Analysis of cancer multigene panel testing for osteosarcoma in pediatric and adults using the center for cancer genomics and advanced therapeutics database in Japan

Abstract

BackgroundOsteosarcoma (OS) is the most common primary malignant bone tumor. Despite advances in multimodal chemotherapy, prognosis for metastatic or recurrent OS remains poor. Next-generation sequencing (NGS) can uncover new therapeutic options by identifying potentially targetable alterations. This study analyzed NGS data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database in Japan, comparing findings with the Memorial Sloan–Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) data from the United States. MethodsWe sequenced tumor and/or germline DNA from 223 high-grade OS samples using the FoundationOne® CDx or OncoGuideTM NCC Oncopanel System, and the FoundationOne® Liquid CDx for multigene panel testing (2019–2023). Genomic alterations were interpreted using the Cancer Knowledge Database (CKDB), with potentially actionable genetic events categorized into A-F levels. ResultsAnalysis of 223 high-grade OS samples revealed 1684 somatic mutations in 167 genes and 1114 copy number alterations in 89 genes. Potentially actionable alterations were identified in 94 patients (42.2 %) at CKDB Levels A-C. These included 2 cases with NTRK fusions (0.9 %; Level A), one case with TMB-high (0.4 %; Level A), 3 with ERBB amplifications (1.3 %; Level B), and 88 cases (39.5 %) with alterations such as CDK4 amplification, PTEN deletion/mutation, and others (Level C). Co-occurring amplifications of KIT, KDR, and PDGFRA at the 4q12 locus were found in 8 cases (3.6 %), while VEGFA and CCND3 co-amplifications at the 6p12-21 locus were seen in 33 cases (14.8 %). These gene amplifications, also reported in US studies, are targetable by multi-kinase inhibitors, although the C-CAT cohort's profiles differed from US cohorts like MSK-IMPACT. ConclusionsPrecision medicine for rare tumors still poses challenges. In this Japanese cohort, 42.2 % of high-grade OSs had potentially actionable alterations per CKDB. Concurrent gene amplifications of KIT, KDR, and PDGFRA at 4q12, and VEGFA and CCND3 at 6p12-21, might offer promising therapeutic options for patients with recurrent/metastatic OS resistant to conventional chemotherapy.