Abstract A007: Is liquid biopsy a reliable surrogate for MSI testing? A concordance study using matched tissue and ctDNA-based NGS

Abstract Introduction: Microsatellite instability (MSI) and tumor mutational burden (TMB) are key biomarkers guiding treatment decisions in oncology. While immunohistochemistry (IHC) remains the standard for MSI detection, next-generation sequencing (NGS) on circulating tumor DNA (ctDNA) from liquid biopsy offers a non-invasive alternative, capable of simultaneously assess MSI-High (MSI-H), TMB, and other genomic alterations. However, concordance between these methods can vary, which may impact treatment decisions. This study aim to evaluate the concordance between MSI-H status determined by IHC in tissue and NGS in ctDNA. Methods: Clinical and molecular data were retrospectively collected from patients (pts) enrolled in the STING trial (NCT04932525) between June 2021 and December 2024. Genomic profiling was conducted using the Foundation One Liquid CDx assay (324 genes). Concordance between MSI status assessed by tissue IHC and ctDNA-based NGS was assessed using Cohen’s kappa coefficient. A logistic regression model was used to identify factors associated with concordant results, including tumor type, tumor fraction and TMB-High (TMB-H defined as ≥10 mut/Mb). Results: Among 9182 pts who underwent liquid biopsies, we found 129 (1.4%) pts with a MSI-H status. Main characteristics were: 68 (53%) male pts with a median age of 65 years [31-96]. Most common tumor locations were gastrointestinal (n= 55, 43%) and gynaecological (n= 23, 18%). From 115 paired MSI-H results from both IHC and NGS, no meaningful concordance was observed as indicated by Cohen's kappa: -0.098 (95%CI: -0.243 to 0.047). Similar findings were observed in gastrointestinal cancers (n = 55), with no significant concordance between the two methods. Interestingly, TMB-H is more likely to show concordant MSI status for gastrointestinal tumors (OR 20.2, 95%CI: 1.4–2983.3, p = 0.027). Conclusion: Overall, MSI status determined by IHC on tissue and by NGS on ctDNA showed low concordance, suggesting these methods are not directly interchangeable when tissue is unavailable. However, elevated TMB appears to predict higher concordance between the two approaches, particularly in gastrointestinal tumors. Citation Format: Julieta E. Rodriguez, Damien Vasseur, Mohamed Amine. Bani, Alexandre Megherbi, Kaissa Ouali, Cedric Pobel, Madona Sakkal, Benjamin Verret, Filippo Dall'Olio, Joana Ribeiro, Marie Morfouace, Sofiane Taleb, Lodovica Zullo, Claudia Parisi, Claudio Nicotra, Maud Ngocamus, Veronica Goldbarg, Christophe Massard, Etienne Rouleau, Ludovic Lacroix, Antoine Hollebecque, Antoine Italiano, Cristina Smolenschi. Is liquid biopsy a reliable surrogate for MSI testing? A concordance study using matched tissue and ctDNA-based NGS [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A007.