JCO PO author Dr. Christian Rolfo shares insights into his JCO PO article, “Liquid Biopsy of Lung Cancer Before Pathological Diagnosis Is Associated With Shorter Time to Treatment.” Host Dr. Rafeh Naqash and Dr. Rolfo discuss how early liquid biopsy in aNSCLC in parallel with path dx is associated with shorter time to treatment.

TRANSCRIPT 

Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the Stephenson Cancer Center, University of Oklahoma.  

Today we are thrilled to be joined by Dr. Christian Rolfo, Associate Director of Clinical Research at the Center of Thoracic Oncology at the Tisch Cancer Institute at Mount Sinai Health System. He is also the lead author of the JCO Precision Oncology article entitled "Liquid Biopsy of Lung Cancer Before Pathological Diagnosis is Associated with Shorter Time to Treatment." 

Our guest's disclosures will be linked in the transcript. 

Christian, it's great to have you here. Welcome to our podcast and we are excited to learn about some of the interesting results from your study. 

Dr. Christian Rolfo: Thank you very much, Rafeh. It's a pleasure to be here and discuss about liquid biopsy.

Dr. Rafeh Naqash: You have a very important role in different liquid biopsy consortiums. This is an initiative that you have been leading and spearheading for quite a while, and it's nice to see that it is becoming something of a phenomenon now on a global scale where liquid biopsies are being implemented more and more in earlier stages, especially. For the sake of our audience, which revolves around academic oncologists, community oncologists, trainees, and patient advocates or patients themselves, could you tell us a little bit about the background of what liquid biopsies are? And currently, how do we utilize them in the management of lung cancer or cancers in general?

Dr. Christian Rolfo: Liquid biopsy has been gaining importance over the years. We started to talk about liquid biopsy in 2009 when we started to see some correlations with EGFR mutations. In practicality, what we are doing is the most common or most applicable indication is to go for liquid biopsies from the blood, peripheral blood. So we are doing a blood draw and from there, what we are capturing is the DNA or fragments of DNA that are still in circulation. But the liquid biopsy definition is a little bit more broad and we can apply the concept of a minimally invasive approach to different fluids of the body, including pleural effusion, urine, and including CSF that is another indication, there, we are going to be a little bit more invasive than peripheral blood, but it is also an emerging tool that we will have to find specific indicators. In cancer, we started the history of liquid biopsy in advanced disease with the identification of biomarkers, and then from there, we are moving to other scenarios, including, nowadays, monitoring minimal residual disease and early detection. And that is applicable also for other tumors.

Dr. Rafeh Naqash: Thank you, Christian, for that summary. Now, as you've rightly pointed out, we have come to implement liquid biopsies more and more, both in the academic setting and the community setting. And this has definitely led to faster turnaround time in some ways compared to tissue. In this study that you have authored with the help of many other collaborators and Foundation Medicine Flatiron Health data, the goal here, from what I understand, was to look at liquid biopsies that were done before, resulted before the pathological diagnosis. Could you tell us a little bit more about the premise of this study, why you thought about this question and how did you try to implement that idea to get to some of the interesting results that you see here?

Dr. Christian Rolfo: Yeah, so what we are seeing generally in lung cancer and also in people with other tumors is that patients are having a journey and that they start seeing different doctors until they get a diagnosis. Generally, after the pathological diagnosis, if you don’t have an in-house technology that is doing reflex testing, generally, oncologists need to request for testing and that is taking time. So if we are looking for comprehensive days until a patients are able to get a molecular profiling before we start the treatment is sometimes very long. We are talking, in some cases, about months. So, how we can speed the process, that was the main question. We tried to include liquid biopsy in the staging procedures that we generally were doing when we have a clinical diagnosis of lung cancer. It’s either images that we are used to do, PET scans, MRIs, and other assessments, we want to include liquid biopsy there before the biopsy. And that's what we did. We were searching for this specific aim using the Flatiron Health Foundation Medicine electronic health records from 280 centers across the United States. We included a big number of patients in this analysis, more than 1000 patients for the first analysis.

Dr. Rafeh Naqash: That's phenomenal that you had real-world data from 200+ centers across the US. Of course, when you have patients on a clinical trial versus patients in the real-world, we all know that there are differences in terms of approaching, overseeing, and managing these individuals. So this data set is an extension of what we could see in the real-world setting. 

Could you tell us a little bit about the number of patients that you eventually identified that had liquid biopsies done before pathological diagnosis? I think you have different cohorts here, a group that was before and a group that was after, and you compared several important metrics treatment-wise from what I see. Could you highlight those for our listeners?

Dr. Christian Rolfo: Yeah. So we were looking for patients who had a liquid biopsy CGP, comprehensive genomic profiling, ordered within 30 days pre diagnosis and post diagnosis. We focused on 5.2% of patients, which corresponded to 56 patients who ordered a liquid biopsy before diagnosis. The median time was eight days between the order and diagnosis and the range was between 1 to 28 days. And that was compared with 1020 patients who ordered a liquid biopsy after diagnosis. It is important to be clear that both cohorts had a similar stage and ctDNA tumor fraction. We can explain later what tumor fraction is, because it was done in addition with a paper that we just published last week. Liquid biopsy patients were consulted to have this CGP median one day after diagnosis, versus 25 days after for patients who had their diagnosis and their liquid biopsy later on. So, from these patients, the majority of the patients, 43% of LBx-Dx were positive for an National Comprehensive Cancer Network driver, and 32% had ctDNA TF >1% but were driver negative, so that is what we call presumed true negative. From here, maybe I can explain what is tumor fraction and, in general, how we use it. 

