“液体活检之父”来中国交流：可靠检测技术结合多中心临床研究是发展关键

 

 

 

国际权威专家全面解读液体活检，全球重要研讨会将于2020年在中国举办。

 

 

 

来源丨医学界肿瘤频道

 

随着基因检测技术的发展，精准治疗被越来越多的提及。利用基因信息指导个体化诊断治疗、预测复发风险和预后，听起来十分鼓舞人心。而液体活检无疑是近年来爆红的“小鲜肉”。

 

2008年至今，每年液体活检领域发表的文献数量呈指数增长。2015年，液体活检被MIT科技综述杂志评为年度十大科技突破之一。液体活检正以难以阻挡的趋势向前发展。

 

为了赶上国际步伐、增强我国临床及科研工作者对液体活检的认知，10月中旬，在上海交通大学施奇惠教授和苏州浚惠生物阎灼辉先生的大力邀请下，液体活检领域的学术领军人物——“液体活检之父”、德国汉堡大学肿瘤生物学中心主任Klaus Pantel教授和法国蒙皮利埃大学LCCRH研究室主任Catherine Alix-Panabières教授一同来到中国，在上海与上海市胸科医院陆舜教授等专家，在北京与国家癌症中心、中国医学科学院肿瘤医院药物临床试验研究中心的李宁教授等中国专家就“液体活检”的国际经验，和中国研究应用现状进行了广泛地交流。

 

借此机会，界哥荣幸地采访了两位国际专家，一起来看看，关于液体活检大佬都怎么说。

 

Klaus Pantel教授和Catherine Alix-Panabières教授

 

 

一

 

大咖面对面，国际专家全方位解读液体活检

 

1. 液体活检越来越受到临床研究者的关注，您能简单介绍一下液体活检的发展历程吗?

 

 

Pantel教授：

 

液体活检事实上就是检测血液中的肿瘤细胞和肿瘤细胞产物，它与组织活检形成互补。正如我们所知，有时，从肿瘤患者获取活组织样本是比较困难的事，尤其当肿瘤位于肺、大脑等部位时，获得组织样本可能十分棘手。并且在临床实践中，对患者进行连续组织活检、以实时监测治疗反应的可行性较低。

 

大约十年前，随着技术上很多新的发展，我们得以深入了解血液。通过获取血液样本，观察是否能得到与组织穿刺活检相同的信息，而这些信息能够帮助更好地治疗患者。因为个体化治疗就是基于从患者的血样中提取的个体化信息进行的。液体活检由此发展起来。

  

2. 目前，哪些液体活检方法是研究最多的，可能显示出很好的应用前景?

 

 

Pantel教授：

 

液体活检领域研究较多的主要有循环肿瘤细胞（CTCs）、循环肿瘤DNA（ctDNA）等，这些方法事实上是互相补充的关系。

 

我们可以捕获血液中的CTCs，分析这些肿瘤细胞的蛋白质含量信息，也可以测量CTCs中的RNA信息，用于指导治疗、预测复发风险等。

 

同样地，我们也可以检测ctDNA，寻找与治疗相关的突变。最典型的如检测EGFR基因突变，一种中国非小细胞肺癌患者最常见的突变类型，用于EGFR-TKI靶向治疗的指导。

 

此外，通过检测CTCs、ctDNA，我们可以寻找耐药突变通路。有时，用于治疗的标准疗法不再有效，最大的原因是肿瘤发生了变化，出现了一些耐药突变。此时，通过液体活检检测出这些突变，可以帮助指导更换另一种药物，或第三种甚至第四种药物。

 

所有这些药物治疗都是基于对ctDNA或CTCs的分析。我认为这可能是精准医疗的未来。

  

3. 液体活检将如何改变临床实践，主要从哪些方面?

