Abstract
BACKGROUND & AIMS: We previously developed HES V2.0, a biomarker panel (age, ALT, platelets, etiology, AFP, AFP-L3, DCP, and their 1-year gradients) for early detection of hepatocellular carcinoma (HCC) among patients with cirrhosis. We externally validated HES V2.0 and compared its performance with HES V1.0, GALAD, and ASAP. METHODS: We conducted a PRoBE (prospective specimen-collection, retrospective blinded-evaluation) cohort study in the HEDS (Hepatocellular Carcinoma Early Detection Strategy) cohort of 1,485 patients with cirrhosis, of whom 119 developed HCC. Patient- and test-level true positive rates (TPR) for HCC were calculated at 6, 12, and 24 months before diagnosis, using thresholds at a fixed false positive rate (FPR) of 10% and 18.1% (corresponding to the GALAD cut-off of -1.36). RESULTS: HES V2.0 and GALAD had the same AUROC (0.79) but differed in TPR/FPR profiles. At 10% FPR, HES V2.0 achieved 2.0%, 6.7%, and 6.0% higher sensitivity than GALAD at 6, 12, and 24 months before HCC diagnosis (one-sided p = 0.24, 0.025, and 0.078, respectively). At 18.1% FPR, GALAD showed 6% and 2% higher sensitivity than HES V2.0 at 6 and 12 months, respectively, and similar sensitivity at 24 months (all p >0.05). HES V2.0 demonstrated 11.9% higher sensitivity than HES V1.0 at 12 months (p = 0.007) and 10.9-16.3% higher sensitivity than ASAP. In patients with the necessary laboratory data to calculate temporal gradients, HES V2.0 outperformed GALAD by 3.5-8.7% at all time points (an 8.7-24.0% relative increase; p <0.05 for several comparisons). CONCLUSIONS: In this phase III biomarker validation study, HES V2.0 showed higher sensitivity than ASAP and comparable or superior sensitivity to GALAD, particularly at 12 months before HCC diagnosis at 10% FPR and when temporal gradients in AFP, AFP-L3, and DCP were available. IMPACT AND IMPLICATIONS: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with early detection being critical for improving survival outcomes. This study provides a rigorous phase III validation of the HES V2.0 biomarker panel, demonstrating its superior or comparable sensitivity to established models like GALAD and ASAP in a large, diverse cirrhosis cohort from the United States. The findings are particularly impactful for clinicians and researchers focused on liver cancer surveillance, as HES V2.0 offers enhanced detection performance, especially when longitudinal biomarker data are available. These results support the integration of HES V2.0 into clinical workflows and future trials, potentially improving early HCC detection and enabling timely curative interventions for at-risk patients.