Baseline Alpha-Fetoprotein, Alpha-Fetoprotein-L3, and Des-Gamma-Carboxy Prothrombin Biomarker Status in Bridge to Liver Transplant Outcomes for Hepatocellular Carcinoma

SIMPLE SUMMARY: An abnormal alpha-fetoprotein (AFP) test is often associated with hepatocellular carcinoma (HCC) development, although as many as 40% of HCC diagnoses are made in the absence of an abnormal AFP test. In Japan and other Asian countries, Lens culinaris agglutinin-reactive AFP fraction (AFP-L3) and des-gamma-carboxy prothrombin (DCP) are used in combination with AFP for HCC diagnosis. Combined testing with all three biomarkers increases early diagnosis in addition to providing a patient-specific profile of HCC aggressiveness. The utility of AFP, AFP-L3, and DCP for HCC prognosis in the bridge to liver transplantation has not been established. The goal of this study is to define prognosis to first-line HCC treatment and the risk of progression prior to liver transplantation associated with biomarker profile at diagnosis. Biomarker profiling may have future implications in precision therapeutic management of HCC as a bridge to transplantation. ABSTRACT: The biomarkers α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP fraction (AFP-L3), and des-γ-carboxy prothrombin (DCP) have emerging implications in hepatocellular carcinoma (HCC) surveillance, overall prognosis, and post-surgical recurrence risk. This retrospective study investigated treatment and bridge to liver transplant (LT) prognosis associated with AFP, AFP-L3%, and DCP biomarker profiles prior to liver-directed therapy (LDT). In a 140-patient cohort, each biomarker was associated with HCC progression risk using the established thresholds of AFP > 20 ng/mL, AFP-L3 > 15%, and DCP > 7.5 ng/mL. Over 60% of the cohort expressed at least one biomarker at baseline. Although most biomarker-positive patients expressed the clinical standard AFP (57/87), only 32% were positive for AFP alone. Biomarker accumulation increased HCC progression risk but was not associated with demographic factors or preserved liver function. Biomarker triple negative patients had smaller index HCC (p = 0.003), decreased multifocal burden (p = 0.010), and a higher objective response rate (ORR, 62% compared to 46%, p = 0.011). Expressing all three biomarkers at baseline was associated with dismal first-line ORR (12%) with a median time to progression (TTP) of only 181 days post-LDT. Patients with triple negative status for the HCC biomarkers AFP, AFP-L3%, and DCP have the highest first-line ORR with < 5% HCC progression 1-year post-LDT. Biomarker profiling can establish baseline prognosis for identifying optimal bridge to LT and downstaging to LT candidates with triple negative biomarker status and providing an ideal post-LDT target as a compliment to radiographic response.