「液體活檢之父」來中國交流：可靠檢測技術結合多中心臨床研究是發展關鍵

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國際權威專家全面解讀液體活檢，全球重要研討會將於2020年在中國舉辦。

來源丨醫學界腫瘤頻道

隨著基因檢測技術的發展，精準治療被越來越多的提及。利用基因信息指導個體化診斷治療、預測複發風險和預後，聽起來十分鼓舞人心。而液體活檢無疑是近年來爆紅的「小鮮肉」。

2008年至今，每年液體活檢領域發表的文獻數量呈指數增長。2015年，液體活檢被MIT科技綜述雜誌評為年度十大科技突破之一。液體活檢正以難以阻擋的趨勢向前發展。

為了趕上國際步伐、增強我國臨床及科研工作者對液體活檢的認知，10月中旬，在上海交通大學施奇惠教授和蘇州浚惠生物閻灼輝先生的大力邀請下，液體活檢領域的學術領軍人物——「液體活檢之父」、德國漢堡大學腫瘤生物學中心主任Klaus Pantel教授和法國蒙皮利埃大學LCCRH研究室主任Catherine Alix-Panabières教授一同來到中國，在上海與上海市胸科醫院陸舜教授等專家，在北京與國家癌症中心、中國醫學科學院腫瘤醫院藥物臨床試驗研究中心的李寧教授等中國專家就「液體活檢」的國際經驗，和中國研究應用現狀進行了廣泛地交流。

藉此機會，界哥榮幸地採訪了兩位國際專家，一起來看看，關於液體活檢大佬都怎麼說。

Klaus Pantel教授和Catherine Alix-Panabières教授

一

大咖面對面，國際專家全方位解讀液體活檢

1. 液體活檢越來越受到臨床研究者的關注，您能簡單介紹一下液體活檢的發展歷程嗎?

Pantel教授：

液體活檢事實上就是檢測血液中的腫瘤細胞和腫瘤細胞產物，它與組織活檢形成互補。正如我們所知，有時，從腫瘤患者獲取活組織樣本是比較困難的事，尤其當腫瘤位於肺、大腦等部位時，獲得組織樣本可能十分棘手。並且在臨床實踐中，對患者進行連續組織活檢、以實時監測治療反應的可行性較低。

大約十年前，隨著技術上很多新的發展，我們得以深入了解血液。通過獲取血液樣本，觀察是否能得到與組織穿刺活檢相同的信息，而這些信息能夠幫助更好地治療患者。因為個體化治療就是基於從患者的血樣中提取的個體化信息進行的。液體活檢由此發展起來。

2.目前，哪些液體活檢方法是研究最多的，可能顯示出很好的應用前景?

Pantel教授：

液體活檢領域研究較多的主要有循環腫瘤細胞（CTCs）、循環腫瘤DNA（ctDNA）等，這些方法事實上是互相補充的關係。

我們可以捕獲血液中的CTCs，分析這些腫瘤細胞的蛋白質含量信息，也可以測量CTCs中的RNA信息，用於指導治療、預測複發風險等。

同樣地，我們也可以檢測ctDNA，尋找與治療相關的突變。最典型的如檢測EGFR基因突變，一種中國非小細胞肺癌患者最常見的突變類型，用於EGFR-TKI靶向治療的指導。

此外，通過檢測CTCs、ctDNA，我們可以尋找耐葯突變通路。有時，用於治療的標準療法不再有效，最大的原因是腫瘤發生了變化，出現了一些耐葯突變。此時，通過液體活檢檢測出這些突變，可以幫助指導更換另一種藥物，或第三種甚至第四種藥物。

所有這些藥物治療都是基於對ctDNA或CTCs的分析。我認為這可能是精準醫療的未來。

3.液體活檢將如何改變臨床實踐，主要從哪些方面?

