Chuma Makoto, Uojima Haruki, Numata Kazushi, Hidaka Hisashi, Toyoda Hidenori, Hiraoka Atsushi, Tada Toshifumi, Hirose Shunji, Atsukawa Masanori, Itokawa Norio, Arai Taeang, Kako Makoto, Nakazawa Takahide, Wada Naohisa, Iwasaki Shuitirou, Miura Yuki, Hishiki Satoshi, Nishigori Shuhei, Morimoto Manabu, Hattori Nobuhiro, Ogushi Katsuaki, Nozaki Akito, Fukuda Hiroyuki, Kagawa Tatehiro, Michitaka Kojiro, Kumada Takashi, Maeda Shin
Gastroenterological Center, Yokohama City University Medical Center, Yokohama 232-0024, Japan.
Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara 252-0375, Japan.
Cancers (Basel). 2020 Jan 26;12(2):293. doi: 10.3390/cancers12020293.
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, = 0.0004; ratio of Ang-2 level at four weeks/baseline: 0.584 vs. 0.810, respectively, = 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; = 0.0012). Furthermore, this combination biomarker showed the greatest independent association with progression-free survival (Hazard ratio, 0.171; = 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.
肝细胞癌（HCC）对乐伐替尼治疗反应的预测生物标志物尚未明确。本研究的目的是确定乐伐替尼治疗反应的具有临床意义的生物标志物，以靶向针对HCC的治疗策略。对74例接受乐伐替尼治疗的Child-Pugh A级HCC患者在基线时和引入乐伐替尼后采集的血样中循环血管生成因子（CAFs）水平进行了分析。作为CAF生物标志物，采用酶联免疫吸附测定法检测血清血管内皮生长因子（VEGF）、成纤维细胞生长因子19（FGF19）、FGF23和血管生成素-2（Ang-2）。结果：与无反应者相比，乐伐替尼反应者中FGF19水平显著升高（FGF19-i），Ang-2水平降低（Ang-2-d）（反应者与无反应者4周时FGF19水平与基线水平之比分别为2.09对1.32，P = 0.0004；4周时Ang-2水平与基线水平之比分别为0.584对0.810，P = 0.0002）。然而，反应者与无反应者相比，4周时FGF23和VEGF水平相对于基线的变化无显著差异。在多变量分析中，血清FGF19-i和Ang-2-d的组合是乐伐替尼反应最独立的预测因素（比值比，9.143；P = 0.0012）。此外，这种组合生物标志物与无进展生存期的独立关联最大（风险比，0.171；P = 0.0240）。循环FGF19和Ang-2水平的早期变化可能有助于预测接受乐伐替尼治疗的HCC患者的临床反应和无进展生存期。
