Abstract
Brain tumors have become the leading cause of cancer-related mortality in young patients. The role of routine sequencing in younger patients with brain tumors is not fully established, and it remains unclear which patient patients will benefit most from the integration of germline/tumor sequencing into routine pediatric neuro-oncology care. The goal of this study was to evaluate the feasibility and utility of DNA and RNA sequencing of children and adolescents with high-risk brain tumors, as well as to document the clinical utility of targeted therapies. Fifty-two children and young adults with brain tumors designated by treating neuro-oncologist to be high risk enrolled in a prospective, observational, consecutive case-series, in which participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed in a multi-institutional brain tumor precision medicine teleconference using a platform (“CNS TAP”) to score targeted agents by their pre-clinical, clinical and pharmacologic properties in the selection of targeted therapies for brain tumors. Sequencing revealed a potentially actionable germline or tumor alterations in 25 (63%) of 40 tumors with adequate tissue, of which 21 (53%) resulted in an impact on treatment or change of diagnosis. Eight (20%) of sequenced tumors harbored an oncogenic fusion isolated on RNA sequencing. Seventeen of 20 patients (85%) with glial tumors were found to have a potentially actionable result, which resulted in change of therapy in 14 (70%) patients. Six (15%) patients who underwent therapy changes had potential clinical benefit (partial response or stable disease greater than 6 months on therapy). Selection of personalized agents for children and young adults with high risk brain tumors based on integrative clinical sequencing is feasible and resulted in a change in therapy in over two-thirds of children and young adults with high-risk glial tumors.