Tumor Fibroblast Growth Factor Receptor 4 Level Predicts the Efficacy of Lenvatinib in Patients With Advanced Hepatocellular Carcinoma.
Tumor Fibroblast Growth Factor Receptor 4 Level Predicts the Efficacy of Lenvatinib in Patients With Advanced Hepatocellular Carcinoma.
复制标题
DOI：
10.14309/ctg.0000000000000179
复制
发表时间：
2020-05-01
影响因子：
3.6
通讯作者：
Chayama, Kazuaki
中科院分区：
文献类型：
--
作者：
Yamauchi, Masami;Ono, Atsushi;Chayama, Kazuaki
目的：尽管进行了深入和全面的基因组研究，但用于优化lenvatinib治疗晚期肝细胞癌患者预后的生物标志物仍有待建立。Lenvatinib的特点是与早期的酪氨酸激酶抑制剂相比，它对成纤维细胞生长因子受体（FGFR） 4具有显著的抑制作用。因此，在本研究中，我们专注于简化肿瘤中FGFR4的量化，将其作为潜在的预测指标。方法：根据癌症基因组图谱数据集管理，在没有基因改变的情况下，FGFR4信使RNA在肝细胞癌中广泛过表达。基因集富集分析显示，肿瘤的侵袭性与FGFR4水平密切相关。为了确认lenvatinib的益处与肿瘤成瘾与FGFR4通路之间的关系，我们分析了57名lenvatinib治疗的前瞻性登记患者的肿瘤和外周血中的蛋白水平。结果：治疗前活检样本中FGFR4免疫组化阳性（肿瘤细胞的10%）与更长的无进展生存期（2.5个月vs 5.5个月，P = 0.01）和有利的客观缓解率（31% vs 81%, P = 0.006）相关。相比之下，通过酶联免疫吸附试验测量的外周血中可溶性FGFR4的浓度与生存结果无关，因为其波动反映了肝纤维化。使用手术标本（n = 90）的额外RNA测序分析表明，癌症中FGFR4的选择性RNA剪接也可以解释这种差异。讨论：肿瘤FGFR4水平是lenvatinib应答的独立预测因子。
OBJECTIVES: Biomarkers for optimizing the outcome of treatment with lenvatinib in patients with advanced hepatocellular carcinoma remain to be established despite intensive and comprehensive genomic research. Lenvatinib is characterized by its prominent inhibitory potency for fibroblast growth factor receptor (FGFR) 4 compared with earlier tyrosine kinase inhibitors. Thus, in this study, we focused on simplified quantification of FGFR4 in tumors as a potential predictive indicator.METHODS: According to The Cancer Genome Atlas data set curation, FGFR4 messenger RNA is broadly overexpressed in hepatocellular carcinoma in the absence of gene alteration. Gene set enrichment analysis revealed that the aggressiveness of the tumor was closely related to the FGFR4 level. To confirm the relationship between the benefits of lenvatinib and tumor addiction to the FGFR4 pathway, we analyzed protein levels in tumors and peripheral blood obtained from 57 prospectively registered patients treated with lenvatinib.RESULTS: Positive immunohistochemistry (>10% of tumor cells) for FGFR4 in biopsy samples before treatment was associated with a longer progression-free survival (2.5 vs 5.5 months, P = 0.01) and a favorable objective response rate (31% vs 81%, P = 0.006). By contrast, the concentration of soluble FGFR4 in peripheral blood as measured by an enzyme-linked immunosorbent assay was not associated with survival outcomes, because its fluctuations reflect hepatic fibrosis. Additional RNA sequencing analysis using archival surgical specimens (n = 90) suggested that alternative RNA splicing of FGFR4 in cancer may also explain this discrepancy.DISCUSSION: The tumor FGFR4 level was an independent predictor of response to lenvatinib.