索拉非尼是晚期肝细胞癌(HCC)的标准全身疗法。早期HCC的切除/局部消融的生存益处受到70%的5年复发率的损害。比较索拉非尼与安慰剂作为辅助治疗的3期STORM试验未达到改善无复发生存率(RFS)的主要终点。生物标志物伴随研究BIOSTORM旨在定义(A)索拉非尼预防复发的预测因子和(B)具有B级证据的预后因素。
收集了在STORM试验中随机接受索拉非尼(83)或安慰剂(105)的188名患者的肿瘤组织。分析包括基因表达谱分析,靶向外显子组测序(19个已知的致癌因子),免疫组织化学(pERK,pVEGFR2,Ki67),荧光原位杂交(VEGFA)和免疫组。在索拉非尼治疗的患者中产生捕获改善的RFS的基因签名。所有70例RFS事件均为复发,因此,复发时间等于RFS。使用Cox回归模型和交互检验评估预测和预后价值。
BIOSTORM概括了STORM的临床病理特征。没有测试的生物标志物(与血管生成和增殖有关)或先前提出的基因特征,或突变预测索拉非尼获益或复发。新产生的146个基因标签鉴定了30%的患者在RFS方面获得了索拉非尼的益处(相互作用的p=0.04)。这些索拉非尼RFS应答者在CD4+T中显著富集,B和溶细胞性自然杀伤细胞,缺乏激活的适应性免疫成分。肝细胞pERK(HR=2.41;p=0.012)和微血管侵犯(HR=2.09;p=0.017)是独立的预后因素。
在生物风暴中,只有肝细胞pERK和微血管浸润预测RFS较差。没有突变,基因扩增或先前提出的基因特征预测索拉非尼的益处。与索拉非尼的改进RFS相关的新生成的多基因签名值得进一步验证。
NCT00692770。
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.
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.
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.
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.
NCT00692770.