSI frameshift alleles in cell-free DNA (cfDNA). Results: Through analysis of cfDNA derived from a combination of healthy donors and patients with metastatic cancer, the error correction and peak-finding approaches produced a specificity of >99% (n ¼ 163) and sensitivities of 78% (n ¼ 23) and 67% (n ¼ 15), respectively, for MSI and TMB-High. For patients treated with PD-1 blockade, we demonstrated that MSI and TMB-High in pretreatment plasma predicted progression-free survival (hazard ratios: 0.21 and 0.23, P ¼ 0.001 and 0.003, respectively). In addition, we analyzed cfDNA from longitudinally collected plasma samples obtained during therapy to identify patients who achieved durable response to PD-1 blockade. Conclusions: These analyses demonstrate the feasibility of noninvasive pan-cancer screening and monitoring of patients who exhibit MSI or TMB-High and have a high likelihood of responding to immune checkpoint blockade.

Original languageEnglish (US)
Pages (from-to)7024-7034
Number of pages11
JournalClinical Cancer Research
Issue number23
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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