Abstract 4284
Background
Microsatellite instability (MSI) is a guideline-recommended biomarker used in assessment of prognosis and treatment choices, including checkpoint inhibitors recently approved for cancers with MSI-high (MSI-H) status. Plasma-based next generation DNA sequencing (NGS) tests are increasingly used for comprehensive genomic profiling of cancer; however, sensitive methods to detect MSI status from cell-free DNA (cfDNA) are not available for clinical patient care. Additionally, the impact of variable tumor shedding on MSI detection has not been evaluated.
Methods
We developed an accurate method to assess MSI status using targeted sequencing of cfDNA using the Guardant360® clinical platform across a many cancer types, which allows broad coverage of simple repeats. For each microsatellite locus, the number of differently-sized repeats in experimental samples is quantified using a probabilistic log likelihood-based score designed to accurately discriminate biological signal derived from cfDNA fragments of somatic origin from noise arising from technical artifacts. Loci are considered unstable if the likelihood score is greater than a threshold computed from a cohort of normal samples. MSI status of a sample is determined by the presence of a minimum 5 unstable microsatellite loci among the 91 scored.
Results
We simulated MSI high (MSI-H) samples across a range of tumor fractions by combining data from 82 healthy donor samples with in silico spike-ins of differentially sized repeats. Simulated data demonstrates a sensitivity of 94% at 0.2% (limit of detection) tumor content for an expected specificity of 99.9% estimated from healthy donor samples. When applied to a prospective test set of 134 advanced cancer samples, this method demonstrated 98.5% (125/127) specificity and 86% sensitivity (6/7) relative to standard tissue PCR-based MSI assessment across a ctDNA range of 0.1%-15%.
Conclusions
Targeted sequencing of cfDNA data can enable highly accurate detection of MSI in cancer samples, even for samples with low tumor shedding. This novel approach enables non-invasive assessment of MSI status concurrent with comprehensive genomic profiling and allows potential access to immunotherapies for patients whose tumor types are not routinely tested for MSI.
Clinical trial identification
Legal entity responsible for the study
Guardant Health, Inc.
Funding
Guardant Health, Inc.
Editorial Acknowledgement
Disclosure
A. Artyomenko, M. Sikora, M. Lefterova, V.M. Raymond, D. Gavino, C. Barbacioru, C. Artieri, E. Helman, D. Chudova, R.B. Lanman, J. Odegaard, A. Talasaz: Employee: Guardant Health, Inc. All other authors have declared no conflicts of interest.
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