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Clinical study on the prevention of postoperative recurrence and metastasis of colorectal cancer by Zuojin pill combined with adjuvant chemotherapy

ABSTRACT: Interventions: experimental group:Zuojin Pill; placebo group:Zuojin Pill placebo Primary outcome(s): recurrence rate Study Design: Parallel

DISEASE(S): Colorectal Cancer

PROVIDER: 2693767 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:BACKGROUND & AIMS: Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). In early-stage HCC, survival benefits of resection/local ablation are compromised by high recurrence rates (70% at 5-years). In this setting, the phase-3 STORM-trial did not achieve its primary end-point of improving recurrence-free-survival (RFS) comparing sorafenib to placebo as adjuvant treatment. Herein we present results of the biomarker companion study BIOSTORM in which we define predictors of recurrence prevention with sorafenib and prognostic factors with B-level of evidence. METHODS: Tumor tissue from 188 patients randomized to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene-expression profiling, targeted exome sequencing (18 known onco-drivers), immunohistochemistry (pERK, pVEGFR2, Ki67), FISH (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 equaled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test. RESULTS: BIOSTORM recapitulates clinical and pathological characteristics of STORM patients. None of the biomarkers tested that are known to be related to angiogenesis and proliferation, or previously proposed gene-signatures, or mutations predicted sorafenib benefit. 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 responders were significantly enriched in CD4+ T, B, and cytolytic Natural Killer cells, and showed absence of activated macrophages and other components of adaptive immunity. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors. CONCLUSIONS: In BIOSTORM, hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene-signatures predicted sorafenib benefit. A newly generated multi-gene signature associated with improved RFS on sorafenib warrants further validation. KEYWORDS: sorafenib; tyrosine-kinase inhibitor; trial enrichment; stratification.

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Clinical study on the prevention of postoperative recurrence and metastasis of colorectal cancer by Zuojin pill combined with adjuvant chemotherapy

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