 

 

Pantel教授：

 

我认为液体活检有不同的应用领域。

 

首先，在肿瘤的早期发现上，液体活检可以提供更加敏感、精准的信息，在癌症较早期即捕捉到信号，而不是等到患者出现症状（例如肺癌患者发热、咳血）时才给予治疗干预。

 

第二，预测肿瘤复发风险和转移进程。通常情况下，大部分患者在手术治疗后肉眼及影像下均观察不到肿瘤，但这并不意味着患者体内不存在残余肿瘤。而CTCs检测则可以灵敏地监测到血液中的肿瘤细胞，及时提示肿瘤可能原位复发或转移至另一器官。

 

第三，通过CTCs和ctDNA检测可以识别治疗靶点和耐药信息。找到确切的治疗靶点，是实现个体化精准治疗的重要前提，临床医生可以据此给予患者个体化的靶向治疗方案。但目前的现状是，大多数靶向治疗最终都会面临耐药问题，此时，利用液体活检找到耐药通路，及时更换治疗药物，也是精准治疗的临床应用之一。

 

此外，液体活检在实时监测治疗状况、进一步理解肿瘤转移进展的生物学信息方面，也极具潜力。这些都将推动着临床肿瘤的治疗迈入新台阶。

 

4. 液体活检领域最大、最重要的进展是什么?

 

  

Pantel教授：

 

我认为液体活检最大的进步表现在技术方面。过去十年里，我们逐渐拥有了非常灵敏和非常精准的手段来捕获CTCs，并对其进行分析。第二代测序技术等也帮助我们能够研究DNA的突变信息。

 

这些精密的技术还在不断改进中，使我们得以在如汪洋大海般的正常细胞和DNA中，检测到目标CTCs和ctDNA。这些技术将进一步与临床研究结果挂钩，而临床研究又对于验证这些新技术的有效性非常重要。

  

5. 在世界范围内，现在是否有与液体活检相关的产品进入临床?

 

 

Pantel教授：

 

我认为EGFR突变的ctDNA或循环游离DNA（cfDNA）检测已经被许多国家接受并应用。我们可以通过采集肺癌患者的血液样本，检测其中是否存在EGF受体基因突变，从而指导靶向治疗。

 

现在一些新的应用也逐渐可及，如利用CTCs监测治疗或决定治疗决策。所以我乐观地认为，在接下来的两到五年内，我们会有更多的液体活检产品获得批准、进入临床。

  

6. 液体活检面临的挑战有哪些?

 

 

Pantel教授：

 

一个挑战是，我们必须使用非常非常敏感的方法。但是，你必须确保这些方法的特异性也要非常好。因为如果你非常敏感，你可能会发现一些与诊断无关的东西。例如，如果人们变老或吸烟很多，他们的血液中DNA可能会有很多突变，这可能并不代表肿瘤突变的结果。所以我们必须小心，我们的技术变得越来越敏感所带来的问题。

 

另一个挑战是，找到新技术真正能帮助我们治愈更多患者、或更好地治疗患者。我们不得不对医生说，好吧，现在你必须改变治疗方法，因为我们对血液检测的标记物说明有问题。这种药物不起作用，其他一些药物可能起作用。但为了真正证明这个概念有效，我们必须证明患者的经过新药物治疗后的寿命更长。

 

有时候标志物检测，并不容易这样提示医生。如果一种疗法不起作用，你必须改为另一种疗法，但也许另一种疗法也不起作用。然后你知道这样建议的治疗方案改变并不好。因此，你必须证明生物标志物具有一定的临床效用，这意味着它有助于更好地治疗患者，更好地管理患者。

 

但这并不容易。需要长时间的临床研究才能获得良好的效果，并且需要非常可靠的检测方法。并且检测方法必须是可重复的，必须检测结果一致。所以你需要那些好的检测，但你也需要非常好的临床研究。你必须将它们结合在一起，这是挑战。

  

7. Catherine Alix-Panabières教授，关于液体活检的现状和发展方向，您的看法如何？

 

 

Alix-Panabières教授：

 

正如Klaus Pantel所说，找到敏感而可靠的方法来检测CTC和所有其他循环标记物非常重要。这正是我们在过去十年中所做的。但重要的是要证明他们的临床有效性和临床效用。

