A comprehensive overview of liquid biopsy applications in pediatric solid tumors

Abstract

Liquid biopsies are emerging as an alternative source for pediatric cancer biomarkers with potential applications during all stages of patient care, from diagnosis to long-term follow-up. While developments within this field are reported, these mainly focus on dedicated items such as a specific liquid biopsy matrix, analyte, and/or single tumor type. To the best of our knowledge, a comprehensive overview is lacking. Here, we review the current state of liquid biopsy research for the most common non-central nervous system pediatric solid tumors. These include neuroblastoma, renal tumors, germ cell tumors, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and other soft tissue sarcomas, and liver tumors. Within this selection, we discuss the most important or recent studies involving liquid biopsy-based biomarkers, anticipated clinical applications, and the current challenges for success. Furthermore, we provide an overview of liquid biopsy-based biomarker publication output for each tumor type based on a comprehensive literature search between 1989 and 2023. Per study identified, we list the relevant liquid biopsy-based biomarkers, matrices (e.g., peripheral blood, bone marrow, or cerebrospinal fluid), analytes (e.g., circulating cell-free and tumor DNA, microRNAs, and circulating tumor cells), methods (e.g., digital droplet PCR and next-generation sequencing), the involved pediatric patient cohort, and proposed applications. As such, we identified 344 unique publications. Taken together, while the liquid biopsy field in pediatric oncology is still behind adult oncology, potentially relevant publications have increased over the last decade. Importantly, steps towards clinical implementation are rapidly gaining ground, notably through validation of liquid biopsy-based biomarkers in pediatric clinical trials.

Fig. 1. Graphical overview of liquid biopsy workflow for pediatric solid tumors.

Frequent anatomical locations where pediatric solid tumors commonly present are indicated. Liquid biopsy matrices (e.g., peripheral blood, bone marrow, and CSF) are sampled and processed for isolation of analytes (e.g., ctDNA, CTCs, RNA (mRNA, miRNA, lncRNA), immune cells, and EVs) that are measured and characterized by specific methods (mostly PCR-based or sequencing-based) for biomarker analysis. The AI vector generator function from Adobe Illustrator was used for detailed visualization of this figure.

Fig. 2. Historical overview of publications focusing on liquid biopsies in pediatric solid tumors.

In (a), the number of unique articles (y-axis) is plotted over time (x-axis), for studies and review articles. All articles used for this plot are also included in Table 1. All articles in the ‘studies’ plot are also included in (b) and Supplementary Tables 2–9. All articles in the ‘reviews’ plot are also included in Supplementary Table 10. In (b), The number of published studies (y-axis) is plotted over time (x-axis), for each tumor type. Studies that included pediatric patients for more than one tumor type are indicated in each respective plot. All studies used for this plot are also included in (a), Table 1, and Supplementary Tables 2–9.