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.

Project description:ObjectiveSorafenib 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.DesignTumour 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.ResultsBIOSTORM 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.ConclusionIn 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 numberNCT00692770.

Project description:Purpose: Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Most of these patients are treated with platinum-based chemotherapies, but there is no biomarker model to guide their responses to these therapeutic agents. We have developed and independently tested our novel multivariate molecular predictors for forecasting patients' responses to individual drugs on a cohort of 58 ovarian cancer patients. Experimental Design: We adapted and applied the previously-published COXEN algorithm to develop molecular predictors for therapeutic responses of patients' tumors based on expression signatures derived from the NCI-60 in vitro drug activities and genomic expression data. Genome-wide candidate biomarkers were first triaged by examining expression patterns of frozen and formalin-fixed paraffin embedded (FFPE) tissue samples. We then identify initial drug sensitivity biomarkers for carboplatin and paclitaxel, respectively. These biomarkers were further narrowed by examining concordant expression patterns between cell lines and a historical set of ovarian cancer patients. Multivariate predictors were obtained from the NCI-60 cell lines and refined using historical patient cohorts. To independent validate these molecular predictors, we performed genome-wide profiling on FFPE samples of 58 ovarian cancer patients obtained prior to adjuvant chemotherapy. Results: Carboplatin predictor significantly stratified platinum sensitive and resistant patients (p = 0.019) with sensitivity = 93%, specificity = 33%, PPV = 65%, and NPV = 78%. Paclitaxel predictor also significantly stratified patients' responses (p = 0.033) with sensitivity = 96%, specificity = 26%, PPV = 61%, and NPV = 86%. The combination predictor for platinum-taxane combination demonstrated a significant survival difference between the predicted responders and nonresponders with median survival of 12.9 months vs. 8.1 months (p = 0.045). Conclusions: COXEN predictors successfully stratified platinum resistance and taxane response in this retrospective cohort, especially based on their FFPE tumor samples. Accurate prediction of chemotherapeutic response, especially to platinum agents is highly clinically relevant and could alter primary management of ovarian cancer. Gene expression data from 58 stage III-IV ovarian cancer patients treated with Carboplatin and Taxol agents

Project description:Purpose: Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Most of these patients are treated with platinum-based chemotherapies, but there is no biomarker model to guide their responses to these therapeutic agents. We have developed and independently tested our novel multivariate molecular predictors for forecasting patients' responses to individual drugs on a cohort of 58 ovarian cancer patients. Experimental Design: We adapted and applied the previously-published COXEN algorithm to develop molecular predictors for therapeutic responses of patients' tumors based on expression signatures derived from the NCI-60 in vitro drug activities and genomic expression data. Genome-wide candidate biomarkers were first triaged by examining expression patterns of frozen and formalin-fixed paraffin embedded (FFPE) tissue samples. We then identify initial drug sensitivity biomarkers for carboplatin and paclitaxel, respectively. These biomarkers were further narrowed by examining concordant expression patterns between cell lines and a historical set of ovarian cancer patients. Multivariate predictors were obtained from the NCI-60 cell lines and refined using historical patient cohorts. To independent validate these molecular predictors, we performed genome-wide profiling on FFPE samples of 58 ovarian cancer patients obtained prior to adjuvant chemotherapy. Results: Carboplatin predictor significantly stratified platinum sensitive and resistant patients (p = 0.019) with sensitivity = 93%, specificity = 33%, PPV = 65%, and NPV = 78%. Paclitaxel predictor also significantly stratified patients' responses (p = 0.033) with sensitivity = 96%, specificity = 26%, PPV = 61%, and NPV = 86%. The combination predictor for platinum-taxane combination demonstrated a significant survival difference between the predicted responders and nonresponders with median survival of 12.9 months vs. 8.1 months (p = 0.045). Conclusions: COXEN predictors successfully stratified platinum resistance and taxane response in this retrospective cohort, especially based on their FFPE tumor samples. Accurate prediction of chemotherapeutic response, especially to platinum agents is highly clinically relevant and could alter primary management of ovarian cancer.

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Molecular predictors of prevention of recurrence in hepatocellular carcinoma with sorafenib as adjuvant treatment in the phase 3 STORM trial

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