Podcast

Domenica Lorusso: [00:00:02] Welcome to TJ talks, a conversation about oncology by Tumori Journal, the Peer Review Oncology journal dedicated to the dissemination of key oncological themes and innovation. I am Domenica Lorusso, section editor at Tumori Journal, and in this episode we will focus on advanced ovarian cancer, discussing what we have learned from the most recent first line trials and how this lessons are shaping future treatment strategies. I am really pleased to be joined by Doctor Fabio Martinelli, which is an expert in gynecological oncology surgery, and Dottoressa Elena Giudice. She is an expert in gynecological medical oncology treatment. Fabio. Elena, thank you so much for being here. Fabio. I will start with you about the hot topic of the frontline surgery in the treatment of advanced ovarian cancer. Looking at the Trust trial, what do you think are the main lesson that we had learned from our clinical practice from this trial?

Fabio Martinelli: [00:01:15] Thank you Ketta. Trust Trial is the last published trial comparing primary debulking surgery versus neoadjuvant chemotherapy, followed by interval debulking surgery, and is a really important trial because it showed us that surgery still play a role in survival in ovarian cancer patients. The point is that we have to clearly decide when surgery has to be included in the process of treatment of ovarian cancer patient. Trust (trial) did not say us that every patient has to go to neoadjuvant chemotherapy, but neither say us that every patient coming with a suspected ovarian cancer needs to go to debulking surgery. What we learn from Trust trial is that we have to select patients to the right time, meaning if a patient is suitable of having a complete cytoreduction, meaning exploiting all tumor visible to R0 without having complication or delaying the start of chemo, patient can go through surgery. Otherwise, we can send patient to neoadjuvant chemotherapy and considering surgery after initial treatment. So what is crucial from Trust trial is patient selection is not what fit all is not operate all patients are frontline and is not giving chemo tool is deciding the best treatment on each patient.

Domenica Lorusso: [00:02:52] Fabio this is a very important lesson. The patient selection the best treatment for each patient. In my mind this emphasize the necessity that these patients are treated in referral centres, where there are the competence and expertise to decide the best treatment for each patient. And this is a great lesson. But Elena, from the medical oncology perspective, also here we see a lot of complexity in the recent year. What do you think are the key lessons that we have learned from the most recent first line trial?

Elena Giudice: [00:03:32] Thank you prof. So I think the most important lesson is that the first line treatment has clearly become more effective with the introduction of maintenance treatment strategies. But the discrepancy we often see between progression free and overall survival outcomes has taught us two other major lessons. First, we reflected more carefully about the value of the overall survival outcome in this such rapidly evolving field. Crossover is very frequent in these trials. And so treatments are also evolving so rapidly. And so the surrogate endpoints are becoming more and more relevant in this setting. And second, the patient selection has become absolutely critical, as Fabio told us before, for surgical point of view. And so the simple dichotomy between this HRT and HRP disease, although very, very clinically useful, is probably an oversimplification to oversimplification. So I would say that in my clinical practice, the treatment decisions are still strongly influenced not only by the biomarkers but also by the overall picture, clinical picture of the patient point of view and our perception about the degree of platinum responsiveness, especially when we have to choose the maintenance treatment strategies among Parp inhibitors alone or bevacizumab alone, or both of them. Also, when we have to evaluate whether the platinum based chemotherapy remains an option in the later settings.

Domenica Lorusso: [00:05:15] So Elena, more and more complexity, both in surgical and medical treatment, this underlined to me more and more the necessity of a multidisciplinary discussion, case by case, to address the best treatment for each patient. Fabio, how does the multidisciplinary team impacting your daily practice?

Fabio Martinelli: [00:05:39] Multidisciplinary team is fundamental in our daily practice is the main core when we decide the best treatment for each patient, it’s mandatory to discuss every single patient in a team composed by gynecologists, medical oncologists, radiologists, anesthesiologists and pathologists, and, if needed, or other colleagues with other specialties. This is really important because we have to select patient that will really benefit for the surgery or they benefit more starting from a chemo. It’s mandatory to have expert teams that are able and capable to perform aggressive surgery. The goal is to reach R0 no residual visible disease at the end of surgery, but it always have to be balanced with the low incidence of side effects. That means that the patient has to recover fast after surgery to start chemo, because the treatment is made both by surgery and medical part.

Domenica Lorusso: [00:06:50] So I think the key point is that one dress does not fit for all. Now in surgery, but probably also in medical treatment. Elena, what about the medical decision making process now for ovarian cancer?

Elena Giudice: So when choosing a maintenance treatment strategy, not only based on the HRD status but also on the platinum responsiveness. I rely on, first, radiologist to confirm the patient response, then sergeants to define the right timing again of the surgery. And finally the pathologist to obtain the CRS information, which can be combined with another tool, a biochemical score called Kelim. And both of these scores can mathematically define the responsiveness of the platinum.

Domenica Lorusso: The treatment of ovarian cancer is becoming more and more complex. And this means that this patient that unfortunately has a relatively rare tumor should be treated in experienced center, high volume center where the best medical treatment, surgical treatment, clinical trial and new opportunities can be offered. And in terms of new opportunities and new technology. Fabio, how do you see the decision making evolving in the future, particularly when this new technology will be available? How this will integrate in our decision making process.

Fabio Martinelli: [00:08:29] We are in a period of varied changes, and we are lucky to be in a period where instruments like AI will help us. The main core, as I said, is that we have to select the right patient for the right sequence of treatment. Selecting the right patient means put together a radiologic evaluation, surgical complexity partner histological evaluation, performance status of the patient. There are a lot of hints that need to be considered when we analyze whether or not the patient is suitable for primary surgery or not. AI will probably help us in this. This is a fantastic tool that is growing a lot all over the world and will help and fasten the decision process that will have in future. So we will have better selection of patients to clearly define which patient will benefit more from a primary debulking surgery, reducing the risk of complication, and which patients will benefit more from having neoadjuvant chemotherapy followed by interval debulking surgery.

Domenica Lorusso: [00:09:42] Well, that’s very interesting, Fabio. And uh, yes, for sure. AI is a potent tool which is expected to improve surgical selection in the next future. But as you said, Elena, also the medical treatment landscape has dramatically evolved in the recent year and probably will evolve more and more in the future. Um, can you update us about the clinical research that I’m sure will continue to shape the future and to define better treatment strategies, particularly in the patient with the poor prognosis.

Elena Giudice: Sure. So in the past years, the most innovation has been focused on the platinum resistant setting. And now we are seeing clinical trials that finally started to deliver meaningful and practice changing results. But what we are seeing now is a clear shift of research toward earlier lines of treatments. The new treatment strategies are being developed for patients with platinum sensitive relapsed now, and spark resistant disease. And with the emergence of these new targets, we are starting to think beyond that traditional HRT versus HRP framework. And among the most promising future strategy, I would mention antibody drug conjugates that may represent an opportunity even to prolong the progression free and overall survival when used in the maintenance setting by delivering a more targeted approach, and they would become particularly relevant in our most important unmet need settings, which are the HRP population and the Parp resistant population.

Domenica Lorusso: So exciting information for the patient platinum resistant has always been an unmet clinical need, and now patients progressing after PARP and other emerging resistant population for which new treatments are urgently needed. So this is very, very interesting. And we are at the end of this very thoughtful conversation. Fabio Elena, thank you both for being with us on TJ Talks.

Fabio Martinelli: [00:12:04] It was a great pleasure for me to be here.

Domenica Lorusso: [00:12:07] Very pleasure. Prof. Thank you. Thank you so much. Both. What emerges for this discussion is that the progress in advanced ovarian cancer depends not only on new treatment, but on the better patient selection. The best treatment for each patient. Multidisciplinary discussion and continuous clinical research on the surgical side. The key point is improving selection of the patient and ameliorating their quality of life. On the medical side, the message is continuing to search for better biomarkers and targets and more personalised over time treatment approach. TJ Talks is available on TumoriJournal.org and on the main podcast platform. Follow us on X and LinkedIn to stay up to date on the latest developments in oncology research and clinical practice. I’m Domenica Lorusso, section editor at the Tumori Journal. Thank you so much for listening.

Dario Trapani: Cancer medicine has never been more innovative, and yet many oncologists are starting to ask a surprisingly uncomfortable question if innovation is accelerating, why are we still struggling to deliver meaningful benefit to so many patients? Because not every new therapy represents real progress. And this brings us to a deeper question for modern oncology. Not how fast we can innovate, but how we decide what innovation is truly worth adopting. This is the spirit behind the common sense oncology. The idea that cancer care should remain ambitious in science but disciplined in judgment. Welcome to TJ Talks Conversation and Oncology, the podcast by Tumori Journal. What we explore the ideas shaping modern cancer care. I am a medical oncologist at the European Institute of Oncology in Milan. Today. I’m delighted to be joined by an extraordinary doctor, Bishal Gyawali from the BG Lab, medical oncology, researcher, professor at Queen’s University in Canada, one of my dearest friends and one of the most thoughtful voices challenging how we evaluate benefit, value and evidence in oncology. Bishal thanks you for joining us. 

Bishal Gyawali: Thank you very much for having me, Dario. That’s a very kind introduction. I don’t think it’s all deserved, but thank you. 

Dario Trapani: Super deserved. My dear friend. I’m so happy we can do this together. 

Bishal Gyawali: Yeah. Like, uh, even before you joined. I was telling them that you are my best friend in oncology, so it’s always a pleasure to talk to you. 

Dario Trapani: So happy to hear this. 

Bishal Gyawali: Any excuse? I’m happy to talk to you, I know. Thanks for that. 

Dario Trapani: Bishal, let me start with the idea itself. The expression “common sense oncology” sounds almost remarkably simple, but behind it there is a rather profound critique on how modern oncology works, what does come common sense oncology actually mean to you? 

Bishal Gyawali: Yeah, that’s a great way to start. I mean, when we started the movement three years ago, as you know, one of the initial criticisms was that people took offense with the term common sense oncology. People were saying that. So anybody who is not aligned with your philosophy, you are saying that they are not common sense. But actually, it comes from a place of, you know, caring for patients in that if we go back to the origins of this movement, I and my colleague Chris both we published a paper in Nature Medicine a few months before we initially started this movement, and it’s called Cancer Treatment Should Benefit Patients. A common sense revolution in oncology. And the idea there was all we are asking for is that our drugs or our interventions should improve outcomes for our patients. Our patients should have longer lives and better lives as a result of receiving those interventions. And that feels like common sense to me. You know, if I’m treating someone, I should be confident to tell my patient that you need this treatment because if you get this treatment, you’re going to live a longer life and a better life, even if not both, at least one of them longer life or a better life. But the reality is most of our treatments don’t offer either of these benefits. 

Bishal Gyawali: So we said that our cancer treatment should benefit our patients, and we thought it was. It is common sense. But then there were some people who said that, you know, oh, your idea that our drugs should have evidence of benefiting patients. It’s a revolutionary thought. And we were like, no, it’s not a revolutionary thought. It’s common sense. Our treatments should benefit our patients. Our or patients should have longer and better lives. And that’s why we purposefully title that piece as cancer treatments should benefit patients or common sense revolution in oncology. But to answer your question, that is the fundamental spirit of common sense oncology. That is, our treatments should benefit patients. So behind that vision lies the philosophy that we need to develop drugs that show benefit to patients, and that should be tested in trials that are designed properly. This would be proper reporting of these results without bias, and the drug should improve these outcomes. And there should be effective communication. And that’s why we are focusing on evidence generation, how we generate high quality evidence, evidence interpretation, how we interpret those results correctly, and evidence communication, how we communicate these results correctly and without bias to our patients. So that, in a nutshell, is what we are working on in common sense oncology. 

Dario Trapani: And I can’t really eat more. You know this how this is important for patients and centered about patients care. But let me make just one step further and ask you to do approve more cancer drugs than ever before. But yet many of these drugs enter the clinical practice with improvements measured in weeks or even just a month often basis, you will get end points. So do you think oncologists become too comfortable with marginal benefits? 

Bishal Gyawali: Yeah, I think, you know there has been a continued downward slope towards what we are accepting as good treatment in cancer care. And that is something that does concern me sometimes because if you think about it, previously we needed two randomized trials demonstrating benefit in survival or quality of life clinical benefit to accept any intervention as a standard of care. So from there, we moved to, okay, one randomized trial is enough, but it has to be survival or quality of life. From that we move to okay, maybe even if we can’t. So survival and quality of life, if it’s a good enough surrogate, we should accept the results from that we move to, okay, if it’s a surrogate, you know, even if it does not correlate with survival or quality of life, even if it’s not a good surrogate, let’s approve these drugs upfront and give it a conditional approval, and then we’ll follow up survival later on. From that, we moved on to, okay, we can even give full approval with surrogate endpoints that are good enough from that to, okay, full approval based on surrogates that are not even good enough, that are not not even been tested. 

Bishal Gyawali: And we used to talk about how PFS has become the most important or the most common endpoint. Nowadays, it’s not even PFS. We are offering full approvals based on response rate alone. So yeah, there I think we are getting more and more comfortable with lower and lower quality of evidence. And there is always a always a tension in oncology between faster drug approval versus making sure that the drug is indeed benefiting patient. But I feel like nowadays we are only taking care of one part of the equation, as in getting drugs to patients as soon as possible. I’m not discounting the importance of that. It is important, but we are not taking care of the other end of that equation that is ensuring that these drugs are indeed meaningful. Yes, patients need access to cancer drugs soon, but they don’t need access to any cancer drugs. They don’t need access to harmful cancer drugs. They need access to cancer drugs that improve their outcomes as soon as possible. So we need to balance both ends of that equation. 

Dario Trapani: And this is I can’t really agree more. This is really the tension of the modern oncology and brings us to the difficult balance between hope and realism. In fact, as oncologists, we naturally want to offer hope to patients. But hope can sometimes be shaped by how evidence is presented that regulatory decisions or even buy. And this is so common commercial narratives about innovation. So as clinicians, how can we maintain honest communication with patients while navigating such a complex landscape? 

Bishal Gyawali: Yeah, that’s something that, uh, you know, I struggle with every day in the clinic, as in how to draw that balance between not depriving patients of hope, but also not feeding them with false hope and not buying into the hype all the time. You know, we have been to several conferences where new results are presented with so much fanfare, and everybody thinks that these are game changers. And, you know, we should start changing our practice from tomorrow only for you to, you know, wait for the publication and find that there are so many problems with the trials and the drug is not as good as everybody is making it out to be. But you’re absolutely right. You know, we need to draw that balance between not depriving patients of hope, which is important, but also making sure that it’s not a false hope. And I think communication skills plays a very important role here. Unfortunately, we don’t train the trainees a lot on how to, you know, on communication skills. We have some training on breaking bad news, but not enough. But breaking bad news alone is not the communication skill that we need in oncology. It’s also about breaking good news, not overselling the results. It’s also about drawing the line between, you know, being honest about the evidence and communicating that evidence well, but also making sure that you continue to care for the patient and the patient does not feel like, you know, they are being uncared for. So it’s a fine balance. But of course, we have to work on more effective communication. The other problem is, you know, in oncology, we have this issue with overtreatment. 

Bishal Gyawali: And we have plenty of data now showing that patients are being treated until the very end of their life, until the very last day of their life, and many patients are still getting treated until the very end. And one of the reasons for this is we we find as physicians, as oncologists, I think we are not very comfortable with discussing what is best for the patient and, uh, when treatment might tilt towards more harms than benefits. It’s far easier for us to say, you know what, okay, the disease has progressed, but there is one more treatment. Let’s try it. It’s very easy to say that. Let’s try one more drug, one more therapy. There are two more options. It’s very difficult to actually sit down with the patient and have an honest conversation about what is in patient’s best interest and and how to best solve the patient’s best interest. And this is something, you know, that the health systems should be honest and, and do an introspection about. Just to give you an example, I treat patients with metastatic colorectal cancers. For instance, I have a patient who is 88 years old. He lives alone. And, uh, you know, he has progressed on two lines of treatment. Folfox. Folfiri. And we are talking about third line treatment option for him. But if I sit down with him and have an honest conversation with him, what I realize is for him, the most important thing is because he lives alone is to have, you know, someone do groceries for him. He wanted some people who would buy groceries and deliver it to his house, or maybe clean his room or, you know, prepare him some food. 

Bishal Gyawali: And if we were to find a person who could help with all of this, probably the expenses for doing all of that would be in the range of, I don’t know. I’m just making it up. But let’s say 3000, $4,000 a month at most. But I cannot make that happen. I don’t have that resources. Our health system does not have the resources. I cannot make that happen. But this is what is going to improve his quality of life a lot. He’s going to feel a lot more happier. He does not care about leaving two months more, but he cares about having all of these things done for him in the last few months that he has. I cannot make any of this happen, but I can easily prescribe him third line treatment. I can do task 1 or 2 plus bevacizumab fruquintinib. I can easily prescribe this in two three clicks in the computer. That is going to cost my health system $10,000 a month, $15,000 a month, and we’ll probably give him toxicities. He might end up in emergency in ICU in the last few months of his life, but I can easily use ten $15,000 a month from our health system to make these drugs available for him. But I cannot use a fraction of that cost to actually do things that will improve his quality of life and happiness towards the end of life. So this is something that does not sound very common sense to me. 

Dario Trapani: This is such an important statement. I’m so impressed because we usually speak about, you know, innovation as new options, but in fact, you’re really giving a context of oncology that speaks to the people, their own values, and also is very conscious about the system where the healthcare happens. And in fact, your work often highlights something that we tend to forget in high income countries. Most patients with cancer live in health systems with limited resources, where most of the cancer burden is distributed worldwide. From that perspective, it’s common sense oncology not only about science, but also about fairness in global cancer care. 

Bishal Gyawali: Yeah, I think you know me very well that I have been advocating for what I call cancer grounds for a for a long, long time now. We you are right. In high income countries, especially, we focus on cancer, moonshot type interventions. These are, you know, how can we have a new molecule developed and how can we, you know, research more into the cancer biology and get a, get a new molecule, uh, immunotherapy, precision oncology, ADC, you know, whatever you want, which are all important. I’m not discounting the importance of this, but if you think about it, only those treatments are going to improve outcomes that are actually reaching patients. And most of our patients, as you said, are majority of our patients. Nowadays, they live in low and middle income countries in poor resource settings, and they don’t have access to forget about these newer ADCs or newer molecules. They don’t have access to classical cytotoxic chemotherapies. We have done this research, write about essential medicine list. Many people, they don’t have access to essential medicine list. It’s unaffordable or unavailable. And even, you know, going beyond drugs, many people in the world with cancer, they die because they don’t have access to proper surgery or radiation therapy. And even when they are dying, they die with pain and misery because they don’t have access to palliative care and pain medications. So if we are talking about how to improve cancer care globally, then our first step should be to implement these things that we already have proven to work. To implement these interventions that are not costly, that are cheap. But we have already shown that these are effective and helpful. 

Bishal Gyawali: And just to give a contrast, like if we’re talking about cervical cancer, it affects most, you know, it is most common in low and middle income countries. And our focus, the cancer moonshot focus is, oh, let’s, you know, dostarlimab or pembrolizumab. These are new immunotherapies for cervical cancer. This is a game changing intervention. But the fact is for an annual cost of dostarlimab for one patient, probably you could provide HPV vaccination to almost the whole city. And, you know, now we have also proven that even a single dose of HPV vaccine might be enough. So just to give an example about how there are so many interventions we could do to save thousands of lives at a fraction of the cost of all these fancy new treatments that we are super excited about. So if we are talking about global cancer equity, then it cannot happen just by producing new molecules. Global cancer equity can happen only once we are able to implement the interventions that we have already proven are important. We let’s talk about breast cancer. You know your field of expertise. We are talking about trastuzumab, deruxtecan and govitecan and all these newer molecules. When in fact, most patients in less than Nepal, my home country, they don’t even get trastuzumab. So, you know, it’s a paradox. Um, and um, absolutely. You’re right. We cannot, we cannot just, uh, make a new drug and hope that it will solve all these problems. We need to implement the things that we have already proven. We need cancer research in parallel to cancer moonshot. Without cancer grounds, we cannot just moonshot our way out of this. 

Dario Trapani: So you really speak about value, intrinsic value of treatments, but also how we can implement in a system perspective, powerful and impact oriented interventions. Because ultimately the question becomes, at this point, what kind of oncology do we want to build? If you could redesign the system from the clinical trials to the drug approval and reimbursement, what would need to change to make oncology more aligned with the true clinical value? 

Bishal Gyawali: Um, yeah. So how can we align oncology more with clinical? That’s a very difficult question to answer of course. And that’s why I made that. Uh, no, but I think we all have a responsibility, right? Um, if we’re thinking in terms of health systems, uh, health systems should be cognizant about what they should prioritize and how they prioritize. Because if we continue to reward low value innovations, innovations that don’t improve outcomes. Because if you think about it, it’s the whole ecosystem is seems to be broken. You have a drug that improves survival by a substantial number of months, and you have a cancer drug that just shrinks the tumor by a little amount and does not do anything to survival or quality of life. That second drug might cost more than the first drug, which sounds bizarre, but that’s how the the markets are. So there is a responsibility for health systems to properly prioritize what interventions are important and how best to use the limited resources. Even high income countries are now strained from cancer care expenditures. So they need to prioritize properly. As you know, organizations, international organizations, or oncology societies, we have responsibilities to think about these matters. And, you know, when we are producing guidelines, for example, the clinical practice guidelines should prioritize patient value, should prioritize what matters to patients, should be written by people without conflicts of interest and then at an individual level, as as physicians, we need to be cognizant about what is most important to our patients rather than just jumping on the bandwagon all the time and saying, oh, this is a game changer. 

Bishal Gyawali: This is this is new breakthrough. And as communicators, we also have the responsibility to communicate this evidence and correctly in an unbiased way to the patients and the public. We need to educate the patients in the public more about these issues. And when we are training the trainees, we need to train the trainees so that they also become cognizant of all these holistic issues that is affecting the patient outcomes and what matters to the patient. So at the end, it’s about alignment of priorities, alignment of interests, and putting patients at the center of everything like it is now. It’s going to sound cliché, but obviously it’s common sense that patients matter the most because it’s their lives are at stake. So if we always think about what matters to patients, and if we put patients at the center of all our decisions, then I think the system will easily be aligned with the with the patient values. 

Dario Trapani: And honestly, I agree with you. I love waiting on these. We live this kind of contemporary oncology in which on one side we have a commodification of health where marketing. We have market access. On the other side, we know the real true value of cancer medicines and also how to identify the most valuable. So the field is really the sector. You know, it’s split between this hype and of course critical appraisal. So let me ask you one final question. For young oncologists entering the field today surrounded by extraordinary technology and innovation, what does common sense in oncology really mean? 

Bishal Gyawali: Dario, you asked a very important question because when, uh, you know, we first started this movement or even now the philosophy behind why I, you know, started with this lab as well is to inspire the next generation to become a role model for the young trainees. And, uh, it’s very obvious that if you are a young trainee in oncology and, uh, you want to look for role models, you want to become like, like someone, then all you come across is, you know, the traditional definition of success. Or a successful oncologist would be someone who is giving the plenary talks, who is flying all over the world every day, funded by the industry, flying first class, going all over the world, giving CME lectures on how to treat this disease, and, uh, writing editorials in these top journals, I don’t know, having a conflict of interest paragraph that’s longer than a editorial. So these are the surrogate markers of success that trainees and young generation have been exposed to. So if someone is in the training program in oncology currently and they want to become the most successful oncologist, then they will look up to people who have all of these features. For them, the definition of success is, is all of these these features? So we wanted to tell the young generation that you can have a good career, an excellent career, without going through that route. You can be a good oncologist. You can be loved by your patients. You can be loved by your trainees. 

