Early Changes in Circulating FGF19 and Ang-2 Levels as Possible Predictive Biomarkers of Clinical Response to Lenvatinib Therapy in Hepatocellular Carcinoma
Early Changes in Circulating FGF19 and Ang-2 Levels as Possible Predictive Biomarkers of Clinical Response to Lenvatinib Therapy in Hepatocellular Carcinoma
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DOI：
10.3390/cancers12020293
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发表时间：
2020-02-01
期刊：
影响因子：
5.2
通讯作者：
Maeda, Shin
中科院分区：
文献类型：
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作者：
Chuma, Makoto;Uojima, Haruki;Maeda, Shin
预测肝细胞癌(HCC)对Lenvatinib治疗反应的生物标志物尚未阐明。这项研究的目的是确定临床上有意义的生物标志物对Lenvatinib治疗的反应，以针对性地制定治疗肝癌的策略。对74例接受伦瓦替尼治疗的Child-Pugh A级肝细胞癌患者在基线和应用伦瓦替尼后的血液样本中循环血管生成因子(CAF)水平进行了分析。以血清血管内皮生长因子(VEGF)、成纤维细胞生长因子19(FGF19)、成纤维细胞生长因子23(FGF23)和血管生成素-2(Ang-2)为CAF生物标志物，采用双抗体夹心酶联免疫吸附分析法检测血清血管内皮细胞生长因子(VEGF)、成纤维细胞生长因子19(FGF19)、血管生成素-2(Ang-2)。结果：与非应答组相比，Lenvatinib应答组FGF19(FGF19-I)水平显著升高，Ang-2(Ang-2-d)水平显著降低(4周/基线时，应答组与非应答组FGF19水平的比率分别为2.09vs.1.32，p=0.0004；Ang-2水平的比率分别为0.584与0.810，p=0.0002)。然而，与基线相比，有反应者和无反应者四周时FGF23和VEGF水平的变化没有显著差异。在多因素分析中，血清FGF19-I和Ang-2-d的组合是Lenvatinib疗效最独立的预测因素(优势比，9.143；p=0.0012)。此外，这种组合生物标记物显示出与无进展存活率最大的独立关联(危险比，0.171；p=0.0240)。早期循环FGF19和Ang-2水平的变化可能有助于预测接受Lenvatinib治疗的肝细胞癌患者的临床反应和无进展生存率。
Predictive biomarkers of the response of hepatocellular carcinoma (HCC) to Lenvatinib therapy have not yet been clarified. The aim of this study was to identify clinically significant biomarkers of response to Lenvatinib therapy, to target strategies against HCC. Levels of circulating angiogenic factors (CAFs) were analyzed in blood samples collected at baseline and after introducing lenvatinib, from 74 Child-Pugh class A HCC patients who received lenvatinib. As CAF biomarkers, serum vascular endothelial growth factor (VEGF), fibroblast growth factor 19 (FGF19), FGF23, and angiopoietin-2 (Ang-2) were measured using enzyme-linked immunosorbent assays. Results: Significantly increased FGF19 (FGF19-i) levels and decreased Ang-2 (Ang-2-d) levels were seen in Lenvatinib responders as compared to non-responders (ratio of FGF19 level at 4 weeks/baseline in responders vs. non-responders: 2.09 vs. 1.32, respectively, p = 0.0004; ratio of Ang-2 level at four weeks/baseline: 0.584 vs. 0.810, respectively, p = 0.0002). Changes in FGF23 and VEGF levels at four weeks versus baseline, however, were not significantly different in responders versus non-responders. In multivariate analysis, the combination of serum FGF19-i and Ang-2-d was the most independent predictive factor for Lenvatinib response (Odds ratio, 9.143; p = 0.0012). Furthermore, this combination biomarker showed the greatest independent association with progression-free survival (Hazard ratio, 0.171; p = 0.0240). Early changes in circulating FGF19 and Ang-2 levels might be useful for predicting clinical response and progression-free survival in HCC patients on Lenvatinib therapy.