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

Background: Osteosarcoma (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.

Methods: We 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.

Results: Analysis 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.

Conclusions: Precision 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.