Blood-Derived Liquid Biopsies Using Foundation One® Liquid CDx for Children and Adolescents with High-Risk Malignancies: A Monocentric Experience

Abstract

Precision oncology requires tumor molecular profiling to identify actionable targets. Tumor biopsies are considered as the gold standard, but their indications are limited by the burden of procedures in children. Blood-derived liquid biopsy (LB) is a potential alternative that is not yet documented in real-world settings, especially in pediatric oncology. We performed a retrospective analysis of children and teenagers with a relapsing or refractory disease, upon whom LB was performed using the Foundation One® liquid CDx from 1 January 2020 to 31 December 2021 in a single center. Forty-five patients (27 boys) were included, with a median age of 9 years of age (range: 1.5–17 years old). Underlying malignancies were neuroblastoma (12 patients), bone sarcoma (12), soft tissue sarcoma (9), brain tumors (7), and miscellaneous tumors (5). Forty-three patients had metastatic disease. Six patients had more than one biopsy because of a failure in first LB. Median time to obtain results was 13 days. Overall, analysis was successful for 33/45 patients. Eight patients did not present any molecular abnormalities. Molecular alterations were identified in 25 samples with a mean of 2.1 alterations per sample. The most common alterations concerned TP53 (7 pts), EWS-FLI1 (5), ALK (3), MYC (3), and CREBBP (2). TMB was low in all cases. Six patients received treatment based on the results from LB analysis and all were treated off-trial. Three additional patients were included in early phase clinical trials. Mean duration of treatment was 85 days, with one patient with stable disease after eight months. Molecular profiling using Foundation One® Liquid CDx was feasible in pediatric patients with high-risk solid tumors and lead to identification of targetable mutations in a subset of patients.

Liquid biopsy‐based circulating tumour (ct)DNA analysis of a spectrum of myeloid and lymphoid malignancies yields clinically actionable results

“…21 In a retrospective study in paediatric patients with high-risk solid tumours such as soft tissue sarcomas and primary central nervous system tumours, 73.3% of patients had successful molecular analysis from peripheral blood sent for F1LCDx, with six patients receiving treatment based on results from LBx analysis. 22 In our concordance analysis between F1LCDx and conventional tissue sequencing, we demonstrated a PPA of 75.7%. The 29.2% of cases with alterations missed by LBx compared to tissue were predominantly explained by low ctDNA shed in the LBx or by clonal dynamics related to the natural history of the patient's disease between biopsies at different timepoints.…”

“…That study found actionable molecular alterations in 52% of patients and that F1LCDx produced similar results from sequencing tissue counterparts, with most discrepancies related to differences in the composition of gene panels 21 . In a retrospective study in paediatric patients with high‐risk solid tumours such as soft tissue sarcomas and primary central nervous system tumours, 73.3% of patients had successful molecular analysis from peripheral blood sent for F1LCDx, with six patients receiving treatment based on results from LBx analysis 22 …”

Combined low-pass whole genome and targeted sequencing in liquid biopsies for pediatric solid tumors

“…Establishing the clinical applicability of plasma-based liquid biopsies in pediatric cancer patients versus adult patients has been challenging due to the limited sample volumes from infants and young children, small cohort sizes for individual tumor types, as well as the varied nature of the genomic alterations that characterize pediatric solid tumors. Nevertheless, several studies have described the feasibility of NGS-based approaches in pediatric solid tumors 19 , 21 – 24 , 30 , 31 , 35 – 37 . For example, to detect neuroblastoma-specific markers for LB biobanking strategies in 84 infants, Lodrini et al showed that as little as 1–2 ml of blood plasma, CSF, or urine had sufficient cfDNA for disease monitoring and ultimately clinical implementation of LB assays 23 .…”

Metastatic Melanoma in Young Child

“…Lactate dehydrogenase values were increased ( > 2500 UI/L). Pathology and molecular analysis using the FoudationOne Liquid CDx test 1 and through the MAPPYACT program 2 of biopsy of the gingival mass confirmed a nonmutated BRAF melanoma with both a mutation and amplification of ERBB2 as well as a somatic TP53 mutation. Metastatic workup showed extensive multiorgan metastasis (Fig.…”