Scientific, regulatory, and practical considerations for bringing hepatocellular carcinoma biomarkers into clinical practice

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide; early detection and accurate prediction of treatment response remain major clinical challenges. Current screening methods suffer from limited sensitivity and low adherence and emerging biomarkers show potential to address these challenges. For early HCC detection, biomarker panels such as GALAD and HES V2.0 have shown promising performance in phase III trials, however newer techniques studying methylation of cell-free DNA, fragmentomics and EV-derived RNA may improve sensitivity though they are in earlier validation phases. Biomarkers like programmed death ligand-1 (PD-L1) expression, tumor mutational burden and microsatellite stability status have limited roles in HCC and only AFP is used in clinical practice for prediction of treatment benefit in patients recieving ramucirumab. Bringing biomarkers to market involves different regulatory pathways. In the United States, developers must choose between laboratory-developed test pathway or as in vitro diagnostic approved by the FDA route, followed by securing reimbursement and demonstrating evidence of clinical benefit. In the European Union, the process involves EMA biomarker qualification procedures and conformity assessment under the In Vitro Diagnostic Regulation. Understanding these scientific, regulatory, and commercial considerations is essential for successfully translating HCC biomarker discoveries into clinical practice.