Abstract 1131: Comprehensive genomic profiling in osteosarcoma: Insights from Japanese cohorts and the AACR Project GENIE

Abstract Background: Osteosarcoma (OS), the most common primary malignant bone tumor, presents challenges in treatment, especially in metastatic or recurrent cases. Genomic profiling may offer novel therapeutic approaches by identifying actionable mutations. This study utilizes data from the Japanese Center for Cancer Genomics and Advanced Therapeutics (C-CAT) and AACR Project GENIE, comparing findings with the MSK-IMPACT dataset to understand differences in genomic landscapes and identify clinically actionable alterations. Methods: We analyzed 223 high-grade OS samples from the C-CAT database, comparing findings to the GENIE cohort and MSK-IMPACT data. Tumor DNA sequencing was performed using FoundationOne® CDx and OncoGuide™ NCC Oncopanel. Genomic alterations were categorized by levels A-F per Cancer Knowledge Database (CKDB) and compared with public databases (cBioPortal). Results: In the C-CAT cohort, 42.2% of samples had actionable mutations (CKDB Levels A-C), including two NTRK fusions (0.9%), one TMB-high case (0.4%), and recurrent ERBB, CDK4, PTEN, and PDGFRA gene alterations. Co-occurring KIT, KDR, and PDGFRA amplifications were observed at 4q12 in 3.6% of cases, while VEGFA and CCND3 co-amplifications at 6p12-21 occurred in 14.8% of cases, suggesting multi-kinase inhibitors as potential treatments. Differences from the MSK-IMPACT dataset (Suehara Y et al, Clin Cancer Res. 2019 25(21):6346-6356), where mutually exclusive amplifications were more pronounced, highlight the genetic diversity between Japanese and U.S. cohorts. Analysis with GENIE and MSK-IMPACT indicates a lower incidence of mutually exclusive alterations in the Japanese cohort. Conclusions: Targetable alterations were present in 42.2% of Japanese OS cases, with a distinct genomic profile compared to U.S. cohorts. Amplifications in 4q12 and 6p12-21, which may be treatable with multi-kinase inhibitors, were found in both datasets, yet mutual exclusivity patterns varied. This study underscores the potential of precision oncology in OS, encouraging continued exploration of genomic data in diverse populations to expand treatment options. Citation Format: Suehara Yoshiyuki, Rina Kitada, Masachika Ikegami, Satoshi Kamio, Koichi Ogura, Shintaro Iwata, Eisuke Kobayashi, Akira Kawai, Shinji Khosaka. Comprehensive genomic profiling in osteosarcoma: Insights from Japanese cohorts and the AACR Project GENIE [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1131.