Implementation of a 1021-gene liquid biopsy assay for real-world tumor genomic profiling in oncology practice

Abstract

The application of advanced next-generation sequencing (NGS) technologies in the analysis of circulating tumor DNA (ctDNA) enabled the comprehensive evaluation of tumor-derived alterations in the bloodstream. In this study, we evaluated the analytical performance and clinical utility of a large-scale liquid biopsy assay in patients with metastatic cancer. A total of 1,110 unique patients underwent ctDNA NGS testing using a 1021-gene panel; matched tissue biopsy data were available for 145 cases. In 16.18% of the cases, at least one on-label variant was identified. In addition, off-label, clinical trial–related, and resistance-associated findings collectively increased the proportion of clinically actionable results by 40.65%. Importantly, 8.65% of the total population could also benefit from immune checkpoint inhibitors (ICI) therapy, based on the high tumor mutational burden (TMB-H) and/or high microsatellite instability (MSI-H) status. Simultaneous analysis in plasma and white blood cells enabled clonal hematopoiesis-associated variants detection, hence increasing the specificity value for ctDNA analysis and confirming the presence of pathogenic germline variants for 11.26% patients. Of interest, concordance for actionable on-label candidates using tissue and plasma analysis was 90.34%, thereby confirming the reliability of liquid biopsy results. Notably, the combination of liquid biopsy analysis, and tissue-based profiling, increased the total number of actionable biomarkers, facilitating targeted therapy and immunotherapy selection, resistance monitoring, and faster clinical decision-making. The broad genomic coverage of the liquid biopsy NGS assay used enabled clinically meaningful genomic characterization across multiple tumor histological types, although tumor-specific generalization is limited by the heterogeneity of the tumor types analyzed. Overall, this study shows that large-scale LB profiling may increase the number of actionable findings detected beyond guideline-based targets. In addition, it provides a more accurate understanding of tumor biology and ctDNA shedding in circulation, while offering the advantage of parallel germline analysis.