Bishal Gyawali: You can be an excellent educator, and you can also do high quality research, high quality research that gets published in the top journals. And also, you know, you can, your research can be impactful enough that you get invited to sit on the guidelines, that you get invited to give invited lectures at these big meetings, you can make a difference by doing good research and by becoming a good oncologist without necessarily needing to, you know, of course, the attraction is there. It’s always attractive and it always looks more lucrative and fancier. But you can pursue an honest path, an honest career without the need to sell your soul and you can still be considered successful. What matters is what you define as success. What are the surrogate markers of success you are chasing? And are those surrogates, uh, good surrogates? Uh, for success. For your happiness. And so our idea was to, you know, collect these role models, these important people in oncology that have achieved success by doing good research, quality research, and carved a path for themselves so that the young people can look up to them and feel like they can also be successful by pursuing this honest path. And you look at the people that you know are involved with CSO. Now, people like our idea is that the young generation will look up to people like you and all other members of CSO. And, you know, these are the people that I interview for my own podcast as well. 

Bishal Gyawali: And this is what I try to inspire through the busy lab fellowship programs as well, and virtual mentorships and so on. Is that. Yes. Look at us. Were. Look at all these people. We have been trying to do good work. We have been and we have been publishing in top journals, and we have been and giving lectures at important places. We are sitting on guidelines. So it is possible, it is possible to do honest work and still hit all those whatever arbitrary surrogate markers of success you think are important. In my opinion, they are not. They are just surrogate markers. What is important is to live a life that you can feel proud of, that you can be happy about and make a meaningful difference in patients lives and make a meaningful difference in patients lives and change lives. That’s all that matters. But yeah, that is one of the one of the reasons for us being being together in that we could inspire the next generation. And that is something that I take very seriously for my mentorship, inspiration, training. These are the pillars of success because these young people, tomorrow they are going to be in positions of power. They are going to be as Cosmo presidents. They are going to be in guideline committee chairs. They are the ones who are going to run this big phase three trials. They are going to be the plenary discussions. So if we can influence them positively, then they are going to make a difference. 

Dario Trapani: Oh my gosh, I love these podcasts. Crossover moments between your podcast and this one is so fun. 

Bishal Gyawali: Let me. 

Dario Trapani: So follow the podcast, but let me say. 

Bishal Gyawali: It in ground set, it’s called grounded in ground. 

Dario Trapani: Set. But let me say something. You know, you’ve researched before, you know, first and then now with the common sense psychology you are creating for the future of oncology, a space that’s conflict free in which you are giving a message that this is feasible. You can develop your own relevant research without any conflict. You can do this because this is happening. And I think the common sense oncology is really shaping the way for the future, for, as you say, for leadership position to develop key guidance, including the guidelines itself for the future of oncology is shaped in a conflict free zone. This is such an important message because we know this can happen. For many years we thought this was not the way. But now this is probably. We know this is probably the only way. Perhaps the real challenge for the contemporary oncology is now real innovation itself. It is learning on how to govern innovation with critical judgment, recognizing that not every new possibility represents meaningful progress. Science constantly expands what we can do. Medicine, however, must still decide what is worth doing. In that sense, the common sense. Oncology is not a rejection of innovation, but a call to restore proportion, clarity and responsibility. At the center of cancer care, a medicine that remains ambitious in discovery but disciplined in its application. My sincerest thanks to my friend and dear colleague, Doctor Gyawali for joining us today. Thanks really for being us. So inspirational. 

Bishal Gyawali: Thank you very much for having me. It’s a pleasure. And you know that I love Italy and the Italian audience, and I’m always looking for any excuse to be there to talk to you, to talk to my Italian colleagues and friends and trainees. After I came back from the AIOM course, I have received like six emails from the young trainees from Italy who attended that course. So Italy and, uh, you of course, but Italy as a whole has a very special place in my heart. So thank you for giving me this opportunity. 

Dario Trapani: TJ Talks is available on TumoriJournal.org and on the main podcast platforms. Follow us on X and LinkedIn to stay updated on the latest developments in oncology research and clinical practice. I’m David Trapani from the European Institute of Oncology, Milan. Thanks for listening. 

Dr. Dario Trapani: Negli ultimi vent’anni abbiamo imparato ad accelerare l’innovazione in oncologia, oggi dobbiamo imparare a governarla. Ecco, il cosiddetto Common Sense Oncology nasce da una domanda semplice: siamo sicuri che più trattamento significhi sempre migliore medicina? E cosa significa trasformare questo principio in politica clinica nel contesto italiano? Ne parliamo in questo episodio di TJ Talks Conversazioni sul oncologia a cura di Tumori Journal, la rivista oncologica peer review dedicata alla divulgazione di tematiche e innovazioni in ambito oncologico. Io sono Dario Trapani, medico della Divisione di sviluppo Nuovi farmaci per terapie innovative dello IEO di Milano e oggi incontro Massimo Di Maio, presidente AIOM e Franco Perrone, Presidente della Fondazione AIOM, Massimo e Franco. Grazie per essere qui con noi.

Prof. Massimo di Maio: Grazie a voi per l’invito.

Dr. Francesco Perrone: Grazie a te Dario, è un piacere.

Dr. Dario Trapani: Cominciamo subito con Massimo. Una domanda per te: le linee guida sono già Evidence based ed AIOM produce linee guida di elevatissima qualità che codificano lo standard nazionale per il trattamento del cancro. Perché serve il Common Sense Oncology? Cosa manca oggi nei nostri processi decisionali?

Prof. Massimo di Maio: Allora innanzitutto direi che AIOM si sforza tantissimo, come sai, come sapete, per produrre e per aggiornare le linee guida che sono uno strumento prezioso per l’oncologia e per la comunità oncologica in Italia. E le linee guida però diciamo possono essere ispirate al concetto anzi dovrebbero essere ispirata al concetto del Common Sense. Questo secondo me vale sia per chi le produce, sia per chi poi le legge per applicarle. Perché per chi le produce, vale a dire per tutti i panelist che sono chiamati a lavorare come estensori alle linee guida, chiaramente questo concetto, i concetti del Common Sense possono ispirare diciamo la valutazione delle evidenze e la produzione delle varie raccomandazioni. Ma soprattutto poi il Common Sense è bene che ci sia in chi le legge in chi le deve le deve applicare perché sostanzialmente il singolo paziente al quale poi si applica una raccomandazione è differente, unico se vogliamo, per età, per patologie concomitanti, per il performance status. Quindi l’applicazione di una raccomandazione teorica al singolo caso necessita Common Sense. E direi che forse è importante essere consci di questa necessità di differenziare, perché per esempio quando si producono raccomandazioni nelle linee guida AIOM queste differiscono per la loro forza, delle raccomandazioni. Alcune sono forti, altre sono condizionate, altre sono addirittura contro l’impiego di un certo trattamento. E anche le decisioni dei clinici devono essere differenziate, come dicevamo, a seconda delle caratteristiche dei singoli pazienti.

Dr. Dario Trapani: Quindi una riflessione che riguarda lo sviluppo delle linee guida che però si innesta all’interno di un approccio di sistema. E allora Massimo voglio rilanciare: le giornate dell’etica dell’AIOM del 2025 si sono concentrate sul fine vita. Possiamo oggi tradurre quella riflessione in strumenti operativi? Si può integrare nei documenti AIOM indicatori di proporzionalità terapeutica in modo esplicito, in modo da orientare non solo l’intensificazione delle cure, ma anche la loro appropriata modulazione lungo tutto il percorso clinico? Insomma, usando il Common Sense, usando un po’ di buon senso.

Prof. Massimo di Maio: Sì, grazie Dario, io penso che la scelta di dedicare le giornate dell’etica al tema del fine vita, che è stata fatta durante il mandato di Di Franco, sia stata una scelta molto importante, molto opportuna. Perché chiaramente, al di là dell’innovazione e al di là del progresso che siamo contenti di raccontare, chiaramente in Italia ancora oggi 180.000 persone circa ogni anno muoiono di un tumore, quindi l’argomento del fine vita e delle cure palliative e delle scelte del fine vita è purtroppo enormemente importante per l’oncologia e deve essere parte integrante, e questo riguarda l’attività di AIOM come produttore produttrice di eventi e di documenti educazionali, deve essere parte integrante della cultura e della formazione nonché della quotidianità di tanti nostri colleghi. E direi deve essere parte importante anche nella comunicazione: noi, per esempio, ogni anno come AIOM dedichiamo un appuntamento, un corso anche con i giornalisti perché anche, come dire, saper parlare e saper comunicare i temi dell’innovazione, del reale valore dei trattamenti sostanzialmente è una parte importante, anche per poter orientare in maniera serena le scelte relative al fine vita. Perché molte volte non è detto che in quel contesto, trattare di più voglia necessariamente dire fare il bene dei pazienti, molte volte invece le scelte migliori sono quelle orientate alla qualità di vita e al rapporto tra benefici e rischi proporzionato rispetto alla situazione clinica.

Dr. Dario Trapani: Grazie davvero, quindi in effetti una scelta tra quello che è il rischio e quello che è l’impatto tangibile che mi porta un pochino a pensare anche in logica di popolazione. E quindi vorrei chiedere a Franco, una domanda per te: dal punto di vista di popolazione qual è oggi il costo invisibile dell’Overtreatment? Ci sono i dati italiani che quantificano questo fenomeno?

Dr. Francesco Perrone: Ma questa è una domanda bella. Da un punto di vista di popolazione, secondo me, prima di tutto dovremmo ragionare sui dati della Overdiagnosis, che in realtà viene prima dell’Overtreatment, e noi sappiamo che, per esempio, sono noti dati in tutto il mondo e anche in Italia sul fatto che la sovradiagnosi, la diagnosi eccessiva, porta poi ad un sovratrattamento. Il caso classico e tipico è quello dei tumori della tiroide, diagnosticati in una percentuale molto elevata di casi dei micro tumori che non avrebbero mai dato segno di sé e che portano poi invece a una serie di interventi chirurgici inutili. Diverso è il peso, che è invisibile solo perché non misuriamo bene, e il carico dell’Overtreatment per quello che riguarda noi oncologi medici. Io in Italia ricordo dei dati prodotti una decina d’anni fa in Emilia Romagna, che con un’analisi che partiva dai dati amministrativi, dimostravano come intorno al 9% dei pazienti che morivano di cancro avesse ricevuto un trattamento nelle ultime due settimane, un trattamento specifico contro il cancro, e circa il 18%, poco meno del 20%, nell’ultimo mese di vita. È chiaro che un trattamento nell’ultimo mese di vita vuol dire che qualcosa non ha funzionato nella nostra stima. Può accadere, ovviamente, ma dovrebbe accadere meno spesso e in questo momento, devo dire dati recenti io non ne conosco. Vorrei dire che c’è bisogno di fare ricerca su questo, anche perché i dati di una decina d’anni fa erano riferiti alla chemioterapia, ma negli ultimi anni, con la presenza di nuovi farmaci, anche meno tossici ma molto più costosi, corriamo il rischio, a mio modo di vedere, che questo uso possa ancora una volta essere un po troppo alto e dovremmo lavorarci sopra.

Dr. Dario Trapani: Ed in effetti Franco, se capisco bene, mi sembra che il grosso del focus si sia spostato su dimostrare differenze di beneficio statisticamente significative su quello che un valore cosiddetto Patient Centric, un valore terapeutico. Ed è per questo che ti chiedo se, secondo te, il Common Sense o comunque l’approccio di Common Sense può diventare un criterio decisionale tipo per Health Technology Assessment, l’HTA. Cioè, oltre alle metriche di efficacia che generalmente utilizziamo, ha senso definire priorità regolatorie fondate sul valore intrinseco dei farmaci, quello effettivo, quello centrato sui valori e le priorità dei pazienti, ossia in ottica Patient Centric?

Dr. Francesco Perrone: Dario, questo avrebbe senso sempre. È una affermazione di tale buon senso dire che ci vorrebbe buon senso anche nella approvazione dei farmaci. Oggi l’HTA è considerato come un tema di grande interesse perché, con le nuove regole europee, dovrebbe entrare, ed entrerà prima o poi sicuramente in maniera importante, nella valutazione del valore dei nuovi farmaci. Non c’è dubbio che questo sia un campo nel quale bisogna fare un passaggio culturale importante, da una filosofia che nasce farmaco centrica, e questo ha delle giustificazioni e se vogliamo ha anche prodotto dei risultati importanti perché grazie alla filosofia farmaco centrica noi abbiamo oggi un progresso nelle modalità di costruzione dei nuovi farmaci che non vogliamo assolutamente ignorare. Si tratta di un valore, ma dobbiamo sempre di più imparare, anche per garantire la sostenibilità, a leggere i farmaci come strumenti introdotti in un contesto che è quello che tu hai definito giustamente paziente eccentrico e che è un contesto che inevitabilmente si basa sul buon senso e si basa su quello che conviene al paziente, al di là della bellezza del nuovo strumento farmacologico. Quindi sì, bisogna inserire Common Sense, bisogna inserirlo nell’HTA, bisogna che l’HTA informi sempre di più il processo che mette a disposizione i nuovi farmaci.

Dr. Dario Trapani: Ed in effetti Franco, ed è importantissimo, questo è uno statement che potrebbe e dovrebbe avere uno sviluppo anche di tipo programmatico. Ed oggi abbiamo l’occasione, e anche il beneficio, di avere qui con noi il Presidente di AIOM e il Presidente della Fondazione, perché una domanda per entrambi. E Massimo inizio con te: quali azioni concrete AIOM, e Franco Fondazione AIOM, stanno già mettendo in campo o intendono avviare per rendere operativo il paradigma del Common Sense Oncology nel contesto italiano?

Prof. Massimo di Maio: Inizio io, grazie Dario. Direi innanzitutto alcune iniziative concrete, per esempio l’aver immaginato un working group in questo biennio di AIOM dedicato proprio al Common Sense, e per esempio poi anche in occasione di eventi educazionali, tra qualche settimana avremo il 4º corso di AIOM con ASCO sulla metodologia della ricerca in un contesto internazionale, direi e anche in quell’occasione promuoveremo alcuni concetti che sono appunto alla base del Common Sense. Direi AIOM concretamente penso debba impegnarsi anche nel rapporto con le istituzioni a declinare questa filosofia, perché se chiediamo con forza che alcuni trattamenti siano tempestivamente disponibili per i pazienti italiani quando rappresentano, a nostro modo di vedere un vero valore aggiunto rispetto agli standard, chiaramente questa enfasi e questa tempestività può essere chiaramente declinata nella sua urgenza a seconda del valore che quei trattamenti hanno dimostrato. E infine direi che AIOM anche come dicevo negli eventi educazionali, ve ne ho citato uno prima, debba sostanzialmente promuovere questa riflessione critica diciamo sul valore dei trattamenti ai quali poi devono ispirarsi le scelte nella pratica quotidiana. E infine noi tutti oncologi sempre più spesso siamo come dire, anche dei comunicatori, usiamo spesso i social e i media e sostanzialmente quindi è importante, AIOM lo ricorda spesso quanto sia importante essere equilibrati nei messaggi che diffondiamo commentando i risultati degli studi clinici ottenuti a congresso oppure presentati sui lavori scientifici. Perché la comunicazione è molto importante da questo punto di vista per trasmettere equilibrio e buon senso.

Dr. Francesco Perrone: Mi sa che tocca continuare a me e rispondere alla tua domanda. Noi con Fondazione siamo convinti che rispetto a cose che non necessariamente funzionano nel migliore dei modi, piuttosto che negare bisogna offrire soluzioni positive, soluzioni ragionevoli. Per fare questo stiamo programmando, a breve spero potremo anche partire, una serie di webinar che sono rivolti ai pazienti e ai caregiver e che coinvolgeranno anche i giovani oncologi. Quelli sono un luogo nel quale è possibile introdurre dei temi che riportano al centro il paziente, che spostano la filosofia da farmaco centrica a paziente centrica. E un po’ anche per fare una battuta sul senso del Common Sense, abbiamo anche incominciato a interrogarci su come provare a essere efficaci in qualche modo rispetto al nonsense. Il nonsense è quello di alcune cosiddette terapie che i pazienti assumono senza che noi oncologi ne sappiamo niente, e che in qualche caso possono creare dei problemi e che sicuramente procurano un sacco di incertezza sia tra i pazienti, i caregiver e mediamente anche agli oncologi possono creare dei problemi. Ecco quali sono le “Nonsense Therapies” per le quali stiamo ragionando e cercando di identificare una strategia per contrastarne l’uso, quando questo non sia realmente giustificato e non sia realmente gestito dagli oncologi. Questo è quello che proveremo a fare.

Dr. Dario Trapani: Quindi impatto comunicazione come ci diceva Massimo, ma anche Common Sense e Nonsense come ci racconta futuristicamente Franco. Ed in effetti mi sembra di capire che le grandi società AIOM e la Fondazione AIOM in effetti abbracciano il paradigma con dedizione ma anche con una programmaticità. Ci tengo a precisare che il Common Sense Oncology non è minimalismo terapeutico ed abbraccia l’innovazione come espressione di impatto. Nasce per delineare una precisione sistemica con una visione interamente costruita e centrata intorno ai bisogni del paziente. L’oncologia italiana ha una maturità scientifica per guidare questa transizione. La domanda oggi è se vogliamo assumerci la responsabilità di farlo, se siamo pronti a una trasformazione del paradigma oncologico. Ancora grazie a Massimo Di Maio, presidente AIOM e Franco Perrone, presidente della Fondazione AIOM, per aver accettato il nostro invito e soprattutto contribuito a portare il Common Sense Oncology dal piano del dibattito a quello dell’azione.

Prof. Massimo di Maio: Grazie a te Dario.

Dr. Francesco Perrone: Grazie a te Dario, è stato un piacere. Ancora una volta lo sottolineo.

Dr. Dario Trapani: Tj Talks è disponibile sul nostro sito web Tumorijournal.org e sulle migliori piattaforme di podcast. Seguiteci su X e su LinkedIn per essere sempre aggiornati sulla ricerca, sul cancro, sulla pratica clinica in oncologia. Sono Dario Trapani, medico della Divisione di sviluppo Nuovi farmaci per terapie innovative dello IEO di Milano. Grazie per averci seguito.

Giuseppe Procopio: Welcome to TJ Talks – Conversations about Oncology by Tumori Journal, the peer-reviewed oncology journal dedicated to the dissemination of key oncological themes and advancements. I’m Giuseppe Procopio, Director of the Prostate Program and Head of the Departmental Genitourinary Medical Oncology Unit at IRCCS Istituto Nazionale dei Tumori in Milan, and in this episode I’m happy to meet Doctor Silke Gillessen, Medical and Scientific Director of the Oncology Institute of Southern Switzerland and Full Professor at USI, The University of Italian Switzerland. Silke, thank you for being with us. 

Silke Gillessen: I’m very happy to be here with you. 

Giuseppe Procopio: So, let’s start with your story, to introduce you to our listeners. 

Silke Gillessen: I am a medical oncologist from Switzerland. I have worked mostly in Switzerland, sometimes in the United States, sometimes in England, which was a very nice experience. I am now the Director of the IOSI, the University of Italian Switzerland, as you have said. I am very, very interested in prostate oncology and GU cancer in general. 

Giuseppe Procopio: I would add one more piece of information. She is a very nice person and a scientist, involved in research programs in prostate cancer, particularly in other genitourinary areas. I would like to ask something about research and advances in the screening of prostate disease. How do you consider PSA screening in the general population? Could this be an opportunity or could it be a problem for the management of the general population? 

Silke Gillessen: As you know, in Europe we have not decided to do a mass screening of men for prostate cancer. We can discuss that for hours. In reality, what is written in the EU guidelines makes a lot of sense. Well-informed men, between fifty and fifty-five years of age, should at least consider to do a screening. A lot of men are a bit afraid of the digital rectal examination, which of course is understandable, and there is a lot of discussion about this. Some guidelines are now starting to question whether you really have to do it. At least the PSA test should be done if you are informed by your doctor about the possible consequences. For example, for my husband, I would tell them to do it, and it is already done in many cases. 

Giuseppe Procopio: PSA screening could help, but it is not for everything, not for all patients, not for the whole population. It may help, but it is important to inform the general population about its role and meaning. This could probably be an opportunity. What are the most relevant challenges in the management of the prostate cancer population? 

Silke Gillessen: I think we have made a lot of progress in the last times. As you know, we now understand how to give combinations in patients with metastatic disease, and we have achieved significant prolongation of overall survival, which is a very good result. Not only that, but for many patients the quality of life is very important, and this is also improving the quality of life. This has been a really big step. Now we are working a lot on treatment intensification, but there are probably some patients with a good prognosis and good response to therapy where we should think about de-escalation of treatment as well. I have together with colleagues from Belgium initiated trials in patients with very good responses to treatment, trying treatment breaks to give patients some time off treatment and off the side effects. We know we tend to intensify treatment a lot, and this is the correct thing for some patients, but we also have to think about patients who could benefit from de-intensification. We need trials for this, and I hope everyone will help to achieve this. 

Giuseppe Procopio: The selection of patients will be crucial to define when to intensify and when to reduce treatment exposure, balancing safety and efficacy. What is your vision regarding clinical trials? How can we better define clinical trials, considering the frequent issues related to the choice of the best endpoint and the control arm? The scenario is rapidly evolving. It is not easy to balance the right treatment strategy with the right control and the right endpoint for patients. 

Silke Gillessen: Yes, absolutely. It has become quite difficult to design trials now because many effective treatments may never exist. Regarding endpoints, personally, in metastatic prostate cancer—and this is because most of my trials are in prostate oncology—I think overall survival is, for me, the gold endpoint. Again, speaking about metastatic prostate cancer, at the moment. If you have a benefit in the PSA, it is also important to have another endpoint. These should include improvements related to quality of life for patients, such as time to progression and time to symptomatic events. I think we have to have a mix between quality of life, which is very important, and oncological outcomes. We also have representatives of patients who remind us that we should think not only about illness, but about patient wellness and well-being. That is very important, and we have to take quality-of-life measures into consideration. 

Giuseppe Procopio: Thank you very much for this very, very important point. Survival is, of course, important, but your consideration about the role of quality of life is crucial. Patients ask us to improve their quality of life, and we have to pay attention to this aspect. So, thank you very much for being with us and for discussing these topics. 

Silke Gillessen: Thank you. 

Giuseppe Procopio: TJ talks is available on our website tumorijournal.org and on the best podcast platforms. Follow us on X and LinkedIn to always be updated on cancer research and clinical practice in oncology. I’m Giuseppe Procopio, Medical Oncologist and Section Editor for Tumori Journal. Thank you for listening! 

Gabriele Zoppoli: Welcome to TJ Talks – Conversations about Oncology by Tumori Journal, the peer-reviewed oncology journal dedicated to the dissemination of key oncological themes and advancements. I’m Gabriele Zoppoli, Associate Professor of Medicine at University of Genoa and Internal Medicine Consultant at Policlinico San Martino, always in Genoa. And in this episode I’m happy to meet Erman Akkus, MD at Ankara University, Faculty of Medicine, Department of Medical Oncology. Erman, thank you for being with us today. 

Erman Akkus: Thanks for having me. I’m happy to join the podcast. 

Gabriele Zoppoli: It’s very good to have this conversation with you about a topic you’re super expert of, which is basically endpoints in clinical trials and biomarkers. I saw your career and it’s dedicated to clinical trials, studies biomarker efficacy activity of oncology drugs. So, my question for you just to begin: what is a clinical trial endpoint? If you had to explain it to somebody who’s not an expert? And why is a clinical trial endpoint central for cancer research? 

