编者按：近年来，随着肿瘤分子靶向治疗药物的临床试验及临床研究的不断深入，人们对于肿瘤的全身治疗开始了全新的思考。当然，肝癌也不例外。有一种趋势是，在传统的肝细胞肝癌（HCC）临床病理分型和分期的基础之上再结合肝癌的分子表型，把肝癌划分成具有不同的肿瘤分子特征的不同亚群，分别采取相应有效的治疗手段，以提高肝癌治疗的疗效。那么，目前肝癌分子分型目前进展及其与临床治疗的关系如何，以及免疫分型对于临床预后有哪些影响？基于这些问题，ILCA现任主席、巴塞罗那大学肝癌研究所Josep Llovet教授在第51届EASL年会上受邀进行了专题报告，会后并接受了我们的采访。
HCC分子标志物的三大进展
目前，我们已经掌握了一些HCC的分子亚型，但问题是我们并不清楚这些分子亚型和治疗策略之间的联系。一旦弄清楚哪些分子标志物可预测治疗反应以后，我们便有充分的理由将其加到临床肝癌的分层中。
这方面，目前已经开展了三项比较完善的临床试验。首先，是一项在MET阳性患者中比较tivantinib和安慰剂作为二线治疗的临床研究。如果有阳性结果，我们将得到一个与治疗反应相关的分子标志物。其次，是在AFP>400 μg/L的患者中比较ramucirumab和安慰剂的作用。如果有阳性结果，我们将得到指导治疗策略的生物标志物。第三，是一项针对占15%~20%比例的FGF19过表达患者的临床试验。这是一个有关FGF受体抑制剂的研究。如果可行的话， FGF19将成为患者临床分层的重要的分子标志物。
分子标志物与临床预后、治疗的联系及展望
分子标志物除了和患者分类、临床治疗相关以外，也与预后相关。主要包括两种类型的基因标记：一种来自于肿瘤自身，另一种则来自可预测生存的相邻组织。当判断复发风险或将其纳入临床试验时，这些预后相关分子标志物可协助我们对患者进行分层。Llovet教授认为在未来的五年内，这些预后相关的分子标志物将有望进入临床实践。
肿瘤分子治疗时代的新型武器——肿瘤免疫检查点抑制剂
“肿瘤分子治疗”的时代即将到来，但它可能并非是我们在多年前所想像的那个样子。届时将会出现两种类型的治疗模式：一种是我们耳熟能详的靶向治疗，依据特定的突变将患者分为不同的亚型，再根据突变情况进行不同的靶向治疗；另一种则是肿瘤免疫检查点抑制剂。如今HCC中靶向PD-1和PD-L1的免疫检查点抑制剂已进入III期临床试验，这些抑制剂是针对所有HCC患者的。前期在恶性黑色素瘤中的一项研究提示免疫组化证实PD-1和PD-L1阳性患者对nivolumab或pembrolizumab的应答更好。在非小细胞肺癌中也是同样的情况。近日，有研究比较了pembrolizumab和标准治疗之间的差异，结果发现PD-1/PD-L1免疫组化染色阳性的患者即是对药物有应答的患者。相信不久，我们也将看到免疫检查点抑制剂在肝癌中的结果。
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1.The main difficulty in treatment of Hepatocellular Carcinoma（HCC）is Stratification treatment. At present, what is the progress of searching the molecular marker which may help us subgroup the HCC patients?
We already know the molecular subclasses of HCC. The problem is that we don’t have a link between the molecular subclasses and the treatment strategy. I think we will incorporate the molecular markers into the clinical stratification once we have a clear biomarker that predicts a response to therapy. At this point, we have three studies driven by trial enrichment. First, the MET-positive patients are included in a trial that will compare tivantinib versus placebo in the second-line. If this is a positive trial, we will have a biomarker that will indicate a response to therapy. The second is ramucirumab versus placebo with AFP>400ng/ml. If this trial is positive, we will have this biomarker which will guide us in the treatment strategy. The third one is for the 15-20% of patients with FGF19 overexpression. This is a trial of an FGF receptor inhibitor. If it works, the FGF19 biomarker will become part of the clinical stratification.
2.Please tell us about the molecular classification of HCC and its relationship with clinical treatment, as well as the implications for prognosis.
I mentioned the relationship between classification with biomarkers and treatment. With regard to the use relationship between biomarkers and prognosis, there are two types of gene signatures. One is from the tumor and one is from the adjacent tissue that are predictors of survival. These prognostic signatures may help us stratify patients when assessing risk of recurrence or when including them in clinical trials. The prognostic signatures may come to clinical practice in the next five years.
3.At present, the development of relevant tumor immune checkpoint inhibitors is a major focus of cancer treatment. Which targets are currently the most expected for the treatment of HCC?
Nowadays, there are checkpoint inhibitors targeting PD-1 and PD-L1 in HCC in phase III, but they are targeting the whole patient population. There is a study in melanoma suggesting that patients that are checkpoint PD-1 and PD-L1-positive on immunostaining, respond better to nivolumab or pembrolizumab for instance. The same happens in non-small cell lung cancer. Recently, a company had the drug pembrolizumab compared to standard-of-care and they identified that patients with positive immunostaining for PD-1/PD-L1 are the ones responding to these drugs. I think we will see the same for HCC.
4.Would you like to talk about the future prospect of HCC treatment？
I think the molecular therapies will be coming. They will not be as spectacular as we thought they would be years ago. We will have two types of treatment: one that definessubpopulations of patients in whom the tumor is dependent on specific mutations and we will target these mutations; secondly, if the trials are successful, we will have another layer of therapy related to immune checkpoint inhibition.