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

Roser Pinyol, Robert Montal, Laia Bassaganyas, Daniela Sia, Tadatoshi Takayama, Gar-Yang Chau, Vincenzo Mazzaferro, Sasan Roayaie, Han Chu Lee, Norihiro Kokudo, Zhongyang Zhang, Sara Torrecilla, Agrin Moeini, Leonardo Rodriguez-Carunchio, Edward Gane, Chris Verslype, Adina Emilia Croitoru, Umberto Cillo, Manuel de la Mata, Luigi Lupo, Simone Strasser, Joong-Won Park, Jordi Camps, Manel Solé, Swan N Thung, Augusto Villanueva, Carol Pena, Gerold Meinhardt, Jordi Bruix, Josep M Llovet

Journal: Gut 2019;68(6):1065-1075

PMID: 30108162

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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 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.

Address: BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain.; Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.; Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan.; Department of surgery, Taipei Veterans General Hospital, Taipei, Taiwan.; Hepatology and Liver Transplantation Unit, Department of Surgery, University of Milan and Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.; Liver Cancer Program, White Plains Hospital, Montefiore Health, New York City, New York, USA.; Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.; Department of surgery, University of Tokyo, Tokyo, Japan.; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.; New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.; Department of Hepatology, University Hospital Leuven, Leuven, Belgium.; Departament of Medical Oncology, Fundeni Clinical Institute, Bucharest, Romania.; Unità Operativa di Chirurgia Epatobiliare e Trapianto Epatico, Azienda Ospedaliera Università di Padova, Padova, Italy.; Unit of Hepatology and Liver Transplantation, CIBERehd, IMIBIC, University Hospital Reina Sofia, Cordoba, Spain.; Sezione Chirurgia Generale e Trapianti di Fegato, Policlinico di Bari, Bari, Italy.; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital-University of Sydney, Sydney, New South Wales, Australia.; Department of Cancer Control and Population Health, National Cancer Center, Goyang, South Korea.; Gastrointestinal and Pancreatic Oncology Group, IDIBAPS-Hospital Clínic, CIBERehd, Barcelona, Spain.; Bayer HealthCare Pharmaceuticals, Whippany, New Jersey, USA.; BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain.; Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

DOI: 10.1136/gutjnl-2018-316408