Mutational profiling of newly diagnosed glioblastoma to identify predictive biomarkers of efficacy and safety of anlotinib combination therapy.

person Shuzhen Lai Guangdong YueBei People's Hospital affiliated to Shantou University, Shaoguan, China info_outline Shuzhen Lai, Peijing Li, Xiaohui Liu, Guihong Liu, Tieming Xie, Xing Zhang, Xiaoxuan Wang, Jing Huang, Yiqiang Tang, Zhigang Liu, Guoping Shen, Chaoming Li, Fangxiao Lu, Lei Wang, Fagui Jiang, Caixing Sun, Yuan yuan Yuan Chen

Authors person Shuzhen Lai Guangdong YueBei People's Hospital affiliated to Shantou University, Shaoguan, China info_outline Shuzhen Lai, Peijing Li, Xiaohui Liu, Guihong Liu, Tieming Xie, Xing Zhang, Xiaoxuan Wang, Jing Huang, Yiqiang Tang, Zhigang Liu, Guoping Shen, Chaoming Li, Fangxiao Lu, Lei Wang, Fagui Jiang, Caixing Sun, Yuan yuan Yuan Chen Organizations Guangdong YueBei People's Hospital affiliated to Shantou University, Shaoguan, China, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China, The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China, State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Nanjing, China, Jiangxi Cancer Hospital of Nanchang University, Nanchang, China, Dongguan Key Laboratory of Precision Diagnosis and Treatment for Tumors,Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, Maoming People's Hospital, Maoming, China, Kecheng District People's Hospital, Quzhou, China, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China Abstract Disclosures Research Funding Other Foundation the Sun Yat-Sen University Clinical Research 5010 Program Background: Glioblastoma (GBM) is highly vascular tumor with the specific pathologic feature of microvascular proliferation. Our previous phase Ⅱ clinical trial (NCT04119674) has firstly demonstrated the antiangiogenic multikinase inhibitor anlotinib combined with STUPP regimen can lengthen progression-free survival (PFS) in patients with newly diagnosed GBM. However, no biomarker for angiogenic therapy has been proved yet. Therefore, the second analysis was performed to identify the predictive biomarkers. Methods: A total of 21 patients with newly diagnosed GBM were enrolled in the retrospective research. The methylation status of the MGMT gene promoter was examined using the MDxHealth PCR assay. DNA-based whole genome sequencing was undertaken to detect the genomic alterations of patients. Results: The differences of gene aberrances between patients who reached and those who did not reach the primary endpoint were observed. ATRX and MYO15A mutations were only found in patients who had yet not experienced relapse. On contrast, the mutations of PIK3CA , HEG1 , HMCN1 and RP1L1 occurred only in the recurrent group. HEG1 (HR 6.0, 95% CI 1.2-28.8, p = 0.026) and RP1L1 (HR 12.5, 95% CI 2.1-74.3, p = 0.005), genes related to angiogenesis, were both independent biomarkers of PFS. RP1L1 was also significantly associated with shorter overall survival (OS) (HR 33.4, 95% CI 3.2-351.4, p = 0.003). Interestingly, PIK3CA alterations were significantly higher in patients with cerebral than in those without ( p = 0.032, OR 16.4). Conclusions: Our study suggested that alterations in HEG1 , RP1L1 and PIK3CA could be novel biomarkers for the newly diagnosed GBM patients received anti-angiogenesis combination therapy, and provided now insights for the precise treatment of GBM.

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