A Living Multi‐Omics PDX Biobank of High‐Risk Sarcomas Reveals ecDNA‐Driven Oncogene Amplification in Osteosarcoma and Enables Preclinical Precision Oncology

Sarcomas are rare, genomically heterogeneous malignancies for which prognosis has remained poor and largely unchanged over recent decades. Patient-derived xenograft (PDX) models are an important tool for cancer research, but their availability and utility remain limited in sarcoma. Here, we establish the SGH sarcoma PDX biobank, a living multi-omics resource comprising 155 xenografts from 132 patients across 11 sarcoma histotypes, with osteosarcoma as the predominant subtype. This cohort is enriched for high-risk sarcomas characterized by poor prognosis and widespread copy-number alterations. Using this biobank, we show that extrachromosomal DNA (ecDNA) frequently drives high-level oncogene amplification in osteosarcoma and that MYC ecDNA may underlie aggressive disease trajectories. Analyses of paired patient and PDX samples demonstrate that ecDNA is preferentially retained over intrachromosomal amplicons during engraftment and is stably maintained in PDX models. In addition, the PDX models largely recapitulate the histopathological and molecular features of their matched patient tumors while exhibiting distinct clonal evolutionary trajectories during engraftment. Finally, we identified potentially actionable genomic alterations within this PDX cohort, demonstrated genotype-matched targeted therapy in a KRAS G12C-mutant PDX model, and prioritized several candidate antibody-drug conjugate targets. Together, this resource provides a platform for biological discovery and preclinical precision oncology for sarcoma.