Prognostic and Predictive Value of Microsatellite Instability Analysis in Circulating Tumor DNA Using Digital Droplet PCR for Patients With Microsatellite Instability Colorectal Cancers

Abstract

Deficient mismatch repair (dMMR) and/or microsatellite instability (MSI) colorectal cancer (CRC) is highly sensitive to immune checkpoint inhibitors (ICI). It is thus becoming increasingly relevant to monitor circulating tumor DNA (ctDNA) and to determine the MSI status (ctDNA-MSI) in CRC. So far, few studies have explored this, even though it could be particularly relevant in evaluating treatment efficacy in patients with dMMR and/or MSI CRC. The ctDNA DIgestive cancers MSI study (ADI-MSI) aims to assess the value of ctDNA-MSI as a predictor of ICI efficacy. Blood samples were collected prospectively in a single-center cohort to analyze circulating cell-free DNA (cfDNA) and ctDNA-MSI before the start of and during treatment. ctDNA-MSI was measured using digital droplet PCR with the 5 microsatellite markers of the Pentaplex panel (Promega Corporation). The primary endpoint was to evaluate ctDNA-MSI levels as a predictor of progression-free survival (PFS). We included 54 patients with dMMR and/or MSI CRC, most of whom had metastatic disease (77.8%) treated in the first (25.9%) or second line (42.6%) with ICI. High-baseline cfDNA and ctDNA-MSI were associated with worse PFS and overall survival. ctDNA-MSI kinetics, but not cfDNA kinetics, was associated with treatment response (P = .006), PFS (P = .03), and overall survival (P = .04). ctDNA-MSI kinetics divided into 3 groups (increase, decrease, and negative) correlated strongly with PFS (PFS at 24 months was 0%, 53.0%, and 77.0%, respectively; P < .001) and remained significant in multivariate analysis (hazard ratio = 7.93; 95% CI, 2.23-28.21; P = .005). As there is no strong predictor of ICI efficacy in patients with dMMR and/or MSI CRC, these results suggest that ctDNA-MSI could help physicians in treatment decision-making in the future.