 

实际上，我们必须在不同的临床试验中证明液体活检对患者有益。我期望明年以后，越来越多的干预性临床试验能够真正证明液体活检有临床效用。而且我相信我们必须将CTC，ctDNA以及外泌体，microRNA，肿瘤影响的血小板结合起来，以全面了解癌症以及每位癌症患者的免疫系统。

 

因此，总之，我们可以更准确地了解癌症进展甚至癌症检测，因为我们将获得来自不同循环生物标志物的信息。它现在是一个非常大的不同标记物的家族，我们需要真正把所有液体活检标志物看做是互补的，而不是互相竞争的关系。

 

 

二

 

搭建中外合作桥梁，液体活检重要研讨会将于中国举办

 

看过两位专家的解读，我们大概知道，液体活检在肿瘤诊断和治疗领域都极具潜力。但最关键的问题是，我国的液体活检发展怎么样？距离临床实践有多远？

 

阎灼辉表示：“尽管今天液体活检的概念对我们不再陌生，但必须承认，我国的液体活检研究和应用整体和国际水平之间还存在着一定差距或某种脱节。因此，加强我国与国际研究者之间的交流非常必要，我们需要吸纳国际学者关于液体活检的最新理念，同时也要多做出来自中国的贡献，以弥合这种差距。

 

“非常荣幸，我们这次邀请到了Pantel教授和Alix-Panabières教授到上海和北京访问，并且由两位专家牵头的第1届The Liquid Biopsy Conference (暨第12届微小残留癌国际研讨会International Symposium on Minimal Residual Cancer, ISMRC）也决定将于2020年首次在中国上海举办。”

 

1^st TLBC2020 大会

 

ISMRC大会由Pantel教授于1996年创立，每两年在世界各地举办一次，旨在将液体活检的最新研究进展传播向全球各个国家。如今，ISMRC已经走过旧金山、大阪、慕尼黑、柏林、奥斯陆、汉堡、巴黎等地，今年的第11届ISMRC也于5月初在法国南部的蒙皮利埃成功举办。作为Liquid Biopsy概念的首先提出者，Pantel教授希望2020年的大会开始使用The Liquid Biopsy Conference 的名字，并且会包括更多肿瘤以外的领域。

 

施奇惠教授表示，我们非常期待这次会议的来临，液体活检对中国的临床医生极具吸引力，这是一个难得的机会，中国的临床和科研工作者能够有机会听到来自国际的液体活检最新进展，对中国开展更多大型多中心临床研究也意义重大。

 

而Pantel教授也打趣地说道，关于液体活检，我已经发了将近400多篇论文，真的不需要更多出版物了。但我非常希望看到的是，液体活检越来越多地被临床接受，当我十年后退休时，液体活检已经广泛应用于临床实践。

 

我们今天推广液体活检的知识，是希望与全球学者分享，不单单是在德国、也不单是在美国或中国，我们希望全球学者共同参与到这个令人振奋的故事中来，一起谱写液体活检的未来，推动临床进步！

 

 

专家简介

 

Klaus Pantel教授，德国汉堡大学肿瘤生物学中心主任，“液态活检”之父。

 

Klaus Pantel教授作为肿瘤权威专家，过去十年为 Nature撰写CTC发展 Review，同时任多个杂志的编委，包括 Cancer Research, Clinical cancer research, British Journal of Cancer等，荣获美国癌症研究学会AACR 2010年乳腺癌杰出研究奖（ Outstanding Investigator Award for Breast Cancer Research）。2018年4月，Pantel教授受邀在美国AACR大会的发表开幕演讲（Open Plenary Session），向全球癌症研究专家介绍了液体活检领域的最新研究进展和未来方向。

 

Catherine Alix-panabieres教授，法国蒙皮利埃大学LCCRH研究室主任。

 

Catherine数授是 EPISPOT技术的专家，该技术用于检测乳腺癌，前列腺癌，结肠癌，头颈癌和黑色素瘤患者的外周血和骨髓中的活肿瘤细胞。她撰写或合著了60多种该领域的科学出版物，拥有液体活检领域三项发明专利。曾得法国医学院于2012年11月颁发的最高荣誉Gallet ct Breton癌症奖，获得AACR 2015年被引用最多科研论文的奖项。

 

 

附英文访谈内容

 

 

1. Nowadays, liquid biopsy has attracted more and more attention from the clinical researchers. Could you please give us a general introduction on the development of liquid biopsy?

