Comparative Evaluation of Multimarker Algorithms for Early-stage HCC Detection in Multicenter Prospective Studies

Background & Aims: We compared the clinical performance of the novel GAAD (gender [biological sex], age, alpha-fetoprotein [AFP], des-gamma carboxyprothrombin [DCP]) and GALAD (gender [biological sex], age, AFP, agglutinin-reactive AFP [AFP-L3], DCP) algorithms to deduce the clinical utility of AFP-L3 for detecting early-stage hepatocellular carcinoma (HCC) from chronic liver disease (CLD).

Methods: An algorithm development study (STOP-HCC-ARP) and clinical validation study (STOP-HCC-MCE) were conducted, recruiting adult participants with HCC (confirmed by radiology or pathology) or CLD in an international, multicenter, case-control design. Serum biomarkers were measured using Elecsys assays (GAAD and GALAD [Cobas]) or μTASWAKO assays (GALAD [μTASWAKO]) while blinded to case/control status.

Results: In STOP-HCC-ARP (algorithm development cohort), 1,006 patients {297 HCC (41.4% early-stage [Barcelona Clinic Liver Cancer {BCLC} 0/A) and 709 CLD} were included. Area under the curve (AUCs) for discriminating between early-stage HCC CLD were 91.4%, 91.4%, and 90.8% for GAAD (Cobas), GALAD (Cobas), and GALAD (μTASWAKO), respectively. The clinical validation cohort of STOP-HCC-MCE comprised 1,142 patients, (366 HCC cases [48% early-stage], 468 specificity samples and 302 CLD); AUCs for GAAD (Cobas), GALAD (Cobas), and GALAD (μTASWAKO) for discriminating between early-stage HCC CLD were 91.4%, 91.5%, and 91.0%, respectively; AUCs were 94.7-95.0% for all-stage HCC. The GAAD and GALAD algorithms demonstrated similar good performance regardless of disease etiology, presence of cirrhosis, geographical region, and within pan-tumor specificity panels ( <0.001).

Conclusions: GAAD (Cobas) demonstrated good clinical performance, similar to GALAD (Cobas and μTASWAKO) algorithms, in differentiating HCC and CLD controls, across all disease stages, etiologies, and regions; therefore, AFP-L3 may have a negligible role in GALAD for HCC surveillance.

Impact And Implications: To improve the detection of early-stage hepatocellular carcinoma (HCC) from benign chronic liver disease (CLD), algorithms combining demographic characteristics and serum biomarkers, such as GAAD and GALAD, have been developed. GAAD combines gender (biological sex), age, alpha-fetoprotein (AFP), des-gamma carboxy-prothrombin (DCP); GALAD combines the same characteristics and biomarkers as GAAD with the addition of agglutinin-reactive AFP (AFP-L3). Changing disease etiologies and treatment paradigms have raised questions regarding the utility of AFP-L3 in HCC surveillance. Our work demonstrates that the GAAD (Cobas) algorithm demonstrated good clinical performance and was as sensitive and specific as the GALAD (Cobas) and GALAD (μTASWAKO) algorithms in differentiating HCC and CLD controls, across all disease stages, etiologies, and geographical regions; therefore, AFP-L3 may have a negligible role in HCC detection. Our study provides supporting evidence that in participants with CLD undergoing guideline-directed HCC surveillance, the GAAD (Cobas) algorithm may be used as an effective method for the detection of HCC, potentially resulting in improved patient outcomes.