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Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial.

ABSTRACT: OBJECTIVE:Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence. DESIGN:Tumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test. RESULTS:BIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These sorafenib RFS responders were significantly enriched in CD4+ T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors. CONCLUSION:In BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation. TRIAL REGISTRATION NUMBER:NCT00692770.

SUBMITTER: Pinyol R

PROVIDER: S-EPMC6580745 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial.

Pinyol Roser R Montal Robert R Bassaganyas Laia L Sia Daniela D Takayama Tadatoshi T Chau Gar-Yang GY Mazzaferro Vincenzo V Roayaie Sasan S Lee Han Chu HC Kokudo Norihiro N Zhang Zhongyang Z Torrecilla Sara S Moeini Agrin A Rodriguez-Carunchio Leonardo L Gane Edward E Verslype Chris C Croitoru Adina Emilia AE Cillo Umberto U de la Mata Manuel M Lupo Luigi L Strasser Simone S Park Joong-Won JW Camps Jordi J Solé Manel M Thung Swan N SN Villanueva Augusto A Pena Carol C Meinhardt Gerold G Bruix Jordi J Llovet Josep M JM

Gut 20180814 6

<h4>Objective</h4>Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognost ...[more]

PMID: 30108162

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Project description:BACKGROUND & AIMS: Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). In early-stage HCC, survival benefits of resection/local ablation are compromised by high recurrence rates (70% at 5-years). In this setting, the phase-3 STORM-trial did not achieve its primary end-point of improving recurrence-free-survival (RFS) comparing sorafenib to placebo as adjuvant treatment. Herein we present results of the biomarker companion study BIOSTORM in which we define predictors of recurrence prevention with sorafenib and prognostic factors with B-level of evidence. METHODS: Tumor tissue from 188 patients randomized to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene-expression profiling, targeted exome sequencing (18 known onco-drivers), immunohistochemistry (pERK, pVEGFR2, Ki67), FISH (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time-to-recurrence equaled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test. RESULTS: BIOSTORM recapitulates clinical and pathological characteristics of STORM patients. None of the biomarkers tested that are known to be related to angiogenesis and proliferation, or previously proposed gene-signatures, or mutations predicted sorafenib benefit. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p-of-interaction=0.04). These sorafenib responders were significantly enriched in CD4+ T, B, and cytolytic Natural Killer cells, and showed absence of activated macrophages and other components of adaptive immunity. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors. CONCLUSIONS: In BIOSTORM, hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene-signatures predicted sorafenib benefit. A newly generated multi-gene signature associated with improved RFS on sorafenib warrants further validation. KEYWORDS: sorafenib; tyrosine-kinase inhibitor; trial enrichment; stratification.

Project description:Background & aimsThe aim of the study was to evaluate the efficacy and safety of adjuvant sorafenib treatment compared with placebo in patients with hepatocellular carcinoma who underwent local ablation.MethodsThe SORAMIC trial is a randomised controlled trial with diagnostic, local ablation, and palliative sub-study arms. After initial imaging within the diagnostic study, patients were assigned to local ablation or palliative arms. In the local ablation cohort, patients were randomised 1:1 to local ablation + sorafenib vs. local ablation + placebo. The primary endpoint was time-to-recurrence (TTR). Secondary endpoints were local control rate and safety in terms of adverse events and quality-of-life.ResultsThe recruitment was terminated prematurely after 104 patients owing to slow recruitment. One patient was excluded because of a technical failure. Fifty-four patients were randomised to local ablation + sorafenib and 49 to local ablation + placebo. Eighty-eight patients who underwent standardised follow-up imaging comprised the per-protocol population. The median TTR was 15.2 months in the sorafenib arm and 16.4 months in the placebo arm (hazard ratio 1.1; 95% CI 0.53-2.2; p = 0.82). Out of 136 lesions ablated within the trial, there was no difference in local recurrence rate between sorafenib (6/69, 8.6%) and placebo groups (5/67, 5.9%; p = 0.792).Overall (92.5% vs. 71.4%, p = 0.008) and drug-related (81.4% vs. 55.1%, p = 0.003) adverse events were more common in the sorafenib arm compared with the placebo arm. Dose reduction because of adverse events were common in the sorafenib arm (79.6% vs. 30.6%, p <0.001).ConclusionsAdjuvant sorafenib did not improve in TTR or local control rate after local ablation in patients with hepatocellular carcinoma within the limitations of an early terminated trial.Impact and implicationsLocal ablation is the standard of care treatment in patients with early stages of hepatocellular carcinoma, along with surgical therapies. However, there is a risk of disease recurrence during follow-up. Sorafenib, an oral medication, is a routinely used treatment for patients with advanced hepatocellular carcinoma. This study found that sorafenib treatment after local ablation in people with early hepatocellular carcinoma did not significantly improve the disease-free period compared with placebo.Clinical trial numberEudraCT 2009-012576-27, NCT01126645.