 

Prof. Pantel:

 

Liquid biopsy is the detection of tumor cells and tumor cell products in the blood, and it is complimentary to tissue biopsy. As we know, sometimes it's very difficult to get a tissue biopsy from a tumor of a patient, because the tumour may be located in the lung or in the brain, and in the lung it's not so easy to put a needle in.

 

About ten years ago, there have been substantial technical developments allowing us to look into the blood. Take a blood sample and see whether you get the same information that you usually get from a needle biopsy from a tissue sample, and this information can be then very helpful to treat the patient better. Because the treatment is based on the individual information that is taken from the blood sample of this particular patient. 

 

2. At present, which detection methods are the most studied, and may show a promising application prospect?

 

Prof. Pantel:

 

I think that these methods are complimentary. You can have circulating tumor cells (CTCs) and get information on the protein content of these tumor cells, also can measure the RNA content of the circulating tumor cells. Then you can get information on resistant pathways like the antigen receptor resistance pathway. 

 

And you can also look at the DNA, like cell free DNA (cfDNA), and at the DNA you can look for mutations that are relevant to therapy. Like mutations of the EGFR gene, which are very important in lung cancer particular in China, as many lung cancer patients have these mutations in China, and there are EGFR-TKIs that targeting these mutations. 

 

Besides you can look at resistance mutations. Sometimes when the standard therapy treating the patients does not work anymore, the reason is that the tumour has changed and has acquired new mutations. You can detect them and give another drug and maybe a third drug or forth drug. And all these drug treatments are based on the analysis of your circulating DNA or your CTCs. And that, I think is probably the future of precision medicine.

 

3. What are the largest advances in liquid biopsy worldwide?

 

Prof. Pantel:

 

I think the largest advances are on one hand at the technology. In the last ten years, we have received very sensitive methods and very precise method to capture CTCs, and also to analyze them. And we have also developed next generation sequencing methods that allow us to look really into DNA very specifically for mutations.

 

And these methods have been even refined, so that you can detect very small amounts of tumour DNA in a sea of normal DNA, and pick up a few tumor cells in a sea of million of normal blood cells. And this kind of technical developments in the CTC but also in the cfDNA field has really made it possible to measure these things in cancer patients, and then related to the outcome in the clinical studies, and of course the studies are very important to validate these new technologies.

 

4. And how will the liquid biopsy change the clinical practice, in what aspects?

 

Prof. Pantel:

 

I think the liquid biopsy have different application areas. One area is early detection of tumour. It would be fantastic if lung cancer can be detected earlier, and not only when the patients have some symptoms like having a cold. Thus, early detection of cancer is one of the applications.

 

Then, you want to find out which patients have a risk to develop a relapse after surgery. There’s no tumor after surgery, but there might be some tumor cells in the body that the radiologist can not see. If you take a blood sample every three or six months, you may see that a patient is having a recurrence of tumour, or a tumour comes back as metastasis in another organ.

 

And the third application is that we identify therapeutic targets and persistent mechanisms through the CTCs, but also the ctDNA, and then we can find out which patient needs which kinds of therapy. So we can make it individualized. As every patient has a bit of different tumour, we have to know exactly the characteristics of this tumor.

 

5. And in the worldwide, are there any products related to liquid biopsy coming into the clinic now?

 

Prof. Pantel:

 

I think the ctDNA or cfDNA measurement for the EGFR mutations has been accepted in many countries. The patients with lung cancer can take a blood sample and you can see from the blood whether they have mutations in the EGF receptor gene, so that you can give certain drugs that is already approved.

