Here, we validated the performance characteristics of the HelioLiver Test in a prospective, blinded, multi-center phase 2 biomarker study (the ENCORE study NCT05059665). Based on this foundational work, we further optimized the candidate cfDNA methylation panel and developed the HelioLiver Test, a multi-analyte blood test that combines cfDNA methylation markers with patient demographic information and clinically available HCC tumor markers (components of the GALAD score) to enable robust and accurate HCC detection. Previously, from a comprehensive methylome profiling of HCC tissue/plasma samples combined with machine-learning analysis, we identified cfDNA methylation markers associated with the presence of HCC in patients with chronic liver diseases as a potential HCC detection biomarker. “Liquid biopsies” assaying the methylation of circulating cell-free DNA (cfDNA) released from cancer cells have been actively explored as a promising noninvasive biomarker to sensitively detect various cancer types, including HCC, at early stages. The GALAD score has shown superior HCC detection performance compared with AFP, but there is room for improvement, indicating the still unmet need for HCC surveillance tests with substantially improved performance characteristics. In an effort to improve HCC detection, the GALAD score was developed by combining age, sex, AFP, Lens culinaris agglutinin-reactive AFP (AFP-元%), and des-gamma-carboxy prothrombin (DCP). Thus, HCC surveillance tests with superior performance are urgently needed. Additionally, the performance of ultrasound is reduced by various factors such as obesity, which is sharply increasing globally. The sensitivity of ultrasound for detecting early-stage HCC is only 45%, and a systematic review and meta-analysis study has suggested that the improvement to ultrasound by adding AFP is limited to only 63%. However, the suboptimal performance of current HCC surveillance tests hinders effective early tumor detection. To increase HCC tumor detection at earlier stages that are more amenable to curative treatment, practice guidelines recommend semi-annual HCC surveillance using ultrasound with or without serum alpha-fetoprotein (AFP) for high-risk populations. HCC prognosis remains dismal (5-year survival <15%) due to frequent diagnoses at late, noncurable stages. Mortality of liver cancer, with hepatocellular carcinoma (HCC) as the major histological type, has substantially increased over the past two to three decades in the United States and worldwide, and its incidence is projected to continue to increase over the next decade. The HelioLiver Test showed superior performance for HCC detection compared to with both AFP and the GALAD score and warrants further evaluation in HCC surveillance settings. The specificities of the HelioLiver Test (91% 95% CI, 85%–95%), AFP (97% 95% CI, 92%–99%), and the GALAD score (94% 95% CI, 88%–97%) were similar for control subjects. Using a prespecified diagnostic algorithm, the HelioLiver Test showed sensitivities of 85% (95% confidence interval, 78%–90%) for HCC of any stage and 76% (95% CI, 60%–87%) for early stage (American Joint Committee on Cancer I and II) HCC. The performance of the HelioLiver Test (area under the receiver operating characteristic curve = 0.944) was superior to both AFP (AUROC = 0.851 p < 0.0001) and GALAD (AUROC = 0.899 p < 0.0001). The performance of the HelioLiver Test was compared with AFP and the GALAD score as established HCC surveillance blood tests. A blinded, multicenter validation study was performed with 247 subjects, including 122 subjects with HCC and 125 control subjects with chronic liver disease. To this end, we have conducted a prospective clinical validation study to evaluate the performance of the HelioLiver Test, a multi-analyte blood test combining cell-free DNA methylation patterns, clinical variables, and protein tumor markers. The limited performance of guideline-recommended abdominal ultrasound and serum alpha-fetoprotein (AFP) highlights the urgent, unmet need for new biomarkers for more accurate detection of early hepatocellular carcinoma (HCC).
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