Accounting for the Unique Molecular Landscape of Pediatric Malignancies Improves Target-Agent Pair Identification for Pediatric Precision Oncology

Precision medicine has significant potential to improve therapy options for patients who have exhausted treatment options for their relapsed or refractory cancers. Next-generation sequencing has enabled the detection of genetic abnormalities in individual tumours that bestow sensitivity to selective agents targeting these dysregulated cellular pathways. Several programs have recently launched that utilize sequencing technology to identify patient mutations and match the patients to clinical trials for agents that target the dysregulted pathway. The Pediatric MATCH trial initiated by the National Cancer Institute (NCI) and Children's Oncology Group (COG) exemplifies this approach, but also emphasizes the numerous obstacles involved in molecularly-guided therapies The target and agent prioritization strategy for the Pediatric MATCH trial was recently outlined. It employs an amplicon-based targeted sequencing panel (OCAV3) that was originally developed to capture informative variants for adult tumours, with the current version 3 including a set of pediatric-specific variants. However, the landscape of genomic alterations across pediatric malignancies differs from adult malignancies, which translate to distinct oncogenic drivers. The fundamental differences in the genomic landscapes observed in adult and pediatric malignancies must therefore be considered in the optimization of target identification for precision oncology. We hypothesized that a pediatric-focused targeted sequencing panel (OCCRA) will be more informative than an adult-focused panel (OCAV3) for pediatric malignancies. To compare target-agent pairs identified by OCAV3 and OCCRA, we performed a retrospective analysis of 28 childhood tumour samples, 10 B-ALL, 4 T-ALL, 6 neuroblastomas, and 8 additional solid tumours. For 12 of these tumours, whole genome sequencing (WGS) was performed on matched samples and all sequencing results were filtered for pediatric cancer driver genes. For the 12 samples tested by all three sequencing modalities, we found that the greatest discordance occurred in samples with low (