Supplementary Material for: VETC+ unresectable HCCs benefit of anti-angiogenic therapy

Introduction. Two distinct molecular groups of HCC have been recently associated with a better response to atezolizumab-bevacizumab (A/B). One of these, “angiogenesis-driven”, is related to HCC vascularization. VETC (vessel that encapsulate tumor clusters) is a morphological form of angiogenesis associated with worse prognosis in resected and transplanted HCC.
Aim of this study is to explore if VETC can be used, at morphological level, to potentially surrogate the angiogenesis-driven molecular subgroup to identify HCC patients who mightbenefit of anti-angiogenic treatments.
Methods. The significance of VETC was first explored in a retrospective, single institution series of 75 patients with unresectable HCC (study cohort) and later validated in an external, retrospective series of 82 patients (validation cohort). The VETC phenotype was identified in the liver biopsy obtained just before the onset of systemic treatment.
Results. Patients with VETC+ HCC experienced a significant survival benefit from anti-angiogenic drugs, as tyrosine kinase inhibitors and/or bevacizumab (TKI/BEVA), across the study, validation, and overall cohorts. In the whole series of 157 patients, those with VETC+ HCC (n=70, 45%) treated with TKI/BEVA had a significantly longer OS as compared to those receiving Immune Checkpoint Inhibitors (ICIs) [19.8 months vs 8.8 months; HR 0.34; 95% CI 0.20-0.59; P=0.0001]. The significant treatment-by-biomarker interaction test (P=0.002) demonstrated that treatment effect varies by VETC status. Case with higher extent of VETC+, or with VETC+ detected before the onset of 1st line treatment showed even longer survival.
Conclusion. VETC+ predicts a significantly longer OS in patients with unresectable HCC treated with TKI/BEVA and can be used as surrogate marker on liver biopsy of angiogenesis-driven molecular class.