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Clinical Trial
. 2019 Jun;68(6):1065-1075.
doi: 10.1136/gutjnl-2018-316408. Epub 2018 Aug 14.

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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Free PMC article
Clinical Trial

Molecular Predictors of Prevention of Recurrence in HCC With Sorafenib as Adjuvant Treatment and Prognostic Factors in the Phase 3 STORM Trial

Roser Pinyol et al. Gut. .
Free PMC article

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.

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.

Figures

Figure 1
Figure 1
Flow chart of the BIOSTORM study. FISH, fluorescence in situ hybridisation; IHC, immunohistochemistry; VEGFA, vascular endothelial growth factor A.
Figure 2
Figure 2
Representative examples of (A) immunohistochemical pERK staining of tumour hepatocytes, (B) pERK staining of tumour endothelial cells, and (C, D) pVEGFR2 positive and negative staining of tumour hepatocytes. (E, F) Representative images of fluorescence in situ hybridisation (FISH) staining to determine vascular endothelial growth factor A (VEGFA) copy number. VEGFA was labelled in red; the control reference Cep6 in green; and DAPI-stained cell nuclei in blue.
Figure 3
Figure 3
Novel 146-gene signature associated with better recurrence-free survival (RFS) in sorafenib-treated patients. (A) 146-gene signature identifying BIOSTORM patients with better RFS when treated with sorafenib. (B) Kaplan-Meier estimates measuring RFS probability over time of patients identified by the 146-gene signature capturing recurrence prevention in individuals treated with sorafenib (in blue) or placebo (in orange). P value of biomarker treatment interaction was 0.040. Left panel shows the Kaplan-Meier estimates for patients identified as ‘sorafenib RFS responders’ by the gene signature, and the right panel, the estimates for those identified as ‘non-responders’. (C) Patients identified by the 146-gene signature as ‘sorafenib RFS responders’ (in green) displayed downregulation of KRAS and JAK/STAT signalling. In contrast, patients recognised as ‘non-responders’ (in red) were enriched in MAPK, mTOR, IGF1R and Notch signalling.
Figure 4
Figure 4
Heatmap displaying the molecular class and immune characteristics of ‘sorafenib RFS responders’ and ‘non-responders’. Differences in RFS profiles in the sorafenib and placebo-treated patients identified by the signature as ‘sorafenib RFS responders’ suggest that placebo patients could have been candidates to respond to sorafenib. Immune profile of ‘sorafenib RFS responders’ highlights absence of CD8+ T cell lymphocytes but enrichment of other adaptive immune elements such as B cells and CD4+ T cells and derivatives. P values describe differences between ‘sorafenib RFS responders’ and ‘non-responders’. #P<0.01 between ‘sorafenib RFS responders’ and HCCs of ‘Immune class’. Signatures are referenced in online supplementary table 11. HCC, hepatocellular carcinoma; IFN, interferon; MHC, major histocompatibility complex; NK, natural killer cells; ns, non-significant differences; RFS, recurrence-free survival; TLS, tertiary lymphoid structures.
Figure 5
Figure 5
Prognostic value of hepatocyte pERK and pVEGFR2. Tumours with hepatocyte pERK staining (A) or pVEGFR2 staining (B) have significantly poorer outcome compared with pERK negative or pVEGFR2 tumours.

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