Marcatori molecolari predittivi di risposta al trattamento con sorafenib in pazienti affetti da carcinoma epatocellulare avanzato

Background The multikinase inhibitor sorafenib has been validated as an effective treatment for advanced hepatocellular carcinoma (HCC). Sorafenib blocks tumour cell proliferation and angiogenesis by targeting Raf/MEK/ERK signaling at the level of Raf kinase, vascular endothelial growth factor receptor-2/-3 (VEGFR-2/-3), and platelet derived growth factor receptor beta (PDGFR-β). To date no predictive factors of the response to sorafenib treatment in HCC have been validated. The aim of this study was to evaluate the prognostic and predictive significance of tissue markers in a group of patients with advanced HCC treated with sorafenib. Method The study base was a retrospective series of 77 HCC patients (male, 82%; median age, 70 years; BCLC C 42%; Child-Pugh B 16%) enrolled into two prospective randomized trials of sorafenib treatment in subjects naive to previous systemic therapy. Continuous oral sorafenib 400 mg twice daily was administered until the occurrence of progressive disease. Tumour evaluation was performed every 6-8 weeks according to RECIST criteria. Seven patients achieved a response and 41 had stable disease. Median progression-free survival (PFS) was 3.8 months and overall survival (OS) was 6.4 months. Standard pathological specimens were available for all patients (16 resections and 146 needle biopsies); in 64 patients the liver primary was examined, in 10 a recurrent lesion; multiple samples were analysed in 20 patients. The tissue samples were evaluated according to a predefined set of architectural and cytological features. The expression of beta-catenin (BCAT), glutamine synthetase (GS), phosphorylated extracellular signal regulated kinase (pERK) (combined nuclear and cytoplasmic staining), phosphorylated v-akt murine thymoma viral oncogene homolog (pAKT) (cytoplasmic staining) and vascular endothelial growth factor receptor-2 (VEGFR-2) (cytoplasmic staining) were evaluated by immunohistochemistry and scored semiquantitatively. Investigators performing the laboratory analyses were blinded to clinical outcome. A control series of 56 HCC patients (male, 80%; mean age, 69 years; BCLC C 46%; Child-Pugh B 46%) receiving only best supportive care was also examined. Univariate and multivariate survival analysis were assessed according to Cox. Results At univariate analysis, poorer PFS and OS were associated with high pERK staining (PFS: 75th percentile 4.4 vs 8.4 months (median: 3.7 vs 3.9), HR 2.15; 95%CI, 1.20-3.85; P=0.01; OS: 75th percentile 7.0 vs 15.0 months (median: 4.9 vs 8.6), HR 2.23; 95%CI, 1.27-3.94; P=0.005) and high VEGFR-2 staining (PFS: 75th percentile 3.8 vs 7.0 months (median: 3.0 vs 3.8), HR 1.97; 95%CI, 1.03-3.75; P=0.039; OS: 75th percentile 6.3 vs 15.0 months (median: 4.6 vs 7.0), HR 2.65; 95%CI, 1.36-5.18; P=0.004). These results were not confirmed in the control group. At multivariate analysis, both pERK and VEGFR-2 staining maintained independent effect on OS (HR 2.09; 95%CI, 1.13-3.86, P=0.019 and HR 2.28; 95%CI, 1.13-4.61, P=0.021, respectively), whereas only pERK expression was significantly correlated with PFS (HR 2.13; 95%CI, 1.17-3.90; P=0.014). Among clinical variables, ECOG PS was significantly correlated with both PFS and OS. Conclusions In patients with advanced HCC treated with sorafenib, high tissue expression of pERK and VEGFR-2 predicts reduced PFS and OS. The clinical relevance of these biomarkers should be validated in larger series.