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Gut. 2018 Aug 14. pii: gutjnl-2018-316408. doi: 10.1136/gutjnl-2018-316408. [Epub ahead of print]

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

Author information

1
BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain.
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
Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan.
4
Department of surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
5
Hepatology and Liver Transplantation Unit, Department of Surgery, University of Milan and Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
6
Liver Cancer Program, White Plains Hospital, Montefiore Health, New York City, New York, USA.
7
Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
8
Department of surgery, University of Tokyo, Tokyo, Japan.
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
New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
11
Department of Hepatology, University Hospital Leuven, Leuven, Belgium.
12
Departament of Medical Oncology, Fundeni Clinical Institute, Bucharest, Romania.
13
Unità Operativa di Chirurgia Epatobiliare e Trapianto Epatico, Azienda Ospedaliera Università di Padova, Padova, Italy.
14
Unit of Hepatology and Liver Transplantation, CIBERehd, IMIBIC, University Hospital Reina Sofia, Cordoba, Spain.
15
Sezione Chirurgia Generale e Trapianti di Fegato, Policlinico di Bari, Bari, Italy.
16
AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital-University of Sydney, Sydney, New South Wales, Australia.
17
Department of Cancer Control and Population Health, National Cancer Center, Goyang, South Korea.
18
Gastrointestinal and Pancreatic Oncology Group, IDIBAPS-Hospital Clínic, CIBERehd, Barcelona, Spain.
19
Bayer HealthCare Pharmaceuticals, Whippany, New Jersey, USA.
20
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

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.

KEYWORDS:

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

PMID:
30108162
DOI:
10.1136/gutjnl-2018-316408
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Conflict of interest statement

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.

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