《肿瘤瞭望》：今天我们有幸邀请到Patrick Tan教授和张小田教授进行对话。已发现及在研的预测性生物标志物有助于开发靶向治疗药物和指导个体化治疗。胃癌抗HER-2治疗的探索值得大家期待，您能介绍一下目前胃癌抗HER-2治疗的主要进展吗？

 　　Professor Zhang:Trastuzumab has been approved and really brings clinical benefit to clinical practice for HER-2 positive gastric cancer. In clinical use， the oncologists major concern is how to best optimize its use beyond clinical practice based on the clinical data from the studies. The first is how to optimize its combination with chemotherapy. Second is that the acquired resistant of Trastuzumab may be overcome by studying agents targeting HER-2 downstream signals. And also we need to find optimize dose of Trastuzumab in gastric cancer， comparing dates that in breast cancer. At last，New agents such aspatuzumab，TDM-1 and other agents targeting HER-2are under investigate. I think maybe it is promising when we see new advancements.

　　张小田教授：是的，针对HER-2靶点的单克隆抗体曲妥珠单抗已获批准，临床实践也证实它能使HER-2阳性的胃癌患者生存获益。在临床实践中，我们面临的最主要问题是如何根据临床研究的数据优化曲妥珠单抗的应用。

　　首先我们应该考虑优化其化疗联合方案，例如卡培他滨联合奥沙利铂在耐受性上优于卡培他滨与顺铂的联合，并且曲妥珠单抗的维持治疗或进展后治疗也是很有意义的临床实践问题。

　　其次，我们也许可以通过研究靶向HER-2下游通路的药物以克服曲妥珠单抗的获得性耐药，如抗HER3抗体，或其他HER通路上的TKI。

　　再者我们需要通过比较曲妥珠单抗在乳腺癌中的研究数据找到它在胃癌中的最佳使用剂量。我们已经研究了最低剂量和最高剂量，目前我们亟需研究曲妥珠单抗治疗胃癌的最佳剂量。

　　最后，我们也正在试图寻找新的药物，如帕妥珠单抗、TDM-1和其他靶向HER-2的药物，我认为它们都非常有治疗前景。

　　《肿瘤瞭望》：谢谢张教授的回答。第二个问题是胃癌的靶向治疗目前所覆盖的人群主要是晚期胃癌，您认为未来靶向治疗的应用前景是否会发生一定的变化？

 　　Professor Zhang:We have the confidence of anti HER-2 therapy from metastatic gastric cancer in this background. However because we are also interested in commercial therapy especially for HER-2 positive advance gastric cancer which might be undetectable at current stage. If patients were HER-2 positive，Trastuzumab can be added to a neoadjuvant setting，which can bring more shrinkage to the tumor and more better opportunities for survival even cure the disease but we need data. Another thing about adjuvant therapy， if we learn from breast cancer， patuzumab has indications for the adjuvant settings in breast cancer，but it is hard to do clinical trials to prove its benefit on the adjuvant setting for gastric cancer. I think based some data in the initial studies，it is also promising.

　　张小田教授：是的，您的问题提得很好。毫无疑问，抗HER-2靶向治疗在转移性胃癌中疗效确切。然而我们还关注它在其他胃癌人群中的应用，特别是HER-2阳性局部晚期胃癌的转化性治疗或新辅助治疗。如果患者表现为HER-2基因阳性，那么新辅助治疗方案中加入曲妥珠单抗可能进一步缩小肿瘤，增加生存和治愈的机会，当然我们仍然需要数据来证实这一点。

　　另一点是，我们已经知道帕妥珠单抗适用于乳腺癌的辅助治疗，但目前还没有临床数据证实它在胃癌的辅助治疗中的价值，然而根据一些初步临床试验的结果，我认为它还是有希望运用于胃癌的辅助治疗。目前日本正在一项胃癌根治术后曲妥珠单抗联合化疗的辅助治疗研究。