Erman Akkus: Let’s start with a simple explanation. In oncology we generally want to know whether a new drug or new treatment strategy is better than the other, than the standard of care. So, to assess this the most reliable and common way is randomized controlled trials. But also single arm trials are also possible. To assess these treatments and compare them, we measure a specific outcome, such as how long patients live without disease progression. So this specific outcome is the “clinical trial endpoint” indeed. These clinical trials are very central because they are the objective parameters of benefit superiority or inferiority. And they are used for drug approvals. And on top of this, these endpoints are what we want to achieve for our patients. 

Gabriele Zoppoli: I see. Practically you mean that these endpoints act as a measure of how effective a new treatment or a new biomarker is. What is exactly the difference between a primary clinical endpoint and what we read as a surrogate endpoint? 

Erman Akkus: The primary endpoints are the endpoints that are inherently highly matters to patients. Oncologists and patients want to achieve a longer life or better life. These are overall survival and quality of life. We call them “primary clinical endpoints”. But, on the other hand, surrogate endpoints are the earlier or indirect measure of these primary endpoints, such as progression free survival, response rate, and so on. So, the aim with the surrogate endpoints are to facilitate trials and drug approvals, but we should say that surrogate endpoints and surrogacy are still an active research area and debate in oncology. 

Gabriele Zoppoli: Yes, because indeed you say “surrogate” seems like a bad word, if you don’t know about it. Why are these concept of surrogate endpoints accepted by the scientific community? How do you accept them rather than others? 

Erman Akkus: Because the surrogate endpoints can facilitate the trials and make us able to access drugs earlier, in fact progression free survival may predict overall survival, and so we can use progression free survival earlier as an overall indicator, and we can access the drug. But the surrogate endpoints should be validated before implementation. 

Gabriele Zoppoli: I understand. To make an easy example, it would be like: using cholesterol as a measure rather than having a stroke, for giving a new heart, as preventive medicine. That’s the concept of surrogate, if I understand it correctly. Do researchers have issues or difficulty when they choose a surrogate or any really trial endpoints? Which ones are they when they choose one versus or another endpoints? For example, disease free survival versus overall survival? how do you choose them? 

Erman Akkus: Related to the previous question, the primary endpoints such as overall survival need long follow-up, large sample sizes, and significant financial resources. So, surrogate endpoints, for example, may overcome these issues. But as I said, they should be validated before implementation. Another point, another difficulty, is that in the last two decades we have had a lot of new drugs in oncology. These drugs have different mechanisms of action and different effects on the tumor. So, the value of an endpoint depends on the tumor type, tumor biology, and disease stage, such as adjuvant, neoadjuvant, or metastatic settings, and also on the drug we use, such as immunotherapy, tyrosine kinase inhibitors, or chemotherapy. On the other hand, if you sequence these different treatments, the effect on overall survival may disappear within a trial. So, multiple factors should be considered when choosing the endpoint. And lastly, different health authorities in different countries may approach endpoints differently, such as in the United States or in Europe. So, this should also be considered. 

Gabriele Zoppoli: I see. So indeed, this also seems to me to depend very much on practical, real-world considerations, right? “Real-world” is actually a term that has become widely used over the last few years. So, how do these trial-conceptual endpoints really influence daily practice, patient care, or even access to novel therapies? You mentioned that the governing agency has a big role in deciding whether an endpoint has a real-world impact or not. Can you share an example — a story — of how the choice of an endpoint can really change how a treatment is delivered or approved for patient use? 

Erman Akkus: Yes, sure. So, health authorities assess clinical endpoints to approve a drug. In most countries in the world, this approval is necessary to prescribe a drug to a patient. But besides these regulatory issues, physicians — practicing oncologists — assess the magnitude of benefit using these endpoints. So, endpoints are directly related to clinical practice and treatment choice. However, we should emphasize that clinical trials provide summary results based on a patient population and sample size. In practice, though, we care for individual patients. This means that not every patient will benefit in the same way as in the clinical trial — some patients may benefit more, while others may have worse outcomes. Therefore, we should translate and adapt trial results to the individual patient in a personalized approach. Lastly, the value of an endpoint can change over time. For example, an approval based on progression-free survival or response rate may be withdrawn if longer follow-up shows no benefit in overall survival. Conversely, some immunotherapies have not shown any benefit in progression-free survival or response rate, but with longer follow-up, an overall survival benefit becomes evident. So, in practice, it’s dynamic and patient-specific — not theoretical. We must assess multiple factors to choose the best treatment for each patient. 

Gabriele Zoppoli: I see. So, I think that patients advocacy groups and the patient’s perception is really important in this regard, even to influence how this technical, theoretical, endpoints translate to real world practice. 

Erman Akkus: Yes, definitely. For example, in some countries in rare cancers, such as cholangiocarcinoma, the drugs are not approved by the regulatory authorities, but these patient advocacy groups make contact with the health authority and they present the unmet need, and then they provide the drug for the patients by convincing the health authorities for approval. 

Gabriele Zoppoli: Nice. This is absolutely relevant, and it highlights the role of people in influencing healthcare decisions. Is very important because I think minorities need to have voices, so that they can get to the right kind of treatment, for the right people. Otherwise, at the end of the day, what you’re doing is personalized medicine. Listen, I’ve got a question for you. Trying to look ahead — because, as you said, drugs evolve very quickly, and endpoints themselves, in a way, change and adapt to society, to reality, and to the needs and possibilities of communities — what should we expect in the future of practical oncology and in the translation of oncology theory into practice? What can be done to improve access to drugs, for example, which is often perceived as a slow process by many people? 

Erman Akkus: Yes. So, as you said, oncology is rapidly evolving. There are numerous trials currently ongoing with different kinds of drugs. So, probably in the future, we will see many more drugs — immunotherapies, antibody-drug conjugates, and so on. These will improve the portfolio of available treatments. But as you said, this will also cause some problems in terms of the availability and accessibility of these drugs. Another point is that, in the future, quality of life — another primary endpoint — is becoming a core component of clinical trials. We will see much more quality-of-life data in future, and future trials will probably also work on validating surrogate endpoints and biomarkers. For example, circulating tumor DNA (ctDNA), which is a very promising tool, could become a future clinical trial endpoint or surrogate marker for practicing oncologists. I think biostatistics and clinical research education in medical school and oncology training are very important, because it’s essential to understand clinical research results, to critically assess them, and to translate them into practice. This should be improved globally, because oncology today is based on clinical trials. Collaborative efforts are also needed to provide access to new drugs in low- and middle-income countries, since this is a major issue with technological and drug development. If we cannot give these drugs to patients, it doesn’t really mean we’ve made progress. But I think that with future developments, we will have more questions than answers. Still, looking at survival data over the decades, it’s clear that we’re moving forward in a good direction. So, let’s keep working together. 

Gabriele Zoppoli: Yes, let’s keep working together. Absolutely. I think this is a very relevant message. The concept of quality versus quantity is starting to be taken as a given here in Europe — you know, in the Western world, where we’re used to having access to healthcare. But, as you said, quantity is still very relevant for developing countries. So, this is a matter of the utmost social importance. So, Erman, thank you for this talk. It was really a pleasure having you here on TJ Talks. Thank you so much. 

Erman Akkus: Thank you so much. It was a great pleasure for me too. 

Gabriele Zoppoli: TJ talks is available on our website tumorijournal.org and on the best podcast platforms. Follow us on X and LinkedIn to always be updated on cancer research and clinical practice in oncology. I’m Gabriele Zoppoli, Associate Professor of Medicine at University of Genoa and Internal Medicine Consultant at Policlinico San Martino in Genoa. Thanks for listening!  

Antonino Musolino: Welcome to TJ Talks – Conversations about Oncology by Tumori Journal, the peer-reviewed oncology journal dedicated to the dissemination of key oncological themes and advancements. I’m Antonino Musolino, associate professor of Medical Oncology at the University of Bologna and director of the Medical Oncology Unit at the IRCCS-Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”, Meldola, Forlì-Cesena. And in this episode, I’m very happy to meet Professor Andrea De Censi, an international well renowned Italian medical oncologist, known for his great work in the prevention and treatment of tumors, particularly breast cancers and prostate cancers. He served as the director of the Division of Cancer Prevention and Genetics at the European Institute of Oncology in Milan, has been the director of the medical oncology unit at the E.O. Ospedale Galliera in Genoa, and since 2014 he has been an honorary professor at Queen Mary University of London within the Wolfson Institute of Preventive Medicine. He has recently been appointed as a director of the Breast Unit at the Champalimaud Foundation in Lisbon, Portugal. Andrea, thank you very much for being with us today.

Andrea De Censi: Thank you for inviting me, Nino. It’s a real pleasure to talk about prevention.

Antonino Musolino: So, first let’s contextualize our conversation. breast cancer pharmaco-prevention is an evidence-based strategy that uses medications to lower the risk of disease in women at increased risk. However, the use of this strategy remains modest due to toxicity concerns, limited awareness, and challenges in patient selection. In this podcast, together with Andrea, we will review where the field stands, which practical solutions can close the gap between pharmaco-prevention, indication and adoption, and we will end with a look at the future perspectives in this setting. Andrea, let’s start from here. Where are we today with breast cancer pharmaco-prevention?

Andrea De Censi: Thank you, Nino. Pharmaco-prevention or preventive-therapy or chemo-prevention, there are several names to define the use of drugs before the onset of the cancer. Breast cancer, in this case, there were nine phase three placebo controlled randomized trials in the 90s showing that serms, particularly tamoxifen and aromatase inhibitors, exemestane or anastrozole, can reduce breast cancer incidence by 40% to 50%. So, there is a strong evidence. However, there were some concerns about the side effects. And another important reason is that all these drugs are generic. So, there was no commercial interest behind. So, there are a number of challenges that we will discuss, but there’s no doubt that this strategy is very effective because it can halve the incidence of a potentially deadly disease.

Antonino Musolino: That’s very interesting. So just to summarize, as you said, the evidence in favor of pharmaco-prevention is somewhat strong. However, uptake and adherence remain limited. Andrea, how often are these drugs used and why do patients and clinicians hesitate?

Andrea De Censi: So, I think we must distinguish between USA and Europe. The uptake in the USA is higher because they have more high risk clinics dealing with patients at increased risk. And according to some data from the Memorial Sloan Kettering or Dana-Farber, the uptake there is about 30% to 40%, but on average, including Europe and other continents, we can say up to 10-15% show to take drug for prevention. The key barriers are the fear of side effects, most importantly menopausal symptoms, which affect quality of life, risk of thromboembolism or uterine cancer for tamoxifen, a risk of bone fracture, and joint pain for aromatase inhibitors. It’s true that it’s not clear who is the doctor who should deal with this, because medical oncologists have no time to dedicate to prevention, and prevention doesn’t feel urgent, unlike treatment, and this is an issue which has been overcome in the cardiovascular medicine with the use of statins or antihypertensive drugs, because they have intermediate biomarkers like, you know, LDL cholesterol and the sphygmomanometer. We we need LDL cholesterol and sphygmomanometer in medical oncology.

Antonino Musolino: Yes, I agree with you. So there are a lot of challenges, and it’s very interesting the difference between what we do in oncology and what our cardiology colleagues do in prevention. So, if those are the biggest challenges, what are the most credible solutions in your opinion?

Andrea De Censi: I think continuing to study biomarkers. There is some data for instance, from our BabyTam study that insulin, like growth factor binding protein three, is a predictive biomarker of efficacy of BabyTam, and Cuzick and colleagues in the Ibis two study have shown that ultrasensitive estradiol over sex hormone binding globulin is a surrogate biomarker for the efficacy of anastrozole. So there is some hope that we can give a look at six months or twelve months. And also mammographic density is very interesting. So if we have these biomarkers to say the drug is working well, you can continue, otherwise you stop. That’s the most important solution. And then we need to grow new clinicians which believe that prevention is important.

Antonino Musolino: Yeah. So we need clinicians interested in pharmaco-prevention.

Andrea De Censi: Exactly.

Antonino Musolino: Andrea, let me say you have offered one of the most important solutions, till date, to overcome the challenges of pharmaco-prevention. And this solution we know that is called BabyTam. What is it?

Andrea De Censi: BabyTam is mutuated from baby-aspirin to speaking about a lowering of the dose because the optimal dose in medical oncology is a very important issue. And recently, the Food and Drug Administration had announced that the majority of the cancer drugs are registered at the dose, which cannot be beard by patients giving a lot of financial and clinical toxicity. So, we reason many years ago that 20mg per day was the dose given in the treatment set, but there were no evidence of the minimal effectives. So, we did a study in the window of opportunity space between the biopsy and the surgery of the breast cancer, and show that lowering the dose to 5mg, and even 1mg per day, was equally effective in decreasing breast cancer proliferation. So we did the phase three trial, which is time zero one, showing a 50% reduction of recurrence of non-invasive disease. Actually, the recurrences were mostly invasive, but we started with patients with DCIs or high risk lesions, and we show no evidence of toxicity. And that actually changed the landscape and the uptake has increased dramatically in the United States with this study, but we are also exploring the minimal effective dose of exemestane. So, there is a number of studies now underway to address this important concept of the minimal effective dose or the optimal dose.

Antonino Musolino: Yes. So, I think that the BabyTam saga was a great story for oncology. Thank you very much, Andrea, for your inspiring and illuminating work. As you said, starting from this point, what’s coming next? Do we have new drugs and or new concepts for pharmaco-prevention?

Andrea De Censi: Yes, we have certainly PARP inhibitors for women who carry high risk mutations, but there is a lot of concern about the toxicity of these drugs in healthy individuals. So again, I think the minimal effective dose of PARP inhibitors has not been well established. There is the idea of immunoprevention or vaccines, for instance in patients with Lynch syndrome there is an active area of clinical research on the vaccine. And we also are interested in the metabolic risk of women using intermittent fasting and metformin, so we have a trial underway which will be released in terms of data very shortly. But the most important avenue for me is the adjuvant setting of women with minimal risk. With the introduction of screening, a huge proportion of women with breast cancer have a low risk, breast cancer below two centimetres ER positive low Ki 67. These women may benefit from a lower dose of endocrine agents. There is a trial underway in the United States supported by the NIH. I hope we can do a European study in that setting comparing BabyTam with BabyExemestane.

Antonino Musolino: This is very interesting and very important. Andrea, another important thing: we know that weight control and exercise are very important in breast cancer risk. Can lifestyle change and pharmaco-prevention be combined meaningfully?

Andrea De Censi: I think yes, definitely. Not only those two modalities but also screening. I think the ideal setting is the screening program, which is a teaching moment for the woman, where you can add, of course, lifestyle changes, which is very important. There were these groundbreaking data in colorectal cancer which were presented at Asco, showing a 40% reduction of mortality. So, we are absolutely enthusiastic of this approach. Weight control, exercise, reduction of alcohol and screening to have an early diagnosis and prevention with medications to address residual risk in women with moderate to high risk. So, I think they are complementary and possibly synergistic.

Antonino Musolino: Andrea, thank you very much! We are finished, but the story of prevention is going in the future and we think that your contribution in the field has been and will be important for Europe and Italy. Thank you so much! It was really a pleasure having you on TJ talks.

Andrea De Censi: Thank you very much, Nino, for hosting this topic and it was a real pleasure to chat with you today.

Antonino Musolino: TJ talks is available on our website tumorijournal.org and on the best podcast platforms. Follow us on X and LinkedIn to always be updated on cancer research and clinical practice in oncology. I’m Antonino Musolino, Associate Professor of Medical Oncology at the University of Bologna and Director of the Medical Oncology Unit at the IRCCS Istituto Romagnolo per lo studio dei Tumori “Dino Amadori”, Meldola, Forlì-Cesena: thanks for listening.

Luca Zambelli: Welcome to TJ Talks – Conversations about Oncology by Tumori Journal, the peer-reviewed oncology journal dedicated to the dissemination of key oncological themes and advancements. I am Dr. Luca Zambelli from the Palliative Care Unit of the IRCCS National Cancer Institute Foundation in Milan, and in this episode, I am joined by Dr. Sergio Defendi, Director of the Complex Structure of Palliative Care and ADI of ASST di Crema. Sergio, thank you for being here with us today 

Sergio Defendi: Thank you, Luca, for the invitation! 

Luca Zambelli: Today we are going to talk about a topic that is not yet very evident in oncology, namely the growing number of migrant patients who are diagnosed with cancer in a foreign country, such as Italy. These patients often come to Italy for work or family reasons, and more rarely—but it does happen—for medical reasons. When they are here, they are clearly taken care of by the National Health System for the treatment of their disease. When cancer treatments begin to falter, palliative care clearly becomes the primary option. In these cases, patients often express a desire to return to their country of origin to receive end-of-life care and be able to die at home. But currently, there are no guidelines or treatment pathways that allow us to manage these patients adequately. Sergio, we have discussed this issue on several occasions in the past and have also written a case report published in Tumori Journal, in which we analyze the case of one of your patients. But when was the first time you had to deal with this problem? 

Sergio Defendi: Well, the first time I dealt with this issue was about twenty years ago. It was the beginning of my first experience in palliative care, with an Eritrean patient. I was standing in front of the elevator with her, saying goodbye because I was leaving. We had already agreed with her family to continue her care in Italy rather than in Eritrea, because the difficulties there were such that home or hospital care was out of the question. In front of the elevator, she looked at me and said, “Gio, I’m going to die.” I replied, “Yes,” and there was a moment of silence between us. Then she replied, “I’m not afraid to die. I’m afraid of bad and dishonest people. Now take me to the bank so I can withdraw my money.” It was 12:00 p.m. on a Friday. We went to the bank and withdrew the money. On Monday, her husband went to the consulate for visas, and we bought the plane tickets. Apart from the airline, which authorized the transport of this patient, who was terminally ill and in a very advanced stage, a nurse volunteered to accompany her, and the departure was scheduled for the following Wednesday. On Wednesday, she was dressed elegantly, in a suit, a hat, and a handbag where she had her money, and we left, accompanying her by ambulance to Malpensa Airport. During the trip, she woke up from time to time. Her concern was the handbag she had with her, not her stomach. When we arrived in Eritrea, the first thing she did was to give this bag to her younger sister. The next day she passed away. This was what she wanted to do. 

Luca Zambelli: Well, you allowed this patient to fulfill her last wish. I must say that it was truly incredible. I remember you telling me that the patient was extremely advanced; she had this elastomer full of drugs—morphine, cortisone—because she was clearly in pain and developing liver failure. But what do you think are the main difficulties encountered in these cases? 

Sergio Defendi: Time is a key factor. Time, because discussions with patients’ families about the feasibility of repatriation are obviously essential. Then there are the requests for authorization, visas from embassies and consulates, the availability of escorts, the involvement of associations to raise funds to cover the costs. Because, as we know, in many countries abroad, the costs are not covered by the National Health System, but unfortunately by the family. Checking the type of care provided locally and the supply of drugs and devices to the patient—so the time factor is necessary. Because if I don’t have time, it’s clear that I can’t do all this. 

Luca Zambelli: Time is crucial, but awareness is also central in this case and in cases like these, because everything here began when you responded honestly to the patient that she was dying. So, awareness is important. We had an Egyptian patient who, thanks to this awareness that was developed early on, managed, before he died, to return home to Egypt to his mother, to say goodbye to his mother and sister, and then return here to Italy, which was his home, and die here. But how important is awareness in these cases for you? 

Sergio Defendi: It is fundamental. The patient must be informed of the diagnosis and prognosis in order to be able to decide; otherwise, others will decide for him. Another important factor is the cultural mediator, who is not only the translator, but also the person who gives you an idea of how illness and death are experienced in different cultures. We don’t have this. Each of us is used to experiencing death and illness in our own reality, in our own culture. But cultures are different, and each reality and culture experiences death and illness differently, and this needs to be understood; otherwise, we risk making big mistakes. So, the role of the cultural mediator is a fundamental one that all hospitals or healthcare facilities must have available. 

Luca Zambelli: But among the problems you have encountered in this case or in other cases, do you think the biggest problem remains time? Because, as you mentioned earlier, you talked about the differences between the various healthcare systems. Sometimes, for example, the healthcare system may not cover the costs of treatment. This is also a very significant problem. In this case, we also had a Moroccan patient who wanted to return to Morocco and die fully aware, completely aware, but a major difficulty for us was ensuring that she could have an adequate end of life in Morocco, precisely because palliative care is less available in Morocco and, on the other hand, it is also paid for—if it is available at all. What has your experience been in this regard? 

Sergio Defendi: Of course, I agree, in the sense that I can tell you about the experience of another young Bolivian patient. Brain tumor. She fell ill and underwent a series of tests and treatments. At a certain point, there were no more specific treatments available. She was admitted to a hospice, where she remained for a year. She was hemiplegic, and at a certain point she developed delirium, a desire to see her son who had remained in Bolivia, and there was no sedative that could control her in the face of this request to see her child. Here too, we organized things, we tried in a certain way to see if it was possible for her to see her son in Italy, but it was not possible because he was a minor. And then, in any case, there was no way to manage her here. Here too, we thought of taking her to Bolivia—a hemiplegic patient—but we organized this transfer by talking to her mother, who would take her in, and to a doctor who would receive her in a small hospital just to assess the case, so that she could then return home. After 24 hours of flights, time zones, and layovers, the patient arrived at the airport. At the airport, I remember this little boy who did not recognize his mother because she was different from the one he had seen before. The child hid behind his grandmother’s skirts, and I can only imagine what that mother felt at that moment, so great was her desire to hug her son. Her son, on the other hand, hid behind his grandmother. She was taken to the hospital just because that was the agreement. But at night she screamed and cried, and the next day I had to take her home and organize home care in four days without any reference points. So, I turned to the local parish priest and a doctor who made himself available—obviously all at my own expense because there was no possibility. So, this is the great difficulty that arises when these patients return, because they need everything. 

 Luca Zambelli: Well, in this case, it was also the effort of the journey that was absolutely incredible. A patient like that facing a journey like this and coping well with it—I understand and remember what you told me, it’s really a lot. But I imagine that when you decided to allow the patient to return home, there were different points of view and opinions within the team. Because if I think about my daily work, I imagine that someone could have said, “I don’t think it’s a good idea to take her home; maybe she’s not able to make this trip…” 

Sergio Defendi: Of course. In both the first and second cases, the team was divided. Because in the first case, they told me, “But this patient is dying.” In fact, she died the next day. And in the second case, there was the distance, the time spent on the plane, and then you can’t guarantee assistance there. So there’s this “managing uncertainty” aspect that needs to be considered, because even if you manage to put all the pieces together, the unexpected is just around the corner. For example, I didn’t mention it, but the Bolivian patient had a first-class ticket, but the captain denied her, so she traveled in second class. And the agreement was that she would go to the hospital, that she could follow her treatment or at least have an evaluation by the doctor—which didn’t happen. So, the issue of “uncertainty” must be considered. The other issue, as you said, is that of the team. The team is divided, and this is my opinion: it is right to talk about it, it is right to talk about it again, it is right that all members are informed, are consulted, and can have their say. However, what I feel I can say is that only those who are providing the care should decide, especially in extreme situations, because of the relationship that is created between doctor and patient that others do not have. And so, this is an added value. 

Luca Zambelli: Of course, I think this is very important, because sharing a course of treatment is the basis for even thinking about getting involved and helping in such a profound way. This is not just about administering therapy or performing tests or whatever normal hospital practice may be, but about getting 100% involved—even accompanying the patient on this journey. Among other things, accompanying the patient exposes the doctor, nurse, or whoever is accompanying them to possible medico-legal problems. We happened to accompany an Albanian patient from our hospice to the airport by car, because of a series of problems the patient had. The car was loaded with the medication she needed, and we left her there at the airport. But it is clear that no one protects us in these situations: if something happens during the car journey, in this case, whose fault is it? Similarly, in your case, whose fault was it? In other words, how can the medico-legal aspect be managed? 

