Early predictive value of circulating biomarkers for sorafenib in advanced hepatocellular carcinoma

Sorafenib is currently the first-line therapeutic regimen for patients with advanced hepatocellular carcinoma (HCC). However, many patients did not experience any benefit and suffered extreme adverse events and heavy economic burden. Thus, the early identification of patients who are most likely to benefit from sorafenib is needed. This review focused on the clinical application of circulating biomarkers (including conventional biomarkers, immune biomarkers, genetic biomarkers, and some novel biomarkers) in advanced HCC patients treated with sorafenib. An online search on PubMed, Web of Science, Embase, and Cochrane Library was conducted from the inception to 15 August 2021. Studies investigating the predictive or prognostic value of these biomarkers were included. The distinction of patients who may benefit from sorafenib treatment is of utmost importance. The predictive roles of circulating biomarkers could solve this problem. Many biomarkers can be obtained by liquid biopsy, which is a less or noninvasive approach. The short half-life of sorafenib could reflect the dynamic changes of tumor progression and monitor the treatment response. Circulating biomarkers obtained from liquid biopsy resulted as a promising assessment method in HCC, allowing for better treatment decisions in the near future. Alpha-fetoprotein (AFP); American Association for the Study of Liver Diseases (AASLD); Angiopoietin (Ang); Barcelona Clinic Liver Cancer stage (BCLC); Circulating endothelial progenitor (CEP); Circulating free DNA (cfDNA); Complete response (CR); Des-γ-carboxy prothrombin (DCP); Endothelium-derived nitric oxide synthase (eNOS); Hepatocellular carcinoma (HCC); Hepatocyte growth factor (HGF); Hepatoma arterial-embolization prognosis score (HAP); High mobility group box 1 (HMgb1); Interferon-gamma (IFN-γ); Long non-coding RNA (lncRNAs); Micro RNAs (miRNAs); Monocyte-to-lymphocyte ratio (MLR); National Comprehensive Cancer Network (NCCN); Neutrophil-lymphocyte ratio (NLR); Newcastle-Ottawa Scale (NOS); Nitric oxide (NO); Overall survival (OS); Partial response (PR); Platelet-lymphocyte ratio (PLR); Prediction of survival in advanced sorafenib-treated HCC (PROSASH); Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA); Prognostic nutritional index (PNI); Progression-free survival (PFS); Progressive disease (PD); Randomized controlled trials (RCTs); Response Evaluation Criteria in Solid Tumors (RECIST); Single nucleotide polymorphisms (SNPs); Sorafenib advanced HCC prognosis score (SAP); Stable disease (SD); Time to progression (TTP); Transcatheter arterial chemoembolization (TACE); Vascular endothelial growth factor (VEGF).

索拉非尼目前是晚期肝细胞癌（hepatocellular carcinoma, HCC）患者的一线治疗方案。然而，诸多患者不仅未从治疗中获得任何临床获益，还需承受严重不良事件与沉重的经济负担。因此，亟需早期甄别出最有可能从索拉非尼治疗中获益的人群。本综述聚焦于循环生物标志物（包括传统生物标志物、免疫生物标志物、遗传生物标志物及部分新型生物标志物）在接受索拉非尼治疗的晚期HCC患者中的临床应用价值。研究人员检索了PubMed、Web of Science、Embase及Cochrane Library自建库至2021年8月15日的相关文献，纳入了探讨上述生物标志物预测或预后价值的研究。精准区分可能从索拉非尼治疗中获益的患者具有至关重要的临床意义，而循环生物标志物的预测作用可有效解决这一难题。多数循环生物标志物可通过液体活检获取，该检测方式属于微创乃至无创手段。索拉非尼半衰期较短，能够反映肿瘤进展的动态变化并监测治疗应答情况。源自液体活检的循环生物标志物已成为肝细胞癌诊疗中极具前景的评估手段，有望在未来为临床优化治疗决策提供支撑。甲胎蛋白（Alpha-fetoprotein, AFP）；美国肝病研究协会（American Association for the Study of Liver Diseases, AASLD）；血管生成素（Angiopoietin, Ang）；巴塞罗那临床肝癌分期（Barcelona Clinic Liver Cancer stage, BCLC）；循环内皮祖细胞（Circulating endothelial progenitor, CEP）；循环游离DNA（Circulating free DNA, cfDNA）；完全缓解（Complete response, CR）；脱-γ-羧基凝血酶原（Des-γ-carboxy prothrombin, DCP）；内皮型一氧化氮合酶（Endothelium-derived nitric oxide synthase, eNOS）；肝细胞癌（Hepatocellular carcinoma, HCC）；肝细胞生长因子（Hepatocyte growth factor, HGF）；肝癌动脉栓塞预后评分（Hepatoma arterial-embolization prognosis score, HAP）；高迁移率族蛋白B1（High mobility group box 1, HMGB1）；干扰素-γ（Interferon-gamma, IFN-γ）；长链非编码RNA（Long non-coding RNA, lncRNAs）；微小RNA（Micro RNAs, miRNAs）；单核细胞-淋巴细胞比值（Monocyte-to-lymphocyte ratio, MLR）；美国国家综合癌症网络（National Comprehensive Cancer Network, NCCN）；中性粒细胞-淋巴细胞比值（Neutrophil-lymphocyte ratio, NLR）；纽卡斯尔-渥太华量表（Newcastle-Ottawa Scale, NOS）；一氧化氮（Nitric oxide, NO）；总生存期（Overall survival, OS）；部分缓解（Partial response, PR）；血小板-淋巴细胞比值（Platelet-lymphocyte ratio, PLR）；晚期索拉非尼治疗HCC患者生存预测评分（Prediction of survival in advanced sorafenib-treated HCC, PROSASH）；系统评价与Meta分析首选报告条目（Preferred Reporting Items for Systematic Review and Meta-Analysis, PRISMA）；预后营养指数（Prognostic nutritional index, PNI）；无进展生存期（Progression-free survival, PFS）；疾病进展（Progressive disease, PD）；随机对照试验（Randomized controlled trials, RCTs）；实体瘤疗效评价标准（Response Evaluation Criteria in Solid Tumors, RECIST）；单核苷酸多态性（Single nucleotide polymorphisms, SNPs）；索拉非尼晚期HCC预后评分（Sorafenib advanced HCC prognosis score, SAP）；疾病稳定（Stable disease, SD）；进展时间（Time to progression, TTP）；经导管动脉化疗栓塞（Transcatheter arterial chemoembolization, TACE）；血管内皮生长因子（Vascular endothelial growth factor, VEGF）。