Pantel教授：

我認為液體活檢有不同的應用領域。

首先，在腫瘤的早期發現上，液體活檢可以提供更加敏感、精準的信息，在癌症較早期即捕捉到信號，而不是等到患者出現癥狀（例如肺癌患者發熱、咳血）時才給予治療干預。

第二，預測腫瘤複發風險和轉移進程。通常情況下，大部分患者在手術治療後肉眼及影像下均觀察不到腫瘤，但這並不意味著患者體內不存在殘餘腫瘤。而CTCs檢測則可以靈敏地監測到血液中的腫瘤細胞，及時提示腫瘤可能原位複發或轉移至另一器官。

第三，通過CTCs和ctDNA檢測可以識別治療靶點和耐葯信息。找到確切的治療靶點，是實現個體化精準治療的重要前提，臨床醫生可以據此給予患者個體化的靶向治療方案。但目前的現狀是，大多數靶向治療最終都會面臨耐葯問題，此時，利用液體活檢找到耐葯通路，及時更換治療藥物，也是精準治療的臨床應用之一。

此外，液體活檢在實時監測治療狀況、進一步理解腫瘤轉移進展的生物學信息方面，也極具潛力。這些都將推動著臨床腫瘤的治療邁入新台階。

4.液體活檢領域最大、最重要的進展是什麼?

Pantel教授：

我認為液體活檢最大的進步表現在技術方面。過去十年里，我們逐漸擁有了非常靈敏和非常精準的手段來捕獲CTCs，並對其進行分析。第二代測序技術等也幫助我們能夠研究DNA的突變信息。

這些精密的技術還在不斷改進中，使我們得以在如汪洋大海般的正常細胞和DNA中，檢測到目標CTCs和ctDNA。這些技術將進一步與臨床研究結果掛鉤，而臨床研究又對於驗證這些新技術的有效性非常重要。

5.在世界範圍內，現在是否有與液體活檢相關的產品進入臨床?

Pantel教授：

我認為EGFR突變的ctDNA或循環遊離DNA（cfDNA）檢測已經被許多國家接受並應用。我們可以通過採集肺癌患者的血液樣本，檢測其中是否存在EGF受體基因突變，從而指導靶向治療。

現在一些新的應用也逐漸可及，如利用CTCs監測治療或決定治療決策。所以我樂觀地認為，在接下來的兩到五年內，我們會有更多的液體活檢產品獲得批准、進入臨床。

6. 液體活檢面臨的挑戰有哪些?

Pantel教授：

一個挑戰是，我們必須使用非常非常敏感的方法。但是，你必須確保這些方法的特異性也要非常好。因為如果你非常敏感，你可能會發現一些與診斷無關的東西。例如，如果人們變老或吸煙很多，他們的血液中DNA可能會有很多突變，這可能並不代表腫瘤突變的結果。所以我們必須小心，我們的技術變得越來越敏感所帶來的問題。

另一個挑戰是，找到新技術真正能幫助我們治癒更多患者、或更好地治療患者。我們不得不對醫生說，好吧，現在你必須改變治療方法，因為我們對血液檢測的標記物說明有問題。這種藥物不起作用，其他一些藥物可能起作用。但為了真正證明這個概念有效，我們必須證明患者的經過新藥物治療後的壽命更長。

有時候標誌物檢測，並不容易這樣提示醫生。如果一種療法不起作用，你必須改為另一種療法，但也許另一種療法也不起作用。然後你知道這樣建議的治療方案改變並不好。因此，你必須證明生物標誌物具有一定的臨床效用，這意味著它有助於更好地治療患者，更好地管理患者。

但這並不容易。需要長時間的臨床研究才能獲得良好的效果，並且需要非常可靠的檢測方法。並且檢測方法必須是可重複的，必須檢測結果一致。所以你需要那些好的檢測，但你也需要非常好的臨床研究。你必須將它們結合在一起，這是挑戰。

7. Catherine Alix-Panabières教授，關於液體活檢的現狀和發展方向，您的看法如何？

Alix-Panabières教授：

正如Klaus Pantel所說，找到敏感而可靠的方法來檢測CTC和所有其他循環標記物非常重要。這正是我們在過去十年中所做的。但重要的是要證明他們的臨床有效性和臨床效用。

實際上，我們必須在不同的臨床試驗中證明液體活檢對患者有益。我期望明年以後，越來越多的干預性臨床試驗能夠真正證明液體活檢有臨床效用。而且我相信我們必須將CTC，ctDNA以及外泌體，microRNA，腫瘤影響的血小板結合起來，以全面了解癌症以及每位癌症患者的免疫系統。

