Peer-review started: July 18, 2016
First decision: August 26, 2016
Revised: October 14, 2016
Accepted: November 21, 2016
Article in press: November 22, 2016
Published online: January 18, 2017
Many patients with hepatocellular carcinoma (HCC) are diagnosed in an advanced stage, so they cannot be offered the option of curative treatments. The results of systemic chemotherapy are unsatisfactory and this has led to molecular targeted approaches. HCC develops in chronically damaged tissue due to cirrhosis in most patients. Several different cell types and molecules constitute a unique microenvironment in the liver, which has significant implications in tumor development and invasion. This, together with genome instability, contributes to a significant heterogeneity which is further enhanced by the molecular differences of the underlying causes. New classifications based on genetic characteristics of the tissue microenvironment have been proposed and key carcinogenic signaling pathways have been described. Tumor and adjacent tissue profiling seem biologically promising, but have not yet been translated into clinical settings. The encouraging first results with molecular - genetic signatures should be validated and clinically applicable. A more personalized approach to modern management of HCC is urgently needed.
Core tip: The complete failure of chemotherapy in previous years gradually shifted hepatocellular carcinoma (HCC) treatment to the molecular targeted therapies. The initial-albeit limited - effectiveness of the currently approved systemic therapy, sorafenib, is due to the successful combination of targeting cancer cells and their microenvironment. Trials on drugs other than sorafenib, alone or in combination with drugs or transcatheter arterial chemoembolization were disappointing. Recently, genomic based analyses in HCC patients have proposed subclasses, based on molecular characteristics and a proliferative or non-proliferative genotypes. Combined targeted therapies, driven by specific molecular signatures for treatment selection and monitoring, potentially with immunotherapy, could be a future personalized approach.