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2018-06-01

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cc-by-nc (c) Pinyol, Roser et al., 2018
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/171989

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

Resum

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.

Matèries

Càncer de fetge, Placebos, Marcadors bioquímics

Matèries (anglès)

Liver cancer, Placebos (Medicine), Biochemical markers

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Articles publicats en revistes (Medicina)

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PINYOL, Roser, MONTAL, Robert, BASSAGANYAS, Laia, SIA, Daniela, TAKAYAMA, Tadatoshi, CHAU, Gar-yang, MAZZAFERRO, Vincenzo, ROAYAIE, Sasan, LEE, Han chu, KOKUDO, Norihiro, ZHANG, Zhongyang, TORRECILLA, Sara, MOEINI, Agrin, RODRIGUEZ-CARUNCHIO, Leonardo, GANE, Edward, VERSLYPE, Chris, CROITORU, Adina emilia, CILLO, Umberto, DE LA MATA, Manuel, LUPO, Luigi, STRASSER, Simone, PARK, Joong-won, CAMPS, Jordi, SOLÉ, Manel, THUNG, Swan n., VILLANUEVA, Augusto, PENA, Carol, MEINHARDT, Gerold, BRUIX TUDÓ, Jordi, LLOVET I BAYER, Josep maria. Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial. _Gut_. 2018. Vol. 68, núm. 6, pàgs. 1065-1075. [consulta: 28 de gener de 2026]. ISSN: 0017-5749. [Disponible a: https://hdl.handle.net/2445/171989]

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