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Cited by 326Hepatocellular Carcinoma Treatment and PrognosisColorectal Cancer Treatments and StudiesRenal cell carcinoma treatment

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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Pinyol, Roser, Montal, Robert, Bassaganyas, Laia, Sia, Daniela, Takayama, Tadatoshi, Chau, Gar-Yang, Mazzaferro, Vincenzo, Roayaie, Sasan +22 more·2019·Gut
DOI 10.1136/gutjnl-2018-316408PMC PMC6580745
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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 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 .

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  • MP genes were enriched for sorafenib resistance-genes.

    “Moreover, MP genes were enriched for sorafenib resistance-genes31”

    From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [31]

    The Results section (‘Molecular factors predicting benefit to sorafenib’; page unavailable) reports that tumours in the proliferation subclass were significantly enriched for a gene signature associated with sorafenib resistance (p=0.002). It does not identify ‘MP genes’ or report enrichment of resistance genes within that gene set, so the specific claim about MP genes is not established. (LLM, conf=0.82)

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Authors
Pinyol, R., Montal, R., Bassaganyas, L., Sia, D., Takayama, T., Chau, G.-Y., Mazzaferro, V., Roayaie, S., Lee, H. C., Kokudo, N., Zhang, Z., Torrecilla, S., Moeini, A., Rodriguez-Carunchio, L., Gane, E., Verslype, C., Croitoru, A. E., Cillo, U., de la Mata, M., Lupo, L., Strasser, S., Park, J.-W., Camps, J., Solé, M., Thung, S. N., Villanueva, A., Pena, C., Meinhardt, G., Bruix, J., & Llovet, J. M.
Affiliations
  • Hospital Clínic de Barcelona (ES)
  • Tisch Cancer Institute (US)
  • Nihon University (JP)
  • Taipei Veterans General Hospital (TW)
  • University of Milan (IT)
  • White Plains Hospital (US)
  • Asan Medical Center (KR)
  • The University of Tokyo (JP)
  • Icahn School of Medicine at Mount Sinai (US)
  • BCLC Group, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)–Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
  • Auckland City Hospital (NZ)
  • Universitair Ziekenhuis Leuven (BE)
  • Institutul Clinic Fundeni (RO)
  • University of Padua (IT)
  • Unit of Hepatology and Liver Transplantation, CIBERehd, IMIBIC, University Hospital Reina Sofia, Cordoba, Spain
  • Azienda Universitaria Ospedaliera Consorziale - Policlinico Bari (IT)
  • The University of Sydney (AU)
  • National Cancer Center (KR)
  • Bayer HealthCare Pharmaceuticals, Whippany, New Jersey, USA
  • Bayer (United States) (US)
  • Institució Catalana de Recerca i Estudis Avançats (ES)
Corresponding author
Llovet, Josep M
ORCID
Venue
Gut
Publisher
BMJ
Published
2018-10-02
Volume
68
Issue
6
Pages
1065-1075
ISSN
  • 0017-5749 (ISSN-L)
  • 1468-3288
DOI
10.1136/gutjnl-2018-316408
PMC
PMC6580745
OpenAlex
W2885162827
Cited by
326
References
4
Citations by year
2026: 17 · 2025: 46 · 2024: 52 · 2023: 53 · 2022: 53 · 2021: 43 · 2020: 38 · 2019: 23 · 2018: 1
FWCI
16.45
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Gut (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Lirias (KU Leuven) (submittedVersion, cc-by-nc)
  • RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by-nc)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by-nc)
  • HighWire Press Open Archive (submittedVersion)
  • CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, cc-by-nc-nd)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc)
Funders
  • Agència de Gestió d’Ajuts Universitaris i de Recerca
  • Generalitat de Catalunya
  • National Cancer Institute
  • Association for International Cancer Research
  • Spanish Health Ministry - Plan estratégico Nacional contra la Hepatitis C
  • Bayer HealthCare
  • American Association for the Study of Liver Diseases
  • Fundación Científica Asociación Española Contra el Cáncer
  • Tisch Cancer Institute
  • Horizon 2020 Framework Programme
  • Spanish National Health Institute
  • Samuel Waxman Cancer Research Foundation
  • Spanish Ministry of Economy and Competitiveness
  • U.S. Department of Defense
  • Instituto de Salud Carlos III
  • Onyx Pharmaceuticals
Topics
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
Keywords
hepatocellular carcinoma, sorafenib, adjuvant therapy, recurrence-free survival, recurrence prevention, prognostic factors, predictive biomarkers, gene expression signatures, microvascular invasion, ERK1/2 phosphorylation, VEGFR2, VEGF-A, immune cell infiltration
MeSH terms
Sorafenib, Adult, Aged, Aged, 80 and over, Biopsy, Needle, Female, Carcinoma, Hepatocellular, Humans, Immunohistochemistry, Liver Neoplasms, Male, Middle Aged, Neoplasm Invasiveness, Neoplasm Recurrence, Local, Neoplasm Staging, Predictive Value of Tests, Prognosis, Survival Analysis, Tissue Embedding, Treatment Outcome, Chemotherapy, Adjuvant, Disease-Free Survival, Angiogenesis Inhibitors, Molecular Targeted Therapy

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