Abstract

Objective

The aim of this study was to investigate the efficacy and safety of Apatinib mesylate in the treatment of metastatic osteosarcoma patients who progressed after standard therapy and the VEGFR2 gene polymorphism analysis.

Methods

Designed as a retrospective study, a total of 105 metastatic osteosarcoma patients who progressed after standard therapy were included in this study. The metastatic osteosarcoma patients received 500–750 mg Apatinib mesylate according to body surface area until disease progression or unacceptable toxicity with 28 days one cycle. Overall response was evaluated after two cycles Apatinib treatment, then progression-free survival (PFS) and overall survival (OS) were evaluated, and safety data were recorded. Additionally. peripheral blood and peripheral blood mononuclear cell (PBMC) specimens in the osteosarcoma patients were collected for the genotyping of VEGFR2 genetic variation and mRNA expression, respectively. Analysis on the association between genotype and baseline characteristics and VEGFR2 gene mRNA expression was analyzed. The univariate analysis of genotypes and prognosis was carried out by Kaplan–Meier survival analysis, and multivariate analysis was adjusted by Cox regression analysis.

Results

The objective response rate (ORR) of the 105 metastatic osteosarcoma patients was 37.14%, disease control rate (DCR) was 77.14%, median PFS was 4.1 months, and median OS was 9.0 months. Regarding the VEGFR2 gene polymorphisms analysis, only − 906 T > C was of clinical significance. The prevalence of − 906 T > C in VEGFR2 among the study population was as follows: TT genotype 62 cases (59.05%), TC genotype 36 cases (34.29%) and CC genotype 7 cases (6.66%), minor allele frequency of − 906 T > C was 0.24. Compared with patients with TC/CC genotype, patients with TT genotype showed longer median PFS (5.0 versus 3.1 months, P = 0.011) and median OS (9.8 versus 7.6 months, P = 0.032). There was no correlation between the polymorphism and adverse reactions. Additionally, the mRNA expression in 69 randomly selected sample indicated that the mRNA expression of VEGFR2 of the patients with CC/TC genotypes were significantly higher than those of the TT genotype patients (P < 0.001).

Conclusion

Apatinib was safe and effective in the treatment of metastatic osteosarcoma patients who progressed after standard therapy. The clinical outcomes of Apatinib may be influenced by the polymorphism − 906 T > C of VEGFR2 through mediating the mRNA expression of VEGFR2.

中文翻译：

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甲磺酸阿帕替尼治疗标准治疗后进展的转移性骨肉瘤患者的疗效和安全性及VEGFR2基因多态性分析。

摘要

客观的

本研究旨在探讨甲磺酸阿帕替尼治疗标准治疗后进展的转移性骨肉瘤患者的疗效和安全性，并通过VEGFR2基因多态性分析。

方法

本研究设计为回顾性研究，共纳入 105 名标准治疗后进展的转移性骨肉瘤患者。转移性骨肉瘤患者根据体表面积接受 500-750 mg 甲磺酸阿帕替尼治疗，直至疾病进展或出现不可接受的毒性，28 天一个周期。在阿帕替尼治疗两个周期后评估总体反应，然后评估无进展生存期（PFS）和总生存期（OS），并记录安全性数据。此外。收集骨肉瘤患者的外周血和外周血单个核细胞（PBMC）标本，分别用于VEGFR2遗传变异和 mRNA 表达的基因分型。基因型和基线特征与VEGFR2的相关性分析分析基因mRNA表达。基因型和预后的单因素分析采用Kaplan-Meier生存分析，多因素分析采用Cox回归分析进行调整。

结果

105例转移性骨肉瘤患者的客观缓解率（ORR）为37.14%，疾病控制率（DCR）为77.14%，中位PFS为4.1个月，中位OS​​为9.0个月。关于VEGFR2基因多态性分析，只有 − 906 T > C 具有临床意义。研究人群中VEGFR2中− 906 T > C 的发生率如下：TT 基因型 62 例（59.05%），TC 基因型 36 例（34.29%）和 CC 基因型 7 例（6.66%），次要等位基因频率为 - 906 T > C 为 0.24。与TC/CC基因型患者相比，TT基因型患者显示出更长的中位PFS（5.0 vs 3.1个月，P  = 0.011）和中位OS（9.8 vs 7.6个月，P = 0.032）。多态性与不良反应之间没有相关性。此外，随机抽取的69份样本的mRNA表达表明CC/TC基因型患者VEGFR2的mRNA表达显着高于TT基因型患者（P  < 0.001）。

结论

阿帕替尼在标准治疗后进展的转移性骨肉瘤患者的治疗中是安全有效的。Apatinib 的临床结果可能通过介导VEGFR2的 mRNA 表达受到VEGFR2的多态性 - 906 T > C 的影响。