Sergio Defendi: Of course, so I’m talking about air travel, which is, let’s say, more complex because, in this case, if the patient is seriously ill, the responsibility lies with the doctor who sends the patient—not the captain—because otherwise, if something happens on the plane, such as an acute condition or death, the captain has to make an emergency landing. So the responsibility lies with the person who sends the patient. This means that if something happens, the captain can continue the flight and arrive at the destination without having to make these emergency landings. So this is also a big risk, but it is a risk worth taking. Conversely, this is what happens. 

Luca Zambelli: Yes, in the end, we take it as individuals, but there is no entity at the moment that protects us in this matter, and the hospital is clearly far away, because we are doing something that we are not even required to do in a certain sense. But it is important for the patients, so sometimes it is done. But among the various practical logistical problems that arise in these situations, there is also clearly the problem of expenses. Who covered the expenses for the cases you told us about? 

Sergio Defendi: Well, voluntary associations certainly play a fundamental role, but so do private individuals who raise funds to cover all the expenses, such as the transport of medicines, medical devices, and aids. This is because these people are often unable to pay for everything themselves, so voluntary associations play an important role in covering these expenses. 

Luca Zambelli: It would also be useful to have more structured procedures regarding “who should pay,” because in Italy we are fortunate to have many voluntary associations that can support us in these matters. However, we cannot rely solely on volunteers and individuals who decide to pay because they are moved by the story, because they find the issue interesting, and so on and so forth. We need to have something well-defined—someone who can provide constant financial support in cases like these. But in reality, we need to structure the whole process more clearly. What do you think is missing to tackle the whole issue in a more structured way? 

Sergio Defendi: Well, first of all, there needs to be awareness of the problem, which is currently lacking. Because I’m talking to you twenty years on, and today it still happens that if I, as a specialist, learn that a patient wants to go abroad—not here in Italy—what happens is that they are discharged, and then the patient has to fend for themselves with their family. So, the first thing is awareness, especially on the part of medical specialists, and then creating guidelines that define the repatriation process, because this is essential today. I wrote a management thesis on complex structures in 2021, trying to see if there was anything in the literature, and I didn’t find anything, except for a few references. There is nothing at all. So, everything needs to be set up, but it needs to be set up because the problem exists. We don’t want to see it, or some people see it, but it will be an increasingly present problem. 

Luca Zambelli: Yes, even when we wrote the article, we actually did a small—let’s call it—a literature review, insofar as it can be called a review, because in fact, as you said, there was nothing in the literature, and no one talks about this issue. There are only a few case reports that describe the experiential problems of some people. But Italian and European societies, especially those specializing in palliative care oncology, really need to devote time to this problem in order to define how to solve it. Sergio, thank you very much for your time. It has been a pleasure to have you on TJ Talks. 

Sergio Defendi: Thank you for inviting me and giving me the opportunity to talk about this topic. 

Luca Zambelli: TJ Talks is available on our website tumorijournal.org, and on the best podcast platforms. Follow us on X and LinkedIn to always be updated on cancer research and clinical practice in oncology. I am Dr. Luca Zambelli from the Palliative Care Unit of the IRCCS National Cancer Institute Foundation in Milan. Thanks for listening! 

Luca Zambelli: Benvenuti a TJ Talks – Conversazioni sull’ oncologia a Cura di Tumori Journal, la rivista oncologica peer-reviewed dedicata alla divulgazione di tematiche e innovazioni in ambito oncologico. Sono il Dottor Luca Zambelli dell’Unità di Cure Palliative della Fondazione IRCCS Istituto Nazionale dei Tumori di Milano e in questa puntata incontra il dottor Sergio Defendi, direttore della Struttura Complessa di Cure Palliative e ADI di Asst. Di Crema. Sergio, grazie per essere qui con noi oggi. 

Sergio Defendi: Grazie Luca dell’invito! 

Luca Zambelli: Allora oggi parliamo di un tema che in oncologia ancora non è molto evidente ed è quello del crescente numero di pazienti migranti che hanno una diagnosi di malattia oncologica in un Paese estero come appunto può essere l’Italia. Spesso questi pazienti vengono in Italia per motivi di lavoro, per motivi familiari, più raramente, ma capita, anche per motivi di cura. E quando sono qua chiaramente vengono presi in carico dal Sistema Sanitario Nazionale per la cura della loro malattia. Quando le cure oncologiche incominciano a vacillare, le cure palliative diventano l’opzione primaria, chiaramente. E In questi casi spesso i pazienti esprimono desiderio di tornare nel loro paese di origine per poter ottenere cure di fine vita e poter morire a casa. Ma al momento non esistono linee guida o percorsi di cura che ci permettano di gestire adeguatamente questi pazienti. Sergio, noi ne abbiamo parlato di questo problema in passato in diverse occasioni e abbiamo anche scritto un case report pubblicato su Tumori Journal, in cui andiamo ad analizzare il caso dei tuoi pazienti. Ma quando è stata la prima volta che tu hai avuto modo di interfacciarti con questo problema? 

Sergio Defendi: Allora, la prima volta che ho affrontato questa problematica è stato circa vent’anni fa. Era l’inizio della mia prima esperienza in ambito di cure palliative con una paziente eritrea. Ero davanti all’ascensore con lei, mi stavo congedando perché me ne stavo andando, avevamo già concordato con i familiari di continuare l’assistenza in Italia e non in Eritrea, perché le difficoltà in loco erano tali per cui non si poteva pensare ad una assistenza domiciliare o comunque ospedaliera. Davanti all’ascensore lei mi guarda e mi dice: “Gio, sto per morire”. Io gli risposi “Sì”, c’è stato un attimo di silenzio fra me e lei. A un certo punto poi lei risponde dicendo “Io non ho paura di morire. Mi fanno paura le persone cattive e bugiarde. E adesso accompagnami in banca che devo ritirare i soldi”. Erano le 12:00 di un venerdì. Siamo andati in banca, abbiamo ritirato i soldi. Il lunedì il marito è andato al consolato per dei visti e abbiamo acquistato i biglietti aerei. L’autorizzazione, a parte la compagnia aerea per il trasporto di questa paziente che era paziente terminale molto avanzata e un’infermiera si è resa disponibile ad accompagnarla e la partenza è stata il mercoledì successivo. Mercoledì lei era vestita in maniera elegante, con un tailleur, un cappellino e una borsetta dove aveva i soldi e siamo partiti accompagnandola con l’ambulanza in aeroporto a Malpensa. Durante il viaggio lei a volte si svegliava. La preoccupazione sua era la borsetta che aveva con sé, non nello stomaco. Arrivati in Eritrea, la prima cosa che ha fatto è stata consegnare questa borsa alla sorella minore. Il giorno dopo è deceduta. Questo era quello che lei voleva fare. 

 Luca Zambelli: Beh, avete permesso a questa paziente di esaudire l’ultimo desiderio. Devo dire che è stato veramente incredibile. Io mi ricordo che mi raccontavi che la paziente appunto era estremamente avanzata, aveva questo elastomero ricco di farmaci, di morfina, cortisone perché c’era una situazione di dolore chiaramente e di insufficienza epatica che si stava sviluppando. Ma quali sono le principali difficoltà, secondo te, che si incontrano in questi casi? 

Sergio Defendi: Sicuramente il fattore tempo è fondamentale. Tempo perché i colloqui con i pazienti familiari per una fattibilità o meno di un rimpatrio sono fondamentali ovviamente. Poi le richieste di autorizzazione, visti di ambasciate e consolati. La disponibilità quindi di accompagnatori. Il coinvolgimento di associazioni per recuperare fondi per sostenere le spese. Perché, come sappiamo, in tanti Paesi all’estero le spese non sono a carico del Sistema Sanitario Nazionale, ma purtroppo a carico dei familiari. Verificare il tipo di assistenza appunto prevista in loco e la fornitura di farmaci e dispositivi al paziente, per cui il fattore tempo è sicuramente necessario. Perché se non ho tempo è chiaro che tutto questo non riesco a metterlo in atto. 

Luca Zambelli: Il tempo è fondamentale, ma la consapevolezza anche centrale in questo caso e in casi come questi, perché tutto qua è nato nel momento in cui tu hai risposto sinceramente alla paziente che lei stava morendo. Quindi una consapevolezza importante. Noi abbiamo avuto un paziente egiziano che grazie a questa consapevolezza che è stata sviluppata precocemente, è riuscito, prima di morire, a tornare a casa in Egitto dalla madre, di salutare la madre, la sorella e poi tornare qua in Italia che per lui era casa e morire qua. Ma per te quanto è importante la consapevolezza in questi casi? 

Sergio Defendi: È fondamentale. Il paziente deve essere informato di diagnosi, di prognosi, per poter poi decidere e altrimenti sono gli altri a decidere per lui. Un altro fattore importante è il mediatore culturale, che non è solo colui che traduce, ma è colui che ti dà una nozione su come la malattia e la morte viene vissuta nelle varie culture. Noi questo non ce l’abbiamo. Ciascuno, cioè noi siamo abituati a vivere la morte e la malattia nella nostra realtà, nella nostra cultura. Ma le culture sono diverse e ciascuna realtà e cultura vive in maniera diversa la morte e la malattia e questo va conosciuto, altrimenti rischiamo di fare grandi errori. Quindi il ruolo del mediatore culturale è una figura fondamentale che tutti gli ospedali o comunque le strutture sanitarie devono avere a disposizione. 

Luca Zambelli: Ma tra i problemi che hai avuto in questo caso o in altri casi, il problema più grosso secondo te rimane il tempo? Perché, anche tu l’hai citato prima, e hai parlato della differenza tra i vari sistemi sanitari. Qualche volta può capitare, ad esempio, che il sistema sanitario non copra i costi delle cure. Ecco, anche questo è un problema molto significativo. Noi abbiamo avuto anche in questo caso una paziente marocchina che voleva tornare in Marocco e a morire molto consapevole, completamente consapevole, ma una grossa difficoltà per noi è stata permetterle di garantirle un fine vita adeguato in Marocco, proprio perché in Marocco le cure palliative sono meno disponibili da un lato e dall’altro sono anche a pagamento, eventualmente quando ci sono. Tu che esperienza ha avuto in tal senso? 

Sergio Defendi: Certo, anch’io condivido, nel senso che ti porto l’esperienza di un’altra paziente giovane boliviana. Tumore cerebrale. Lei si ammala, fa tutta una serie di accertamenti di cure. A un certo punto non ci sono più cure specifiche. Viene ricoverata in hospice, rimane un anno ricoverato in hospice. Un paziente emiplegica, ed a un certo punto sviluppa un Delirium, un desiderio di vedere il figlio che è rimasto in Bolivia e non c’è sedativo che possa controllarla a fronte di questa richiesta di vedere appunto il bambino. Anche qua organizziamo, cerchiamo in un certo qual modo di vedere se era possibile far vedere il figlio in Italia, ma non è stato possibile perché era un minorenne. E poi comunque qua non c’era la possibilità di gestirla. E anche qua abbiamo pensato di portarla in Bolivia una paziente emiplegica, ma abbiamo organizzato questo trasferimento parlando con la mamma che l’avrebbe accolta, parlando con un medico che l’avrebbe ricevuta in un piccolo ospedale giusto per inquadrare il caso, per poi poter permettere un ritorno a casa. 24 ore tra voli e e fusi e scali, la paziente è arrivata all’aeroporto. All’aeroporto ricordo questo bambino piccolino che non riconosce la mamma perché la mamma è un’altra rispetto a quella che lui aveva visto. Il bambino si nasconde dietro le gonne della nonna e quindi immagino anche per dire cosa ha provato quella mamma in quel momento, tanto era il desiderio di abbracciare suo figlio. Il figlio invece si nasconde dietro la nonna. Viene portato in ospedale giusto per perché gli accordi sono questi. Solo che di notte urlava, gridava e ho dovuto il giorno dopo riportarla a casa e organizzare l’assistenza domiciliare in quattro giorni senza avere nessun punto di riferimento. Quindi avvalendomi del parroco della zona, di questo medico che si è reso disponibile, ovviamente tutto a pagamento perché lì non c’era nessuna possibilità. Quindi questa grossa difficoltà che c’è quando questi pazienti rientrano perché hanno bisogno di tutto. 

 Luca Zambelli: Beh, in questo caso è stato anche lo sforzo del viaggio assolutamente incredibile. Una paziente del genere che affronta un viaggio come questo e che lo affronta bene, mi sembra anche di capire e di ricordare quello che mi raccontavi, è veramente tanto, ma immagino che quando avete scelto di permettere alla paziente di tornare a casa, ci fossero dei punti di vista delle opinioni diverse nelle equipe perché se io penso alla mia realtà di lavoro quotidiana immagino che qualcuno poteva dire “non mi sembra una grande idea portarla a casa, forse non è in grado di fare questo viaggio…” 

 Sergio Defendi: Certo, allora sia nel primo caso che nel secondo, l’equipe era divisa. Perché nel primo caso mi hanno detto “ma questa paziente sta morendo”. Difatti è morta il giorno dopo. E l’altra la seconda, di fatto la distanza, il tempo in aereo e poi là non puoi garantire un’assistenza quindi c’è questo “gestire l’incertezza” è che un aspetto che va considerato perché qualora anche tu riesca a mettere insieme tutti i tasselli ma di fatto l’imprevisto è dietro l’angolo. E ad esempio non ho citato ma la paziente boliviana aveva un biglietto in prima classe ma il comandante gliel’ha negato, quindi ha viaggiato in seconda classe e l’accordo era che andasse in ospedale, che potesse fare il suo percorso o comunque un tempo di valutazione da parte del medico che non c’è stato. Quindi il tema “incertezza” è da considerare. L’altro tema, come dicevi tu, quello dell’équipe. L’équipe è divisa e, questo è il mio parere personale, è giusto parlarne, è giusto riparlarne, è giusto che tutti i componenti siano informati, siano interpellati, possono dire la loro. Quello però che mi sento di dire è solo chi ha in mano l’assistenza è giusto che decida, soprattutto su situazioni estreme, per quel rapporto che si crea tra medico e paziente che gli altri non hanno. E quindi questo un valore aggiunto. 

 Luca Zambelli: Certo, è importantissimo questo secondo me, perché comunque condividere un percorso di cura è la base poter anche solo pensare di mettersi all’opera e dare una mano in un modo così profondo perché qua non è soltanto somministrare una terapia o fare un esame o quello che può essere la normale pratica ospedaliera sanitaria, ma è proprio mettersi in gioco al 100% anche accompagnando il paziente nel contesto di questo viaggio. Tra l’altro accompagnare il paziente porta medico, infermiere o chiunque accompagni a dei possibili problemi medico legali. A noi è capitato di accompagnare una paziente albanese dal nostro hospice all’aeroporto con la macchina per una serie di problemi che la paziente aveva. Macchina carica di farmaci che ha bisogno e lasciarla là in aeroporto, ma è chiaro che nessuno ci tutela in questi contesti: se succede qualcosa nel viaggio in macchina in questo caso di chi è la colpa? Stessa cosa, nel vostro caso, di chi era la colpa? Cioè come si può gestire la parte medico legale? 

 Sergio Defendi: Certo, allora io parlo del viaggio in aereo che è diciamo già più complesso perché voglio dire in questo caso se il paziente è grave la responsabilità è del medico che invia il paziente, non se la assume il comandante, perché in caso contrario se succede qualcosa in aereo o di fattore acuto o di morte, il comandante deve effettuare un atterraggio di emergenza, per cui la responsabilità è di chi invia. Vuol dire che se succede qualcosa, il comandante può continuare il volo ed arrivare a destinazione senza dover fare questi atterraggi di emergenza, per cui anche questo è un grosso rischio, che però è giusto correre. Vale la pena correre, ecco. Viceversa quello che succede è questo. 

 Luca Zambelli: Sì che poi alla fine appunto lo corriamo come singoli ma non c’è un’entità adesso al momento che ci tutela in questa cosa, e l’ospedale chiaramente è lontano perché noi stiamo facendo una cosa che non saremmo neanche tenuti a fare in un certo senso, però per i pazienti è importante quindi delle volte viene fatta. Ma tra i vari problemi logistici pratici che sono poi problemi che si vivono in situazioni, c’è anche chiaramente il problema delle spese. Cioè chi è che ha coperto le spese dei casi che ci ha raccontato? 

 Sergio Defendi: Beh, sicuramente un ruolo fondamentale hanno le associazioni di volontariato, ma anche i privati, che raccolgono questi fondi per spese che sono tutte le spese, quindi del trasporto dei farmaci, dei presidi, degli ausili. E perché spesso e volentieri queste persone non sono in condizione appunto di pagarsi tutto e quindi l’associazione di volontariato ha un ruolo importante in questo per affrontare queste spese. 

 Luca Zambelli: E sarebbe utile che anche ci fossero dei percorsi più strutturati anche per quanto riguarda il “chi deve pagare” perché in Italia abbiamo da un lato la fortuna di avere molte associazioni di volontariato che ci possono dare un supporto in queste cose. Però non si può fare soltanto affidamento sul volontariato e sul singolo che si lancia a pagare perché la storia gli fa tenerezza, perché trova che la tematica sia una tematica di interesse, eccetera eccetera eccetera. Bisognerebbe avere qualcosa di appunto ben definito, qualcuno che costantemente in casi come questi può dare un supporto economico eventualmente. Ma bisognerebbe in realtà strutturare tutto il percorso in modo più chiaro. Ma cos’è che manca, secondo te, per affrontare il tutto in modo più strutturato? 

 Sergio Defendi: Beh innanzitutto ci deve essere la consapevolezza del problema che ad oggi non c’è, perché io ti parlo a distanza di vent’anni, oggi succede ancora che se vengo a sapere come specialista che il paziente vuole andare all’estero, non qui in Italia, quello che succede che viene dimesso e poi il paziente si arrangia con la famiglia. Quindi la prima cosa è la consapevolezza, soprattutto da parte dei medici specialisti e poi creare dei percorsi di linee guida che definiscono l’iter del rimpatrio, perché di fatto questo è fondamentale ad oggi. Io ho fatto una tesi manageriale di struttura complessa nel 21 cercando anche di vedere se c’era qualcosa in letteratura e non l’ho trovata, se non accenni. Manca proprio tutto. Quindi è tutto da impostare, ma va impostato perché di fatto il problema c’è, noi non lo vogliamo vedere o alcuni lo vedono, ma sarà un problema sempre più presente. 

 Luca Zambelli: Sì, anche quando abbiamo scritto l’articolo effettivamente abbiamo fatto una piccola, chiamiamola revisione di letteratura per quanto si può chiamare revisione perché in realtà infatti, come tu hai detto, di letteratura non c’era più nulla e nessuno parla di questa tematica. Ci sono solo dei case report un po spot in cui viene raccontato così il problema esperienziale di alcuni. Ma bisognerebbe davvero che anche le società italiane ed europee, quello che è specifico e quindi ad esempio di Oncologia di cure palliative dedicassero del tempo a questo problema per definire come risolverlo. E Sergio, ti ringrazio davvero per il tempo che ci hai dedicato, è stato un piacere averti a TJ Talks. 

Sergio Defendi: Grazie a voi dell’invito e di avermi dato la possibilità di parlare di questo tema. 

 Luca Zambelli: TJ Talks è disponibile sul nostro sito web tumorijournal.org e sulle migliori piattaforme di Podcast. Seguiteci su X e LinkedIn per essere sempre aggiornati sulla ricerca, sul cancro e sulla pratica clinica in oncologia. Sono il Dottor Luca Zambelli dell’Unità di Cure Palliative della Fondazione IRCCS Istituto Nazionale dei Tumori di Milano e grazie per l’ascolto!

Luca Moscetti: Welcome to TJ Talks – Conversation about Oncology by Tumori Journal, the peer-reviewed oncology journal dedicated to the dissemination of key oncological teams and advancements. I’m Doctor Luca Moscetti, Adjunct Professor in Oncology at the Residency Program in Oncology at the University of Modena Reggio Emilia. In this episode I’m happy to meet Francesco Pignatti, Scientific advisor for Oncology in the Human Medicine Division of the European Medicines Agency. Francesco, thank you so much. It is really a pleasure having you on TJ Talks.

Francesco Pignatti: Thank you, Luca. Buongiorno!

Luca Moscetti: Buongiorno, Francesco. I wanted to start with the first question, and I want to ask you Francesco what extent does the European Medicines Agency currently rely on the real world data as primary evidence for oncology drug approvals? What specific criteria determine its acceptability?

Francesco Pignatti: Thanks, Luca. It’s a great question. And it really depends what you mean by let’s say primary role, because, I guess from the outside, sometimes you might have the impression that the EMA approves a drug if the trial hits the P value or refuses if it doesn’t. But actually, drug evaluation at the EMA and the following drug approval is based on a huge amount of quality, safety, efficacy data. And so, sure, clinical trials play a big part, and sort of clinical data, whether from trials on real world data, play a role. Now, the difficulty in answering your question is: how do you disentangle the importance of this each piece of this huge puzzle? And we have a number of colleagues who have tried to look at this. And I think the bottom line is that in a number of situations in oncology, in a number of submissions up to up to half of the submissions, real world data do play a role. If you look at the role itself, is it a critical role? Is it primary or not? It’s difficult to say, but in some probably single applications the main data about the efficacy of the drug, what are the good things that the drug does, that was based on real world data. So there are examples. It’s a moving field. And I think we should brace ourselves for big changes in this domain as we learn more about this type of data.

Luca Moscetti: Yes. Thank you very much, Francesco. Very interesting. Because we are going deep to evaluate the real world data. And I think that with an increase in the reliability of the statistical methods and the collecting of the data for a real world studies become very important to increase the reliability of this trial. So I hope that in the future the European Agency, but also the researchers are going to be more in deep in this type of evaluation. Anyway, in what specific scenarios within oncology drug development does the EMA consider the single-arm trial enough for approval, and what are the key factors that justify their use over the randomized controlled trials?

Francesco Pignatti: That’s a great question. And in fact, what I ask normally people, is not to focus on the design of the study because, if you think of it, there can be single-arms trials that are incredibly convincing. Everybody has a complete response that is very durable. You don’t need randomization for that, for being convinced that the drug works. And there can be randomized studies that show you a minuscule difference in a secondary endpoint that are not going to be convincing at all. So the issue is not so much the design, but is: do these trials show efficacy and safety? Are the data comprehensive? And then what does comprehensive mean? Well, it depends on the uncertainty that you are willing to accept in a specific situation. So coming back to your original questions, because single-arm trial comes with a lot of uncertainty, mostly about the time related endpoints like survival and so on. Then you have to you tend to accept them more in situations where uncertainty is acceptable, which is where you have high unmet medical needs. So these are patients that are typically, you know, have tried all the available options. And there are no standard options that are effective and safe that are available. And then there is poor prognosis, there is progression, etc. And then in those situations, sometimes single-arm trials showing a very convincing response rate, well, that might be enough for approval.

Luca Moscetti: So, again, some trials are used for a proof, some drugs especially in some type of setting. And I wonder if it could be in the future new statistical methods, as I said before, in this case the use of synthetic data to produce a control-arm in order to compare the population of the single-arm trial, maybe could be a solution about that, to increase the credibility?

Francesco Pignatti: Absolutely. And I think one of the examples of an application submitted to EMA that was approved on the basis of real world data used that design, so a single-arm trial with an external comparator based on real world data, what you might call it a synthetic comparator. And we’ve actually recently conducted a study with doctors from ESMO and the European Hematology Association. And this was recently presented at a rare cancer meeting in Lugano. And we asked clinicians, oncologists, hematologists to tell us how convincing are single-arm trials versus how convincing our single-human trials, plus such an external control versus a randomized control trial, and designing that study, we thought that externally controlled trials, like the one you mentioned, would be similar to a single-arm trial, I thought people were more or less skeptical of this design. On the contrary, what we found is actually that a well high quality, externally controlled study, is actually very close to being as convincing as a randomized controlled trial in specific situation. So that was an eye opener, and I think what people focus on is, first of all, what does this trials show, again, like a single-arm trial. It isn’t so much about the design, but if you have an external control trial that shows you a big difference in survival, well, it becomes an important signal. And now the other point is the quality of the data that you’ve used. Because no matter how good is your design, if there are flaws, biases in the data that you collect, well, you’re not going to get convincing results out of that. And so our focus on quality of the data can really make or break these so-called real world data studies. It’s really going to be critical, as you mentioned before, critical to focus on what are the factors that are important for the quality of the data.

