Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment

Area of Science:

• Oncology
• Genomics
• Biomarker Discovery

Background:

• Microsatellite instability (MSI) is a key pan-cancer biomarker for guiding immune checkpoint blockade (ICB) therapy.
• Widespread MSI testing is limited by tissue availability, particularly outside gastrointestinal cancers.

Purpose of the Study:

• To develop and validate a blood-based algorithm for detecting MSI.
• To evaluate the utility of blood MSI (bMSI) for predicting ICB efficacy.
• To explore the pan-cancer landscape of bMSI.

Main Methods:

• Developed a next-generation sequencing-based algorithm using 100 microsatellite markers.
• Validated the algorithm on clinical plasma samples and compared it to tissue PCR.
• Evaluated bMSI for predicting ICB efficacy in 60 advanced gastrointestinal cancer patients.
• Analyzed the pan-cancer prevalence of bMSI in 5138 advanced solid tumors.

Main Results:

• The bMSI algorithm demonstrated high accuracy (94.0%) with 82.5% sensitivity and 96.2% specificity compared to tissue PCR.
• Blood MSI-high (bMSI-H) status significantly predicted improved progression-free and overall survival in GI cancer patients.
• Concurrent profiling of blood tumor mutational burden (bTMB) identified a subset of bMSS patients with favorable outcomes.
• Pan-cancer bMSI-H prevalence generally mirrored tissue MSI, with notable exceptions in prostate, endometrial, and GI cancers.

Conclusions:

• A reliable, next-generation sequencing-based bMSI detection strategy has been developed.
• Combining bMSI with bTMB profiling from a single blood draw may enhance ICB treatment guidance.
• This blood-based approach offers a promising alternative for MSI testing, overcoming tissue availability limitations.