We conducted integrative somatic–germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management.

The causes of pediatric cancers’ distinctiveness compared to adult-onset tumors of the same type are not completely clear and not fully explained by their genomes. In this study, we used an optimized multilevel RNA clustering approach to derive molecular definitions for most childhood cancers. Applying this method to 13,313 transcriptomes, we constructed a pediatric cancer atlas to explore age-associated changes. Tumor entities were sometimes unexpectedly grouped due to common lineages, drivers or stemness profiles. Some established entities were divided into subgroups that predicted outcome better than current diagnostic approaches. These definitions account for inter-tumoral and intra-tumoral heterogeneity and have the potential of enabling reproducible, quantifiable diagnostics. As a whole, childhood tumors had more transcriptional diversity than adult tumors, maintaining greater expression flexibility. To apply these insights, we designed an ensemble convolutional neural network classifier. We show that this tool was able to match or clarify the diagnosis for 85% of childhood tumors in a prospective cohort. If further validated, this framework could be extended to derive molecular definitions for all cancer types.

Soft-tissue sarcoma (sts) is rare and represents approximately 7% of cancers in children and in adolescents less than 20 years of age. Rhabdomyosarcoma (rms) is most prevalent in children less than 10 years of age and peaks again during adolescence (16–19 years of age). Multi-agent chemotherapy constitutes the mainstay of treatment for rms. In other non-rhabdomyosarcoma soft-tissue tumours, such as synovial sarcoma, evidence for routine use of chemotherapy is less robust, and alternative treatment options, including targeted agents and immunotherapy, are being explored. In this review, we focus on chemotherapy for pediatric-type rms and discuss the advances and challenges in systemic treatment for select non-rhabdomyosarcoma soft-tissue tumours in children and adolescents. We support an increasingly cooperative approach for treating pediatric and adult sts.

Ewing sarcoma is an aggressive bone and soft-tissue cancer affecting adolescents and young adults. In vitro and in vivo models of Ewing sarcoma have been instrumental in advancing our understanding of Ewing sarcoma biology and essential in evaluating potential therapies, particularly for metastatic or relapsed disease for which effective treatment options remain limited. Through an international collaborative effort between the Children’s Oncology Group Bone Tumor Committee and the Euro Ewing Consortium, we review the current landscape of preclinical modeling used in Ewing sarcoma research encompassing both in vitro (cell lines and tumor organoids) and in vivo (mouse and nonmammalian xenografts) model systems. We discuss factors that can influence experimental results, provide testing considerations for both in vitro and in vivo studies, and descriptions of existing preclinical data repositories. We highlight current needs in Ewing sarcoma modeling and the importance of enhanced international cooperative research and patient advocacy efforts which will be critical in expanding our resources of biologically relevant Ewing sarcoma models to enable translation of preclinical findings into effective therapeutic strategies for patients with Ewing sarcoma.

Background: The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to “out‐of‐trial” use of innovative therapies. We conducted a retrospective analysis of requests for innovative anticancer therapy in Canadian pediatric oncology tertiary centers for patients less than 30 years old between 2013 and 2020.Methods: Innovative therapies were defined as cancer‐directed drugs used (a) off‐label, (b) unlicensed drugs being used outside the context of a clinical trial, or (c) approved drugs with limited evidence in pediatrics. We excluded cytotoxic chemotherapy, cellular products, and cytokines.Results: We retrieved data on 352 innovative therapy drug requests. Underlying diagnosis was primary CNS tumor 31%; extracranial solid tumor 37%, leukemia/lymphoma 22%, LCH 2%, and plexiform neurofibroma 6%. RAS/MAP kinase pathway inhibitors were the most frequently requested innovative therapies in 28% of all requests followed by multi‐targeted tyrosine kinase inhibitors (17%), inhibitors of the PIK3CA‐mTOR‐AKT pathway (8%), immune checkpoints inhibitors (8%), and antibody drug conjugates (8%). In 112 out of 352 requests, innovative therapies were used in combination with another anticancer agent. 48% of requests were motivated by the presence of an actionable molecular target. Compassionate access accounted for 52% of all requests while public insurance was used in 27%. Mechanisms of funding varied between provinces.Conclusion: This real‐world data collection illustrates an increasing use of “out‐of‐trial” innovative therapies in pediatric oncology. This new field of practice warrants further studies to understand the impact on patient trajectory and equity in access to innovative therapies.