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High-Accuracy Determination of Microsatellite Instability Compatible with Liquid Biopsies
Amanda Bortolini Silveira1, François-Clément Bidard1,2,3, Amélie Kasperek1
1Circulating Tumor Biomarkers Laboratory, Institut Curie, PSL Research University, INSERM CIC 1428, Paris, France.
Clinical Chemistry
|March 17, 2020
Summary
Noninvasive detection of microsatellite instability (MSI) using droplet-digital PCR (ddPCR) assays shows promise for immunotherapy patient screening and treatment monitoring. This method accurately identifies MSI in tumor and blood samples, correlating with clinical response.
Area of Science:
- Biomarkers and Diagnostics
- Molecular Oncology
- Immunotherapy
Background:
- Microsatellite instability (MSI) is a key biomarker for predicting immunotherapy response across various cancers.
- Developing large-scale, noninvasive diagnostic tools for MSI is crucial for patient selection and treatment monitoring.
- Circulating tumor DNA (ctDNA) offers a promising avenue for noninvasive MSI detection.
Purpose of the Study:
- To develop and validate droplet-digital PCR (ddPCR) assays for noninvasive MSI detection.
- To assess the performance of these assays in tumor and blood samples.
- To evaluate the utility of ctDNA-based MSI detection for patient screening and treatment monitoring.
Main Methods:
- Development of drop-off ddPCR assays targeting BAT-26, ACVR2A, and DEFB105A/B microsatellite markers.
- Assay validation using reconstitution experiments with varying mutant allelic fractions.
- Testing on 185 tumor samples and 72 blood samples from patients with advanced colorectal or endometrial cancers.
Main Results:
- The ddPCR assays achieved analytical sensitivity below 0.1% variant allelic frequency.
- High concordance was observed between the ddPCR test and the reference pentaplex method (93-100%).
- Assays demonstrated strong correlation with other ctDNA markers, and dynamic changes correlated with clinical response.
Conclusions:
- The developed ddPCR approach provides a noninvasive, cost-effective, and rapid method for MSI detection.
- This tool is suitable for large-scale screening of patients eligible for immunotherapy.
- The assays enable effective monitoring of treatment responses through dynamic ctDNA analysis.
