20. Comparative Analysis of RNA Expression Identifies Druggable Targets in Difficult-to-treat Pediatric Solid Tumors

Most pediatric cancers have a low incidence of actionable somatic mutations. Here we examine the clinical utility of incorporating comparative analysis of RNA expression (CARE) into the molecular workup of recurrent/refractory and rare pediatric tumors. Patients treated at Stanford Medicine Children's Health (n=33) with a recurrent/refractory or rare pediatric solid tumor underwent tumor RNA sequencing (RNA-seq) analysis and standard-of-care tumor DNA profiling. The Treehouse Childhood Cancer Initiative compared each patient's tumor RNA-seq profile with over 11,000 uniformly analyzed tumor profiles from public data repositories. These comparisons reveal candidate cancer genes and pathways that represent potential therapeutic targets. Thirty-three patients underwent tumor RNA-seq and CARE analysis, which was potentially useful for 31 of 33 (94%) patients, identified new treatments for 5 of 31 patients, and produced a definitive clinical response in 3 of 5 patients treated with an identified therapy. The new treatments would not have been considered by the clinical team without the CARE analysis. In comparison, DNA mutations alone were potentially useful for treatment identification in only 15 of 28 (54%) tumors for which mutation data were available. CARE analysis may identify additional cancer driver pathways and druggable targets in patients with rare or difficult-to-treat pediatric cancers relative to standard-of-care DNA profiling. This study highlights the clinical utility of RNA profiling of pediatric tumors and underscores the need for further evaluation of this approach to improve patient outcomes. Most pediatric cancers have a low incidence of actionable somatic mutations. Here we examine the clinical utility of incorporating comparative analysis of RNA expression (CARE) into the molecular workup of recurrent/refractory and rare pediatric tumors. Patients treated at Stanford Medicine Children's Health (n=33) with a recurrent/refractory or rare pediatric solid tumor underwent tumor RNA sequencing (RNA-seq) analysis and standard-of-care tumor DNA profiling. The Treehouse Childhood Cancer Initiative compared each patient's tumor RNA-seq profile with over 11,000 uniformly analyzed tumor profiles from public data repositories. These comparisons reveal candidate cancer genes and pathways that represent potential therapeutic targets. Thirty-three patients underwent tumor RNA-seq and CARE analysis, which was potentially useful for 31 of 33 (94%) patients, identified new treatments for 5 of 31 patients, and produced a definitive clinical response in 3 of 5 patients treated with an identified therapy. The new treatments would not have been considered by the clinical team without the CARE analysis. In comparison, DNA mutations alone were potentially useful for treatment identification in only 15 of 28 (54%) tumors for which mutation data were available. CARE analysis may identify additional cancer driver pathways and druggable targets in patients with rare or difficult-to-treat pediatric cancers relative to standard-of-care DNA profiling. This study highlights the clinical utility of RNA profiling of pediatric tumors and underscores the need for further evaluation of this approach to improve patient outcomes.