Sorafenib is the most recommended first‐line systemic therapy for advanced hepatocellular carcinoma (HCC). Yet there is no clinically applied biomarker for predicting sorafenib response. We have demonstrated that a vascular pattern, named VETC (Vessels that Encapsulate Tumor Clusters), facilitates the release of whole tumor clusters into the bloodstream; VETC‐mediated metastasis relies on vascular pattern, but not on migration and invasion of cancer cells. In this study, we aimed to explore whether vascular pattern could predict sorafenib benefit. Two cohorts of patients were recruited from four academic hospitals. The survival benefit of sorafenib treatment for patients with or without the VETC pattern (VETC+/VETC–) was investigated. Kaplan‐Meier analyses revealed that sorafenib treatment significantly reduced death risk and prolonged overall survival (OS; in cohort 1/2, P = 0.004/0.005; hazard ratio [HR] = 0.567/0.408) and postrecurrence survival (PRS; in cohort 1/2, P = 0.001/0.002; HR = 0.506/0.384) in VETC+ patients. However, sorafenib therapy was not beneficial for VETC‐ patients (OS in cohort 1/2, P = 0.204/0.549; HR = 0.761/1.221; PRS in cohort 1/2, P = 0.121/0.644; HR = 0.728/1.161). Univariate and multivariate analyses confirmed that sorafenib treatment significantly improved OS/PRS in VETC+, but not VETC–, patients. Further mechanistic investigations showed that VETC+ and VETC– HCCs displayed similar levels of light chain 3 (LC3) and phosphorylated extracellular signal‐regulated kinase (ERK) in tumor tissues (pERK) or endothelial cells (EC‐pERK), and greater sorafenib benefit was consistently observed in VETC+ HCC patients than VETC– irrespective of levels of pERK/EC‐pERK/LC3, suggesting that the different sorafenib benefit between VETC+ and VETC– HCCs may not result from activation of Raf/mitogen‐activated protein kinase kinase (MEK)/ERK and vascular endothelial growth factor (VEGF)A/VEGF receptor 2 (VEGFR2)/ERK signaling or induction of autophagy. Conclusion: Sorafenib is effective in prolonging the survival of VETC+, but not VETC–, patients. VETC pattern may act as a predictor of sorafenib benefit for HCC.

中文翻译：

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包裹肿瘤簇 (VETC) 模式的血管是肝细胞癌患者索拉非尼获益的预测因子

索拉非尼是晚期肝细胞癌（HCC）最推荐的一线全身治疗。然而，尚无临床应用的生物标志物可用于预测索拉非尼反应。我们已经证明，一种名为 VETC（包裹肿瘤簇的血管）的血管模式有助于将整个肿瘤簇释放到血流中；VETC 介导的转移依赖于血管模式，而不依赖于癌细胞的迁移和侵袭。在这项研究中，我们旨在探讨血管模式是否可以预测索拉非尼的益处。从四家学术医院招募了两组患者。研究了索拉非尼治疗对有或没有 VETC 模式 (VETC+/VETC–) 的患者的生存益处。Kaplan-Meier 分析显示，索拉非尼治疗显着降低了死亡风险并延长了总生存期（OS；队列 1/2，P = 0.004/0.005；风险比 [HR] = 0.567/0.408）和复发后生存期（PRS；队列 1） /2，P = 0.001/0.002；HR = 0.506/0.384）在 VETC+ 患者中。然而，索拉非尼治疗对 VETC 患者无益（队列 1/2 中的 OS，P = 0.204/0.549；HR = 0.761/1.221；队列 1/2 中的 PRS，P = 0.121/0.644；HR = 0.728/1.161） . 单变量和多变量分析证实，索拉非尼治疗显着改善了 VETC+ 患者的 OS/PRS，但未改善 VETC- 患者。进一步的机制研究表明，VETC+ 和 VETC-HCC 在肿瘤组织 (pERK) 或内皮细胞 (EC-pERK) 中显示出相似水平的轻链 3 (LC3) 和磷酸化细胞外信号调节激酶 (ERK)，无论 pERK/EC-pERK/LC3 水平如何，在 VETC+ HCC 患者中始终观察到比 VETC– 更大的索拉非尼益处，这表明 VETC+ 和 VETC– HCC 之间的不同索拉非尼益处可能不是由 Raf/丝裂原活化蛋白的激活引起的激酶激酶 (MEK)/ERK 和血管内皮生长因子 (VEGF)A/VEGF 受体 2 (VEGFR2)/ERK 信号传导或自噬诱导。结论：索拉非尼可有效延长 VETC+（而非 VETC-）患者的生存期。VETC 模式可作为索拉非尼对 HCC 获益的预测指标。表明 VETC+ 和 VETC-HCC 之间不同的索拉非尼获益可能不是由 Raf/丝裂原活化蛋白激酶激酶 (MEK)/ERK 和血管内皮生长因子 (VEGF)A/VEGF 受体 2 (VEGFR2)/ERK 信号传导的激活引起的或诱导自噬。结论：索拉非尼可有效延长 VETC+（而非 VETC-）患者的生存期。VETC 模式可作为索拉非尼对 HCC 获益的预测指标。表明 VETC+ 和 VETC-HCC 之间不同的索拉非尼获益可能不是由 Raf/丝裂原活化蛋白激酶激酶 (MEK)/ERK 和血管内皮生长因子 (VEGF)A/VEGF 受体 2 (VEGFR2)/ERK 信号传导的激活引起的或诱导自噬。结论：索拉非尼可有效延长 VETC+（而非 VETC-）患者的生存期。VETC 模式可作为索拉非尼对 HCC 获益的预测指标。