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

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 may help address these limitations. For early HCC detection, biomarker panels such as GALAD and HES V2.0 have shown promising performance in phase III trials; however, newer approaches examining cell-free DNA methylation, fragmentomics, and extracellular vesicle-derived RNA may improve sensitivity, although these are still in earlier stages of validation. Biomarkers such as programmed cell death ligand 1 (PD-L1) expression, tumour mutational burden, and microsatellite instability status have limited roles in HCC, and only alpha-fetoprotein (AFP) is used in clinical practice to predict treatment benefit in patients receiving ramucirumab. Bringing biomarkers to market involves different regulatory pathways. In the United States, developers must choose between a laboratory-developed test pathway or FDA-approved in vitro diagnostic routes, followed by securing reimbursement and demonstrating 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.