ESMO国际视野丨胡夕春、Linda、Manel教授、徐清华博士：揭秘CUP，中外大咖探讨原发不明肿瘤诊治进展

肿瘤瞭望

2024-09-25 10:54发布于北京

编者按：随着基因检测技术的飞速发展，原发不明肿瘤（cancer of unknown primary，CUP）患者的治疗策略正经历着革命性变革。在2024年ESMO大会期间，世界原发不明肿瘤联盟（the World CUP Alliance）在ESMO大会上专门召开了“精准肿瘤学的获取和认知圆桌会议”（Roundtable on access & awareness of precision oncology），就当前CUP患者的治疗进行了展望。会议结束后，《肿瘤瞭望》特邀复旦大学附属肿瘤医院胡夕春教授与澳大利亚Peter MacCallum癌症中心Linda Mileshkin教授、西班牙Josep Carreras白血病研究所Manel Esteller教授、可帮基因徐清华博士共聚一堂，深入探讨了原发不明肿瘤的治疗新进展。从CUPISCO试验的积极数据到Fudan CUP-001研究结果，专家们不仅分享了前沿研究成果，还就如何提升CUP患者诊断准确率、推动个性化治疗方案的实施提出了宝贵见解，为全球CUP患者带来了新的治疗希望。

胡夕春教授：Linda Mileshkin 教授、Manel Esteller教授、徐清华博士，很高兴再次与你们见面。我们今天共同讨论CUP患者的治疗问题。今天上午我们看到了有关CUPISCO试验的总生存期（OS）数据，因此第一个问题想请教Linda教授，您作为这篇发表在《柳叶刀》杂志上的论文的通讯作者，对OS结果有何看法？

Dear Prof. Mileshkin Linda, dear Prof. Manel Esteller, dear Prof. Xu, nice to meet you again. We have a free talk about the treatment of CUP patients. Professor Linda, the first question for you is that this morning we have the OS data about the CUPISCO trial. As a correspondent also of this paper in The Lancet, what are your thoughts about these OS results?

Linda Mileshkin 教授：目前该研究的OS数据尚未成熟，我们仍旧在等待中。我们原本希望能在这次会议上获得成熟的数据，但现在来看还需要更多时间。患者的状况比我们预期的要好，整体趋势确实在朝着积极的方向发展。分子引导疗法（molecularly guided therapy，MGT）似乎真正改善了CUP患者的预后，这让我们非常振奋。这也是ESMO首次专门为CUP患者设立专题会议，这要特别感谢世界CUP联盟的患者支持者们。他们主动联系ESMO说：“为什么你们的会议上没有关于CUP患者的内容？这并不是一种罕见的癌症。”因此，ESMO为我们安排了一个完整的专场，这真的令人欣喜。

Yes, so we're still actually waiting for the mature overall survival data. We hope to have it for this conference, but it's not yet mature. The patients are doing better than we hoped, but certainly the trend is in the right direction and it does seem that molecularly guided therapy is actually really improving outcomes for our CUP patients. And we're very excited. This is the first time at ESMO we had a dedicated session about CUP and that was thanks to our patient advocates from the World CUP Alliance. They actually wrote to ESMO and said, you don't have anything about CUP, why not? It's not a rare cancer. And so ESMO actually put together a whole session for us, which was fantastic.

胡夕春教授：实验组中有14种不同的MGT治疗。那么，哪一种对最终结果的影响最大呢？

And in the experimental arm, there are 14 different MGT treatments, right? So, which MGT treatment contributes most to the final results?

Linda Mileshkin 教授：在CUPISCO试验中，我们发现大约30%的患者都存在可用于治疗的可操作靶点。而70%的患者没有，因此他们接受了化疗联合免疫治疗，虽然这部分患者也有一定的获益，但真正推动CUPISCO试验取得显著效果的是那30%具有明确可操作靶点的患者，例如那些具有高肿瘤突变负荷的患者，接受了阿替利珠单抗（atezolizumab）的治疗。

So what we found in CUPISCO was that about 30% of patients actually had an actionable target for treatment. 70% did not, and so they received chemotherapy plus immunotherapy. And they got some benefit, but it was really the 30% that had a true actionable target, like a very high tumor mutation burden, who received treatment with atezolizumab that drove the benefit in the CUPISCO trial.

