Rationale: Despite intensive multimodal treatment, survival of paediatric and adolescent and young adult (AYA) sarcoma patients remains poor. These sarcomas are rare, extremely heterogenous, harbour few actionable genomic drivers and no targeted therapies are routinely available. Accurate identification of clinically actionable targets and associated drug (combinations) therefore remains a critical challenge.
Here, we report the utility of the Zero Childhood Cancer (ZERO) precision medicine platform, incorporating molecular genomic and transcriptomic profiling with in vitro and in vivo drug testing, for pinpointing targeted therapeutic agents for young, high-risk (HR; expected survival <30%) sarcoma patients.
Methods and Results: HR sarcomas are the second largest patient group within the ZERO National Clinical Trial (PRISM) (29%; n=71). Using WGS (tumour, germline DNA) and RNA-Seq analysis, comprehensive molecular profiles have been established for 56 sarcoma patients comprising >13 different histological subtypes. Reportable somatic SNVs, fusions, CNVs and aberrantly expressed genes (RNA) were identified in 45%, 64%, 45% and 64% of patients, respectively. These molecular profiles, supplemented with functional drug profiles when available, resulted in a targeted and/or immunotherapy recommendation for 71% (n=40) of sarcoma patients. Recommendations most commonly included PI3K/mTOR, receptor tyrosine kinase (RTK), MEK, CDK4/6 and PARP inhibitors, mostly in rationally selected combinations. We have also identified previously unreported aberrations and novel oncogenic signatures in a variety of sarcoma subtypes. Excitingly, for 13 heavily pre-treated sarcoma patients where targeted treatment recommendations were acted upon, partial responses (PR; n=4) and stable disease (SD, n=1) are reported within 9 evaluable patients. Additional mechanism-of-action studies are ongoing and 7 (54%) of these HR patients are currently still in follow-up.
Conclusions: This study is one of the most comprehensive clinical efforts ever undertaken in precision medicine in advanced paediatric and AYA sarcoma. It not only provides a unique resource to study biology and therapeutic opportunities in a diverse set of rare HR sarcomas; our interim results also highlight the feasibility and clinical utility of precision medicine in HR sarcomas.