Actionable Gene Expression-Based Patient Stratification for Molecular Targeted Therapy in Hepatocellular Carcinoma

Abstract

BackgroundThe effectiveness of molecular targeted agents is modest in hepatocellular carcinoma (HCC). Efficacy of molecular targeted therapies has been better in cancer patients with high expression of actionable molecules defined as cognate target molecules. However, patient stratification based on the actionable molecules dictating the effectiveness of targeted drugs has remained understudied in HCC.Experimental Design & ResultsPaired tumor and non-tumoral tissues derived from a total of 130 HCC patients were studied. Real-time RT-PCR was used to analyze the mRNA expression of actionable molecules in the tissues. mRNA levels of EGFR, VEGFR2, PDGFRβ, FGFR1, and mTOR were up-regulated in tumors compared to non-tumors in 35.4, 42.3, 61.5, 24.6, and 50.0% of patients, respectively. Up-regulation of EGFR was observed at early stage and tended to gradually decrease toward late stages (BCLC stage A: 41.9%; B: 30.8%; C: 17.6%). Frequency of VEGFR2 expression in tumors at stage C was lower than that in the other stages (BCLC stage A: 45.9%; B: 41.0%; C: 29.4%). PDGFRβ and mTOR were observed to be up-regulated in more than 50% of tumors in all the stages whereas FGFR1 was up-regulated in only about 20% of HCC irrespective of stages. A cluster analysis of actionable gene expression revealed that HCC can be categorized into different subtypes that predict the effectiveness of molecular targeted agents and combination therapies in clinical trials. Analysis of in vitro sensitivity to sorafenib demonstrated that HCC cells with up-regulation of PDGFRβ and c-Raf mRNA are more susceptible to sorafenib treatment in a dose and time-dependent manner than cells with low expression of the genes.ConclusionsmRNA expression analysis of actionable molecules could provide the rationale for new companion diagnostics-based therapeutic strategies in the treatment of HCC.

Impact of epidermal growth factor receptor protein and gene alteration on Taiwanese hepatocellular carcinomas

“…However, 67% (37/55) of the HCC tumors with high tumor grades and 65% (15/23) of the tumors with an advanced clinical stage were negative for EGFR expression (Table ). This result is supported by the findings of Kwon et al ., who showed that downregulation of EGFR was found in advanced stage HCC tumors, as evaluated by the egfr mRNA expression in 130 HCC tumor and non‐tumoral samples . In addition, alcoholism, chronic HBV, and HCV infections were linked to the phosphorylation of EGFR in our study.…”

“…This result is supported by the findings of Kwon et al, who showed that downregulation of EGFR was found in advanced stage HCC tumors, as evaluated by the egfr mRNA expression in 130 HCC tumor and non-tumoral samples. 22 In addition, alcoholism, chronic HBV, and HCV infections were linked to the phosphorylation of EGFR in our study. The finding might provide new insight into the mechanism of hepatocarcinogenesis.…”

Recent developments of c‐Met as a therapeutic target in hepatocellular carcinoma

“…In summary, greater liver toxicity associated with c‐Met inhibition may be anticipated in patients with more severe liver disease. The degree to which underlying disease might restrict the use of c‐Met inhibitors for the treatment of patients with HCC has yet to be established and may depend on additional factors including the subtype and grade of HCC, ethnicity, and hepatitis B and C virus infection …”

A Study of Complication Identification Based on Weighted Association Rule Mining

“…Many hospitals use the Electronic Health Records system (EHRs) to integrate different kinds of medical data [1,2]. The data mining technology is widely applied on the EHRs to support clinical decision, including drug supervision [3], complication identification [4], disease prediction [5], patient stratification [6] and other related directions [7]. Among them, medical complication identification gets special attention.…”