Project description:BackgroundLiver Transplantation (LT) is treatment of choice for patients with hepatocellular carcinoma (HCC) within MILAN Criteria. Tumour progression and subsequent dropout from waiting list have significant impact on the survival. Transarterial chemoembolization (TACE) controls tumour growth in the treated HCC nodule, however, the risk of tumour development in the untreated liver is increased by simultaneous release of neo-angiogenic factors. Due to its anti-angiogenic effects, Sorafenib delays the progression of HCC. Aim of this study was to determine whether combination of TACE and Sorafenib improves tumour control in HCC patients on waiting list for LT.MethodsFifty patients were randomly assigned on a 1:1 ratio in double-blinded fashion at four centers in Germany and treated with TACE plus either Sorafenib (n = 24) or placebo (n = 26). The end of treatment was development of progressive disease according to mRECIST criteria or LT. The primary endpoint of the trial was the Time-to-Progression (TTP). Other efficacy endpoints were Tumour Response, Progression-free Survival (PFS), and Time-to-LT (TTLT).ResultsThe median time of treatment was 125 days with Sorafenib and 171 days with the placebo. Fourteen patients (seven from each group) developed tumour progression during the course of the study period. The Hazard Ratio of TTP was 1.106 (95% CI: 0.387, 3.162). The results of the Objective Response Rate, Disease Control Rate, PFS, and TTLT were comparable in both groups. The incidence of AEs was comparable in the placebo group (n = 23, 92%) and in the Sorafenib group (n = 23, 96%). Twelve patients (50%) on Sorafenib and four patients (16%) on placebo experienced severe treatment-related AEs.ConclusionThe TTP is similar after neo-adjuvant treatment with TACE and Sorafenib before LT compared to TACE and placebo. The Tumour Response, PFS, and TTLT were comparable. The safety profile of the Sorafenib group was similar to that of the placebo group.Trial registrationISRCTN24081794.

Project description:BackgroundEarly recurrence of hepatocellular carcinoma (HCC) is a major obstacle to improving the prognosis, and no widely accepted adjuvant therapy guideline for patients post-liver resection is available. Currently, all available methods and biomarkers are insufficient to accurately predict post-operation HCC patients' risk of early recurrence and their response to adjuvant therapy.MethodsIn this study, we downloaded four gene expression datasets (GSE14520, GSE54236, GSE87630, and GSE109211) from the Gene Expression Omnibus database and identified 34 common differentially expressed genes associated with HCC dysregulation and response to adjuvant sorafenib. Then, we constructed a novel 11-messenger RNA predictive model by using ROC curves analysis, univariate Cox regression analysis, and LASSO Cox regression analysis. Furthermore, we validated the predictive values of the risk model in GSE14520 and TCGA-LIHC cohorts by using Kaplan-Meier survival analysis, multivariable Cox regression analysis, and decision curve analysis, respectively.ResultsThe risk score model could identify patients with a high risk of HCC recurrence at the early stage and could predict the response of patients to adjuvant sorafenib. Patients with a high risk score had a worse recurrence rate in training cohorts (2-year: p < 0.0001, hazard ratio (HR): 4.658, confidence interval 95% CI [2.895-7.495]; 5-year: p < 0.0001, HR: 3.251, 95% CI [2.155-4.904]) and external validation cohorts (2-year: p < 0.001, HR: 3.65, 95% CI [2.001-6.658]; 5-year: p < 0.001, HR: 3.156, 95% CI [1.78-5.596]). The AUC values of the risk score model for predicting tumor early recurrence were 0.746 and 0.618, and that of the risk score model for predicting the response to adjuvant sorafenib were 0.722 and 0.708 in the different cohort, respectively. Multivariable Cox regression analysis and decision curve analysis also showed that the risk score model was superior to and independent of other clinicopathologic characteristics. Moreover, the risk score model had excellent abilities to predict the overall survival and HCC recurrence of patients with the same tumor stage category.ConclusionsOur risk model is a reliable and superior predictive tool. With this model, we could optimize the risk stratification based on early tumor recurrence and could evaluate the response of patients to adjuvant sorafenib after liver resection.

Project description:BackgroundTo identify whether adjuvant transarterial chemoembolization (TACE) can improve prognosis in HCC patients with a low risk of recurrence (tumor size ≤ 5 cm, single nodule, no satellites, and no microvascular or macrovascular invasions) after hepatectomy.MethodsThe data of 489 HCC patients with a low risk of recurrence after hepatectomy from Shanghai Cancer Center (SHCC) and Eastern Hepatobiliary Surgery Hospital (EHBH) were retrospectively reviewed. Recurrence-free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier curves and Cox proportional hazards regression models. The effects of selection bias and confounding factors were balanced using propensity score matching (PSM).ResultsIn the SHCC cohort, 40 patients (19.9%, 40/201) received adjuvant TACE, and in the EHBH cohort, 113 patients (46.2%, 133/288) received adjuvant TACE. Compared to the patients without adjuvant TACE after hepatectomy, patients receiving adjuvant TACE had significantly shorter RFS (P=0.022; P=0.014) in both cohorts before PSM. However, no significant difference existed in OS (P=0.568; P=0.082). Multivariate analysis revealed that serum alkaline phosphatase and adjuvant TACE were independent prognostic factors for recurrence in both cohorts. Furthermore, significant differences existed in tumor size between the adjuvant TACE and non-adjuvant TACE groups in the SHCC cohort. There were differences in transfusion, Barcelona Clinic Liver Cancer stage and tumor-node-metastasis stage in the EHBH cohort. These factors were balanced by PSM. After PSM, patients with adjuvant TACE after hepatectomy still had significantly shorter RFS than those without (P=0.035; P=0.035) in both cohorts, but there was no difference in OS (P=0.638; P=0.159). Adjuvant TACE was the only independent prognostic factor for recurrence in multivariate analysis, with hazard ratios of 1.95 and 1.57.ConclusionsAdjuvant TACE may not improve long-term survival and might promote postoperative recurrence in HCC patients with a low risk of recurrence after hepatectomy.

Dataset Information

Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial.

Publications

Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial.

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