Abstract
Abstract Pediatric cancers have distinct molecular landscapes compared to adult cancers, with low point mutation rates, distinct mutated genes, and a prevalence of structural rearrangements. These complex features suggest genomic analyses alone will have limitations for translation into clinical benefit, and a multifaceted approach is therefore needed to maximize the number of patients for whom a therapeutic recommendation can be made. The Zero Childhood Cancer Program (ZERO) aims to assess the feasibility of precision medicine to identify targeted therapeutic agents for patients with high-risk (HR) pediatric malignancies (newly diagnosed, relapsed or refractory, overall expected survival <30%). Comprehensive molecular profiling, involving whole genome sequencing (tumor, germline DNA), whole transcriptome RNA sequencing and methylation profiling (brain tumors and sarcomas), is combined with preclinical drug testing using in vitro high-throughput drug screening (HTS, 125 compound library, single agent) and patient-derived xenograft (PDX) drug efficacy testing. Results are curated and recommendations (targeted therapy, change of diagnosis or genetics referral for a germline cancer predisposition gene mutation) are made by a national Multidisciplinary Tumor Board. Following the successful completion of a 2-year pilot feasibility study (TARGET, 2015-17), results demonstrated high-throughput in vitro drug screening and patient-derived xenografting expanded the therapeutic options and improved clinical outcomes in a cohort of 56 high-risk pediatric patients, with the HTS and PDX providing orthogonal confirmation of targetable molecular aberrations in 21% of patients and unique therapeutic options for 16% of patients. The national multicenter prospective trial (PRISM, 2017-20) is open at all 8 pediatric oncology centers around Australia. PRISM has enrolled 290 patients at January 2020 across the broad spectrum of HR cancers. This unique comprehensive platform has resulted in at least one recommendation (tiered by the level of supportive evidence) being issued for 75% of patients, and a reportable germline finding in 17% of patients. Early clinical response data indicates that 54% of patients who were treated with a recommended therapy demonstrated clinical benefit (complete response, partial response or stable disease >=6 months), with 38% demonstrating an objective response. ZERO demonstrates the feasibility of a comprehensive precision medicine platform to identify treatment recommendations in HR pediatric cancer patients. Plans are underway for subsequent enrolment expansion, introduction of emerging methods and technologies and extension of research projects in immunoprofiling, liquid biopsy, psychosocial impact of pediatric precision medicine, health economics and health implementation. Citation Format: Michelle Haber, Mark J. Cowley, Paul Ekert, Loretta Lau, Emily Mould, ZCC PRISM Omics Core, ZCC Prelinical Drug Testing Core, Andrew Gifford, Richard B. Lock, Glenn M. Marshall, Murray D. Norris, Tracey O'Brien, Dong Anh Khuong Quang, David Thomas, Toby Trahair, Katherine Tucker, David S. Ziegler, Vanessa Tyrrell. Zero Childhood Cancer: A comprehensive precision medicine platform for children with high-risk cancer in Australia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr SY09-02.
Published Version
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