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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

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Hepatology
Original article
Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial
  1. Roser Pinyol1,
  2. Robert Montal1,
  3. Laia Bassaganyas1,
  4. Daniela Sia2,
  5. Tadatoshi Takayama3,
  6. Gar-Yang Chau4,
  7. Vincenzo Mazzaferro5,
  8. Sasan Roayaie6,
  9. Han Chu Lee7,
  10. Norihiro Kokudo8,
  11. Zhongyang Zhang9,
  12. Sara Torrecilla1,
  13. Agrin Moeini1,
  14. Leonardo Rodriguez-Carunchio1,
  15. Edward Gane10,
  16. Chris Verslype11,
  17. Adina Emilia Croitoru12,
  18. Umberto Cillo13,
  19. Manuel de la Mata14,
  20. Luigi Lupo15,
  21. Simone Strasser16,
  22. Joong-Won Park17,
  23. Jordi Camps18,
  24. Manel Solé1,
  25. Swan N Thung2,
  26. Augusto Villanueva2,
  27. Carol Pena19,
  28. Gerold Meinhardt19,
  29. Jordi Bruix1,
  30. Josep M Llovet1,2,20
  1. 1 BCLC Group, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)–Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
  2. 2 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
  3. 3 Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
  4. 4 Department of surgery, Taipei Veterans General Hospital, Taipei, Taiwan
  5. 5 Hepatology and Liver Transplantation Unit, Department of Surgery, University of Milan and Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  6. 6 Liver Cancer Program, White Plains Hospital, Montefiore Health, New York City, New York, USA
  7. 7 Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
  8. 8 Department of surgery, University of Tokyo, Tokyo, Japan
  9. 9 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
  10. 10 New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
  11. 11 Department of Hepatology, University Hospital Leuven, Leuven, Belgium
  12. 12 Departament of Medical Oncology, Fundeni Clinical Institute, Bucharest, Romania
  13. 13 Unità Operativa di Chirurgia Epatobiliare e Trapianto Epatico, Azienda Ospedaliera Università di Padova, Padova, Italy
  14. 14 Unit of Hepatology and Liver Transplantation, CIBERehd, IMIBIC, University Hospital Reina Sofia, Cordoba, Spain
  15. 15 Sezione Chirurgia Generale e Trapianti di Fegato, Policlinico di Bari, Bari, Italy
  16. 16 AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital–University of Sydney, Sydney, New South Wales, Australia
  17. 17 Department of Cancer Control and Population Health, National Cancer Center, Goyang, South Korea
  18. 18 Gastrointestinal and Pancreatic Oncology Group, IDIBAPS–Hospital Clínic, CIBERehd, Barcelona, Spain
  19. 19 Bayer HealthCare Pharmaceuticals, Whippany, New Jersey, USA
  20. 20 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
  1. Correspondence to Dr Josep M Llovet, Liver Cancer Translational Research Laboratory, Barcelona Clinic Liver Cancer Group (BCLC), IDIBAPS-Hospital Clinic, Barcelona, 08036 Catalonia, Spain; jmllovet{at}clinic.cat

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.

  • hepatocellular carcinoma
  • molecular oncology
  • clinical trials
  • tumour markers
  • cancer

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gutjnl-2018-316408

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    Footnotes

    • 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.