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.
- hepatocellular carcinoma
- molecular oncology
- clinical trials
- tumour markers
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Contributors RP, RM, LB, AV, ST, DS, AM, LRC, JC, MS, SNT and ZZ were involved in study concept and design; data acquisition, analysis and interpretation; manuscript drafting. TT, GYC, VM, SR, NK, HCL, EG, CV, AEC, UC, MM, LL, SS, JWP, CP and GM provided specimens for genomic analysis or clinical data, and critically revised the manuscript. JML and JB were involved in study concept and design; interpretation of data; critical revision of the manuscript; study supervision; and obtained funding.
Funding This study was supported by Bayer HealthCare Pharmaceuticals and Onyx, a wholly owned subsidiary of Amgen. JML is supported by the European Commission (EC)/Horizon 2020 Program (HEPCAR, Ref 667273-2), US Department of Defense (CA150272P3), Asociación Española Contra el Cáncer (AECC), National Cancer Institute (P30-CA196521), Samuel Waxman Cancer Research Foundation, Spanish National Health Institute (SAF2016-76390) and the Generalitat de Catalunya/AGAUR (SGR-1162 and SGR-1358). JB has received grant support from Instituto de Salud Carlos III (ISCIII) (PI14/00962), AECC, AGAUR (SGR-605), WCR (AICR) 16-0026, and Spanish Health Ministry (Plan Estrategico Nacional contra la Hepatitis C). Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas is funded by ISCIII. RP and AM are funded by AECC and EC. ST, RM, LB and JC are supported by MINECO (BES-2014-068300), Río Hortega (ISCIII-SEOM), Beatriu de Pinós (AGAUR) and Miguel Servet (ISCIII-CP13/00160) grants, respectively. AV is supported by the US Department of Defense (CA150272P3), the Tisch Cancer Institute, and the American Association for the Study of Liver Diseases Foundation (AASLDF) Alan Hofmann Clinical and Translational Award.
Competing interests JML, JB, VM and AEC received research support and consultancy fees from Bayer. AV and SS received consultancy fees from Bayer. CP and GM are employees of Bayer HealthCare Pharmaceuticals.
Patient consent Obtained.
Ethics approval Hospital Clinic, Barcelona, Spain. Each participating centre obtained their own required institutional review board approval.
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it published Online First. The abstract and significance of this study box has been updated as well as the patient consent statement.
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