胡夕春教授：Manel Esteller教授，您对这个结果有什么看法，对此有何评论吗？

And Professor Esteller, what are your thoughts on this result? What are your comments about it?

Manel Esteller 教授：我认为CUPISCO试验是转化医学中一个很好的例子。在传统肿瘤学中，加入分子特征并显示可以产生不同的治疗效果，这本身就是一种突破。即使目前的成功率只有50%，未来有望提升到60%甚至更高。这一领域一直在期待这样的进展。如今，我们终于有了初步的数据，未来还会有第二个更成熟的数据，其他类型的数据也会不断补充。此外，还会有新的药物出现。随着我们对这种特定类型肿瘤的生物学特性有更深入的理解，我们可以考虑为这些患者提供更个体化的治疗。因此，我认为这是一项持续推进的研究。我个人和患者、患者支持者们，对于这类研究的开展感到非常欣慰。

I think the CUPISCO trial has been a good example of translational medicine. In the classical oncology, adding the molecular features there and showing that can make a difference. Even if it's still 50%, in the future it's going to be 50%、60%. There's something to be added there. I think it's something that the field was expecting for many years. So finally we have this first data, there will be a second, more mature data maybe, another type of data that will be added there. And new drugs will appear, new drugs. And when we understand even better the biology of this particular type of tumor, even we can think about better treatments that are more personalized for these patients. So I think this is an ongoing research. Myself and I think the patients, of course the patients and the advocates are very happy this type of research that is taking place.

胡夕春教授：徐博士，您是90基因检测的发明者。您能简要介绍一下这个检测方法吗？

Now, Professor Xu, you are the inventor of the 90-gene assay. Could you please give a brief introduction of this assay?

徐清华博士：实际上，这一检测方法是基于RNA技术和PCR平台开发的。正如我们今天讨论的那样，在许多国家（无论是发达国家还是发展中国家），仍然无法获得PCR或二代测序等技术，我们希望利用这一事实。因此，我们希望从第一阶段开始，推出一种基于qPCR的检测，让大多数医院都能使用它。然后，第二阶段将整合更多基因、RNA、表观基因组学和DNA突变，为医生提供更全面的信息，从而帮助他们为患者制定更精准的治疗方案。

我们发现，在澳大利亚和欧洲等地，人们对90基因检测的可用性始终表现出浓厚的兴趣。然而，这类检测和治疗的推广似乎面临着可及性不足的问题。在复旦团队的帮助下，我们希望通过Fudan CUP-001试验将90基因检测应用于临床。

Okay, so actually, the assay was developed using RNA technologies with a PCR platform. We hope to take advantage of the fact that, as we discussed this afternoon, many countries, both developed and developing, still cannot access technologies like PCR or NGS. So, we hope to start from the first level by applying a qPCR-based test that most hospitals can use. Then, we move to the second level, incorporating more genes, RNA, epigenomics, and DNA mutations to provide doctors with a more comprehensive picture, allowing them to make more precise treatment decisions for patients.

With the help of the Fudan team, we hope the 90-gene assay can be applied clinically through the Fudan CUP-001 trial. We have seen that in places like Australia and Europe, there is always interest in the availability of the 90-gene assay. It seems that the lack of availability is an issue for this type of test and treatment support.

Manel Esteller 教授：我认为，我同事的重要发现确实强调了整合多组学数据的必要性。我们可以利用包括DNA甲基化、基因表达和基因序列等多种组学数据来更好地表征CUP本身，并判断其原发部位。将靶向治疗与器官特异性结合起来，我认为这是最具协同效应的策略。有些药物对非小细胞癌效果更好，有些对胰腺癌效果更好，但对其他类型的肿瘤，比如结肠癌就没有那么好的效果。因此，将这些信息结合起来，或许会对这些病人产生真正的影响。

I would say that the relevant discovery of my colleague adds really to this necessity to put together different multiomics, different omics ourselves, we have a lot of DNA methylation, expression, genetic sequence, to characterize the CUP itself. And to have an idea if the primary that originated these caps. Because putting together the target therapy and the organ side is the best, in my opinion, the synergistic effect. Some drugs work better in a non-small cell cancer, others work better in a pancreatic, but not that much, but in other tumour types, in colon cancer. And this information together is what really will make the difference for these patients.

