Vessels that encapsulate tumor clusters (VETC) pattern is a predictor of sorafenib benefit in patients with hepatocellular carcinoma

Abstract

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 the migration and invasion of cancer cells. In this study, we aimed to explore whether the 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, HR=0.567/0.408) and post‐recurrence 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 the OS/PRS in VETC⁺, but not VETC^‐, patients. Further mechanistic investigations showed that VETC⁺ and VETC^‐ HCCs displayed similar levels of LC3 and the phosphorylated ERK in tumor tissues (pERK) or endothelial cells (EC‐pERK), and greater sorafenib benefit was consistently observed in VETC⁺ HCC patients than VETC^‐ ones irrespective of the levels of pERK/EC‐pERK/LC3, suggesting that the different sorafenib benefit between VETC⁺ and VETC^‐ HCCs may not result from activation of Raf‐MEK‐ERK and VEGFA‐VEGFR2‐ERK signaling or induction of autophagy.

Conclusions

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.

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