Luca Moscetti: Thank you very much, Francesco. Is an important question because to evaluate the quality of the data collected that represented crucial points, sometimes, you know, for the real world trials or for single-arm trials. This is an important signal from this type of research that you conducted with other colleagues, because we need to change our mind in methodology and to evaluate the data observed in the real world. Thank you very much for your answer.

Francesco Pignatti: Now that you mentioned quality, I have some personal views on this. And I think if you look at clinical trials, it is difficult sometimes not to kind of see that we have created an environment where quality of data is taken to such an incredible degree that it almost seems a bureaucratic approach. We have lost the spirit of, you know, focusing our efforts on what really matters, on what’s really important. Everything is theoretically important, and therefore every minuscule, most tertiary piece of data in a clinical trial deserves as much attention as everything else. And we’ve created this huge, huge enterprise around quality of the data. And as we approach designing the systems for the real world data, let’s try to be more efficient, more clever and design quality criteria that are fit for purpose and that are proportionate to the objectives. And I think all of us, regulators, but also academics and the sponsors, we all need to get this right to really facilitate this type of research and not create more and more hurdles that will stifle the opportunities that come from this type of data.

Luca Moscetti: Yes, thank you very much. And I think that you answered by now to the next question. So looking forward to the future, the anticipated trends and challenges regarding the increasing utilization of real world data and single-arm trials in the oncology drug approval pathway by EMA is very important, especially in the context of personalized medicine that will become the future, and the future is now. So, we can skip to the other question, and how does the EMA weight the potential benefit of accelerated access to innovative oncology drugs? Facilitated by the use of singular trials or real world data, as we mentioned, against the need for robust evidence of efficacy and safety established through traditional randomized controlled trials, we mentioned the statistical methods, the change of methodology, the change of mind of researcher. But also I know that EMA is involved in the program as Darwin, as the European Network of Centers for Pharmaco-Epidemiology and Pharmaco-vigilance at the end that are going to establish the right guidelines to increase the reliability of the data collected. What do you say about that?

Francesco Pignatti: Yeah, again, a lot to unpack in your question, I would say formally the European Pharmaceutical Legislation gives us tools like the, what we call the conditional marketing authorisation, the conditional approval, tools for really embracing innovation in the sense that we can approve drugs even when the data are not comprehensive. And that is based really on a trade of whether it is more important to have access to a new drug, even if there are uncertainties about, for example, whatever long term effects, or to wait until we’re sure about what these effects are. But potentially a number of patients will not have access to the drug through an approval during that time period. And I think it’s a tricky issue. And we’ve also studied what regulators think about this conditional approval. They’re actually recently published in a scientific journal our results and what’s interesting is that a key element for allowing this type of approvals is managing the communication effectively. So making sure that patients and doctors are fully informed about what are the uncertainties about drugs approved early and that this can be discussed in a clinical decision making and so on. And I think what I want to focus on in the future is this type communication tools that we have, how we can improve them, how we can make sure that they inform the decisions of patients in the real world.

Luca Moscetti: So you mentioned patients and this is linked to the next question on the last question. What role do patients advocacy groups and their perspectives play in influencing the EMA acceptance and evaluation of real world data and single-arm trials in the context of oncology drug approvals, particularly for rare or aggressive cancer, or phase three trial?

Francesco Pignatti: I will get there in a minute. I just wanted to circle back one moment to the Darwin Project that you mentioned, because I think it’s really a key to see how much investment that has been on the side of the agency, on the side of European institutions, there are a number of initiatives that are really, you know, trying to make the most out of this data and to the point that the Darwin program has really established in a few years an incredible capability to address scientific questions and do some research on the basis of real world data. So this incredible effort really shows how much confidence, or at least hope, there is that we can really progress. Then in, let’s say, adding to the tools we have to generate scientific evidence for informing clinical practice, for informing decisions, including regulatory decisions and so on. So it’s working progress, but there is great, great enthusiasm from this type of studies. And in the end, it’s not going to be real world data yes or no, quality good or bad…You know, we all have to move to a situation where we manage the quality, we manage the uncertainty, we manage different sources of data and find, you know, all the positive and negative aspects that no matter what the design of the study have to get a view and, you know, put together all the data, in order to get as efficiently as possible, as quickly as possible, answers, let’s say, about the treatment for cancer patients. So I think you will see all of these efforts come together not as one offs or let’s say, a shift in paradigm from now on, I don’t know, single-arm trials disappear and it’s only going to be externally controlled trial. No, you’re going to see more and more different types of evidence working together, each assessed for its contribution. And so right, now you raise a very important question, which is about the contribution of patients and, well, patients are so central to all of the activity of EMA that my answer is going to be, you know, a necessity limited to what I am more involved in and, as you say, about real world data. And there is the whole aspect of patients initiatives that directly contribute data to various databases that can be analyzed. And again, it’s a matter of quality of the data, it’s a matter of representativeness of the data, etc. But these are not, as I said before, yes or no, accept or refuse, type of criteria. Every piece of data has its value, has its place. It’s a matter of managing the uncertainty and getting the key messages out of it. I think there is one type of patient contribution on which there is a lot of attention at the moment, which is really when assessing things like the one we discussed before, is a certain type of uncertainty, acceptable or not. Are the benefits outweighing the risk? These type of trade offs that are not really objective in the sense that it’s something that you can derive from the drug, but it’s something that is more subjective and you derive from the people who might use the drug, or for the people who are using the drug. These, what we call preferences, is something that we have a lot of interest at the moment. And in fact, at international level, we are recognising that these type of studies really collecting systematically the preferences of patients, the trade of patients, how much importance they give to a certain effect, survival improvement or a certain toxicity. We see there are wide distributions. Patients have different risk attitudes and so on. And now in the past I think we have always been interested, but we have not been collecting these things systematically, let’s say conducting formal studies or only rarely. And now more and more, you see attention by the sponsors, by the academic groups, by the patient groups. They see how doing formal studies on these systematic studies and delivering, the voice not of 1 or 2 individuals, but of a wide group of patients is much more informative, much more incisive.

Luca Moscetti: So you point out a very important question about this topic, because I think that to collect the patient reported without consent, to collect the voices of a multitude of patients is very important to have more data about the safety of the treatment and the preferences of the patient, when a drugs is granted by the EMA and using clinical practice. So I think we have to move on about this type of research. And I hope in the future there will be a lot of trial or a lot of academic type of study regarding this topic. Also, just a comment on the Darwin program, I think is a huge program is a very important. And I think that it’s very important to homogenize the medical terms to obtain and collect the data, because only through this type of approach, we can increase the quality of data to have more reliability on the data collected. So I want to ask you if you have other some comments, Francesco. And otherwise it was a pleasure to have you in the podcast.

Francesco Pignatti: Thank you Luca. It’s my pleasure. And really this is such a fascinating topic.  Real world data that I entered, you know, some time ago, a bit skeptically. I was, you know, I spent many years at the RTC, and in the 90s when I was there, we were only doing randomized controlled trials for this idea of real world data was in some sort of a exotic, exotic idea. And I think over the years and the 20 plus years that I have been at the EMA, I’ve really learned that, you know, there are no good or bad data. It’s just there are data, and you can make the most out of any type of evidence that is available. And I think that is the mindset that we have to keep as we evolve in this field. And there will be, you know more type of data, more end points, as you said. Quality of life is an endpoint that people are are really putting a lot of importance. And perhaps that has been neglected in the past for various reasons. So I think we are looking forward to a really exciting time. So Luca, I thank you very much for having me here and for allowing me to sort of give my thoughts on this important developing topic. Thank you!

Luca Moscetti: Thank you, Francesco, thank you for your effort and to your colleagues of EMA, every day to increase the well-being of our patient. Thank you very much. Goodbye! TJ Talks is available on our website tumorijournal.org, and on the best podcast platforms. Follow us on X and LinkedIn to always be updated on cancer research and clinical practice in oncology. I am Doctor Luca Moscetti, Adjunct Professor in Oncology at the Residency Program at the University of Modena Reggio Emilia. Thanks for listening!

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Giancarlo Pruneri: Welcome to TJ Talks Conversations on Oncology by Tumori Journal, the peer-reviewed oncology journal dedicated to disseminating topics and innovations in oncology. I am Professor Giancarlo Pruneri, Editor-in-Chief of Tumori Journal. In this episode I am very pleased to meet Professor Paolo Marchetti, Scientific Director of IDI-IRCCS and Full Professor of Medical Oncology at Sapienza University of Rome, as well as President of the Foundation for Personalized Medicine and promoter of the Clinical Trial Rome. Paolo, thank you for being here with us today.

Paolo Marchetti: Thanks for inviting me Giancarlo.

Giancarlo Pruneri: Paolo, can you tell us about your journey and what is the most precise definition today in your opinion for the term precision oncology?

Paolo Marchetti: A question that is certainly extremely interesting and would require a symposium to be fully illustrated, but from a practical point of view we can identify in precision oncology all those pathways that want to identify in the presence of certain genomic alterations. Besides mutations, in precision oncology we now consider more complex metrics, such as mutational tumor load or homologous recombination deficiency, as well as silencing through methylation of non-mutated genes that also condition certain types of therapies. So, a broad concept based on the study of the genome of tumor cells, both on biopsy and on liquid biopsy. Metaphorically, we cannot study the most minute details of lunar craters and hope to illustrate the complexity of the universe. Furthermore, the possible response to a certain drug, drug interactions, such as significant changes in the microbiota, lifestyles, physical activity that we have seen to be so important in helping to obtain better clinical results. Therefore, there’s an extremely complex picture that will force clinicians, molecular biologists, pathologists, geneticists to always deal with an increasing number of information before making a single decision.

Giancarlo Pruneri: You have described very well with the metaphor of the moon the difficulty of how to say for a clinician or even for a group of clinicians, in multidisciplinary teams, to manage this enormous and very heterogeneous quantity of data. And in this regard obviously the technological implementation and the entry of artificial intelligence into our world, which is now, let’s say, more than a promise, it is certainly a reality. It can certainly help us, but here too we will need to find a way to be able to translate the innovations and possibilities of artificial intelligence into the lives of our patients as quickly as possible. In this regard, I know your activities very well in this area too, and I am curious to know what activities in particular you carry out in your artificial intelligence laboratory.

Paolo Marchetti: I was very struck by the extremely low number of patients who are included in clinical studies not only at the level of my institution but at the national level, but I must say even more so at the international level. The published data are sadly stuck at around 10% of patients who are globally followed by very advanced cancer centers. What we initially evaluated was precisely that of associating the ability of artificial intelligence to elaborate increasingly precise summaries, complete and usable for the clinician, of the clinical histories of our patients that are now based on dozens of laboratory tests on dozens of radiological tests and therefore each require a significant amount of time for evaluation. It has been calculated that preparing a patient for a multidisciplinary discussion generally takes between 20 and 90 minutes, a really significant amount of time, so a first artificial intelligence system that we have implemented thanks to the collaboration with CBM, concerns the possibility of summarizing in a very efficient and precise way complex clinical histories. This is the basis for the second artificial intelligence tool that goes to analyze those clinical characteristics of that patient at that moment, to evaluate if there are clinical studies currently active on a national level and therefore this should allow a notable acceleration of the recruitment in clinical studies of our patients.

Therefore, we must never think of artificial intelligence in medicine as a substitute for the role of the doctor, but only as a way to shorten the evaluation times of information that ultimately is not useful in a specific situation, which allows us to have more time to dedicate to the relationship with the patient.

Another point will then concern the artificial intelligence systems that we are instead developing with Replay and with the Alliance against Cancer for the analysis of the interactions between the signal pathways inside the tumor cells. Once again, artificial intelligence does not replace the doctor, but it signals attention alerts. Here there could be a serious limitation because it is true that there is this mutation, it is true that you could use this drug, but this alteration downstream of the mutation that you have found would make the treatment with that drug useless. Finally, all this information must be linked together and, through an orchestration of different artificial intelligence agents, we will be able to have a synthesis for the final clinical decision.

Giancarlo Pruneri: Paolo I totally agree that artificial intelligence can naturally be a very useful tool for us. You referred to the Molecular Tumor Board. Surely in genomics, in the evaluation of precision oncology, the use of this tool can be very useful to better select our patients, offer more specific therapies. You have already mentioned the topic of pharmacokinetics and pharmacogenomics, but at this point it is a point that I believe deserves a further comment from you. How can pharmacokinetics and pharmacokinetics be used to better treat our patients in precision oncology?

Paolo Marchetti: The mantra is trial and error, which is an elegant way of saying I give the drug in the meantime, then if there is something wrong I come back and change it. This is what we have available today. Only incidentally do I recall that more than 14 million Italians take from five to more drugs a day. If we have the intellectual honesty to recognize it, then go and specifically verify the compatibility between these treatments. But let’s remember that indications of attention towards indications deriving from genomic analysis are present for more than half of the drugs available on the market today, both in the oncology and psychiatry fields, and in internal medicine, therefore we have worked in the last 15 years together with the Charité in Berlin, developing a platform called Drug Queen which allows precisely this therapeutic reconciliation, associating the information deriving from literature data with the individual characteristics of the patient. I remember that some time ago with the analysis of polymorphisms was particularly expensive. Now in Lazio Region there is a pilot project coordinated by Sant’Andrea and Professor Simmaco focusing on around 200,000 patients who will be profiled in the coming months to try to identify what are the best ways to put together different treatments.

Sometimes just changing a pump inhibitor is enough to see significant reductions in the negative interaction score between these drugs. We wanted to demonstrate this also in melanoma and lung cancer we have a reduction of six to eight months of PFS in the presence of a report of medium-severe interactions compared to the absence of interactions. Six to eight months of advantage is what we get with the best drugs we authorize. So, one aspect that will certainly have to have further attention and that in the alliance project against cancer on the Molecular Tumor Board, which will soon be proposed to all regions, is an element of requalification of the therapeutic offer. Once the drug has been decided, it is assessed that all the clinical conditions of the patient and above all the other drugs that the patient takes are in harmony with this treatment chosen after so much effort and commitment.

Giancarlo Pruneri: Yes, I think it is a very, very important project. No, it goes a little beyond the mechanistic aspect of molecular alteration and target drug the epigenetic characteristics of patients, which naturally have comorbidities, peculiar characteristics. I would like now your comment on the trial. Rome, you are the promoter of this study. I also participated in the first steps of this study and I can testify to how your vision was truly open to the future. A truly visionary approach and also a little against a way of thinking that at that time, when the study was conceived and created, had not yet included precision oncology and the mutational approach among the possibilities of treating patients. We know that it has already been presented in international meetings, but can you summarize what are the most significant results of this study?

Paolo Marchetti: I would say that the main result of this study was the demonstration of an extraordinary ability of Italian oncologists to work together in a non-profit project. It was an extremely complex protocol because I remember that in addition to genomic profiling on tissue and liquid biopsy, it required that the biopsy was obtained after the last effective treatment. So, the doctors had to take on the burden of explaining and, as you rightly said, of a study that was very complicated at the time in which it was difficult to convey the potential innovation to patients and their families. I would say that the first result was to demonstrate to the entire world that Italy was able to carry out a very large country study thanks to the dedication of the doctors and the many who worked. We had – and you were part of it – a dedicated Molecular Tumor Board for this study, meeting for 126 consecutive weeks I would say the main result of the study was the achievement of the primary objective in term of responses, with an advantage in the group with molecularly targeted drugs compared to the treatment chosen by the investigator.

But the even more important advantage is certainly that of progression free survival, in which at one year we have a truly extremely significant advantage both in terms of hazard ratio and in absolute values of disease control. We don’t have time to go into detail but let’s remember had a stability of the microsatellites, they have demonstrated an advantage of over 40% of PFS. We also had important results in terms of concordance between solid biopsy and liquid biopsy. This confirms that there is greater homogeneity in the prevalence of genomic alterations between tissue and liquid biopsy which corresponds to a greater possibility find a biomarker for a specific drug.

Giancarlo Pruneri: Paolo thanks for this overview. I guess that sooner or later there will be a full manuscript on the Rome trial. What are your next projects that you believe could really further implement precision oncology in the next, let’s say three years.

Paolo Marchetti: The Foundation for Personalized Medicine is focusing on one project that has the ambition to collect everything we have said so far in one large container. It will be called Beyond the Rome. Because we go beyond the trial and try to introduce into a national adaptive platform a series of specific information regarding genomic profiling, not limited to the study of mutations, but probably also including methylation and in some subgroups of patients also transcriptomic. It will be a study aimed at evaluating a series of primary objectives, because through the platform study we can now collect in a homogeneous and prospective manner all the information recorded. We have more than 80 centers that have already asked to participate in the trial. I must add that at the European level, the Joint Action of Europe Cancer, where I am a member of the Scientific Committee evaluating new projects, is dealing with how it is possible to include this innovation in the harmonization pathways at a European level. That will be another milestone in which our trial is already brought as an example of the Italian way to innovation. One aspect that amazed colleagues from other countries was the introduction of artificial intelligence also in the training pathways with the creation of avatars dedicated to illustrating to clinicians and to all the researchers who will deal with these platforms what the data acquisition methods are, the methods of interpretation of evaluation with extremely important insights. The avatar is able to repeat the recorded video, but also to interact with the user by giving information on specific questions thanks to a specific adaptive artificial intelligence training that is able to answer the questions. The avatar certainly represents a useful integration, because we cannot think that a single expert is available 24 hours a day to everyone. The Be Rome will be conducted on no less than 5,000 patients and will have patient reported outcomes as the primary objective of the study together with PFS.

Giancarlo Pruneri: You are right to underline how this is an extraordinary opportunity for the health system and for oncology of this country to be really at the forefront in Europe. Thank you very much Paolo, it was really a pleasure to have you with us here at TJ Talks.

Paolo Marchetti: Thank you Giancarlo, it was a great pleasure for me, and I thank you for the opportunity you gave me to reach your many listeners with our projects but also with the achievements of our country in this field.

Giancarlo Pruneri: Thank you Paolo. TJ Talks is available on our website. Tumori Journal dot org and on the best podcast platforms. Follow us on ECS and LinkedIn to stay up to date on research, cancer and clinical practice in oncology. I am Professor Giancarlo Brunetti, director of Tumori Journal. Thanks for listening!

Giancarlo Pruneri: Welcome to TJ Talks – Conversation about Oncology by Tumori Journal, the peer-reviewed oncology journal dedicated to the dissemination of key oncological themes and advancements. I am Professor Giancarlo Bruni, editor in chief of Tumori journal, and in this episode I am happy to meet Professor Andrea Sartori Bianchi, full Professor of Oncology at the University of Milan and director of the Division of Clinical Research and Innovation, Medical Oncologist at Grand Hospital Metropolitano Niguarda in Milan. Andrea, thank you for being with us today. 

Andrea Sartore Bianchi: Giancarlo, thanks so much for inviting me. 

Giancarlo Pruneri: Andrea, no doubt you are one of the most important key opinion leaders in colon cancer. Could you tell us something about your educational and professional background? 

Andrea Sartore Bianchi:  Yes. So, I’m a medical oncologist., I work in the Niguarda cancer center, and I’m professor of oncology at University of Milano, and my journey in oncology, let’s say, started at the University of Pavia, where I completed my medical degree and also the specialization in oncology. Then I had a research experience at Brown University in Providence, Rhode Island, at the Division of Clinical Pharmacology of Professor Calabresi. And that really led me to the interface between the clinical and practice and the molecular research. Subsequently, I work in Niguarda hospital, mainly focusing on colon rectal cancer. So, my interest was always centered on, let’s say, on precision oncology, including both biomarkers on solid tissue and also liquid biomarkers, so liquid biopsy, CTDNA, to guide treatment decision and to improve clinical efficacy of oncological treatment. So, I always had the goal to make cancer care more personalized and dynamic, something that I think we will cover this is becoming to have some results in colon rectal cancer. 

Giancarlo Pruneri: Andrea this is a fantastic path taking together, you know, education and research and clinical care, and it’s also a very good news knowing that you are, you know, integrating your education in Italy and working here in order to get research insights to Italy and to our community.  And, Andrea, you mentioned that you and your team are authors of seminal works on precision oncology in colon cancer based on liquid biopsy. In your opinion, what is the current use of liquid biopsy in this setting and what are the future developments? 

Andrea Sartore Bianchi: Yes, you know right now I think that the real actual use of liquid biopsy is very limited in colorectal cancer, clinical practice, because mostly now we can rely on liquid biopsy when tumor tissue is not available or insufficient., and you can detect, rash mutation, for example, another molecular alteration on the blood instead of tissue, and also there is an application to guide Anti-egfr challenge. This is mentioned in ESMO guidelines and many guidelines. And this is also based on results from our group for example. But really I think that this is just the beginning because the real potential of liquid biopsy is really, you know, unfolding in several directions, and some of these are really exciting. And I would say that, for example, one of the most promising, of course, is detecting the minimal residual disease, MRD. This is one of the most promising applications, and the limit here is sensitivity, but you know that now we have the newer tests that are integrating methylation, fragmentation or also broader genomic coverage, like whole exome sequencing. Now we are starting to see also in ctDNA. So, this will definitely enhance the clinical application of liquid biopsy for MRD, I think, and this is very important for oncologists in colorectal cancer field, you know to drive and to guide prognostication, and at the end, also the use of adjuvant treatment. Then of course there are also other applications, for example, in rectal cancer also MRD is important because it can support upfront intensive treatment to aim to non-operative strategy, and under this regard, at Niguarda, we conducted the no-cut trial, and the results were presented at ESMO last year and the results important part in ctDNA for improving the prediction of complete response. And also, I would like to highlight how the newer adjuvant trial will, I think, really be impacted by ctDNA. Because with ctDNA, I think that we will aim to have personalized adjuvant treatment, because once you are focusing on a population of MRD positive patient, probably also some targeted agents that we know are not now used in the adjuvant setting, at the end probably will prove to be efficacious because you are aiming to the right population. 

Giancarlo Pruneri: Andrea, I fully agree with you that liquid biopsy is absolutely the new goal in precision oncology. What I always wondering is that now we are forced to switch from clinical trials to clinical practice, and this is something that is forcing us to revolutionize, you know, our infrastructures and the way we are working on precision oncology by integrating liquid biopsy in our clinical paths. In this regard, precision oncology is experiencing a technological and cultural revolution, as you just mentioned: how do you see scientific research in oncology and particularly in colon cancer evolving over the next five years? 

