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

Abstract

Presupposti: L’inibitore multichinasico sorafenib si è dimostrato in grado di aumentare significativamente la sopravvivenza in pazienti affetti da carcinoma epatocellulare avanzato. Sorafenib interferisce sia con la proliferazione delle cellule tumorali sia con i processi angiogenetici agendo sulla cascata intracellulare Ras/Raf/MEK/ERK e sui recettori tirosinchinasici VEGFR-2/-3 (vascular endothelial growth factor receptor-2/-3) e PDGFR-β (platelet derived growth factor receptor beta). Ad oggi non esistono parametri clinici o biologici che possano essere considerati predittivi di risposta al trattamento. Lo scopo di questo studio è stato quello di analizzare il ruolo di marcatori tissutali nel predire l’efficacia clinica di sorafenib in pazienti affetti da carcinoma epatocellulare avanzato. Metodi: È stata analizzata una popolazione di 77 pazienti affetti da carcinoma epatocellulare avanzato trattati con sorafenib nell’ambito di 2 studi prospettici randomizzati. I campioni tissutali sono stati valutati sulla base delle caratteristiche architetturali e citologiche secondo criteri predefiniti. L’espressione di beta-catenina (CAT), glutammina sintetasi (GS), pERK (phosphorylated extracellular signal regulated kinase), pAKT (phosphorylated v-akt murine thymoma viral oncogene homolog) e VEGFR-2 (vascular endothelial growth factor receptor-2) è stata valutata mediante immunoistochimica e l’intensità di colorazione misurata impiegando un sistema semiquantitativo. E’ stata utilizzata come gruppo di controllo una popolazione di 56 pazienti trattati con la sola terapia di supporto. Risultati: La sopravvivenza libera da progressione (PFS) e la sopravvivenza globale (OS) sono risultate significativamente ridotte nei pazienti con elevata espressione cellulare di pERK. Inoltre, un’elevata espressione di VEGFR-2 è stata correlata in maniera statisticamente significativa con una ridotta OS ottenuta dopo trattamento con sorafenib. Questi risultati non sono stati confermati nel gruppo di controllo. Conclusioni: Un’espressione cellulare elevata di pERK e di VEGFR-2 predicono una ridotta sopravvivenza libera da progressione ed una ridotta sopravvivenza globale in pazienti affetti da carcinoma epatocellulare trattati con sorafenib. Questi dati suggeriscono che i carcinomi epatocellulari contenenti livelli di pERK e di VEGFR-2 più elevati sono meno sensibili, o responsivi a sorafenib. In considerazione del disegno retrospettivo del nostro studio sono richieste ulteriori indagini, nell’ambito di studi prospettici, per confermare il ruolo di questi biomarcatori nel predire l’andamento clinico dei pazienti affetti da carcinoma epatocellulare in trattamento con sorafenib.

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.