TY - JOUR
T1 - Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial
AU - Pinyol, Roser
AU - Montal, Robert
AU - Bassaganyas, Laia
AU - Sia, Daniela
AU - Takayama, Tadatoshi
AU - Chau, Gar Yang
AU - Mazzaferro, Vincenzo
AU - Roayaie, Sasan
AU - Lee, Han Chu
AU - Kokudo, Norihiro
AU - Zhang, Zhongyang
AU - Torrecilla, Sara
AU - Moeini, Agrin
AU - Rodriguez-Carunchio, Leonardo
AU - Gane, Edward
AU - Verslype, Chris
AU - Croitoru, Adina Emilia
AU - Cillo, Umberto
AU - De La Mata, Manuel
AU - Lupo, Luigi
AU - Strasser, Simone
AU - Park, Joong Won
AU - Camps, Jordi
AU - Solé, Manel
AU - Thung, Swan N.
AU - Villanueva, Augusto
AU - Pena, Carol
AU - Meinhardt, Gerold
AU - Bruix, Jordi
AU - Llovet, Josep M.
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2019.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
KW - cancer
KW - clinical trials
KW - hepatocellular carcinoma
KW - molecular oncology
KW - tumour markers
UR - http://www.scopus.com/inward/record.url?scp=85052733724&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2018-316408
DO - 10.1136/gutjnl-2018-316408
M3 - Article
C2 - 30108162
AN - SCOPUS:85052733724
SN - 0017-5749
VL - 68
SP - 1065
EP - 1075
JO - Gut
JF - Gut
IS - 6
ER -