Clinical Genomic Sequencing of Pediatric and Adult Osteosarcoma Reveals Distinct Molecular Subsets with Potentially Targetable Alterations.

Abstract

Although multimodal chemotherapy has improved outcomes for patients with osteosarcoma, the prognosis for patients who present with metastatic and/or recurrent disease remains poor. In this study, we sought to define how often clinical genomic sequencing of osteosarcoma samples could identify potentially actionable alterations.<b>Experimental Design:</b> We analyzed genomic data from 71 osteosarcoma samples from 66 pediatric and adult patients sequenced using MSK-IMPACT, a hybridization capture-based large panel next-generation sequencing assay. Potentially actionable genetic events were categorized according to the OncoKB precision oncology knowledge base, of which levels 1 to 3 were considered clinically actionable. We found at least one potentially actionable alteration in 14 of 66 patients (21%), including amplification of <i>CDK4</i> (<i>n</i> = 9, 14%: level 2B) and/or <i>MDM2</i> (<i>n</i> = 9, 14%: level 3B), and somatic truncating mutations/deletions in <i>BRCA2</i> (<i>n</i> = 3, 5%: level 2B) and <i>PTCH1</i> (<i>n</i> = 1, level 3B). In addition, we observed mutually exclusive patterns of alterations suggesting distinct biological subsets defined by gains at 4q12 and 6p12-21. Specifically, potentially targetable gene amplifications at 4q12 involving <i>KIT, KDR,</i> and <i>PDGFRA</i> were identified in 13 of 66 patients (20%), which showed strong PDGFRA expression by IHC. In another largely nonoverlapping subset of 14 patients (24%) with gains at 6p12-21, <i>VEGFA</i> amplification was identified. We found potentially clinically actionable alterations in approximately 21% of patients with osteosarcoma. In addition, at least 40% of patients have tumors harboring <i>PDGFRA</i> or <i>VEGFA</i> amplification, representing candidate subsets for clinical evaluation of additional therapeutic options. We propose a new genomically based algorithm for directing patients with osteosarcoma to clinical trial options.