pERK/pAkt phenotyping in circulating tumor cells as a biomarker for sorafenib efficacy in patients with advanced hepatocellular carcinoma
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Jun Li1,*, Lehua Shi1,*, Xiaofeng Zhang1,*, Bin Sun1, Yefa Yang1, Naijian Ge1, Huiying Liu1, Xia Yang1, Lei Chen1, Haihua Qian1, Mengchao Wu1, Zhengfeng Yin1
1Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
*These authors have contributed equally to this work
Zhengfeng Yin, e-mail: email@example.com
Keywords: ERK/Akt, circulating tumor cells, hepatocellular carcinoma, sorafenib
Received: June 16, 2015 Accepted: October 13, 2015 Published: October 26, 2015
Sorafenib is a multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma (HCC). However, therapeutic response to sorafenib was not equal among HCC patients. Here we present a novel system to provide quantitative information concerning sorafenib-related targets by simultaneous detection of phosphorylated ERK (pERK) and pAkt expressions in circulating tumor cells (CTCs) isolated from HCC patients. Our results showed that 90.0% of patients had a molecular classification of tissues concordant with that of CTCs. CTC counts showed a shaper decline in patients with pERK+/pAkt− CTCs after two weeks of sorafenib treatment (P < 0.01). Disease control rates were significantly different between patients with pERK+/pAkt− CTCs (11/15; 73.3%) and those without (13/44; 29.5%) (P < 0.05). Univariate and multivariate analysis indicated pERK+/pAkt− CTCs as an independent predictive factor of progression-free survival (PFS) (hazard ratio = 9.389; P < 0.01). PFS correlated with the proportion of pERK+/pAkt− CTCs (r = 0.968, P < 0.01), and was higher in patients with ≥ 40% pERK+/pAkt− CTCs compared to those with < 40% (8.4 vs. 1.3 mo; P < 0.05). In a validation set of twenty HCC patients, CTCs from patients with ≥ 40% pERK+/pAkt− CTCs had significantly higher inhibition rates of spheroid formation compared to those with < 40% (61.2 vs. 19.8%; P < 0.01). Our findings demonstrated that CTCs can be used in place of tumor tissue for characterization of pERK/pAkt expression. pERK+/pAkt− CTCs are most sensitive to sorafenib and an independent predictive factor of PFS in HCC patients treated with sorafenib.
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