Editor's Note: With the rapid development of genetic testing technology, the treatment strategies for patients with cancer of unknown primary (CUP) are undergoing revolutionary changes. During the 2024 ESMO Congress, the World CUP Alliance held a special "Roundtable on Access & Awareness of Precision Oncology" at the ESMO Congress, looking forward to the current treatment of CUP patients. After the meeting, Oncology Frontier specially invited Prof. Xichun Hu from Fudan University Shanghai Cancer Center, Prof. Linda Mileshkin from Peter MacCallum Cancer Center in Australia, Prof. Manel Esteller from Josep Carreras Leukemia Research Institute in Spain, and Prof. Qinghua Xu from Hangzhou Gene Help Technology Co., Ltd Help to gather together and discuss in depth the new advances in the treatment of CUP. From the positive data of the CUPISCO trial to the results of the Fudan CUP-001 study, the experts not only shared cutting-edge research results but also proposed valuable insights on how to improve the diagnostic accuracy for CUP patients and promote the implementation of personalized treatment plans, bringing new treatment hopes for CUP patients worldwide.

1. Prof. Xichun Hu：Dear Prof. Linda Mileshkin, dear Prof. Manel Esteller, dear Prof. Xu, nice to meet you again. We have a free talk about the treatment of CUP patients. Prof. 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?
2. Prof. Linda Mileshkin：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.
3. Prof. Xichun Hu：And in the experimental arm, there are 14 different MGT treatments, right? So, which MGT treatment contributes most to the final results?
4. Prof. Linda Mileshkin：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.
5. Prof. Xichun Hu：And Prof. Esteller, what are your thoughts on this result? What are your comments about it?
6. Prof. Manel Esteller：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.
7. Prof. Xichun Hu：Now, Professor Xu, you are the inventor of the 90-gene assay. Could you please give a brief introduction of this assay?
8. Prof. Qinghua Xu：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.
9. Prof. Manel Esteller：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.
10. Prof. Linda Mileshkin：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.
11. Prof. Xichun Hu：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.
12. Prof. Qinghua Xu：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.
13. Prof. Xichun Hu：Yes. That’s why I suggest that for the other 70% of patients, we can try to use the 90-gene assay. 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.
14. Prof. Manel Esteller：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.
15. Prof. Qinghua Xu：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.
16. Prof. Xichun Hu：In your country, in Spain, do you do genomic profiling?
17. Prof. Manel Esteller：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.
18. Prof. Qinghua Xu：And it’s fully reimbursed?
19. Prof. Manel Esteller：Yes, that’s fully reimbursed. It’s fully reimbursed by the state.
20. Prof. Qinghua Xu：It’s like a target in genomics?
21. Prof. Manel Esteller：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.
22. Prof. Xichun Hu：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?
23. Prof. Manel Esteller：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.
24. Prof. Xichun Hu：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?
25. Prof. Manel Esteller：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.
26. Prof. Qinghua Xu：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.
27. Prof. Xichun Hu：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.
28. Prof. Manel Esteller：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.
29. Prof. Xichun Hu：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.
30. Prof. Qinghua Xu：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.
31. Prof. Manel Esteller：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.

Prof. Xichun Hu

Chief of the Department of General Medicine, Fudan University Affiliated Cancer Hospital, Doctoral Supervisor

Chief of the Department of General Medicine, Fujian Hospital of Fudan University Affiliated Cancer Hospital (Fujian Cancer Hospital) ESMO Breast Cancer Faculty Member ESMO乳腺癌Faculty Member

International ABC 5-7 Panelist

Deputy Director of the Expert Committee of Oncology, Oncology Branch of the Chinese Medical Association

Honorary Chairman of the Multi-primary and Unknown Primary Tumor Professional Committee of the Chinese Anti-Cancer Association

Vice Chairman of the Clinical Chemotherapy Professional Committee of the Chinese Anti-Cancer Association

Vice Chairman of the Molecular Targeting Professional Committee of the Chinese Anti-Cancer Association

Vice Chairman of the Breast Disease Professional Committee of the Chinese Research Hospital Association

Vice President of the Shanghai Medical Association Oncology Branch

Executive Director of the Shanghai Anti-Cancer Association

Director of the Clinical Research Professional Committee of Oncology Drugs, Shanghai Anti-Cancer Association

Former Director of the Cancer Rehabilitation and Palliative Care Committee, Shanghai Anti-Cancer Association

Review Expert of the Center for Drug Evaluation, National Medical Products Administration

Published over 300 papers, including in “The Lancet Oncology” and “Journal of Clinical Oncology”

Editor-in-Chief of “Adverse Drug Reactions and Countermeasures in Oncology” and “Common Diagnostic and Treatment Questions in Oncology – A Record of Dr. Hu Xichun’s Ward Rounds”

Leads the “Major New Drug Creation” Science and Technology Major Project during the 13th Five-Year Plan

Shanghai Leading Talent, Second Prize of the Chinese Anti-Cancer Association Science and Technology Award, First Prize of the National Maternal and Child Health Science and Technology Award, and First Prize of the Shanghai Medical Science and Technology Progress Award, etc.

Prof. Linda Mileshkin

Peter MacCallum Cancer Centre, Australia

Prof. Manel Esteller

Josep Carreras Leukemia Research Institute, Spain

Prof. Qinghua Xu

Founder and CEO of Hangzhou Gene Help Technology Co., Ltd.

International exchange student at the University of Leuven, Belgium, from 2003 to 2008, obtained dual master’s degrees in Biochemistry and Bioinformatics

Doctoral degree in Oncology from Fudan University Shanghai Medical College, from 2010 to 2013