Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC). However, molecular predictors of sorafenib efficacy have not yet been identified. In retrospective studies, conducted on different HCC patients treated with sorafenib, polymorphisms (SNPs) of major genes involved in the angiogenic process (eNOS, Ang2, VEGF, VEGFR, HIF-1α) showed to be able to predict the clinical outcome in these series. On the basis of these preliminary results, our aim was to validate in a prospective study these data in patients with advanced HCC patients treated with sorafenib (INNOVATE study, NCT02786342). 182 patients were enrolled in the study and they were treated with sorafenib between March 2015 and June 2018, 17 did not fulfil the inclusion criteria and they were considered screening failure. Out of the 165 patients who met the selection criteria, 114 patients were dead and 127 had progressed after a median follow-up time of 25.9 months at the time of database lock in February 2019. We present the results of the first part of the analyses planned, regarding eNOS and Ang2 (SNPs). We analyzed eNOS 786 T>C and Ang2 rs55633437 G>T by Real Time PCR method or by direct sequencing in relation to the primary end point (PFS). Event-time distributions were estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test. The main characteristics of these patients are: Child–Pugh (CP) class-A was the most represented (91.9%), 65.7% had BCLC-C stage disease and 24.1% of patients had α-fetoprotein (AFP) level >400 ng/ml. The most common underlying aetiology was hepatitis infections from C virus (39.3%) and others aetiologies (23.3%). Median PFS was 5.2 months (95% CI 4.5-6.5) and median OS was 13.1 months (95% CI 10.4-15.7). At univariate analysis, we confirmed that eNOS 786 TT genotype was significantly associated with a lower median PFS (2.4 vs 5.9 months, HR 0.43, 95% CI 0.26-0.70 p=0.0007) and OS (8.1 vs 15.7 months, HR 0.38, 95% CI 0.24-0.60 p<0.0001) than the other genotypes. At univariate analysis, we not confirmed that Ang2 rs55633437 TT+GT genotypes were significantly associated with a lower median PFS (2.4 vs 5.7 months, HR 1.93, 95% CI 0.91-4.07 p=0.0833) and OS (15.1 vs 13.0 months, HR 2.68, 95% CI 1.67-4.29 p=0.55) than the other genotype. No significant association was found between the main clinical-pathologic patients characteristics and eNOS polymorphisms. Following adjustment for clinical covariates (Gender, Child Pugh, Portal Vein Thrombosis, LDH, aetiology and eNOS), multivariate analysis confirmed eNOS as only independent prognostic factor predicting survival. Conclusions: Our Italian multicenter, prospective study confirmed that eNOS-786 TT genotype may be capable of identifying a subset of HCC patients who have a lower median OS and PFS than the other genotypes. For the first time in ten years of sorafenib research our study confirms the prognostic role of a biological marker in a prospective study.
MULTICENTER PROSPECTIVE STUDY OF ANGIOGENESIS POLYMORPHISM VALIDATION IN HCC PATIENTS TREATED WITH SORAFENIB: THE INNOVATE STUDY
FALOPPI, LUCA
2019-06-10
Abstract
Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC). However, molecular predictors of sorafenib efficacy have not yet been identified. In retrospective studies, conducted on different HCC patients treated with sorafenib, polymorphisms (SNPs) of major genes involved in the angiogenic process (eNOS, Ang2, VEGF, VEGFR, HIF-1α) showed to be able to predict the clinical outcome in these series. On the basis of these preliminary results, our aim was to validate in a prospective study these data in patients with advanced HCC patients treated with sorafenib (INNOVATE study, NCT02786342). 182 patients were enrolled in the study and they were treated with sorafenib between March 2015 and June 2018, 17 did not fulfil the inclusion criteria and they were considered screening failure. Out of the 165 patients who met the selection criteria, 114 patients were dead and 127 had progressed after a median follow-up time of 25.9 months at the time of database lock in February 2019. We present the results of the first part of the analyses planned, regarding eNOS and Ang2 (SNPs). We analyzed eNOS 786 T>C and Ang2 rs55633437 G>T by Real Time PCR method or by direct sequencing in relation to the primary end point (PFS). Event-time distributions were estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test. The main characteristics of these patients are: Child–Pugh (CP) class-A was the most represented (91.9%), 65.7% had BCLC-C stage disease and 24.1% of patients had α-fetoprotein (AFP) level >400 ng/ml. The most common underlying aetiology was hepatitis infections from C virus (39.3%) and others aetiologies (23.3%). Median PFS was 5.2 months (95% CI 4.5-6.5) and median OS was 13.1 months (95% CI 10.4-15.7). At univariate analysis, we confirmed that eNOS 786 TT genotype was significantly associated with a lower median PFS (2.4 vs 5.9 months, HR 0.43, 95% CI 0.26-0.70 p=0.0007) and OS (8.1 vs 15.7 months, HR 0.38, 95% CI 0.24-0.60 p<0.0001) than the other genotypes. At univariate analysis, we not confirmed that Ang2 rs55633437 TT+GT genotypes were significantly associated with a lower median PFS (2.4 vs 5.7 months, HR 1.93, 95% CI 0.91-4.07 p=0.0833) and OS (15.1 vs 13.0 months, HR 2.68, 95% CI 1.67-4.29 p=0.55) than the other genotype. No significant association was found between the main clinical-pathologic patients characteristics and eNOS polymorphisms. Following adjustment for clinical covariates (Gender, Child Pugh, Portal Vein Thrombosis, LDH, aetiology and eNOS), multivariate analysis confirmed eNOS as only independent prognostic factor predicting survival. Conclusions: Our Italian multicenter, prospective study confirmed that eNOS-786 TT genotype may be capable of identifying a subset of HCC patients who have a lower median OS and PFS than the other genotypes. For the first time in ten years of sorafenib research our study confirms the prognostic role of a biological marker in a prospective study.
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