Clinical utilization of testing for cell-free DNA in hepatocellular cancer

HCC is one of the leading causes of cancer-related death globally. HCCs are often diagnosed in advanced stages, and most patients are not eligible for curative treatments. Semiannual abdominal ultrasound with serum alpha-fetoprotein is the current recommended surveillance strategy; however, it has suboptimal sensitivity and implementation, thereby lowering its effectiveness for early-stage HCC detection. Further, post-treatment monitoring of HCC recurrence or progression is not tailored to tumor aggressiveness. These failures highlight critical unmet needs, which can be addressed by novel biomarkers that enable early detection and guide individualized surveillance and post-treatment follow-up for HCC, ultimately leading to improved outcomes in this disease. Cell-free DNA (cfDNA), consisting of small fragments of DNA released from tumor and normal cells into the bloodstream, reflects tumor-specific molecular alterations and has emerged as a promising noninvasive biomarker. This review summarizes recent advances in cfDNA applications in HCC, including risk stratification, early detection, prognostication, and minimal residual disease assessment. Among them, cfDNA has made the most progress in early detection. cfDNA assays, combined with clinical and serum parameters, demonstrate sensitivity noninferior or superior to ultrasound for detecting early HCC, with larger phase 3 validation studies ongoing. In contrast, the use of cfDNA for risk stratification, prognostication, and minimal residual disease detection remains in the early stages of clinical development. Future multicenter studies with standardized methodologies and rigorous validation will be essential to translate cfDNA into routine clinical practice for the management of HCC.