Abstract 5935: Analytical validation of a robust, integrated multiomics tissue assay powered by the Guardant Infinity platform

Abstract Introduction: Next-generation sequencing (NGS) of tumor tissue is an integral technique to identify actionable alterations and inform oncology treatment. While established, tissue NGS is limited by variability in quantity and quality of both samples and test platforms, which limits its effectiveness. A robust workflow with high sample success rate, providing comprehensive molecular profiling, and fast turn-around time can improve this technology and support patient care. Here, we report the analytical validation of Guardant360 Tissue, a comprehensive molecular profiling test comprising DNA and RNA analysis of 950 genes and epigenomic methylation profiling po​​wered by Guardant Infinity technology. Methods: The analytical and clinical performance for DNA and RNA profiling was assessed using clinical FFPE samples and reference material at 50-100 ng inputs for DNA (N=556) and 25-50 ng inputs for RNA (N=282). Samples from over 10 common cancer types were analyzed, with tumor fractions as low as 5%, using as little as 6 slides (30 µm) of FFPE tissue as input. Results: Guardant360 Tissue demonstrated high sample success rates detecting somatic alterations in >98% of DNA and >91% of RNA samples, including challenging specimen types like fine needle aspirates and core needle biopsies. Panel-wide limits of detection (LoD) were 1.8% MAF for SNVs, 1.5% MAF for indels, 0.4% MAF for DNA fusions, 3.5 copies for CNAs, 37.9% TF for gene deletions, 3.3% TF for microsatellite instability-high (MSI-H), 1.8% for promoter methylation, and 15.1 copies for RNA fusions and splice isoforms. Clinical samples demonstrated 100% sensitivity for SNVs (N=4149), indels (N=646), and MSI-H (N=19), and ≥95% sensitivity for CNAs (N=121), DNA rearrangements (N=34) and RNA fusions/splice isoforms (N=59) against FISH, ddPCR or multiple DNA/RNA/methylation based NGS platforms. High clinical specificity was also established at 100% for all guideline approved biomarkers and ≥99.99996% across the entire panel. Guardant360 Tissue TMB score demonstrated a strong linear correlation (R=0.95, Spearman method) and 94.2% categorical concordance (cutoff of 10 mut/Mb) with an orthogonal NGS panel. Conclusions: Guardant360 Tissue offers a high success rate with minimal input, delivering competitive performance in detecting a wide range of actionable alterations. With a low limit of detection and excellent specificity, this assay achieves comprehensive molecular profiling using as little as 30 μm of FFPE tissue. Its robust capabilities not only enable precise clinical insights but also support the acceleration of novel biomarker discovery through a multiomics approach. Citation Format: Tingting Jiang, Gayatri Premasekharan, Jeffrey Werbin, Yelia Huo, Ankit Jambusaria, Che-Yu Lee, Claire Olson, Arancha Sanchez, Yueyuan Zhang, Jing Zhao, Andreas Papoutsis, Lauren Lawrence, Jill Tsai, Soni Shukla, Drew Kennedy, Stefanie Mortimer. Analytical validation of a robust, integrated multiomics tissue assay powered by the Guardant Infinity platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5935.