Abstract 3111: Zero Childhood Cancer: A comprehensive precision medicine platform for children with high-risk cancer

Abstract

Abstract Molecular genomics analyses aim to identify subsets of patients harboring actionable aberrations as a pathway to improved targeted treatment selection. However, recent pan-cancer analyses of the molecular landscape of pediatric cancers1,2 have emphasized the stark contrast with adult cancers, with low mutation rates, distinct mutated genes and a prevalence of structural rearrangements suggesting that genomic analyses alone have limitations for translation into clinical benefit. The Zero Childhood Cancer (ZCC) program aims to assess the feasibility of precision medicine to identify targeted therapeutic agents for patients with high-risk (HR) pediatric malignancies (expected survival <30%). We combine comprehensive molecular profiling analysis [whole genome sequencing (tumor, germline DNA), deep sequencing of a 386 cancer associated gene panel, whole transcriptome (RNASeq), methylation profiling] with in vitro high-throughput drug screening (124 compound library, single agent) and patient-derived xenograft (PDX) drug efficacy testing. Results are curated and recommendations made by a national Multidisciplinary Tumor Board. Recommendations consist of targeted therapy, change of diagnosis or genetics referral for a germline cancer predisposition gene mutation. The national multicenter prospective trial (PRISM) opened in September 2017 at all 8 pediatric oncology centers around Australia, following the successful completion of a 2-year pilot feasibility study. PRISM has enrolled 131 patients to date (35% central nervous system tumors, 29% sarcoma, 13% leukemias/lymphomas, 6% neuroblastoma, 17% other rare or unknown cancers). The unique ZCC testing platform has resulted in at least one recommendation being issued for 67% of patients. Fifteen % of patients have a reportable germline cancer predisposition. We have developed an analytical pipeline to interrogate and cross-validate the full range of variants, structural abnormalities and mutational signatures identified in pediatric cancers and incorporate the molecular data with in vitro and in vivo drug sensitivity data where possible. The highest yield of reportable variants is derived from the integrated analysis of WGS and RNASeq; unique to ZCC compared to other pediatric precision medicine programs internationally. ZCC demonstrates the feasibility of a comprehensive precision medicine platform to identify treatment recommendations in HR pediatric cancer patients. The national trial is planned to run for 3 years, recruiting ~400 patients. In addition, ZCC is partnering nationally and internationally to conduct parallel research studies in immunoprofiling, liquid biopsy, psychosocial impact of precision medicine, health economics and health implementation. 1. Gröbner et al. Nature. 2018; 555(7696):321-327. 2. Ma et al. Nature. 2018; 555(7696):371-376. Citation Format: Emily V. Mould, Loretta Lau, Greg Arndt, Paulette Barahona, Mark J. Cowley, Paul Ekert, Tim Failes, Jamie Fletcher, Andrew Gifford, Dylan Grebert-Wade, Michelle Haber, Alvin Kamili, Amit Kumar, Richard B. Lock, Glenn M. Marshall, Chelsea Mayoh, Murray Norris, Tracey O'Brien, Dong Anh Khuong Quang, Patrick Strong, Alexandra Sherstyuk, Toby Trahair, Maria Tsoli, Katherine Tucker, Meera Warby, Marie Wong, Jinhan Xie, David S. Ziegler, Vanessa Tyrrell. Zero Childhood Cancer: A comprehensive precision medicine platform for children with high-risk cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3111.