Abstract
BACKGROUND & AIMS: The membrane proteoglycan glypican-3 (GPC3) is expressed in ∼70%-80% of hepatocellular carcinomas (HCCs), and its soluble fragment is released into the circulation by protease cleavage. We investigated correlations between tumor and plasma GPC3 levels and their associations with clinical outcomes in advanced HCC. METHODS: We analyzed 186 patients with advanced HCC treated between 2017 and 2023. Tumor GPC3 expression was assessed using immunohistochemistry and RNA sequencing, and plasma GPC3 by ELISA. Clinical outcomes were investigated in 106 patients receiving first-line atezolizumab plus bevacizumab. RESULTS: Plasma GPC3 was detectable in 59.3% of patients (median 11.4 pg/ml), and correlated with tumor expression (H-score: R = 0.40, p <0.001). Plasma GPC3 positivity (>0 pg/ml) increased across H-score strata (p <0.001) but remained undetectable in 25.9% with H-scores >200. High plasma GPC3 (>10 pg/ml) was associated with shorter progression-free survival (3.4 vs. 9.4 months, p = 0.003), overall survival (12.3 vs. 30.6 months, p <0.001) and lower objective response rates (17.9% vs. 47.9%, p = 0.001). Compared to tumor values, plasma GPC3 better predicted 6- and 12- month outcomes, and was independently associated with worse progression-free survival (hazard ratio 1.70, 95% CI 1.07-2.69, p = 0.02) and overall survival (1.96, 1.12-3.40, p = 0.02) on multivariable analyses. CONCLUSIONS: While plasma GPC3 levels showed moderate concordance with tumor expression, meaningful discrepancies were also noted in a significant fraction of patients. High plasma GPC3 independently predicted worse survival outcomes in patients treated with atezolizumab plus bevacizumab, showing superior prognostic performance over tumor-based measures. IMPACT AND IMPLICATIONS: Glypican-3 (GPC3) is a promising biomarker and therapeutic target in hepatocellular carcinoma (HCC), yet the relationship between plasma and tumor GPC3 levels remains unclear, and their clinical relevance has not been well defined, particularly in patients receiving atezolizumab plus bevacizumab. Our study provides clinical evidence supporting plasma GPC3 as a non-invasive biomarker in HCC, showing that circulating GPC3 levels are associated with tumor expression but more closely linked to clinical outcomes, serving as an independent predictor of survival and treatment response in patients treated with atezolizumab plus bevacizumab. These findings suggest that plasma-based assessment may complement tissue-based evaluation and support real-time risk stratification in advanced HCC, although further validation in diverse, prospective cohorts is warranted.