Plasma Vascular Endothelial Growth Factor‐A Identified by Proximity Extension Assay Predicts Early Progression in Hepatocellular Carcinoma Treated With Atezolizumab and Bevacizumab

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AIM: Hepatocellular carcinoma (HCC), a major cause of cancer death, highlights the need for biomarkers predicting early progressive disease (PD) under atezolizumab/bevacizumab (Atezo/Bev) therapy. We used the proximity extension assay (PEA) to identify plasma biomarkers linked to early PD. METHODS: This study included 47 patients with unresectable HCC treated with Atezo/Bev, divided into derivation (n = 27) and validation (n = 20) cohorts. To identify plasma biomarkers for early PD, 92 cytokines were measured by PEA; enzyme-linked immunosorbent assays (ELISA) were then used to determine key protein cutoffs in derivation. Cutoff validity was confirmed in validation. RESULTS: PEA showed vascular endothelial growth factor (VEGF)-A, angiopoietin-2 (ANGPT2), and Tie-2 were elevated in early PD cases. ELISA confirmed significantly higher levels in early PD versus nonearly PD (VEGF-A: 78.3 pg/mL vs. 53.2 pg/mL and p = 0.002; ANGPT2: 18.4 ng/mL vs. 12.7 ng/mL and p = 0.007; and Tie-2: 24.5 ng/mL vs. 17.6 ng/mL and p = 0.009). After establishing cutoff values for each protein, multivariate logistic regression analysis incorporating clinical background identified VEGF-A as the sole independent predictor of early PD (cutoff: 73.9 pg/mL, OR: 40.00, and p = 0.006). The predictive value of VEGF-A for early PD was evaluated in the validation cohort. With a cutoff of 73.9 pg/mL, early PD occurred in 21.4% and 83.3% of the low (n = 14) and high VEGF-A groups (n = 6), respectively (p = 0.018). CONCLUSIONS: Plasma VEGF-A levels were identified as a significant biomarker for early PD in individuals with HCC receiving Atezo/Bev therapy.

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