Andrea Sartore Bianchi: Well, yes, I think that we are definitely entering a new phase, as you are mentioning where possibly, you know, technology, biology and the clinical inside the clinical part will be more convergent. And possibly ctDNA will be crucial for this transition, I think. So, one of the main advancements, I think it will be, again, to have more and more ctDNA integrated as a routine tool. So, think about prognostication. I foresee that possibly on top of the TNM, we will have a, let’s say a B parameter, the B for blood B1 or B0, depending on the presence or absence of MRD after surgical resection. So, this will be, I think, an advancement and also many more applications of liquid biopsy for driving treatment, also in the metastatic setting. But this is diagnostic, this is a diagnostic advancement. On the treatment front I see some trends that I think will be more and more important over the next five years, I think that we are increasingly going to move target therapies earlier on in the treatment pathway, so, we are seeing this, for example, the first example is Braf inhibition. So, we very recently had this important data of the breakwater study where for the first time, we have a targeted therapy against an oncogene in colon-rectal cancer that is Braf. Now with results also from the very early part of the patient in first line, so, chemo plus encorafenibcetuximab. So, this is an application of precision oncology in first line, and I think that we will see more and more targeted therapy moving in this space earlier on in the treatment pathway. This is very important for rectal cancer, because there is a lot of heterogeneity, intratumor heterogeneity, so these accumulate over lines of treatment, and it’s more and more difficult to treat patients after first line. And, on the same side of treatment, I think that we will see more and more about RAS inhibition. This is a huge chapter of oncology in general, but also in colon-rectal cancer we have 50% of patients with RAS mutation and I think we will expand treatment beyond the G12c, but also we will be able to have newer drugs and with Pan-ras inhibitory activity, so this will be very, very impactful on the field. R2 also, you know that we our group provided first results about the R2 amplification and the possibility of having a treatment with a dual vertical blockade for the patient with R2 amplification, and I think that also here we will see results from first line treatments and possibly we will have sequencing in this patient.  

So, we have we will have more patients treated with Anti-R2 strategy receiving possibly more course of another Anti-R2 regimen, let’s say a rechallenge in this field, this is completely new. And finally, I think that one of the most important player will be the drug development, meaning that the targets are there, I think that we know about the most important genes that can be targeted, but we will have newer agents that are more impactful, and I think firstly to ADC antibody drug conjugates, so especially bispecific, and this may bring this new mechanism of action also to patients with colon-rectal cancer, and this I think will be very important also in this histology. 

Giancarlo Pruneri: Andrea, I mean, this is very fascinating because I think that what we are going to accomplish now is getting more and more reliable and robust in identifying the patients that should be treated with a molecularly driven therapies. And in the same time, for example, by using minimal residual disease, we could spare the side effects to patient with particular and, I mean, prognostic, and, you know, better prognostic, clinical course, so, I think that, you know, coupling these two approaches will be increasing, you know, the chance to be cured to our patients. As you know, Tumori Journal has promoted a discussion on the ethics of scientific publishing. What are the aspects of a scientific journal that you consider a priority when deciding to submit your work? 

Andrea Sartore Bianchi: Yeah, that’s a great question. It’s a very up-to-date topic, I think, because we have increasingly more and more journals every day, a lot of publications and also a lot of confusion in some for some aspect in clinical research and in also preclinical research. I think that what should be valuable and of course are the gold standard of scientific integrity, so the peer review process is so important. Also, there are issues also on this side from big journals in terms of having the proper compensation for a good review process. But this is, of course, very important. Also, I would say that I really appreciate those journals that foster interdisciplinary publication, interdisciplinary thinking. This is very important in oncology, and I think this is an aspect that is important. Of course, nowadays it’s important that a paper should be accessible, so accessibility is a key point for researchers to reproduce results. So, I appreciate of course, journals with open access options. And that’s important. And also, I have to say that it’s also nice to see, you know, journals becoming more engaged through social media, podcasts and other activities to, you know, to disseminate knowledge and, and results of paper.  

So, this is, I think, what Tumori is doing, what Giancarlo you are doing with your journal, and I think it’s very important because it really helps bring science closer to people, researchers, but also to communicate to the broad public and at the end, making communication of research more accessible and timely. 

Giancarlo Pruneri: I mean, Andrea, I completely agree. I mean, I think that what we are going to do is to keep discussing this issue because, you know, the ethics in publication is one of the most, uh, important and hot topics today. We have plenty of predatory journals, there is I mean, there is an editorial that came out in a Nature Medicine this month underlining the importance of choosing the right journal for publishing and for disseminating reliable data. Today we have discussed with Andrea about research and care and in, especially, in colon-cancer, but also in general we had, his view in the future of research in colon cancer. And, we have also discussing of, you know, life and attitude of the researcher Andrea Sartore Bianchi. And Andrea, I mean, thank you so much, it was really a pleasure having you on TJ talks. 

Andrea Sartore Bianchi: Thank you Giancarlo. It was a pleasure also by my side. Thank you so much! 

Giancarlo Pruneri: TJ talks is available on our website tumorijournal.org and on the podcast platforms. Follow us on X and LinkedIn to always be updated on cancer research and clinical practice in oncology. I’m Professor Giancarlo Pruneri, editor in chief of Tumori journal. Thanks for listening!

Lorenzo Ferrando: Welcome to TJ Talks – Conversation about Oncology by Tumori Journal, the peer-reviewed oncology journal dedicated to the dissemination of key oncological themes and advancements. I am Professor Lorenzo Ferrando, Section Editor at Tumori Journal, and in this episode I’m really happy to meet Professor Matteo Benelli, Associate Professor of Biochemistry at University of Florence. Matteo, thank you for being here with us today.

Matteo Benelli: Thank you, Lorenzo, for the invitation. It’s really a pleasure to be here and to talk with you about what I think is partly our shared passion.

Lorenzo Ferrando: Yes, indeed. So, Matteo, the first question for me would be what led you to specialize in bioinformatics?

Matteo Benelli: Well, thank you, Lorenzo, for the question. It was really an opportunity that happened by chance, I would say, because I was finishing my master’s degree in Nuclear Physics when I heard about a group at Careggi Universital Hospital that is the main hospital here in Florence that was offering a sort of predoctoral fellowship in what at the time was an emerging field, the bioinformatics. And I have to say that I didn’t know anything about bioinformatics at the time. But then, as you can imagine, studying nuclear physics, I had some programming experience because I knew how to analyze and interpret massive amounts of data. So, I took this opportunity and started working with R, a programming language that was new to me at the time and start analyzing data from high throughput technologies that it was back in 2008. So more than 15 years ago. And so, the dominant technology at the time were microarrays, then were followed by NGS. And after that, I joined an exciting PhD Program at University of Florence that was called Non-linear Dynamics and Complex Systems. That was really a multidisciplinary because we were physicists, biologists, psychologists, mathematicians that collaborate to study and solve complex systems. And you know that biological systems are maybe the most fascinating example of this complexity. So, to conclude, the course of the career that led them to specialize in bioinformatics, then after my PhD, I moved to the laboratory of Francesca De Michelis at University of Trento, because I wanted to really specialize in a specific field that is Cancer “Omics”. And that experience was incredible because it really shaped my approach to research. And the two years that I spent there were fantastic. I had the chance to contribute to really important studies primarily focus on advanced breast cancer. And I would say that consider that experience may be the most important one in defining my career, because after that I had clear ideas that I wanted to do exactly that work.

Lorenzo Ferrando: So, I think that it’s a very interesting and rich journey, like citing a very famous song. It’s a long way if you want to do bioinformatics basically. Right?

Matteo Benelli: Yes. Very long.

Lorenzo Ferrando: Yeah, but really exciting. So, you are the Co-Principal Investigator of AURORA, which is an international research program with a very important aim, which is improving the knowledge of the molecular mechanisms leading to response or resistance to therapy. Metastatic breast cancer patients are a very important effort from Europe and from several labs here in Italy, Belgium and Spain. So, what led you, what inspired you to join the AURORA program?

Matteo Benelli: Yes. You know, AURORA is an incredible effort and incredible project. And my involvement in AURORA is thanks to one person who changed the following course of my career, who was Angelo Di Leo. Because indeed, after completing my Postdoc at University of Trento, I moved to the oncology department at the hospital of Prato that was led at the time by Angelo, who was a really an internationally renowned breast cancer oncology. And he offered me an incredible, and I would say, unexpected opportunity that was to establish my first lab, the focus on bioinformatics and cancer omics. And this was especially, um, surprising because Prato, that is my hometown, is known for its textile industry, not cancer research. And so, I took this opportunity and started my first lab there. And while I was running the lab, Angelo invited me to join AURORA as an expert bioinformatician because Angelo at the time played a key role in the Breast International Group, that is the organization that coordinates this study and working on AURORA. You know, Lorenzo also, I think is and was at the time an exciting experience because it brings together a multidisciplinary team of clinicians, molecular biologists, bioinformaticians, pathologists. And the project is unique because, as you mentioned before, it provides access to primary tumor metastasis. And we generated the data multi-omics profiling of these samples to better understand how breast cancer develops resistance to human therapies, and which are the molecular alterations that characterize metastasis. At the beginning, we work very hard for two, maybe three years, and our work led to the first publication of this project that was published in Cancer Discovery. So, what was the path that led me to assume the role of Pi? This was quite incredible for me because at the time, AURORA was led by two clinical co-pis. And after the manuscript was published, I think that, you know, our work received recognition. And I think that it became clear to the Breast International Group that a more technical, non-clinical lead, was also essential to move the project forward. And so I was invited to join AURORA as also as Co-pi.

Lorenzo Ferrando: Yeah. I think that the fact that you join the AURORA program as Co-pi is like a great opportunity for the right person, the right moment for the right person. And I think that it is clear that bioinformatics is getting more and more central and relevant in this kind of cancer research. So how does bioinformatics, in your opinion, contribute to understanding the evolution of breast cancer, especially in identifying new therapeutic targets? And especially can you share if you can, of course, some of the most exciting findings that your team has made so far.

Matteo Benelli: Yes, I agree completely with you, Lorenzo. Bioinformatics has become an essential tool for studying cancer. AURORA is a prime example. And because I think because it enables to deal with the complexity of cancer. For instance, helping us to understand the emergence, the evolution, response to treatments, identifying new therapeutic targets, as you mentioned before. And this is because today cancer research relies on high throughput biotechnologies such as sequencing that we use every day, but also some new technologies that we are approaching in the in the last years that are imaging techniques that generate a data set, including thousands to millions of variables. And bioinformatics has the tools, the methodology that can deal with this complexity, but also enable to identify the most relevant features among these huge amounts of data. And the AURORA, which you mentioned before, is an example of how our expertise is essential in understanding how breast cancer develop resistance to therapy, for instance, because with our methodology, we are able to integrate multiple data to analyze simultaneously different layers of molecular information, such as genomics, transcriptomics. Because our goal in this project is to investigate molecular alterations acquired by tumors, to identify those that could be targeted by specific treatments. But in general, in addition to AURORA, the primary focus of the research of my group is in precision medicine, precision oncology. And among the most exciting findings you were referring to, I would like to mention that we work hard on circulating biomarkers. You know very well, particularly to the study of epigenetic alterations such as DNA methylation. We know, you know, that the liquid biopsy, especially the analysis of circulating tumor DNA. That is, these fragments of DNA released by tumors into the bloodstream is exciting and is an emerging tool for monitoring disease status in patients with cancer. So we are working on developing new methods that are both from the lab point of view, but also computational, obviously, that exploit these epigenetic features to improve the technical aspects of this test, so to improve sensitivity and specificity of this assay, but also to going beyond, because we would like in the future to have a phenotypic characterization from these non-invasive tests, a sort of capability that is only mainly done on tissue biopsy. We would like to have the possibility to do this also in a non-invasive way.

Lorenzo Ferrando: Yeah. I think that we could continue discussing this kind of topics for the entire day. I mean, it’s really exciting, but as you said, I think it’s a matter of complexity. I mean, informatics is just a very central part of cancer research, and it’s very complementary to the other domain of knowledge biology, medicine and bioinformatics as a tool to unlock the capability to answer very complex questions because technology is evolving like super-fast. The data generated is getting huge, really difficult to handle to manage. So, informatics has the tool to answer this kind of new wave of complexity. You know.

Matteo Benelli: I agree. And uh, maybe the most important term for us is, and for us, studying cancer is multidisciplinarity. So orthogonal and complementary skills. So, this is very important. Bioinformatics plays a key role in complementing the division.

Lorenzo Ferrando: Yeah. In fact, the next question I was thinking about would be how do you think bioinformatics will shape the future of personalized medicine? But now the question after listening to you is how is shaping the present right of personalized medicine?

Matteo Benelli: Yeah, I think that I agree with you that will and is playing a central role in cancer research and in personalized medicine. And let’s think about, for instance, the Molecular Tumor Board. Now are defined as multidisciplinary because they are, in terms of clinics, multidisciplinary. But imagine that in a near future these boards will involve clinicians as currently are involved in from different disciplines, but also molecular biologists, bioinformaticians that will help a clinician to interpret the results that they have, for instance, received from a comprehensive cancer gene panel test where hundreds of cancer genes are screened, but only few alterations are important to decide on the management of the patient. So, I think that this integration of our skills in these boards will happen soon. Hopefully soon, will happen for sure, but I hope also soon.

Lorenzo Ferrando: Yeah. You talked about the very hot topic here, the MTB right. Uh, let’s discuss a little bit about what does it mean to be a principal investigator, a Pi, in this country, in Italy. And how do you see the future of bioinformatics in this country? What are the challenges? You know, being performative and especially a principal investigator in bioinformatics?

Matteo Benelli: Yeah. So compared to the other countries that we know very well, Europe and also US, one consideration that we can do is that we are few.

Lorenzo Ferrando: True! Unfortunately, it’s true.

Matteo Benelli: Especially in relationship to the needs at least talking about the academic research. So, I think that this is due to the absence of specific academic course for sure, but also maybe most importantly, to the absence of a biotech industry, a solid biotech industry that is able to employ people with our skills out of academia. You know that being few can be seen as you are in a privileged condition because it’s easier to collaborate with other colleagues. But I think this has also some negative aspect related, for instance, to a limited competition that is usually not beneficial for improving the quality of the field. In some cases, your collaborators tend to consider you as a sort of service for their project. And this is really a problem for us because this situation limits the definition of bioinformatics as a valid research field. However, you know that being a Pi also means carrying on research projects and managing the lab, searching for funds. And I have to say that in Italy we are lucky because the Italian Association for Cancer Research is really a pillar for supporting us in our everyday work life, because they provide hundreds to thousands of researchers with the funding to conduct cancer research, including also researchers in the field of bioinformatics. And I am a recipient of a grant from ERC. So, I’m incredibly grateful for their support that they provide us for our activities. But, you know, regarding how I see the future of variable informatics in Italy, or last part of the question, I see it, I would say as bright because I’m optimistic for my group for sure, because I have a fantastic group of young researchers, both wet and dry, who work really with dedication and commitment. So, I am sure we will do some exciting work in the future. For the bioinformatics in general, I think it will be bright because the need for these skills will increase in the future. And I think also that we will assist a more balanced representation of computational water researchers in the in the future. But however, we also have to talk about some obstacles that we have in Italy. And we, Lorenzo, we discussed this a little bit in the past out of this podcast, because, you know, that Italy has some rigidity in the, in the system because it requires you to be, um, I mean, sort of labeled into specific categories, no disciplinary categories. So molecular biology, oncology, genetics, biochemistry. But our work is interdisciplinary per se. So, the categories do not easily apply to us. And we should work in some way to try to dismantle this bureaucratic rigidity and just let the research flow.

Lorenzo Ferrando: Yeah. I think that you touched a very relevant issue here because informatics being so hybrid, you know, touches different fields of from biology to medicine. So my hope and I think it’s your hope as well, is that in the future institutes the governments will be a little bit more elastic, let’s say, and will be more inclusive and maybe will Recognize officially in public institutes, hospital, etc. the professional figure of the Bioinformatician, which is now a little bit, you know, it’s not that easy to include and offer a long term job as a Bioinformatician is in a public institute. So, let’s see how the future will shape this next generation figure of researcher.

Matteo Benelli: I agree, Lorenzo, I think it will happen with some delay, obviously, because we are in Italy, but this is a real need, so in some way will happen.

Lorenzo Ferrando: Yeah, the need is there. So, let’s see. In the meantime, technology advances and as you know better than me, everyone like everyone is talking about AI and its use. So related to bioinformatics, what is the role of AI in analyzing big data and in this case big genomic data? Are there any emerging technologies or approaches that you are particularly excited about?

Matteo Benelli: Yeah, I agree with you that today AI has pervaded our language because everything is AI, but maybe nothing is important. Or I would say cool without AI, you know, you can stay out of AI because we have seen incredible stories of success of using AI in medicine, pathology, genomics. But these results have created an enormous hype around AI and obviously in our field. So, I think that we were in some way experts of AI, and we have always worked with different forms of AI, including also the classical machine learning, for instance, in the past. We have unethical role in not promoting too much AI. For instance, in cases where AI is not needed because you know that in some way it can be, AI has some disadvantages compared to other more classical approaches. And I think that there are many also of these disadvantages. One maybe the most important is that it depends on training using a huge amount of data to train these that are called the models now that are the core of the AI. But these models now in particular, if you think about the diagnostic test that exploit AI are proprietary of private biotech companies that are the only that have the budget to create them. So, think about, for instance, our health system. This situation could create some issues related to the dependency that our health system can in some way have with this private company. So, to be clear, I am a fan and supportive of AI, but only when it is needed. In other cases, let’s try to stay with more simple and also explainable approaches, because also explainability is a huge problem. I think that we are going to lose with some AI approach in the future.

Lorenzo Ferrando: Again, super interesting topic here because AI is really pervasive. Like everyone can use it, but whenever you talk about AI in diagnostics and etc., there is no competition. There is this gigantic investment in private companies developing tools. And they are really, really, really hungry for new data. And it can happen sometimes that public hospital can sell data sometimes, not sell is not the right word, but you know there must be some regulation between these private companies hungry for new data, hungry to develop new models and the data, and the data are of the people. Right? It’s a very interesting but complicated.

Matteo Benelli: Also, I have no mention. I did not mention another maybe limitation with the AI. That is the I have some doubts about some the issue of reproducibility because AI works very well when the context is clearly defined. No? The models are built on some training data that depends on some specific, for instance, assays, some specific technologies. But is it possible to translate this assay from the central lab in these private companies to a hospital? So how the model translates and how the model performs when we translate from the private company to the hospital? This I think it’s an open question. It’s problematic for the future.

Lorenzo Ferrando: True. So, you are a professor at University of Florence. Your lab is plenty of brilliant young researchers and students, but your lab is not the most common bioinformatics lab in this country, right? So, there are not so many labs like yours. And what advice would you give to young researchers who want to enter this field?

Matteo Benelli: I would have many advices, but maybe the most important one is to be prepared to work at the boundaries of many disciplines and languages, because our main role, if I have to define a single one, is to first understand or ask ourself a diagnostic, clinical or molecular question, then exploit our skills, our knowledge to solve this problem using computational statistics and mathematical strategies. And then we have to translate back the results that we obtained to molecular biologists, clinicians and so. So, we have to learn multiple languages because a clear communication between the declinations, the molecular biologist, for instance, and us is essential because we have to reach together the goal of solving some clinical question. And knowing multiple languages means also knowing multiple disciplines, or at least the discipline bioinformatics is applied to. So, I would suggest to interested students, researchers coming from computer science, engineering, physics, mathematics, statistics, study biology or medicine. The other way around, for those coming from biology, biotechnology and medicine, study statistics and computer science.

Lorenzo Ferrando: Yeah, I think that you said it perfectly. I mean, don’t be afraid. One student studied biology, right? Okay. Now, after finishing the university, if you want to do bioinformatics, he must study statistics and sometimes can be, you know, let’s say not trivial, right? And the other way around. And in my opinion, sometimes it’s more difficult the other way around. So, a Stem guy wants to study a little bit of cancer biology. So, it’s difficult at the beginning, but it’s really rewarding.

Matteo Benelli: Yeah. You have to be very committed, dedicated. But I think that at the end the results are clear.

Lorenzo Ferrando: Yeah, absolutely. Matteo, we are going to the end of this very nice and super interesting conversation. But where can people follow your work and learn about these really exciting AURORA program?

Matteo Benelli: Oh yes. Lorenzo, thanks for the question. So, you can have a look at my research group on the website of my university department in Florence. The site is sbsc.unifi.it. You can follow me and all news about the research we are doing on LinkedIn, my personal page. While regarding AURORA, there are much information on the website of the Breast International group that coordinate the study. The website is big against cancer.org. If you are interested, you can read the first manuscript that was published on Cancer Discovery a few years ago. It’s very easy to retrieve from PubMed, Google scholar, first name is Philippe Aftimos. He’s a friend of mine and co-pi of the study. But also, for other many, many new exciting findings from AURORA, I am sure you will hear very soon.

Lorenzo Ferrando: So, to all the listeners, I really encourage to follow Matteo because there are some very interesting surprises, let’s say, or publication in the really next future. So, it has been my pleasure to have you here. Thank you so much for being with us on TJ Talks.

Matteo Benelli: Thank you again, Lorenzo. And it was really a pleasure also for me chatting with you.

Lorenzo Ferrando: In this episode we found out how bioinformatics is transforming oncology from understanding breast cancer at the molecular level to uncovering new therapeutic targets. Professor Matteo Benelli shared insights from the AURORA program and highlighted the impact of AI on personalized medicine. We also explored the future of bioinformatics in Italy and heard valuable advice for the next generation of researchers. TJ Talks is available on our website tumorijournal.org and on the best podcast platforms. Follow us on X and LinkedIn to always be updated on cancer research and clinical practice in oncology. I am Professor Lorenzo Ferrando, Section Editor at Tumori Journal. Thanks for listening!

Paola Perego: Welcome to TJ Talks – Conversations about Oncology by Tumori Journal, the peer-reviewed oncology journal dedicated to the dissemination of key oncological themes and advancements. I am Professor Paola Perego, Section Editor for Pharmacology of Tumori Journal. Over time, there has been a shift in understanding the mechanisms of drug resistance of tumors: from considering just the relevance of genetic features of tumor cells, to also thinking of their plasticity, driven by epigenetic mechanisms. And we also look at the tumor as an ecosystem composed by tumor cells and several players from The Tumor Microenvironment. To discuss approaches to overcome drug resistance in cancer, with reference to mechanisms and experimental models, I’m happy to welcome Professor Sven Rottenberg. Sven, thank you so much for joining us to TJ talks.

Sven Rottenberg: Hi, Paola. Thank you very much for inviting me.

Paola Perego: Sven, let me introduce you to our listeners. You are Chair of the Department of Infectious Diseases and Pathobiology at the University of Bern, where you are investigating cancer drug resistance. Your group studies “Genetically Engineered Mouse Models of Human Breast Cancer” uses drugs that are frequently employed in the clinic. Okay, here’s my first question: what are the key challenges when it comes to anti-cancer drug resistance?

Sven Rottenberg: Yeah, well, drug resistance is unfortunately still the most common cause of death of patients with metastasized cancer. So, for example, if you have a tumor with breast cancer, with a Her2 positive receptor, and there’s a targeted therapy, then challenges that often many of these patients do not respond upfront. So that’s a first key challenge in this response to predict which patients really benefit from a certain therapy. And then another big challenge is that those patients that do respond, that where the tumors basically melt down, that the tumor cells in these patients cannot be completely eradicated. So, you have a few residual cells that basically persist. And from these residual cells then tumors relapse. And that brings me to the third challenge is that these relapsing tumors then often show secondary resistance. So acquired resistance and no longer respond to the treatment.

Paola Perego: Sven, how can your models be useful to define drug resistance mechanisms and particularly their overcoming?

Sven Rottenberg: So basically, we work with genetically engineered mouse models. And that has the advantage that we can, under very defined conditions, introduce genetic alterations and study these in mice that have a fully functional immune system. And the advantage of the mouse models is also that there is less of this genetic variability that we see in patients, which makes it much more difficult to identify, clearly identify mechanisms in patients. Moreover, the clinical trials in patients are very expensive, and they are often not enough patients to test all the various combinations. So basically, I think that our models are complementary tool where we can first check what are the most promising approaches to overcome resistance. And then these can be further tested in clinical trials. Moreover, we also have in vitro tools, so we have 2D cell lines, also 3D organoids that we have derived from these models, and so in these we can also do functional genetic screens. While these functional genetic screens you often get many hits and you’re not exactly sure which of these hits is now really relevant in vivo setting. And there this overlay between these in vitro assays with our models I think is also a powerful combination to see which mechanisms are identified in vitro are really relevant in vivo.

