Abstract A005: Nationwide Genome-Guided Precision Oncology in Pediatric Solid Tumors: Results from the STREAM Program

The STREAM (Strategic TREatment And Magic for pediatric cancers) program, launched in March 2023, is the first nationwide precision medicine initiative for pediatric solid tumors in Korea. The platform integrates high-depth whole-genome sequencing of matched tumor–germline samples with transcriptomic, methylomic, and in vitro drug-response profiling. All findings undergo centralized pathology review and are discussed at a multidisciplinary molecular tumor board (MTB). Between March 2023 and December 2024, 308 children with malignant solid tumors were enrolled (243 newly diagnosed, 65 relapsed/refractory), meeting predefined quality criteria. Diagnoses included 123 CNS tumors, 54 sarcomas, 38 germ cell tumors (GCTs), 38 neuroblastomas, 22 bone tumors, 9 renal, 7 hepatic, and 17 miscellaneous tumors. Somatic driver alterations were identified in 253 patients (82.1%, median two per patient), totaling 1,082 events across 404 genes, including single-nucleotide variants (n=521), copy-number variants (n=238), and structural variants (n=323) with 65 gene fusions. The most frequently altered genes included TP53, BRAF, CTNNB1, and CDKN2A. Pathogenic germline variants were detected in 32 patients (10.4%) across 25 known cancer predisposition genes (e.g., TP53, BRCA1/2, BRIP1, VHL). Molecular profiling contributed to diagnosis in 85 patients, impacted risk stratification in 20, and revealed 117 actionable targets in 99 cases (Tier 1: 48; Tier 2: 61; Tiers 3–5: 8). Drug sensitivity testing in 58 cases across 76 agents yielded 496 sensitive and 1,376 resistant drug–tumor interactions, informing therapeutic potential in 53 and resistance in 54 patients. Unsupervised multi-omic clustering aligned with histopathology and uncovered pathway-dominant molecular subsets: MAPK pathway activation in pilocytic astrocytoma, Langerhans-cell histiocytosis, and polymorphous low-grade neuroepithelial tumor of the young (PLNTY); cell cycle and epigenetic dysregulation in atypical teratoid/rhabdoid tumor and supratentorial ependymoma; both patterns aligned with observed drug sensitivities. Further stratification of medulloblastomas confirmed WNT- and SHH-driven signatures in medulloblastoma Groups 1 and 2, while Groups 3–4 were molecularly diverse, marked by SBS39 mutational signatures suggestive of homologous recombination deficiency (HRD). Similar HRD-associated signatures were enriched in neuroblastoma and osteosarcoma with high-level copy-number alterations (CNAs). Intracranial GCTs demonstrated greater CNA burden and whole-genome duplication compared to gonadal tumors, indicating distinct evolution. STREAM marks a milestone for precision oncology in Asia, and confirms that real-world, genome-guided oncology is feasible in routine pediatric care and can complement histologic diagnosis to inform treatment. Building on this experience, sustained efforts are needed to implement genome-driven workflows in routine clinical practice and ultimately improve treatment outcomes for pediatric cancer patients. Citation Format: Ji Won Lee, Chang Yeon Kim, Joo Whan Kim, June-Young Koh, Jung Yoon Choi, Seung-Ah Choi, Seung-Ki Kim, Se Hoon Kim, Ji Hoon Phi. Nationwide Genome-Guided Precision Oncology in Pediatric Solid Tumors: Results from the STREAM Program [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr A005.