Personalized therapy in hepatocellular carcinoma: Molecular markers of prognosis and therapeutic response

Hepatocellular carcinoma (HCC) represents a growing worldwide health crisis with rising incidence, limited effective therapies and persistently poor prognosis. Five-year survival remains less than 20% despite decades of research. One byproduct of research efforts is the identification of numerous biomarkers of disease. From prognosis to therapeutic response, biomarker identification parallels a deeper molecular understanding of the disease that to date has generated limited gain in clinical outcomes. As one example, the classical prognostic biomarkers of tumor Ki-67 protein expression and TP53 gene mutation have been repeatedly demonstrated to correlate with poor prognosis. There have been several studies throughout the past two decades identifying other gene-based biomarkers of prognosis. Critically, translation into the clinic has been slow and focus has shifted to a search for markers of therapeutic response in hopes of generating novel approaches to the disease. With this focus, many of the correlates are based on retrospective review of sorafenib effectiveness. Sorafenib, an oral targeted multi-kinase inhibitor, is currently the standard of care systemic agent for non-resectable disease. The Wnt-pathway, particularly when activated, is the most commonly cited molecular marker of sorafenib responsiveness. Additional work has identified a profile of genes involved in drug absorption, processing, and elimination that also appears to increase responsiveness. Overall, despite promising clinical data the use of biomarkers in the clinic for HCC is limited. In this piece, progress and opportunities for future work “beyond the genome” are highlighted, including metabolomic, epigenetic, and non-coding RNA studies. Additionally, barriers to the implementation of personalized therapeutic selection in HCC are reviewed.