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The HCC biomarkers, Lens culinaris agglutinin fraction of AFP (AFP-L3) and des-gamma-carboxyprothrombin (DCP) with AFP, have been approved for surveillance in HCC but have not yet impacted disease management. In this prospective study, AFP, AFP-L3, and DCP were assessed as a non-invasive strategy to monitor residual disease and post-LDT changes in association with risk of disease progression. The biomarkers were measured at HCC diagnosis and following first cycle LDT. Response to LDT was evaluated using mRECIST. Time to event endpoints included time to advanced-stage disease progression, duration of overall complete response (oDoCR), and overall survival. The study included 182 patients with diverse biomarker profiling both at diagnosis and following first cycle LDT. Despite treatment, persistent biomarker expression was found in 36% (66/182) of patients with most (50/66) having elevations in AFP-L3 and/or DCP (AFP-L3⁺/DCP⁺). Overall CR rates were highest in patients treated to triple negative/AFP⁺ only (61%) compared to AFP⁺AFP-L3⁺/DCP⁺ (30%) or AFP_NEGAFP-L3⁺/DCP⁺ (22%) phenotypes. In patients expressing AFP-L3⁺/DCP⁺ that achieved an overall CR, the oDoCR was lower compared to patients treated to triple negative/AFP⁺. Higher 1-year stage progression rates were also observed in patients with AFP-L3⁺/DCP⁺ phenotypes. Overall survival was lowest in patients expressing AFP⁺AFP-L3⁺/DCP⁺ (2-year rate: 36%). In patients with an incomplete response, triple negative/AFP⁺ phenotypes had longer TTP compared to AFP-L3⁺/DCP⁺ phenotypes (median TTP: 63 months vs 10 months). Sustained AFP-L3⁺/DCP⁺ expression following LDT may be associated with aggressive residual tumor contributing to an incomplete response, increased risk of disease stage progression, and inferior survival outcomes.