Circulating tumor DNA precision oncology enables effective and sensitive molecular diagnostics and actionable target detection in pediatric solid tumors - the INFORM experience.
Summary
This study, conducted within the INFORM program, optimized liquid biopsy methodologies for high-risk pediatric solid tumors. Researchers demonstrated that low-coverage whole-genome sequencing (lcWGS) reliably detects circulating tumor DNA (ctDNA). An in silico ctDNA estimation score, combining fragment length and genome segment alterations, improved sensitivity and specificity to 95%, enabling plasma-based tumor detection in 93% of patients. Whole-exome sequencing (WES) and targeted panel sequencing effectively identified clinically relevant, potentially druggable molecular targets, and liquid biopsy showed potential for tracking tumor evolution and refining patient stratification. These advancements lay the groundwork for integrating liquid biopsy into personalized medicine programs and pediatric clinical trials.
Analysis
CLINIQUE: This multicenter, prospective study represents a significant advance for pediatric oncology, where established biomarkers are scarce. The improved ctDNA detection with 95% sensitivity and specificity via an in silico score could transform early diagnosis, minimal residual disease assessment, and treatment monitoring. The ability to identify actionable molecular targets and track tumor evolution paves the way for more precise patient stratification and tailored clinical trials. Clinical impact could be seen in the medium term (3-5 years), justifying phase II/III trials evaluating the integration of these methodologies into standard care pathways to guide therapeutic decisions. BIOMOL: The main discovery is the optimization of liquid biopsy methodologies for pediatric tumors, characterized by low mutational burdens. The study utilized low-coverage whole-genome sequencing (lcWGS), whole-exome sequencing (WES), and targeted panels on plasma samples. It was demonstrated that lcWGS is reliable for ctDNA detection, while WES and panels are effective for identifying molecular targets. A key distinction is that SNVs are more sensitively captured by panel sequencing and WES, whereas CNVs are better represented by lcWGS and WES. This analytical validation of different sequencing approaches on liquid biopsies (plasma) is crucial for guiding the selection of assays based on the underlying tumor genomic profile, leading to more precise clinical testing. BIOINFO: The study developed an in silico ctDNA estimation score, combining fragment length and genome segment alterations, which achieved 95% sensitivity and specificity for plasma-based tumor detection. This novel bioinformatic approach significantly enhances the performance of sequencing methods for ctDNA detection in a pediatric context. The optimization of bioinformatic tools for pediatric settings is critical, as it enables better molecular tumor characterization and identification of targetable alterations. If deployed clinically, this tool could streamline the analysis of liquid biopsy sequencing data, prioritizing patients for molecular tumor board discussions or clinical trials.