Linda Mileshkin 教授：这就是Fudan CUP-001研究中生存优势的原因，因为不仅利用该方法来确定诊断，还关注与癌症相关的突变，并基于这些突变进行治疗。因此，在试验中，许多患者接受了靶向治疗或免疫治疗，而不仅仅接受传统的化疗。

And that's why you saw the survival advantage in the Fudan CUP-001, because you were using it to say what the diagnosis was, but you were also looking at the mutations relevant to that cancer and treating based on that. So a lot of people, didn't they, in the trial they had targeted therapies or immunotherapy, not just plain old chemotherapy.

胡夕春教授：我们很幸运，因为有很多患者接受了靶向治疗和免疫治疗，尽管只有少部分患者有PFS和OS方面获益。但我认为，中位OS延长了9.2个月，临床获益是显著的。相比其他试验，包括其他基因表达谱试验和随机对照试验，我们确实更为幸运，因为在我们的试验中，许多患者都接受了这些治疗。这也是我们能够取得阳性结果的原因。

We are lucky because more patients received targeted therapy and immunotherapy, though fewer patients benefited from the PFS and OS improvements. I think the clinical benefit, with a median OS prolongation of 9.2 months, is significant. We are fortunate compared to other trials, including other gene expression profiling trials and active randomized trials, because many patients in our trial received these treatments. That's why we obtained positive results, I believe.

徐清华博士：我认为我们也在充分利用新药的优势，一些靶向治疗方法已经开始取得效果。这正是我们紧急开展临床研究的原因，因为随着更多靶向治疗的出现，我们可以根据这些标志物筛选出适合这些治疗的患者。正如我们在讨论中提到的，有些人可能会选择折中的方法，认为不应忽视肿瘤的原发部位。当然，这对于我们的诊疗系统而言至关重要。同时，我们也关注靶向治疗所提供的关键信息。这正是我们Fudan CUP-001试验设计的理念。正如教授刚才所说，这两者并不相互排斥。我们应将这些方法结合起来，发挥两者的协同作用，从而全面了解CUP患者。

I think we are also taking advantage of the new drugs that have come out. Some targeted therapies are starting to work. That's actually the reason for conducting acute clinical studies, because with more targeted therapies to be optional, we can select those markers and identify patients who are suitable for these therapies. You could imagine, as we discussed during the session, some people may choose the middle ground, saying that we should not disregard the tumor origin. Of course, it's fundamental to our system. Meanwhile, we focus on the meaningful information provided by targeted therapy. This is exactly what we designed for the Fudan CUP-001 trial. The professor said that it's not mutually exclusive. These approaches should be combined to achieve a synergy between the two directions, allowing us to fully understand CUP.

胡夕春教授：这就是为什么我建议对另外70%的患者尝试使用90基因检测的方法。

Yes. That's why I suggest that for the other 70% of patients, we can try to use the 90-gene assay.

胡夕春教授：徐博士，您知道的，尽管90基因检测已经获得了监管部门的批准，但目前尚未被医疗保险覆盖，因此患者需要自费。在中国，全面的基因组分析同样不在医保报销范围内。

Also, although the 90-gene assay is regulatory approved, it is not covered by medical insurance, so patients have to pay for it themselves. In China, comprehensive genomic profiling is also not covered.

Manel Esteller 教授：我认为这种方法的优势在于，首先可以通过全面的基因组学分析进行深入研究，以取得初步发现。随后，可以使用一种成本更低、标志物更少但疗效相似的检测方法，从而更广泛地应用于整个群体。这对中国尤为重要，因为中国人口众多，样本量大，患病人数也多，因此必须降低检测成本，确保其可行性。尽管如此，我认为目前针对基因检测的指南是相当不错的，我们始终需要找到并遵循一个统一的标准。

I would say that this type of approach is that you do a big genomics for results and the first discovery using genomics at the comprehensive level, but later you have a test that is cheaper with less markers but similar efficacy is a way that you can access the whole population. For China, it's very important. It's a huge population, many samples, many people with the disease. You have to put the price down and make it work. Still, I think the guide for the gene assay is very good. You always need to find the standard.

