National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Department of Liver Surgery, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Clin Cancer Res. 2020 Aug 15;26(16):4302-4312. doi: 10.1158/1078-0432.CCR-19-1858. Epub 2020 Apr 24.
To identify a predictive biomarker of sorafenib for hepatocellular carcinoma personalized therapy.
The patients treated with or without sorafenib after hepatocellular carcinoma recurrence from multicenters were matched with propensity score matching analysis. The expression levels of Fms-like tyrosine kinase 3 (FLT3) in hepatocellular carcinoma specimens of the matched patients ( = 276) were analyzed by IHC. The optimal cut-off point of FLT3 levels for overall survival (OS) was defined via Cutoff Finder. Subgroup analysis of OS was employed to investigate the association between FLT3 levels and sorafenib benefit. The predictive value was assessed via Cox regression models with an interaction term. Hepatocellular carcinoma and paratumoral normal tissues were used to investigate the expression and copy-number variation of FLT3. Patient-derived xenograft (PDX) models were used to confirm the association between FLT3 levels and sorafenib response.
Patients with FLT3-high hepatocellular carcinoma exhibited a superior OS upon sorafenib treatment. High FLT3 levels were predictive of sorafenib benefit in terms of OS ( = 0.00006). Copy-number losses and decreased expression of FLT3 in hepatocellular carcinoma were detected in about 64% of patients. Moreover, the PDXs derived from tumors with high FLT3 levels also displayed a better response to sorafenib.
Sorafenib may be able to delay tumor progression in patients with FLT3-high hepatocellular carcinoma. This potential biomarker needs to be further validated in independent cohorts prior to helping stratify patients for precision therapy in advanced hepatocellular carcinoma.
确定索拉非尼用于肝细胞癌个体化治疗的预测生物标志物。
对来自多个中心的肝细胞癌复发后接受或未接受索拉非尼治疗的患者进行倾向评分匹配分析。采用免疫组化法分析匹配患者（n=276）肝癌标本中 Fms 样酪氨酸激酶 3（FLT3）的表达水平。通过 Cutoff Finder 定义 FLT3 水平对总生存期（OS）的最佳截断点。采用 OS 亚组分析探讨 FLT3 水平与索拉非尼获益的关系。采用 Cox 回归模型评估预测价值，并加入交互项。使用肝癌和癌旁正常组织研究 FLT3 的表达和拷贝数变异。使用患者来源的异种移植（PDX）模型来验证 FLT3 水平与索拉非尼反应之间的关联。
FLT3 高表达的肝癌患者在接受索拉非尼治疗后具有更好的 OS。高 FLT3 水平是 OS 获益的预测因素（ = 0.00006）。约 64%的患者存在 FLT3 拷贝数丢失和肝癌中表达降低。此外，源自高 FLT3 水平肿瘤的 PDX 也对索拉非尼有更好的反应。
索拉非尼可能能够延缓 FLT3 高表达的肝癌患者的肿瘤进展。在为晚期肝细胞癌的精准治疗分层患者方面，该潜在生物标志物需要在独立队列中进一步验证。
