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 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.

Vessels Encapsulating Tumor Clusters (VETC) Is a Powerful Predictor of Aggressive Hepatocellular Carcinoma

“…This vascular phenotype can be detected with increasing frequency, from the earliest stages of HCC, and its assessment is easy and reliably reproducible even in small‐sized tissues such as liver biopsy. In advanced HCC, VETC has been recently suggested to act as a predictor of sorafenib benefit; however, our data support the assessment of the VETC phenotype also in nonadvanced and resectable HCC for the identification of HCC patients at high risk of a more rapid tumor progression. VETC is a noncapillary network of HCC vessels that is prone to open into larger ones, as to deliver metastatic tumor cell clusters …”

“…Although conducted in a limited HCC population (hepatitis B virus [HBV]‐related and >5 cm), the authors elegantly showed VETC clusters delivering tumor emboli into larger vessels. Moreover, the same authors recently claimed sorafenib therapy to be more effective in VETC HCC …”

“…Moreover, the same authors recently claimed sorafenib therapy to be more effective in VETC HCC. (12) To lend further support to the hypothesis that a VETC pattern can primarily affect patient prognosis, we collected a large series of surgically resected HCCs with various etiologies from different geographic areas of high HCC incidence, where VETC was evaluated against consolidated and novel prognostic markers.…”

Evaluation of Intra-Tumoral Vascularization in Hepatocellular Carcinomas

“…Dingand and colleagues revealed that the sinusoidal-like vascular patterns were associated with a low overall survival rate and high early recurrence rate (70). Additionally, Fang et al unprecedentedly used threedimensional reconstruction to confirm that sinus vessels formed an interconnected network around a single HCC nodule, while capillaries showed discrete and disorganized patterns (71,72). They suggested that this vascular pattern was an effective mode of HCC metastasis independent of epithelial-to-mesenchymal transition.…”

The Predictive Value of Vessels Encapsulating Tumor Clusters in Treatment Optimization for Recurrent Early-Stage Hepatocellular Carcinoma

“…Moreover, the VETC pattern may act as predictor of sorafenib bene t in patients with HCC, especially those with VETC. VETC can be an indicator for guiding the treatment of patients with recurrent HCC [21]. However, there are no studies regarding the prognostic value of the VETC pattern in recurrent early-stage HCC.…”