　　《肿瘤瞭望》：有研究发现不同部位的胃癌组织和正常胃黏膜组织的分子分型有很大差异。至2013年，胃癌的分子分型渐渐被分为三种类型：增殖型、代谢型和间充质型。您能和大家谈一下这种分子分型的意义在哪里吗？

　　Professor Yan :To answer that question we must start at the beginning and realize that for many gastric cancer patients the disease is not the same in every single individual patient. For example only about 10% ~15% of patients had the application of HER-2，so all of this classification is with an attempt to subdivide patients and understand the biology that is driving the disease in each patient so that we can begin to target these patients with more appropriate therapies.There are many ways of classification， for example，with histology you can look at the appearance of the tumor and you can do it by different types of gene mutations or different types of pathways and gene expressions. In this 2013 paper which was published in Gastroenterology we actually used gene expression transcript profiles to subdivide tumors and gastric cancers into three distinct subtypes which we referred to as proliferative， mesenchymal， and metabolic. I think one of the appeals of that particular classification was that it had some responses in the pre-clinical setting which suggested that different subtypes might respond well to different types of therapy. So specifically we found that in the mesenchymal subtype those tend to be more responsive to agents targeting the PI3K/m-TOR pathway. There are other subtypes that have recently been described， the most important one probably being the TCGA subtype and there was a recent subtype published in Nature Medicine from the Asian Cancer Research Group on the three subtypes. I think the field is still debating on which of these subtypes is the most clinically impact able. Certainly for our work and what I am trying to do now is to validate the clinical utility of these subtypes in clinical trial cohorts and we are collaborating with a few Asian cancer centers to look at these in the phase I to phase II group of cohorts. Those results should be coming out sometime early next year. 

　　Patrick Tan教授：要回答这个问题，我们必须认识到每个胃癌患者都存在个体差异，正如张教授在刚才的讨论中提到的HER-2靶点，仅有约10％~15％的患者适用于HER-2靶向治疗。因此，胃癌分型的真正目的是区分每个患者的分子亚型以及肿瘤驱动基因以达到个体化和精准治疗。

　　胃癌有多种分类方法，如根据胃癌表型、组织学、突变基因以及基因表达等进行分类。2013年Gastroenterology的一篇文献报道根据基因表达谱将胃癌分为三种亚型：增生型、间质型和代谢型。我认为这种分型的好处之一是，一些临床前研究证实不同的亚型对治疗的敏感性不同，例如我们发现，间质型胃癌对于靶向PI3K/m-TOR的药物反应性好。其他一些重要的亚型包括TCGA亚型和亚洲癌症研究小组最近在Nature杂志发表的一类亚型。我认为这方面最值得讨论的是明确临床预后最好的亚型。当然，我们现在工作是证实该分子分型在临床试验人群中的应用价值，目前我们正在和一些亚洲癌症中心进行相关I/II期临床试验的合作，这些结果应该在明年初发表。

　　张小田教授：我对您所谈到的分子亚型非常感兴趣。您如何进行比较呢？正如您所说，每个亚型的临床特征和治疗方式都不相同，我们需要时间和数据去证实，您现在正在根据这三种分子亚型进行临床试验吗？

 　　Professor Yan : I think you have asked two questions. To describe them， there are many different subtypes， which are described in the literature， but obviously the question is ‘which is the best’? And the way I see it as a story about the six blind men and the elephant and everybody is seeing a different top of the elephant but it is the same elephant. I think all of these subtype schemes are based upon different types of patterns and they are all capturing similar features but maybe in a slightly different way. For instance the mesenchymal subtype is in the way we describe， probably very similar to stable subtype in gene classification. The key question is which of those is most clinically relevant. Which of these is the most useful for directing the patient prognosis and which of those is more accurate in directing the selection of therapy? I think that remains to be seen. For example in the TCGAstudy they actually reported that while they have 4 subtypes，those subtypes do not have any differences in clinical work up. So the way to validate all of these is then to take these different subtyping schemes and validate them in prospective clinical trials or in retrospective clinical trials where you would have patients who are uniformly treated. We are working with a variety of cancer centers whom are either embarking on these trials or have finished these trials and have the patient’s materials and then we can do a large scale unbiased validation – not just of our own subtype but also of all the subtypes. So that we can actually find out which one is the most clinically useful and which one is the easiest to implement in the clinic. Not every clinic has the ability to do a transcription profiling. So if we can get down to a simple way to do the subtypes， then perhaps that is better even if it is not so accurate.