 

And there are also new applications coming into the place, using CTCs for monitoring or for deciding therapies. So I'm quite optimistic that within the next two to five years we have more of those clinically approved applications.

 

6. What are the challenges of liquid biopsy？

 

Prof. Pantel:

 

One of the challenges is that, we have to use very, very sensitive methods. You have to make sure that the methods are all still very specific. Because if you're very sensitive, you may find something that is not relevant to the clinic. For example, if people get older or smoke a lot, they may have a lot of mutations in their blood in the DNA, it may not mean the necessarily of all the mutations. So we have to be careful, and our technologies will become more and more sensitive.

 

And another challenge is to find out how the technology helps us to cure more patients or to treat patients better. We have to say to the doctor in the clinic, okay, now you have to change your treatment because our mark on the blood assays said something. The drug is not working, some other drug should work. But in order to really prove that concept works, we have to show that the patients live longer.

 

Sometimes it's not easy to say yes, if one therapy doesn't work, you have to change to another one, but maybe the other one also doesn't work. And then you know it's not good. Thus, you have to show that the biomarker has some clinical utility, which means that it's helpful for better treatment of the patients, better management of the patients.

 

But that is not so easy. It takes long clinical studies to achieve good development and it requires very robust assays. And the assays need to be reproducible, they have to measure exactly the same. So you need those good assays, but you also need very good clinical studies. You have to bring them together, these are the challenges.

 

7. The ISMRC 2020 will be held in China, could you please introduce the background and the intention of the conference?

 

Prof. Pantel:

 

I start to organize this conference in nineteen ninety-six, more than twenty years ago. And we have this conference every two years all over the world. We had the congress this year in Montpellier in the south of France. In fact, the conference has been held in San Francisco, Osaka, Munich, Berlin, Oslo, Athens, Hamburg, Paris and so on. So we really disseminated this Symposium through the world and it would be the first time that we will organize this conference in China.

 

The Shanghai meeting would be the first one in China which is fantastic, because there's a lot of activity in China going on in medicine and also in the liquid biopsy field. So we are very happy actually to have this conference two years from now in the beautiful city of Shanghai.

 

8. what's your opinion on promoting the development of liquid biopsy in China and around the world through the conference?

 

Prof. Pantel:

 

I think what I want is really that when I retire ten years from now that liquid biopsy has been introduced in the clinic. I have more than four hundred publications on liquid biopsy. I do not need more publications, but I would be more satisfied if any of the liquid biopsy tests are really more and more accepted in the clinic.

 

By disseminating this information how to use it and what needs to be done to bring it in the clinic in the entire world, I hope that it will get accepted throughout the world, and not only in Germany or only in China, or only in the US. This is really my wish that different countries participate on this very successful story.

 

9. Professor Catherine Alix-Panabières, here, I also have a question for you. And we know you are also committed to liquid biopsy and have achieved many good research findings, could you please talk about the latest progress in the field of liquid biopsy. And what do you think of the prospects for liquid biopsy?

 

Prof. Alix-Panabières:

 

As Klaus Pantel just said that it's very important to have sensitive and robust methods to detect CTCs and all the other circulating biomarkers. It's really what we have done during the last decade. But the important thing is to prove now that their clinical validity and clinical utility.

 

Indeed, we have to prove in the different clinical trials that there is a benefit for the patients. It's really what I expect for the next year, that more and more interventional clinical trials can really show that there is a clinical utility for the liquid biopsy. And also what I believe is that we have to combine CTCs, ctDNA but also exosomes, microRNA, tumor-educated platelets to get a full picture of cancer as well as the immune system of each cancer patient.

 

Thus, all together, we can have a more precise view of the cancer progression or even cancer detection, because we will have information from the different circulating biomarkers. It's a very big family of different biomarkers now, and we need to really see everything as complimentary more than competitive thing.