徐清华博士：这就是我们试图进行研究转化的逻辑，目的是最终为临床医生提供一种工具。除此之外，其他的都很顺利。我在会议期间听到了很多关于检测的信息，但我认为一位来自澳大利亚的专家说的非常好。你似乎总能找到标准，否则你不能在临床中使用它。

Well, I think so. That's the logical that we try to do the transfer translation of research so called finally provide a kind of tools for to the clinicians. Otherwise it was good. Where I heard a lot of discussions during the sessions of check all the Information, but still, I think it's an expert from Australia saying very good. You always seem to find the standards, otherwise you cannot use it in the clinical.

胡夕春教授：在您的国家西班牙，是否开展基因组分析？

In your country, in Spain, do you do genomic profiling?

Manel Esteller 教授：是的，对于CUP患者，我们目前主要进行的是综合基因检测，而不是全基因组测序。这是一种包含所有可用药物靶点的综合面板，也就是所谓的“可施治靶点”。我们之前讨论过这个，并且我们有一些非常优秀的病理学家。这需要肿瘤科和病理科之间进行团队合作，共同对这些基因进行详细的鉴定。

Yes. For CUP’S, what we do now is mostly a comprehensive panel. It's not a whole genome like that. It's a comprehensive panel that includes all targets that there is a drug. So, actionable targets in this case. We're talking about this before. We have some very good pathologists. This is a team effort between the oncology and the pathology to characterize very well this gene.

徐清华博士：这些都能报销吗？

And it's fully reimbursed?

Manel Esteller 教授：是的，这部分是完全由国家报销的。

Yes, that's fully reimbursed. It's fully reimbursed by the state.

徐清华博士：综合基因检测与基因组学中的靶点检测类似吗？

It's like a target in genomics?

Manel Esteller 教授：是的，它的规模大约在中等水平，包括50到60个基因，以及一些突变、内分泌相关的指标和一些基因失活。

Yes. It starts at the middle size. You should imagine that you have 50 genes or 60 genes. Also mutations, endocrine numbers, some gene immobilization.

胡夕春教授：今天下午的讨论非常愉快，我认为关于世界原发不明肿瘤联盟（the World CUP Alliance）的讨论是非常富有启发性的交流。您对这次会议有什么看法？

This afternoon, we had a nice discussion. I think it was a stimulating conversation about the World CUP Alliance. What are your thoughts about this conference?

Manel Esteller 教授：我认为这非常了不起，因为这样的机会并不常见。我们现在有足够的样本量和研究能力来证明这类疾病可以获得药物批准。我们需要汇集来自不同国家和地区的力量，而世界原发不明肿瘤联盟正是以这种方式运作的。通过联盟，我们可以将更多标准化的治疗方案和临床试验整合在一起。此外，联盟的支持工作也至关重要。他们强调：“这是一个非常重要的领域，应该加大对这种疾病研究的投入。”

I think this is great because this is not so common. We have enough samples, enough power to show that you can approve drugs for this. You need to get together different countries and different places. And the World Cup Alliance works in that way. And we can put more standardized treatments and clinical trials together. And also, the work of advocacy. These people are saying this is important. You should invest in research on this disorder.

胡夕春教授：我们原以为这是一种罕见疾病，但数据显示情况并非如此，其发病率约为每百万人中有2到5例，所以说，这并不是一种罕见病。

Based on our impression, it's a rare disease. But according to statistics, it's not rare, as the incidence rate is about 2 to 5 in 10 million, right?

Manel Esteller 教授：它绝对不是一种罕见疾病，可以想象，2%到5%的发病率意味着全球范围内有相当多的患者。而且这些患者的预后通常较差，这确实是一个亟待解决的医疗需求。我认为，我们应该在这种情况下积极采取行动。

Absolutely. So, it's not a rare disease.So you can imagine the rates between 2-5%. This is a lot of patients around the world. And these patients have a poor outcome still. So it's really a medical need. I think we should do something in these scenarios.

徐清华博士：我想请教Esteller教授和胡教授一个问题。今年是ESMO首次设立专门针对CUP患者的专题会议，讨论了今年在CUP治疗领域取得的进展。我认为今年对CUP来说是非常重要的一年，尤其是胡教授的论文发表在《柳叶刀·肿瘤学》杂志上，以及CUPISCO研究成果发表在《柳叶刀》杂志上。那么，胡教授，您对CUP在近期发展的前景有何看法？无论是在中国，还是在欧洲和美国。

And perhaps I have a question for Esteller and Professor Hu. This is the first time at the ESMO Congress that we had a dedicated CUP session, discussing the advancements in CUP this year. I think this year is a good year for CUP, especially since we have your manuscript published in The Lancet Oncology, and the CUPISCO paper published in The Lancet. So, Professor Hu, I would like to hear your perspective on the near future of CUP, maybe in China, as well as in Europe and the US.