　　Patrick Tan教授：是的，你提了两个问题。目前的文献中提及许多不同的胃癌亚型，最关键的问题是“哪种分类方式最好？”我认为这类似于“盲人摸象”的故事，每个人摸到的部位不同，但终究是同一只大象。虽然分类的方式有所不同，但都抓住了某些相似的特征，例如，间充质亚型与基因分型中的稳定型非常相似，关键是哪种分型与临床最相关，哪种分型方式对于预测患者的预后以及指导治疗最有价值，我认为还有待研究。例如，TCGA研究称，虽然他们发现了4种分子亚型，但它们在临床特征方面没有差异。因此我们需要开展前瞻性或回顾性临床试验以验证这些不同分类方法的临床意义。

　　我们正在与多家癌症中心的研究人员一起分析这些已完成或正在进行的临床试验，通过对大规模患者的资料进行非偏倚性分析，可以确定最有效且最易行的分类方法。并不是所有的医疗机构都有能力做分子分型检测，因此，简单的分型方式更易在临床实施，即使不那么准确。

　　Professor Yan : I think this is what you are referring to， In a recent study we published in the journal where we actually came across something that was very surprising and when we compared the expression profile of the Asian gastric cancer patients and non-Asian patients with gastric cancer on a large scale， about 1，600 tumors， we found that the major difference we saw were signatures related to immune cell biology specifically T cells. We also saw some differences in the macrophages and we have seen emerging clinical trials where gastric cancer patients from Asia seem to be behaving differently from patients in the non-Asian countries.There are at least 2 or 3 clinical trials reporting this phenomena and I don’t think anyone quite knows what is going on. We think that this may play a role in influencing some of the tumor signs. We do not have an answer yet and it may play a role in future trials as a kind of look at the immune cells. We actually do not have any data on that but I think it would be useful in trials， particularly those looking at immunotherapy and those considering at least to do a subset analysis and to subset data in the immune cell profile or basal point the geographical region. This should be known in a few years.

　　张小田教授：今天上午您在报告中提到，您的研究中发现东西部患者的分子分型方面差异不大而T细胞的基因型存在显著差异。对此，我提两个问题：1、区分东西方患者的基因分型是否没有必要？2、T细胞基因型的差异对将来的临床研究和治疗有什么影响？

　　Patrick Tan教授：最近我们在杂志上发表了一项研究结果，该研究比较了1600名亚裔与非亚裔胃癌患者的基因型，发现免疫细胞尤其是T细胞的表型差异明显，此外巨噬细胞的表型也存在一定差异。我认为这项发现有一定的临床意义，因为至少有两项临床研究报道亚裔与非亚裔胃癌患者临床表现不一，目前尚无法解释该现象。我们的研究可能会影响一些关于免疫治疗以及基于地域差异的分子分型等方面的临床研究。

