Format

Send to

Choose Destination
Clin Cancer Res. 2019 Sep 10. doi: 10.1158/1078-0432.CCR-19-1372. [Epub ahead of print]

Noninvasive Detection of Microsatellite Instability and High Tumor Mutation Burden in Cancer Patients Treated with PD-1 Blockade.

Author information

1
Personal Genome Diagnostics, Baltimore, Maryland.
2
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
3
Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, Maryland.
4
Swim Across America Laboratory at Johns Hopkins, Baltimore, Maryland.
5
Resphera Biosciences, Baltimore, Maryland.
6
Department of Pathology, Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins School of Medicine, Baltimore, Maryland.
7
Center for Molecular Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
8
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
9
Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York. msausen1@gmail.com ldiaz@mskcc.org.
10
Personal Genome Diagnostics, Baltimore, Maryland. msausen1@gmail.com ldiaz@mskcc.org.

Abstract

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.Patients and Methods: 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 = 163) and sensitivities of 78% (n = 23) and 67% (n = 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 = 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.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center