Paola Perego: Sven, what type of treatments are you studying?

Sven Rottenberg: Well, we are using novel targeted inhibitors that are now also frequently used in the clinic. We also use immunotherapy. We are looking also at newly developed therapies, but we are also looking at classical chemotherapy and radiotherapy because they are still frequently applied in the clinic. And so basically, we are particularly interested in treatments that are really used in the clinic.

Paola Perego: So, is there a common mechanism that you find in your models and that we can target?

Sven Rottenberg: Well, unfortunately not really. So, it’s very interesting that even in our genetically defined models, we see that there are really many different ways how these tumors can acquire resistance. So, for example, many of the current anti-cancer therapies they target a defect in the repair of DNA damage. So many tumors have lost DNA repair pathways. That’s how additional mutations occurred. This is how the tumor evolved. And so, this one can target with different treatments. And often these tumors that lack this DNA repair are very sensitive and will really shrink substantially. However, they are not easily eradicated. And then the tumors regrow, become resistant, and in these resistant tumors we see that they now manage to deal with the DNA damage again. And they do that in very different ways. But, maybe if you want what is common about these mechanisms, is that basically the way how the cells can deal with the DNA damage well, has improved, but in very different ways.

Paola Perego: But why is it so difficult to eradicate tumors that are initially drug sensitive?

Sven Rottenberg: Yeah, that’s a very good question. And this is also really very interesting. And well, we think that there are several mechanisms behind that, and they are based on the intratumoral heterogeneity and also on the plasticity of the tumor cells, because the tumor cells can basically relatively easily go from one state to another. So, one mechanism in this resistance is, of course, that in the tumor upfront by chance, because of this large heterogeneity, there may already be some mutations present in some cells that give them an advantage during treatment. And then of course these cells will be selected out and be resistant. Another option is that these mutations occur then during the treatment and also then basically acquired. But what I find even more surprising is that there are tumors that are, well, that are even sensitive again, when the tumor relapses, but still the cells cannot be easily eradicated.

Paola Perego: How is this possible, Sven?

Sven Rottenberg: Well, yeah. So, there’s again a very good question. So basically, our research suggests that these persisting tumor cells, we call them “drug tolerant cells” are transiently lying low or hibernating, if you want, and thereby avoid the cell death, because the cell death is often inflicted when cells replicate their DNA. And basically, when these cells are lying low and then eventually the drug is gone, then they reenter the cell cycle. And we think that there are epigenetically regulated programs behind this involving reprogramming factors and chromatin remodeling.

Paola Perego: So, is there a role for the tumor microenvironment in this context?

Sven Rottenberg: Yes, absolutely. So, because it’s very well possible that the tumor microenvironment influences these epigenetic programs. And this is indeed part of our current investigations.

Paola Perego: This sounds somehow frustrating. Is there no way to kill this persisting tumor cells?

Sven Rottenberg: Well, in our model systems, we found that if sufficient DNA damage is inflicted, also the persisting cells will give in and eventually be eradicated. But of course, this high dose chemotherapy has obviously more side effects, and we are currently investigating new vulnerabilities of these persisting cells.

Paola Perego: How do you do this?

Sven Rottenberg: Well, we successfully managed to mimic these residual cells in 3D organoid cultures in vitro. And this gives us now a very useful tool to apply more high throughput genetic screens to test which genes are really essential for these residual cells to survive. And our hope is that, when we inhibit the proteins that are encoded by these genes, the tumors no longer relapse.

Paola Perego: It sounds like there is still a long way to go. Could results from your research be applied to the clinic?

Sven Rottenberg: Well, we work for example, with mouse models for Brca1 and Brca2. Brca2 mutated breast cancer, and in these we found that combination therapy where the tumors first treated with platinum based drugs, followed by a maintenance therapy with Parp inhibitors, is very promising, and this treatment approach could then indeed be proven to be also highly effective in patients with Brca1 or Brca2 mutated breast and ovarian cancer. And this has become now a standard of care for these specific tumor subtypes. Moreover, we have also identified a channel which is crucial for platinum drug uptake. So how the platinum drugs enter the cells. And we found that in some tumors this channel is dysfunctional. And then specific platinum drugs are not the best choice for these patients. Or because they do not enter the cells, they do not target the DNA, do not induce the damage then. And so, we are currently testing ways to identify these patients and look for other treatment options that might be better suited for these individual patients.

Paola Perego: If drug-resistance arises, one would hope that this comes at a cost for the resistant cells and there may be a new vulnerability that one can target.

Sven Rottenberg: Absolutely. This is indeed we find some or we find examples in our models where resistance to one type of therapy increases the sensitivity to another one. And finding such new vulnerabilities of the resistant tumor cells is an important part of our research.

Paola Perego: Do you think that this is the future of cancer therapy? When resistance comes up, administering new combinations of drugs that then make use of the new vulnerability gained.

Sven Rottenberg: Yeah. So, I think there will be definitely cases where this is useful, but unfortunately there is also the frequent clinical observation that tumors that have the acquired resistance are also resistant to all sorts of therapy. Showing this, a so-called pen resistance and the precise mechanisms behind this pen resistance are not entirely clear. So, one mechanism for tumors that originally have a defect in the DNA repair is certainly this restoration of the DNA repair function, like genetic reversion, the case of Brca1 and Brca2 mutations. Because if the Brca1 or Brca2 work again, of course there’s no longer this sensitivity to or increased sensitivity to DNA targeting or DNA damage inducing drugs. But basically, for many of the tumors, we still do not know exactly what this is and or what causes this pun resistance. And therefore, I think that our goal should really be to try to eradicate the tumors upfront during the initial cycle of the treatments and avoid that these tumors relapse and subsequently acquire this pen resistance. And so I therefore think that the understanding of why tumor cells in a sensitive tumor persist is very important to understand, and also to find ways how to specifically kill these residual tumor cells. I think this is really crucial to achieve the overall goal of really get fully tumor eradication.

Paola Perego: Sven, thank you so much for being with us on TJ Talks and good luck with your research.

Sven Rottenberg: Paola, it has been a pleasure. Thank you very much.

Paola Perego: TJ Talks is available on our website tumorijournal.org and on the best podcast platforms. Follow us on X and LinkedIn to always be updated on cancer research and clinical practice in oncology. I am Professor Paola Perego, Section Editor for Pharmacology of Tumori Journal. Thanks for listening!

Giancarlo Pruneri: Welcome to TJ Talks – Conversations about Oncology by Tumori Journal, the peer-reviewed oncology journal dedicated to the dissemination of key oncological themes and advancements. I am Professor Giancarlo Pruneri, editor in chief of Tumori Journal, and in this episode I’m happy to meet Arsela Prelaj, a thoracic oncologist who works at the National Cancer Institute of Milan and has recently become the director of the Artificial Intelligence for Oncology Lab. Arsela, thank you for being with us today. 

Arsela Prelaj: Thank you, Giancarlo, for inviting me in this fantastic podcast. 

Giancarlo Pruneri: First of all, I would like to share your story with your listeners. How did you become an oncologist and later on, the director of an artificial intelligence lab? 

Arsela Prelaj: Oh, thank you for this question. I think it’s a really funny story. So basically I am originally from Albania and I used to study in Rome and became a medical oncologist in Rome. And then I came here in Milan to practice my oncology, let’s say path as a thoracic oncologist. But however, I for my whole life I love math. So some years ago I wanted to do a PhD, and the idea, let’s say to do wet lab was a bit difficult, so I didn’t love so much wet Lab. So I love numbers and this is why I decided to focus more in dry. And I have seen, let’s say, different programs, including statistics. However, five years ago I saw this artificial intelligence PhD, and also inspired from my previous boss, Doctor Garassino, I started this interesting PhD, which I mean changed my life, I can say. 

Giancarlo Pruneri: And this is a very interesting and thank you for contributing to the development of science in our country. Listen, our listeners, they are very curious, you know, what activities do you carry out in your artificial intelligence lab? 

Arsela Prelaj: So basically, there are many activities that we are working on focused the AI on lab. It’s focused more in using AI techniques for oncology needs. Now I recently reorganized the lab, let’s say in this last year, because we have grown from 10 people to 30 people around. So it’s meant to be a joint research platform with Politecnico di Milano. And I divided the team in six different subgroups focusing in AI tools, the Radiomics group, the digital pathology group, also the translational AI, explainable AI, and more recently large language models. 

Giancarlo Pruneri: Wow, this is a fantastic Arsela. And listen, artificial intelligence has for sure enormous potential, but I’d like you to hear from you what are, in your opinion, three goals that artificial intelligence could achieve in the specific field of oncology over the next three years. 

Arsela Prelaj: Oh, this is a very good question. I mean, I hopefully let’s say I will focus on three goals. However, I really believe that not only in the next year, but also in the further years, there will be many fields that will be changed and started already to change. However, if we think about the short-term results, let’s say that the main focus for sure will be in practice the screening, because we have done a lot of advancements in terms of screening and the use of images such as radiomics images to differentiate, for example, between a good benign lesion or malignant lesion. The other very good piece of advancements, I think, is the digital pathology, which for example, with the recent advancements of foundation models, it has been very interesting to use all these labeled data that are spread within different cancer centers. And I think this can can be very relevant, for example, for a diagnostic task which are simple tasks, but also why not for the prognosis and prediction tasks. And the digital pathology is this next very relevant field. The other field, which I think will change within also the next year and is already changing the way we are using AI, is the large language models which are used, for example, in this case more for automatic tasks. For example how we can automatize data collection. Imagine how much efforts we put there now to insert our data one by one. So this can be really and not only for the data management but also for the administrative tasks. 

Giancarlo Pruneri: This is amazing Arsela. And of course, these are great opportunities for the future. But we know that there is always a downside, especially whenever you like to implement a new technology in medicine and in oncology in particular. So which are the current hurdles in the development of artificial intelligence in your field? 

Arsela Prelaj: So this is another very nice point. So I wanted to share with you I think that also here I can mention three points which are crucial in this case. The first one to my opinion is the digitalization process, which is not very easy because obviously we have to take a lot of decisions, for example, how we can build cool rooms, which are all these rooms with big hardwares within the hospitals. But on the other hand, we have also these cloud advancements. And so how we can use the cloud, let’s say possibility also to to run our tasks, so hard level tasks and the digitalization we know that have costs. However I believe that for sure in this case we will find a solution, at least to do big investments in long-term purpose. So this is the first one, the second one, which is another interesting point and I think still a very weak point is the ethical and legal frameworks, which to my opinion, it’s not only the simple things, because the ethical and legal frameworks are also linked with the normal data, not only with AI, but in field of AI, especially, for example, to adapt for the adoption of generative AI within clinical practice, we know that there are a lot of big advancements and logarithmic advancements in terms of oncology. And imagine the whole, for example, lawyers and all these persons can stay and can remain up to date among all these technologies. So I think this is a very big deal. And I think that putting more expertises and more, for example, lawyers that are dedicated only in these tasks can be a solution. And the third one is how we can adapt all these tools in clinical practice. I think this is one of the third and main point, and I think that, for example, with explainable AI and other techniques which try to explain doctors how these tools work and explain also the responsibilities in this case, I think this can can can be a type of solution. 

Giancarlo Pruneri: I completely agree with you Arsela. Beside the ethical and legal stuff for sure, implementing data storage within a hospital is for sure a tough task for the future. But you are drafting a brand new world where physicians will be interacting with artificial intelligence. In your view, what will be the relationship between doctors and artificial intelligence in the near future, and what benefits will patients gain from it? 

Arsela Prelaj: Oh, I think this is my favorite question, honestly, because I think that it’s very connected with the hurdle that we discussed before related to why we do not adapt today and we are not adapting very, very quickly today to the tools. I think that this interaction has a paradigm shift today. So what we are doing with AI is not only trying to develop them, not only trying to explain them, but also having the human in loop. So the human in this case gives some feedback to the AI tools that not only take the explanation, but also say if they are satisfied with these explanations. So one of the main things is that obviously the human in the loop and also the human feedback, so there is also this paradigm shift which I do not aim to high level of performance. But I would prefer maybe to have a lower performance in the tools but to have a very good explanation because this would allow me absolutely a very good adaptation. So this is the main point. I think that also, for example, the educational part, it’s very important because doctors need to be in the loop in the education and training, and they have to be specialized. For example, if we think about the radiologist, which is specialized and has to know a bit on radiomics and the same for the digital path and the oncologist, I think we need absolutely to exploit more and more the education, the training and the exchange between the two players. So the interaction of human and AI intelligence. 

Giancarlo Pruneri: This is absolutely fascinating, having a brand-new world in oncology where, you know, technology and doctors, they have a crosstalk. And this will be for sure benefiting our patients. So Arsela, thank you very much for being with us on TJ Talks. 

Arsela Prelaj: Thank you for inviting me. Thank you. 

Giancarlo Pruneri: In this episode, we found out how artificial intelligence is crafting the future of oncology. Arsela told us the hurdles in its implementation, but she learned how to overcome them to fully develop the oncology of the future. TJ Talks is available on our website tumorijournal.org and on the best podcast platforms. Follow us on X and LinkedIn to always be updated on cancer research and clinical practice in oncology. I’m Professor Giancarlo Pruneri, editor in chief of Tumori Journal. Thanks for listening. 

Luca Agnelli: Welcome to TJ Talks – Conversations about Oncology by Tumori Journal, the peer-reviewed oncology journal dedicated to the dissemination of key oncological themes and advancements. I’m Doctor Luca Agnelli, section editor in bioinformatics at Tumori Journal, and in this episode, I’m really glad to meet George Calin, professor at the MD Anderson Cancer Center in Houston in Texas. And first of all, hi, George, I’m happy to talk with you. Thanks for being here with us.

George Calin: Hi, Luca. My my pleasure to be here with you. And also because I was working years in Italy: “Piacere di essere con noi, è sempre un piacere parlare italiano e interagire con italiani. I miei migliori anni sono stati probabilmente a Ferrara quando ho imparato genetica molecolare”. It’s my pleasure to be with you. Thank you.

Luca Agnelli: Well, nice to start as such. So let me give a brief overview of your brilliant career, since we have to introduce you to our listeners. You earned your degree in medicine from the University of Medicine in Bucharest. And then you worked in Ferrara, you said before, by Massimo Negrini’s lab. And later you became a postdoc with the Carlo Croce at the Kimmel Cancer Center in Philadelphia and then at the Columbus University. And finally, in 2007, you joined the MD Anderson as a professor in experimental therapeutics. And now you currently serve in the Department of the Translational Molecular Pathology, in the Division of Pathology. I summarized also your primary research interests, I hope to do this correctly: the role of microRNAs and non-coding RNAs in human disease and cancers, the sepsis, the study of familial predisposition to cancers and last, but not certainly the least, you are the editor in chief of the non-coding RNA journal, where I collaborate with you as the section editor in bioinformatics as well. So a very impressive path, George.

George Calin: Thank you, luca. You are too kind. I think in life you have to be lucky. So I was lucky to be at the right moment, in the right place. And what I tell to my fellows, I had over 200 fellows in my lab in the last 20 years, is that parents you cannot choose. It’s unconditional love for parents in both directions. But the mentors, you can choose very carefully. And I had a huge privilege to have wonderful mentors in Romania, a great Cytogeneticist D. Stefanescu. Then I went in Italy, where Beppe Barbanti Brodanò and Massimo Negrini were wonderful mentors in Ferrara, and then in Kimmel Cancer Center, Carlo Croce. So I had a lot of wonderful training in my life. Then I was very lucky to have excellent fellows who work with me because, let’s be fair, they are the people who are working in the lab. They are our mind and our hands. You have to make them believe in what research you are doing, and also you have to you have to teach them that science is about making discoveries at first, but at the end, they are the ones who move forward the science and then push forward. So really, I was lucky. And also I never pay attention to the hours of working because I was initially a gastroenterologist and intensive care physician. So I’m used to work and work and work, and in fact, in the United States only the sky is the limit for science. So again, you are very kind. But I was really a lucky one. Thank you.

Luca Agnelli: Yeah, wonderful. George, could you repeat the number of fellows?

George Calin: Over 200, because I think I started in a communist country. You know, 1980s Romania was a communist country, and genetics was forbidden because it was done by reactionary Americans and Western people. So I learned by myself first years molecular genetics and genomics in cancer. So taking from here, the point was that I have to train as many people as I can to widespread the knowledge on microRNAs. And I was lucky to be with Carlo Croce as the first one who discovered microRNA involvement in cancer. So really we have to widespread, I would say, an excellent discovery and the opening of a new field in medicine and in genetics.

Luca Agnelli: Yeah, that’s fantastic, and it’s the first very important message of this podcast. The first question can only be about the event of the year, you know, the Nobel Prize in Medicine, awarded to Victor Ambros and Gary Ruvkun, and 2024 is the year of the Nobel Prize for all the people who study microRNAs and their role in the post-transcriptional regulation and their role in cancer. But now my question is not about the past, but about the future. What challenges does non-coding RNA research have to face today, in your opinion?

George Calin: So it’s a wonderful question and it’s also well timed because this week starts the Nobel Prize ceremonies in Karolinska, so Gary Ruvkun and Victor Ambros will be there. So it’s wonderful timing. And I think it’s one of the most well-deserved at a long listed Nobel Prize, because it took 31 years from the time of discovery and publication of the two cell papers until they got the word, so it’s a wonderful time for microRNAs and for the teams that work with Ambros and Ruvkun. So the past of microRNAs is wonderful because we know so many things on how microRNAs are functioning, how many microRNAs are in the human body, over 2500, how they are involved in cancer hallmarks and in any type of disease. What I think is important is in fact, what you ask: the future. And the future will be developed, in my opinion, on two different directions. One is a biomarker development, how we can use the microRNAs from all the tissues and most important, from all the body liquids (plasma, urine, cerebrospinal fluid) in order to identify early cancer occurrence, early metastasis, dormant cells, minimal residual disease and any other type of clinical characteristics. This is a big challenge because for proteins it took quite 50 years to have the first proteins as biomarkers for different type of diseases. The second, which I think is extremely important, is the therapeutics. And what is the issue with new therapeutics is the fact that all of us, we compare what we create new therapeutics with a huge success of checkpoint inhibitors. And in fact, checkpoint inhibitors are a revolution. I say that I’m very happy to be to be here and everything we are doing in non-coding RNAs from now on as therapeutics will be compared with this huge success. In 1997, scientists got Nobel Prize for siRNAs and only in 2020, the first clinical trial with siRNAs were very successful. So I anticipate in the next decade microRNAs will go into clinical practice. And I tell to all of you who are listening one idea: start developing small molecules targeting RNAs. It’s a strange idea. We develop small molecules for proteins. But you who are listening, if you are a chemist or if you are love science seem to the concept of targeting RNAs with small molecules. Why is this is an important concept? Seeing how many of your friends colleagues in Italy, in Romania, my home country, in the United States suffered because of Covid 19 is because Covid 19 is generated by a single strand RNA virus. What would be the outcome of Covid 19 if the scientific, society and medical world would have small molecules targeting RNAs from 2017-2018? Very many lives would be saved. So I think next ten years, next decade will be a bright future for microRNA therapeutics if we are thinking out of the box.

Luca Agnelli: Thank you. So biomarkers and therapeutics, and  I would also remember that you were among the the group that for the first time discovered microRNAs as agents of cancer in chronic lymphocytic leukemia with Carlo Croce. So it’s an important step also for your career. And I would just focus on your career since in your journey between clinical practice and the research, you moved across three completely different worlds, from Eastern Europe to Western Europe, Italy, and finally to the United States. And my question is, what are, in your opinion, the main differences that you can highlight and if present, what are the common threads?

George Calin: Thank you. So I would start with the second part. What is the common in all these three places where I was. I was in contact with people who really love science and teach me science, as I told you from Romania, cytogenetics. Then I moved in Italy, where I learned molecular biology, and I saw my first time in the life of a pipette under Massimo Negrini. And then I went to the famous Carlo Croce, where we discovered the involvement of microRNAs cancer. So I think the commonality was that I pick really people who were able to teach me what to do and how to do because they had a huge passion for science. Now, what are the differences? Certainly each place is different. I would say, you know, I love Romania because it’s a place where I was born and the place where I was trained in school and medical school. I love Italy because it’s a place where I learn molecular genetics and I love Italy also because of the very nice, nice personalities of Italians. And I think Italians are very creative people, including in science. This is why you Italians have so wonderful scientists all over the world. And certainly I love United States. It’s the second time in these meetings when I say it, because only the sky is the limit in science. The amount of of money, the amount of intellectual interest, the amount of outstanding colleagues who are surrounding you is unbelievable. It’s a critical mass of people who are living to make discoveries and to do science. Many of them are clinician scientists, physicians with a love, a passion for science. So I would say in life is good to know how to take what is the best from each of the places. And I was lucky, thanks also to the fact that I had a family surrounding me. I have very good friends. I remain very good friends with Massimo Negrini, a very good friend with Carlo Croce, a very good friend with Drago Stefanescu, and I was able to keep these relations for what, for over quite 35 years from now.

Luca Agnelli: Great. Now a question, apart from your research activity, what are the best memories for these places?

George Calin: So I think in Romania the best memories is family because that is the route that you take the genes and you move forward with the genes that you took from your family. In Italy certainly is a friendship and the warmth of the people and the beautiful way that Italians are living and are doing science. And in the United States, certainly the scientific accomplishments and scientific results.

Luca Agnelli: Good, nice. But now, a tricky question. Where did you drink the best wine?

George Calin: Italy, Barolo. I’m a big fan of Barolo. I’m a big fan of Barolo all the time. When we go here to restaurants, we are drinking Barolo, one of the finest wines in the world. And it has this a little bitterness to make you aware that the life has a good side, you know.

Luca Agnelli: Great choice. I said before that you are the editor in chief of a journal, the Noncoding RNA Journal, and I’m happy to collaborate with you there. And I would talk about your editorial activity since I have a challenge for you now. There’s a topic we have already discussed informally in front of a beer I can remember in another occasion that I’d like to bring it up again here for our listeners. The era of peer review in impacted journals has come to an end? Or does it remain the guiding criterion for research? And if it remains the guiding criterion, what tools do you think that might be necessary to address the major issues of these systems, for example, the endemic shortage of reviewers?

George Calin: It’s a very important question, and I have to tell you that my experience as editor is much larger as a non-coding RNA journal. So I am a senior editor to cancer research and molecular cancer research, to molecular oncology, to molecular cancer, to cancer therapeutics, and so on. So I try to contribute because I think editing and reviewing and helping your colleagues to improve their manuscripts is an important, an essential part of research activity. I think a way to solve this shortage is quite simple: to have a payment for reviews, because reviewing is a very professional activity. You have to spend hours in order to give a good advice to your colleagues. So journals are making a large amount of money on the fees. I don’t know if you know, but Nature Communication is publishing over 10,000 papers a year. Wonderful papers and so on, but each cost many thousand dollars, so I’m a big proponent of a payment for the reviewers, and of course the reviewers have to do the review in a more professional way, on the side with the timing on how much they spend for the review and so on. So this will, I think, be a solution. Other journals try to go with a double blind option so you don’t know who are the reviewers, you don’t know who are the authors. I don’t think this will increase the amount of reviewers who want to take the job. Now you have also the eLife type of approach: doesn’t matter if the reviewers agree or not, your paper is published not as accepted, but as submitted. Anyway, I think this is a big issue, an issue which will be accelerated by the increase of the number of journals which is, on one side, a beauty of new science. You don’t depend on the 10-20 major journals in the field, but also it’s a big challenge because you don’t know what are the journals who have a good reputation and the ones who will disappear. And I have to thank you, Luca, for for your activity in the editorial board of of non-coding RNA, because really we need dedicated people like you for this type of activity, which is very important because in science not only is making discovery important, not only training our our mentees, but also helping our colleagues to publish great papers. And the help is in a fair and detailed review, which will also assure the accuracy of data and publications.