　　《肿瘤瞭望》：生物标志物已成为胃癌研究领域的热点之一，越来越多的研究试图寻找更多具有预后预测意义的治疗靶点，您可以介绍一下这方面的内容吗？

 　　Professor Yan : I think the field now of gastric cancer is quiet interesting because I think with all of these studies that I just described， we have a pretty good sense of the major targets that are presented， for instance MET， EGRF，HER-2 and so on. The main problem is that we do not have many therapies that can target these. For instance， we know that there are certain transcription factors， which are proteins that control the gene expression. These are also amplification in the same way that HER-2 is. The problem is that we don’t have drugs to target them. I think the future of the cancer therapy and gastric cancer will be to look at these targets that we seen in the primary tumors and identify the right treatment for tumors with these identified targets. I think this will lead us into a whole new area of research including immunotherapy and cancer metabolism where we are targeting not the signaling pathways but the metabolism of the cancer cells， and maybe even looking at cancer epigenetics where you are looking at how the DNA comes and modifies itself to control gene expression. I think the challenge in the field is how do we use those targets and understandthose targets to devise better treatments. I think that is really at the start. We know what the targets are and now we need to function and understand what they do so that we can put the right blockade.

　　Patrick Tan教授：目前我们在胃癌中发现的主要靶点有HER-2、MET和 EGRF，问题是缺乏针对这些靶点的治疗方法。例如，我们了解一些如HER-2一样过表达的可调控基因表达的转录因子，但是却没有针对该靶点的有效药物。因此，我认为将来的研究方向根据这些靶点研发特异性的治疗药物，这将引领我们进入胃癌研究的新领域，如免疫治疗、肿瘤细胞的新陈代谢或肿瘤的表观遗传学等。现在我们面临的挑战不是发现这些生物标志物，而是了解它们的具体功能以制定更合理的治疗方案。

　　Patrick Tan教授：我想问张教授一个问题，曲妥珠单抗既可以用于乳腺癌也可以用于胃癌，然而两者在HER-2的表达方式上存在差异，这种差异是否会影响胃癌患者对靶向HER-2治疗的疗效？

　　Professor Zhang: We think it influences but however it may not the reason of the drug itself but whether we can find the general population who is really HER-2 positive. You know that gastric cancer has digestive enzymes so the protein might be digested. It is more difficult to find the HER-2 positive patients with gastric cancer. Another thing is that the transtzumab in the blood of the gastric cancer is lower than in breast cancer so there are studies initially for these patients looking to increase the initial dose to higher doses but in fact those has not been published， so currently we do think it is different.Currently we have trastuzumab only，of course we also have ramucirumabandAfatinib which cannot be compared to trastuzumab so I think in the near future， HER-2 will possibly still be the role marker in gastric cancer.

　　张小田教授：是有一定的影响，这是不同器官的HER-2表达有其各自特点，由于胃液中消化酶的作用以致无法准确筛选出真正HER-2阳性的患者。另一方面，曲妥珠单抗在胃癌患者中的血药浓度要低于乳腺癌患者。临床试验正在评估增加曲妥珠单抗剂量对于胃癌疗效的影响。因此，虽然曲妥珠单抗在胃癌中的疗效不如乳腺癌，但由于目前我们并没有更多的选择，如其他靶向药物如ramucirumab和阿帕替尼的生存受益不如曲妥珠单抗，因此我认为在未来一段时间，HER-2仍然会是胃癌领域中的“明星”标志物。

　　张小田教授

　　现任北京大学肿瘤医院消化肿瘤内科主任医师。CSCO执行委员会委员、青年专家委员会秘书、肿瘤营养治疗专家委员会委员。

　　致力于胃癌、食管癌、结直肠癌、胰腺癌等消化道恶性肿瘤的个体化药物治疗与综合治疗，特别是进展期胃癌的综合治疗和恶性肿瘤的营养支持治疗。参与起草、执笔《NCCN胃癌指南中国版》，《卫生部胃癌诊疗规范（2010）》、《CSCO肿瘤营养治疗共识》、《CSPEN恶性肿瘤营养治疗指南》等指南。

　　Patrik Tan教授

　　新加坡杜克国立医学研究生院

　　新加坡基因组研究院

　　新加坡国立大学癌症科学研究所

　　主要研究领域：目前担任国际癌症基因组协会胆管癌项目的联席牵头人

　　曾荣获总统奖学金、青年科学家奖以及新加坡青年奖