Landscape Of Fgfractivating Aberrations In Chinese Non-Small Cell Lung Cancer

Background Dysfunction in fibroblast growth factor receptor (FGFR) signaling has been reported in non-small cell lung cancer (NSCLC), particularly in lung squamous cell carcinoma (LUSC). We hereby assessed the frequency of FGFR aberrations in a large Chinese NSCLC population. Methods A total of 10,966 NSCLCs whose tumor specimen and/or circulating cell-free DNA (cfDNA) underwent hybridization capture-based next-generation sequencing (NGS) of 400+ cancer-related genes were retrospectively reviewed. Patients9 clinical characteristics and treatment histories were further evaluated. ResultsFGFR aberrations, including mutations, fusions, and gene amplifications, were detected in approximately 1.9% (210/10,966) of the population. FGFR abnormalities were more frequently observed in LUSCs (6.8%, 65/954) than lung adenocarcinomas (1.3%, 128/9596). Previously reported FGFR oncogenic mutations were identified in 19 patients (~0.17%), of which, 68% were male LUSC patients. Eleven out of the 19 patients (58%) had concurrent altered PI3K signaling, thus, highlighting an intriguing molecular characteristic and potential combination therapeutic strategy of dual-targeting FGFR and PI3K signaling in those patients. Furthermore, FGFR fusions retaining the intact kinase domain were identified in 12 patients (0.11%), including nine FGFR3-TACC3 cases, one FGFR2-INA fusion, one novel FGFR4-RAPGEFL1 rearrangement event, and one novel gene fusion between FGFR1 and the SLC20A2 59-untranslated region, which may result in FGFR1 overexpression. Concomitant EGFR mutations or EGFR amplifications were observed in six patients, four of whom were previously treated with EGFR tyrosine kinase inhibitors, suggesting that FGFR fusions may act as acquired resistance to anti-EGFR therapies. In addition, FGFR amplification was detected in 24 patients, with FGFR1 amplification being the most common event. Notably, FGFR oncogenic mutations, fusions, and gene amplifications were almost always mutually exclusive events. Conclusion We herein report an incidence of FGFR anomalies in a large Chinese NSCLC population, including mutations, gene amplifications, and previously characterized and novel FGFR fusions involving TACC3, INA, RAPGEFL1, and SLC20A2. Keywords: FGFR, activating mutation, fusion, gene amplification, NSCLC, FGFR inhibitors Citation Format: Zhen Zhou, Zichuan Liu, Qiuxiang Ou, Xue Wu, Xiaonan Wang, Yang Shao, Hongyan Liu, Yu Yang. Landscape of FGFRactivating aberrations in Chinese non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 745.