因此，總之，我們可以更準確地了解癌症進展甚至癌症檢測，因為我們將獲得來自不同循環生物標誌物的信息。它現在是一個非常大的不同標記物的家族，我們需要真正把所有液體活檢標誌物看做是互補的，而不是互相競爭的關係。

二

搭建中外合作橋樑，液體活檢重要研討會將於中國舉辦

看過兩位專家的解讀，我們大概知道，液體活檢在腫瘤診斷和治療領域都極具潛力。但最關鍵的問題是，我國的液體活檢發展怎麼樣？距離臨床實踐有多遠？

閻灼輝表示：「儘管今天液體活檢的概念對我們不再陌生，但必須承認，我國的液體活檢研究和應用整體和國際水平之間還存在著一定差距或某種脫節。因此，加強我國與國際研究者之間的交流非常必要，我們需要吸納國際學者關於液體活檢的最新理念，同時也要多做出來自中國的貢獻，以彌合這種差距。

「非常榮幸，我們這次邀請到了Pantel教授和Alix-Panabières教授到上海和北京訪問，並且由兩位專家牽頭的第1屆The Liquid Biopsy Conference (暨第12屆微小殘留癌國際研討會International Symposium on Minimal Residual Cancer, ISMRC）也決定將於2020年首次在中國上海舉辦。」

1^st TLBC2020 大會

ISMRC大會由Pantel教授於1996年創立，每兩年在世界各地舉辦一次，旨在將液體活檢的最新研究進展傳播向全球各個國家。如今，ISMRC已經走過舊金山、大阪、慕尼黑、柏林、奧斯陸、漢堡、巴黎等地，今年的第11屆ISMRC也於5月初在法國南部的蒙皮利埃成功舉辦。作為Liquid Biopsy概念的首先提出者，Pantel教授希望2020年的大會開始使用The Liquid Biopsy Conference 的名字，並且會包括更多腫瘤以外的領域。

施奇惠教授表示，我們非常期待這次會議的來臨，液體活檢對中國的臨床醫生極具吸引力，這是一個難得的機會，中國的臨床和科研工作者能夠有機會聽到來自國際的液體活檢最新進展，對中國開展更多大型多中心臨床研究也意義重大。

而Pantel教授也打趣地說道，關於液體活檢，我已經發了將近400多篇論文，真的不需要更多出版物了。但我非常希望看到的是，液體活檢越來越多地被臨床接受，當我十年後退休時，液體活檢已經廣泛應用於臨床實踐。

我們今天推廣液體活檢的知識，是希望與全球學者分享，不單單是在德國、也不單是在美國或中國，我們希望全球學者共同參與到這個令人振奮的故事中來，一起譜寫液體活檢的未來，推動臨床進步！

專家簡介

Klaus Pantel教授，德國漢堡大學腫瘤生物學中心主任，「液態活檢」之父。

Klaus Pantel教授作為腫瘤權威專家，過去十年為 Nature撰寫CTC發展 Review，同時任多個雜誌的編委，包括 Cancer Research, Clinical cancer research, British Journal of Cancer等，榮獲美國癌症研究學會AACR 2010年乳腺癌傑出研究獎（ Outstanding Investigator Award for Breast Cancer Research）。2018年4月，Pantel教授受邀在美國AACR大會的發表開幕演講（Open Plenary Session），向全球癌症研究專家介紹了液體活檢領域的最新研究進展和未來方向。

Catherine Alix-panabieres教授，法國蒙皮利埃大學LCCRH研究室主任。

Catherine數授是 EPISPOT技術的專家，該技術用於檢測乳腺癌，前列腺癌，結腸癌，頭頸癌和黑色素瘤患者的外周血和骨髓中的活腫瘤細胞。她撰寫或合著了60多種該領域的科學出版物，擁有液體活檢領域三項發明專利。曾得法國醫學院於2012年11月頒發的最高榮譽Gallet ct Breton癌症獎，獲得AACR 2015年被引用最多科研論文的獎項。

附英文訪談內容

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.

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