Luca Agnelli: Yeah. Well, George, I have to thank you for the great opportunity that you have offered to me in the past. So it’s a reciprocal opportunity. But you faced three great issues, so the payment of reviewers, the idea of double blind peer review and the opportunity to publish in the form of, for example, bio archives, so the content is as such without any kind of review. Recently, in the world of non-coding transcripts, the amount of omics data has increased exponentially. This is my field in bioinformatics field in particular, I am very interested in this topic and from my perspective, from my point of view, the risk of false positive data and results has grown as well. And my question for you now is should we invest much more resources on producing data or maybe it’s better to invest resources in utilizing the data that we already have generated? What’s your opinion?

George Calin: It’s a very clever question, and my answer is we have to use both in both ways, not only to continue analyzing the data, but also to spending for additional generation of additional data. So the data that are already generated should be analyzed with a new type of in silico methods, and you can know you are on the top of the field, and you can develop such new methods daily. But further, there are new types of analyzing and generating omics data that were not not available years ago. For example, I moved from from experimental therapeutics to translational molecular pathology right during Covid 2020 because I anticipated a huge development of spatial transcriptomics and digital pathology and in fact, in the last year, in the last 12 months, there were developed a lot of pathology assays in which you can do single cell analysis on a geographical map of the slides. This was unbelievable and unanticipated two-three years ago. So the way in which the technologies are developing is absolutely extraordinary. So I would answer to your question in both ways. Use more effort for what was generated to analyze, and don’t forget to put a large amount of money in these new type of technology who really change the way the medicine is done.

Luca Agnelli: Yeah, thanks George, i totally agree with you. So finally I would like to to play a game with you for this podcast. The game is: who would you throw off a tower? And I will start with Richard Dawkins or Stephen Jay Gould?

George Calin: None of them I like both what they they said,punctual evolution and genes are extremely important, so I will keep them alive.

Luca Agnelli: Okay. J.K. Rowling or Emmanuel Carrère?

George Calin: I’ll throw off Carrère because who doesn’t love Harry Potter? Everybody loves Harry Potter. So Rowling will be with me.

Luca Agnelli: Okay, and last but not least, Rafael Nadal or Novak Djokovic?

George Calin: I’d say Nadal because I pride Djokovic because he is born in Eastern Europe and it’s much more difficult to achieve greatness born in a place where the resources are less and exactly in the years of forming new personalities, you have to live that reality of less money, less knowledge, less amount of training camps, different type of diet. Nadal is wonderful, but I pride Djokovic because he started from a place where really is difficult to grow at this number one greatness.

Luca Agnelli: Great, great. So thank you very much George for being with us in TJ Talks. It has been a pleasure to talk with you. And I do really hope to see you in Italy early. So it’s a sort of invitation for you to come here in Milan to talk about microRNAs and science. So thank you very much.

George Calin: Thank you very much. It was my pleasure. So grazie mille caro Luca and good luck with the Tumori Journal because journals are a very important. It’s a way to widespread the news to all the world.

Luca Agnelli: Grazie George, un abbraccio.

George Calin: Grazie di cuore. Buona giornata a tutti. Grazie, grazie.

Luca Agnelli: To close this episode, I would like to recap the first words said by George. I was lucky in my life, and I want to do the same with my fellows. More than 200 fellows, 230 fellows to spread the research and science in university, in academic context and all over the world. TJ Talks is available on our website tumorijournal.org and on the best podcast platforms. Follow us on the social networks to always be updated on cancer research and clinical practice in oncology. I am Doctor Luca Agnelli, Section Editor in Bioinformatics at Tumori Journal and thank you very much for listening.

Giancarlo Pruneri: Welcome to TJ Talks: Conversation about Oncology by Tumori Journal, the peer reviewed oncology journal dedicated to the dissemination of key oncological themes and advancements. I’m your host, Professor Giancarlo Pruneri, editor in chief of Tumori journal, and in this episode, I’m happy to meet Giuseppe Curigliano, MD, PhD, and chair of the Division of Early Drug Development at the European Institute of Oncology in Milan, Italy. Giuseppe is also full professor of oncology at the University of Milan School of Medicine, among other things. Hi Giuseppe, thanks for being here.

Giuseppe Curigliano: Thanks for inviting me, Giancarlo.

Giancarlo Pruneri: Giuseppe, in the last two decades, you have had a very active role in clinical care and research, focusing on drug discovery in phase one trials. Can you outline how research on innovative drugs has changed the landscape of oncology in the last few years, and what is foreseeable for the next future?

Giuseppe Curigliano: You know, I believe the most important revolution was the agnostic approach to drug development. Specifically, we developed a lot of umbrella trial and basket trial in which selection of patients is not based on the organ of origin, but is based specifically on the genetic alteration of the tumor. I just would like to remind to you that many new agents have been approved based on agnostic development pembrolizumab and nivolumab in patients with microsatellite instability, larotrectinib and entrectinib in patients with intra fusion gene. Recently, BRAF inhibitors for V600E mutation and also for RET fusion gene positive selpercatinib. So it’s really a revolution where you select patients based on a genomic alteration.

Giancarlo Pruneri: So and this is something that we can forsee as a switch from an a histology approach to a more mutational profiling approach. So tumor profiling with all the available omics to date, we are just sticking on genomics, but in the next future we will be probably introduced to transcriptomics and proteomics as well, is a crucial step for translational and clinical research, but unfortunately it is not widely distributed even in the US and Europe and of course, also in Italy. Giuseppe, how do you think biology can drive clinical trials and real world care and how we could implement NGS profiling within our clinical practice?

Giuseppe Curigliano: This is really an excellent question. What I believe we have is to think about a precision oncology program in any single country. So we need to think globally, but to act locally specifically. NGS is not available all over the world. But if you centralize genomic platform, of course you can think about sequencing tumors of our patients in one single site, and then generate a model of network where patients can be referred to single centers to receive treatment. So coming back to your question, how we can drive clinical trials in real world care, what I believe is that in the future we will have more real world trials. And specifically we have some examples, like in the Netherlands with the droop model in which you perform locally and NGS, and then you have a network of cancer center where patients can be allocated to experimental treatment or to agnostic treatment based on availability. This is a very complicated network to be built. We have many challenges. The first, of course, is economical sustainability that in some continent, like Latin America or Africa or also China is not so feasible. But the key problem is to generate a network: if you generate a network, this will be feasible everywhere.

Giancarlo Pruneri: So this is a fantastic view. I think that this is something that we discussed a lot in the past, and maybe it is becoming a reality in the next future. Of course, we have to implement the infrastructure of our institution and this is probably the next goal. Giuseppe, you are also, among other things I already mentioned, a very passionate mentor and teacher for medical students and postdocs. Could you briefly explain your opinion on the role of education in future precision oncology, and how we could work together in order to create new professionals working within these important disciplines?

Giuseppe Curigliano: You know, this is a very important question because this was one of my aim also in the ESMO presidential program. So we have actually a workforce shortage in cancer. There are some countries in the world where you don’t have Pathologist to review the slides of a patient with a cancer. You don’t have a radiation oncologist. And in the future I will also see very few medical oncologists. So what we need is to boost, of course, cancer doctors and to offer opportunities to very young people in order to build a career of clinician scientists. It’s crucial, really, to create and generate this new professional figure that is specifically a cancer doctor that also understands about precision oncology. In the future, we will have much more technology engaged in cancer treatment. And this can be related, of course, to the impact of NGS of digital pathology Multi-omics analysis, artificial intelligence. So we need to have some people that will take care in high volume comprehensive cancer center in a multi-dimensional approach to cancer care. And then we need to generate locally medical oncologists that of course, at least know the standard of care for any single disease and can apply the clinical practice guidelines with high quality of care. So two different professional profiles: advanced, to do research and innovate, and of course basic, with an high level of clinical care.

Giancarlo Pruneri: So this is a very important goal that we have to achieve. We already mentioned in a previous episode the importance of Masters and PhD, we mentioned the fact that there is a the chance to have a PhD programs focusing on new and new figure of a professional that is a scientist and a clinical doctor together. This is absolutely important. You already mentioned that you have been elected as ESMO president. This is for the next to 2027-2028 biennium. So this is a truly important let me congratulate with you because this is a truly important achievement for you, for us and the European oncologists. So firstly, it is very important to me that you know, a guy like you that with this open mind with regard to precision oncology and to the implementation of technology for carrying our patients, has been elected as ESMO president. So my question here for you is how do you foresee oncology in the next ten years, and which role should be played by national and international associations?

Giuseppe Curigliano: Well, you know, I believe oncology in the next years will be a platform for interconnections across disciplines. So in my mission, there was really to generate a scientific society that can be a platform in order to integrate different aspects of cancer care, starting from diagnostic to pathology and of course also to surgery, radiation oncology and medical oncology. In my opinion, per definition, cancer care is multidisciplinary and in order to optimize outcome of our patients, we need a multidisciplinary approach. And now, with the new technologies that are driven by artificial intelligence and by algorithms that eventually can refine diagnostic and also treatment algorithm is very essential to have a governance of all this process. So in my opinion, the future of medical oncology in the next ten years will be much more related to a better knowledge of the biology of the disease, to an interception of cancer before appearance or interception of cancer before recurrence. So what I envision is to start treatment before cancer will develop with the really primary prevention program, or eventually in case patients have cancer to intercept recurrence with new cancer treatment that can delay the metastatic disease.

Giancarlo Pruneri: Giuseppe, thank you very much for being with us on TJ talks. It was a very pleasure for me.

Giuseppe Curigliano: Thank you very much for inviting me and see you soon.

Giancarlo Pruneri: So in this episode, we found out how to craft the new avenues for precision oncology. We have been discussing with Giuseppe Curigliano, an eminent scientist, oncologist, teacher and mentor, and the new elected president for ESMO. TJ talks is available on our website tumorijournal.org and on the best podcast platforms. Follow us on Twitter and LinkedIn to always be updated on cancer research and clinical practice in oncology. I’m your host, Professor Giancarlo Pruneri, editor in chief of Tumori Journal. Thanks for listening.

Giancarlo Pruneri: Food is medicine. This was the title of an editorial published in Nature, and the evidence is growing that targeted dietary interventions can treat, delay, and even prevent some illnesses. Today we are focusing on this topic with Professor Claudio Vernieri. I am Professor Giancarlo Pruneri, editor in chief of Tumori Journal, the peer reviewed oncology journal dedicated to the dissemination of key oncological themes and advancements. Welcome to TJ talks, conversation about oncology by Tumori Journal. Hi Claudio, thanks for being here.

Claudio Vernieri: Hi Giancarlo, thanks for inviting me.

Giancarlo Pruneri: Claudio, let me introduce you. For those who don’t know you yet, you are a breast oncologist working at the National Cancer Institute of Milan and a university professor and the PI of a prospective study on the efficacy of a metabolic intervention added to chemo immunotherapy for patients with triple negative breast cancer. Wow. That’s a lot for someone as young as you. Is there anything you’d like to add?

Claudio Vernieri: Yes, I’m also a group leader at IFOM, where I direct a group of eight scientists, basic and translational scientists who are studying novel approaches to target cancer metabolism. And this is an especially exciting moment because now in the clinic, we are investigating approaches that were studied in the laboratory 10 or 5 years ago, and at the same time, in the lab, we are studying new approaches that will be the focus of clinical trials in the future.

Giancarlo Pruneri: Wow, that’s exciting and I’m truly hoping that your day is lasting more than 24 hours. Claudio, can you explain how you came to hypothesize that a metabolic intervention could help in cancer treatment?

Claudio Vernieri: Yeah. Thank you for your question. So when I got interested in this research field in the cancer metabolism field, about ten years ago, what I did first was to study a lot of literature, trying to understand among several metabolic approaches that were being investigated in several laboratories around the world at the time, which of them could be potentially more feasible and potentially also more effective in cancer patients? And so this process lasted for a couple of years, during which I designed a specific calorie restricted regimen that we started to investigate in cancer patients at the beginning of 2017.

Giancarlo Pruneri: Wow. I mean, so it’s starting from basic science and getting to patients quite quickly. And here we are today with a breakfast-2 to study. And what are the goals of this study and where are we currently?

Claudio Vernieri: So the breakfast-2 study is a phase two randomized, multicenter clinical trial, which is randomized in patients with stage two or stage three triple negative breast cancer to undergo a specific calorie restricted regimen in combination with standard preoperative chemoimmunotherapy. And the primary objective of this study is to investigate whether the addition of this calorie restricted regimen to the standard medical therapy is able to increase the rate of pathologic complete responses when compared to the standard treatment alone. So now we have started recruiting patients about one year ago, and very soon other Italian cancer institutions will adhere and will start enrolling patients in the context of this trial.

Giancarlo Pruneri: So this is very interesting. So it’s I mean a clinical intervention. Are you planning to get, you know, some translational studies in order to answer some biological question?

Claudio Vernieri: Yes, of course, I will be conducting collaborations with you, with your group, several genomic and transcriptomic analysis, both at bulk and single cell levels, with the main aim of understanding what is the impact of the experimental interventions on the intratumoral immune system, and also on systemic and intratumoral metabolism, because we hypothesized, based on results of preclinical experiments, that specific metabolic changes that occur at the tumor level very precociously may predict the response of the tumor to the experimental approach.

Prof Giancarlo Pruneri: So this is very interesting. Let me tell you from an organizational point of view, is that completely an academic study or do you receive funding from companies and industries?

Claudio Vernieri: So this is a very important point, and I’m proud to say that this is a fully independent study. So we received different types of fundings from foundations, organizations but not from pharma companies. And this will allow us to be totally free in the design and in the analysis of the clinical results, but also in the conduction and analysis of translational data. That will be so important to understand the biology that is behind this type of experimental intervention.

Giancarlo Pruneri: Sure, Claudio, it must not be easy for a woman with cancer carrying all the anxiety and legitimate fear to follow a diet. How do you support your patients and what tools do you use to comfort and provide them with precise instructions for following the diet?

Claudio Vernieri: Yeah, this is a very crucial point. I have to say that this is a very peculiar historical moment because cancer patients are more and more interested in investigation and nutritional interventions. Everybody basically is asking, what should I eat? What should I drink during my cancer treatment? And so in general, patients who are proposed this type of experimental intervention accepted very enthusiastically. So what we are doing now to support these patients is to follow them very closely, to monitor them and to this aim we have developed, in collaboration with Arama Precision Oncology, a specific instrument, which is a web app that will allow us to collect on a daily basis information about the side effects, tolerability not only of the diet, but also of the medical treatment, and to provide timely suggestions and recommendations to prevent and to manage these side effects. So I’m pretty optimistic that also on a multisensory base, this trial will be successful on this point.

Giancarlo Pruneri: Yeah, sure. Claudio, this is very interesting. So please explain it a bit more precisely. I mean, so the patients are able to contact the clinicians through this app whenever they have some doubts or are requesting some advice?

Claudio Vernieri: Yes. Patients have the opportunity to use this chat, which is open with the investigators of the breakfast trial, both oncologists and nutritionists, and to ask whatever they want regarding side effects, doubt about their nutritional regimen and so on. So this is an opportunity to have a very close contact with the patient, to improve the participation of the patients and also their compliance, and also to prevent and timely manage side effects that are related either to the medical treatment or to the investigation and nutritional intervention.

Giancarlo Pruneri: And I mean, I guess that they can do that 24 hour per day. So this is meaning that, you know, you have a lot of free time left. And I mean, Claudio, I would like to thank you for being with us on TJ Talks.

Claudio Vernieri: Thank you, Giancarlo, for this invitation. It was a great pleasure to be here today.

Giancarlo Pruneri: And as I wrap up, let’s circle back to Feuerbach idea: we are what we eat. It’s a simple reminder of how crucial our food choices are, not just for the daily health, but also in the fight against serious diseases like cancers. These therapies are all about disrupting cancer cell bioenergy, proving that our battle against cancer can indeed start on our plates. And remember, choosing the right foods is not just about good health, it’s a key part of our fight against cancer. Follow us on Twitter and LinkedIn to always be updated on cancer research and clinical practice in oncology. I am Professor Giancarlo Pruneri, Editor in chief of Tumori Journal. Thanks for listening. TJ Talks is available on our website tumorijournal.org and on the best podcast platforms.

Giancarlo Pruneri: What are the reasons that make really unique the role of pathologists in the model of precision oncology today? and which are the reasons why doctors should be involved in a specialization course in Milan? To find out, I invited Doctor Emanuele Frigo, who is completing his specialization course here in Milan. We will discover his story, follow his path and very importantly, which are the opportunities offered by the specialization course and the PhD course. I am Professor Giancarlo Pruneri, editor in chief of Tumori Journal, the peer reviewed oncology journal dedicated to the dissemination of key oncological themes and advancements. And this is TJ talks: Conversation about Oncology by Tumori Journal. Hi Emanuele, thanks for being here.

Emanuele Frigo: Hi, Giancarlo, thank you for inviting me. I’m really pleased to be here.

Giancarlo Pruneri: Emanuele, would you like to introduce yourself to our listeners?

Emanuele Frigo: Sure. I am Emanuele Frigo, a resident in pathology currently working at fourth and last year of the residency program here at the University of Milan. And I am also, since January 2024, PhD candidate in IFOM in Milan. And I’m currently working on research, preclinical and translational research on tumor metabolism with a focus on melanoma.

Giancarlo Pruneri: Wow. That’s great. But we will talk about a PhD maybe later on. Firstly, Emanuele, could you describe what today does a pathologist involved in precision oncology?

Emanuele Frigo: Sure. Traditionally, pathologists have been at the forefront of clinical diagnosis in tumors, and they had profound knowledge of cancer biology, its clinical settings and also the molecular profile of tumors. So I think that pathologists among many medical specialists are probably the most appropriate professional figure to be a bridge between a morphology, the clinical settings, and the molecular profile of tumors. If we think that the recent advancements in the genetic testing have profoundly modified the traditional classification of tumors, and so also the knowledge that pathologists have also in the technical aspects of the molecular testing, can have a huge impact into the field of precision oncology. Pathologists have different roles in different aspects of the management of the patients in oncology, from the pre-analytical phases to, for example, the management and the proper choice of the tissue samples, cytological samples, both in terms of quality and quantity, in situ techniques, for example fish RNA sequencing and so on, and also they can integrate molecular data into the clinical Oncology Reports. We also participate in the multidisciplinary team and the clinical decisions, among other professional figures, and they can participate in the core aspects of the precision oncology, which are the discovery of the new biomarkers or targets inside the tumors that are exploitable from a therapeutic point of view. So, I think that pathologists are really they cover a really important and crucial role in oncology.

Giancarlo Pruneri: Impressive, Emanuele. So, it’s a kind of balance between the traditional pathology with classification and the new molecular avenues. And in order to do that, you choose the specialization course in pathology at the University of Milan. Can you explain why?

Emanuele Frigo: Yeah, that’s a great question. Um, initially, after my medical training, I wasn’t sure to be a pathologist. Actually, I was unsure whether it was the diagnostic of tumors or the clinical aspects of tumors to be my main topic of interest. So I undertake a residency program in the radiation oncology at a European Institute of Oncology here in Milan. And during that period of one year, I became progressively more interested in the diagnostic aspect of diseases through the participation at many, many multidisciplinary meetings in European Institute of Oncology with pathologists and oncologists across different fields of oncology. So, I decided to undertake the residency program here at the University of Milan in pathology. And thanks to its extensive networks of big hospitals with high quality standards and also a wide range of clinical expertise across many sub specializations in pathology, doing residency pathology residency in Milan offers a huge possibility of professional growth through also the rotation through across all these different big hospitals.

Giancarlo Pruneri: That’s great. And it’s very interesting. I mean, and can you quite schematically, you know, describe us a normal day life in, in the life of a pathologist?

Emanuele Frigo: As a resident, we participate in every aspect of the clinical routine, diagnostic routine in the pathology department of our current rotation. Starting from the first and second year, our activities mainly centered around acquiring basic knowledge into the gross microscopic examination of tissue samples and autopsies, and also basic general histology. From the third year, we dive deeply into the special histology cases and the final year we have also the opportunity to follow research, but clinical and preclinical, like what I’m doing with a PhD at this opportunity the last year. We also have the opportunity to do up to 18 months abroad that can widen our knowledge in, in the field. So, it’s pretty varied activity across the whole four years.

Giancarlo Pruneri: Emanuele, you mentioned earlier that during the specialization course there is also a PhD course that is the physician scientist course. I think that it’s a fantastic opportunity for young doctors and specialization students to get a quite comprehensive approach in education. And in fact, you can work in a cancer center like the Fondazione Istituto Nazionale dei Tumori, Milano, and in a research center like IFOM, in order to get, you know, skills either in oncology and in tumor classification, but also in the biological basis of disease with a very translational approach. Can you just underline quite quickly what are you doing at the moment?

Emanuele Frigo: Thank you. Yeah, I really think that, as you mentioned, this is a great opportunity for us residents to reach clinical and preclinical research through a PhD and a clinical aspect of our activity as a residence in the Istituto Nazionale dei Tumori. To just give you an insight of what I’m doing during my PhD course, I work on two more metabolism, and in particular, I’m trying to dissect the mechanistic impact of specific metabolic pathways in affecting the response to immunotherapy in melanoma patients. And I’m trying to do this through the development of an in vitro and ex vivo models that are able to explore deeply the heterogeneity of the tumor and also its microenvironment.

And to do this, at the beginning, it was very demanding, but also a little bit of chaos, I would say, because I had to go back to the basics, and I was the start of my fourth year as a resident in pathology, but really I had no knowledge about how to manage an Eppendorf, for example, or how to also prepare media, for example, for the cells. So, I had to discover a lot of new things to learn, a lot of new things day and night, basically. But I also had the opportunity to meet very, very welcoming colleagues there in IFOM that are very open to help me through this journey.

I am three and a half months into my PhD course, and I’m starting now to realize that by doing this, it really gives an open up new opportunities from a professional point of view, but also it offers me to be able to bridge the world of pathology and the world of clinical research into one thing. That’s one of the main purposes of doing this.

When you, Giancarlo, proposed us residents to participate in this PhD program, I was in at the University of Leuven in Belgium, and I was doing a fellowship, working on clinical aspects of melanocytic tumors and melanoma. And I had also the opportunity to work on clinical research on that topic that brought me to present work on at the National Belgian Congress in Brussels and the Anglo-French meeting in Paris. And so, by doing this PhD, I really, took the opportunity to work on my main field of interest from the clinical point of view at Instituto Nacional de Tumori, where I work on the classification of tumors and in the diagnosis of them, and from the research point of view at IFOM. And this is really exciting, and I can’t wait to progress on this.

Giancarlo Pruneri: Exciting indeed. Emanuele, and thanks for being with us on TJ talks.

Emanuele Frigo: Thank you very much, Giancarlo.

Giancarlo Pruneri: [00:09:59] In this episode we found out how the role of pathologist is central in precision oncology. The pathology training is indeed rich and multifaceted. The training is focusing on classifying tumors and pinpointing biomarkers for treating patients with tailored therapies, mainly using molecular biology techniques. And yeah, we’ve learned about these cool new PhD program which is shaping new physician scientists. These professionals are going to be a bridge between traditional clinical care, patient treatment and research. And it just seems like this is the best way to take care of our patients. TJ talks is available on our website and on the best podcast platforms. Please follow us on Twitter and LinkedIn to keep updated on cancer research and clinical practice in oncology. I’m Professor Giancarlo Pruneri, editor in chief for Tumori Journal. Thanks for listening.