Molecular determinants of outcome in sorafenib-treated patients with hepatocellular carcinoma View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2013-04-09

AUTHORS

Nicola Personeni, Lorenza Rimassa, Tiziana Pressiani, Annarita Destro, Claudia Ligorio, Maria Chiara Tronconi, Silvia Bozzarelli, Carlo Carnaghi, Luca Di Tommaso, Laura Giordano, Massimo Roncalli, Armando Santoro

ABSTRACT

PurposePreclinical studies show that sorafenib, a multitarget kinase inhibitor, displays anti-proliferative, anti-angiogenic, and pro-apoptotic properties in hepatocellular carcinoma (HCC). However, the determinants of sorafenib sensitivity in vivo remain largely unknown.MethodsWe assessed the expression of Mcl-1, activated/phosphorylated extracellular signal-regulated kinase (pERK) 1/2, and activated/phosphorylated AKT (pAKT) in pretreatment tumor specimens from 44 patients with advanced HCC who received sorafenib. Furthermore, we assessed MYC and MET gene copy numbers (GCN) by fluorescence in situ hybridization.ResultsPoorer overall survival (OS) times were correlated with pERK expression [hazard ratio (HR) 1.013; 95 % CI 1.003–1.035] and Mcl-1 expression (HR 1.016; 95 % CI 1.002–1.030) in pretreatment tumor samples. Expression levels of pERK and Mcl-1, however, were not correlated with time to tumor progression (TTP). Increased pERK expression was positively associated with higher Cancer of Liver Italian Program scores (P = 0.012) and was prognostic in patients with scores 2–6 but not in those with scores 0–1. pERK expression was significantly less frequent in specimens sourced from previous surgical procedures compared to biopsy samples (9.6 vs. 92.3 %, respectively; P < 0.0001). Analysis of pAKT expression, MET and MYC GCN, did not indicate any prognostic nor predictive values for these biomarkers in terms of survival.ConclusionsExpression levels of Mcl-1 and pERK are associated with reduced OS in HCC patients treated with sorafenib and might be useful markers for risk stratification. However, in contrast to previous findings, pERK expression levels, as well as other biomarkers tested, did not affect TTP. More... »

PAGES

1179-1187

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00432-013-1429-x

DOI

http://dx.doi.org/10.1007/s00432-013-1429-x

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1004452529

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23568548


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38 schema:description PurposePreclinical studies show that sorafenib, a multitarget kinase inhibitor, displays anti-proliferative, anti-angiogenic, and pro-apoptotic properties in hepatocellular carcinoma (HCC). However, the determinants of sorafenib sensitivity in vivo remain largely unknown.MethodsWe assessed the expression of Mcl-1, activated/phosphorylated extracellular signal-regulated kinase (pERK) 1/2, and activated/phosphorylated AKT (pAKT) in pretreatment tumor specimens from 44 patients with advanced HCC who received sorafenib. Furthermore, we assessed MYC and MET gene copy numbers (GCN) by fluorescence in situ hybridization.ResultsPoorer overall survival (OS) times were correlated with pERK expression [hazard ratio (HR) 1.013; 95 % CI 1.003–1.035] and Mcl-1 expression (HR 1.016; 95 % CI 1.002–1.030) in pretreatment tumor samples. Expression levels of pERK and Mcl-1, however, were not correlated with time to tumor progression (TTP). Increased pERK expression was positively associated with higher Cancer of Liver Italian Program scores (P = 0.012) and was prognostic in patients with scores 2–6 but not in those with scores 0–1. pERK expression was significantly less frequent in specimens sourced from previous surgical procedures compared to biopsy samples (9.6 vs. 92.3 %, respectively; P < 0.0001). Analysis of pAKT expression, MET and MYC GCN, did not indicate any prognostic nor predictive values for these biomarkers in terms of survival.ConclusionsExpression levels of Mcl-1 and pERK are associated with reduced OS in HCC patients treated with sorafenib and might be useful markers for risk stratification. However, in contrast to previous findings, pERK expression levels, as well as other biomarkers tested, did not affect TTP.
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46 ConclusionsExpression levels
47 HCC patients
48 Italian Program scores
49 Liver Italian Program (CLIP) score
50 MET gene copy number
51 Mcl-1
52 Mcl-1 expression
53 MetS
54 MethodsWe
55 Myc
56 OS
57 PERK
58 Program score
59 PurposePreclinical studies
60 ResultsPoorer overall survival (OS) times
61 TTP
62 advanced hepatocellular carcinoma
63 analysis
64 biomarkers
65 biopsy samples
66 cancer
67 carcinoma
68 contrast
69 copy number
70 determinants
71 expression
72 expression levels
73 extracellular signal-regulated kinase 1/2
74 findings
75 fluorescence
76 gene copy number
77 hepatocellular carcinoma
78 higher cancer
79 hybridization
80 inhibitors
81 kinase 1/2
82 kinase inhibitors
83 levels
84 markers
85 molecular determinants
86 multitarget kinase inhibitor
87 myc gene copy number
88 number
89 outcomes
90 overall survival time
91 pAkt expression
92 pERK expression
93 pERK expression levels
94 patients
95 predictive value
96 pretreatment tumor
97 pretreatment tumor samples
98 previous findings
99 previous surgical procedures
100 pro-apoptotic properties
101 procedure
102 progression
103 properties
104 reduced OS
105 risk stratification
106 samples
107 score 0
108 score 2
109 scores
110 sensitivity
111 signal-regulated kinase 1/2
112 situ hybridization
113 sorafenib
114 sorafenib sensitivity
115 sorafenib-treated patients
116 specimens
117 stratification
118 study
119 surgical procedures
120 survival
121 survival time
122 terms
123 terms of survival
124 time
125 tumor progression
126 tumor samples
127 tumors
128 useful marker
129 values
130 vivo
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