胡夕春教授：首先，我想简单介绍一下我在CUP临床诊疗中的一些经验。诊断是治疗最关键的一步。根据我们的经验，大约有三分之一在其他医院或诊疗中心被诊断为CUP的患者，在我们中心（复旦大学附属肿瘤医院多原发和不明原发肿瘤诊治中心）找到了原发部位。因此，准确诊断显得尤为重要。其次，需要提升公众和医疗界对CUP的认识。第三，在精准和个性化治疗方面，我们目前有两种主要方法：一种是利用基因表达谱来预测癌症的原发部位；另一种是将CUP视为一种独立的癌症实体，通过基因组学手段寻找可操作的驱动突变，并为患者制定个体化的治疗方案。我认为这两种方法都正在改变临床实践，并为患者带来新的希望。

对CUP患者而言，他们是幸运的。今年对我来说也是如此幸运。去年，我们的研究摘要在ESMO会议上进行了展示，今年，我们的研究成果又发表在了《柳叶刀》和《柳叶刀·肿瘤学》上。我相信这些研究已经对临床实践产生了积极的影响，但仍有进一步改进的空间。

First, I briefly introduced some experiences in my clinic. Diagnosis is the most important step. Based on our experience, about one-third of patients with CUP who were diagnosed as CUP in other hospitals or centers had their primary sites identified in our center. So, diagnosis is very important. Next is to increase awareness of CUP.Third, in precise and personalized treatment, we now have two approaches. One approach is to use gene expression profiling to predict the cancer's primary site. The other approach considers CUP as an independent cancer entity, using a genomic approach to find actionable driver mutations and select treatments for our patients. I think both approaches are practice-changing. We can use these approaches to treat our patients.

For patients with CUP, they are fortunate. This year, I'm also fortunate. Just last year, the abstract was presented at ESMO, and this year, our work was published in The Lancet and The Lancet Oncology. I think both have been practice-changing, but there is still room for further improvement.

Manel Esteller 教授：我认为，直到最近，CUP患者一直像“孤儿”一样，因为他们的癌症没有明确的名称。而现在，他们有了更具体的命名和分类，而且首次有临床数据支持，表明这些治疗确实在发挥作用，真正改善了患者的整体生存率。这是首次取得这样的进展，对所有患者来说无疑是一个巨大的好消息。

I think. I would say that until very recently, CUP patients, they feel like orphans because they don't have a name of their cancer. Now they have more names, more classifications and the first time there is clinical data supporting that the treatments are doing something, are really improving our overall survival. This is the first time. I mean, it's good for all these people.

胡夕春教授：是的，我们还有进一步提升的空间。此外，对于世界原发不明肿瘤联盟，我们可以采用相同的治疗方案来处理这些罕见癌症，从而收集更多数据和证据，进一步改善这些患者的预后。

Yes, we can improve even more. Also, for the CUP World Alliance, we can use the same protocol to treat these rare cancers, allowing us to gather more data and evidence to improve the outcomes for these patients.

徐清华博士：或许您可以向中国观众简要介绍一下自己，也可以用西班牙语简单介绍CUP。让大家更了解您。

Maybe it's time for you to give a very brief introduction about yourself to the Chinese audience, and perhaps say a little bit about CUP in Spanish. Let's help people get to know you.

Manel Esteller 教授：我叫Manel Esteller，是巴塞罗那大学的遗传学系主任，我长期从事癌症和表观遗传学研究。我的研究兴趣之一是非原发性癌症，例如不明原发灶的转移癌。理解转移的生物学机制非常重要，因为最终导致癌症患者死亡的往往是转移，而不是原发肿瘤。因此，对我来说，这在肿瘤学领域是一个至关重要的问题。

So my name is Manel Esteller I am the chairman of genetics here at the University of Barcelona and I have been studying cancer, epigenetics for a long time and I have an interest in cancer of a non-primary like an example of unknown metastasis and it's relevant to understand the biology of metastasis because what at the end is killing the cancer patients is the metastasis, not the primary side. So for me it's a critical issue in oncology.