Dr. Rafeh Naqash: I think that would be great for our listeners. We see this often in more and more liquid biopsy results nowadays, and I've tried to explain it to some of my fellows also. So, it would be nice if you explain for the sake of our listeners what tumor fraction is, what does it mean clinically, can you use it in a certain way, what biological relevance does it have.

Dr. Christian Rolfo: So we are analyzing another paper that came out this week in cancer research on the concept of tumor fraction and it’s a new definition. So what we are doing with tumor fraction is an algorithmic calculation or mathematical calculation on the amount of DNA of the cells also taking into consideration the math, the quantity of DNA present in the sample. So we are going very low in the sensitivity of this analysis and capturing there the real informative results of the ctDNA of the liquid biopsy. So in practicality, when you see a report that says the threshold that was established in this study was more than 1% or less than 1%, so patients who have a tumor fraction of more than 1%, we can really consider this liquid biopsy informative. And also in this next publication, we compared with tissue. In patients with a tumor fraction of more than 1%, were completely 100% correspondent with what we found in the reflected tumor tissue, the NGS. But what happened in patients with a tumor fraction of less than 1%, we can say that these patients are not informative. So we need to wait for the tissue biopsy result to come in because we were able to recuperate several patients that the liquid biopsy was negative with the tissue biopsy positive.

This is an important concept because we are distinguishing not only the informativeness of liquid biopsy, but also we can distinguish between patients who are considered not shedder based on what is considered a shedder. And that was a problem until this kind of introduction was a problem before with the technology because the technology wasn't very fast to distinguish the sensitivity or high sensitivity. Now, the sensitivity is no longer a problem. Maybe, there is really value of information in what we have in liquid biopsy, and using this mathematical help, we can get these patients distinguished and help more people. So that would be really interesting.

Dr. Rafeh Naqash: You touched on a few important concepts here, and one question I have, and I think there's no better person to answer this question. You're the right person to answer this question for our audience. Do you think when you have a liquid biopsy tumor fraction of less than 1%, and you have a tissue that is pending with an NGS, where tissue NGS has not resulted yet, but liquid biopsy results come in and tumor fraction is less than 1%. But let's say you have a non-smoker with a typical driver mutation and clinical characteristic positive individual in the clinic, and the tumor fraction is less than 1%. How much can you trust that liquid biopsy when the tumor fraction is less than 1%. Because do you think some of these driver mutations, like you mentioned, could be low shedders and you could miss a potentially actionable mutation on a liquid biopsy if the tumor fraction is less than 1%? Is that something that you've looked at or correlated or understood what would be the clinical meaning of that?

Dr. Christian Rolfo: Absolutely. So there are two concepts here. A liquid biopsy could be non-informative, and that is what we saw in this paper. So you have patients that have a liquid biopsy negative, and that we see in the clinic, a liquid biopsy negative tissue biopsy positive. That could be because the liquid biopsy is not informative, but it could be also that the patient, for some biological reason, and we don't have an answer about that, they are not shedding the ctDNA in the bloodstream, ctDNA that we can capture. What we saw in different studies, including one of the papers that we presented also in ASCO last year with a MET amplification and  METex14, for example. In the study that was the VISION study using tepotinib, you see that patients who have a liquid biopsy negative are doing a better outcome compared to a patient who have a liquid biopsy positive. So I believe that we still have patients who are not shedders for some biological reason, that could be put in together with patients who have more bone metastasis than organ metastasis, or patients who have more in location, for example in the brain. These patients are difficult to capture in ctDNA due to some biological reasons. But also you have patients who are non-shedders. For the technicality of the parts of this tumor fraction analysis, it is really important to distinguish that and we will hear more and more. So, as you say, we have already some reports in some companies like Foundation are doing, but some others like to incorporate this tumor fraction. And several in-house technologies allow also to have this kind of mathematical calculation. So that is what we are facing now, to really understand better the power of liquid biopsy.

Dr. Rafeh Naqash: Now, some of the other things that your project or paper that you published with JCO PO does not necessarily cover is the payer aspect of this. Now, we've had more and more discussions, obviously, and more and more information has been highlighted with the payers that this is an important test and needs to be reimbursed, even though if you do tissue NGS, liquid biopsies are complementary to tissue. So taking both together is probably a better view of the overall tumor or the mutational status of the tumor. But one of the biggest holes in this whole process, and this is my personal experience, I want to know what you think, is that we can't order these tests when the patient is admitted to the hospital, and 50% or more patients end up getting diagnosed in the hospital during an inpatient stay. The average hospitalization for someone with lung cancer is five to seven days on average, and then another one to two weeks to get into the clinic to see an oncologist. So what would your thoughts be there? How can we improve things there in terms of, can we try to do something different so that the payers agree that, yes, you can send a liquid biopsy when the patient is admitted, because there's that 14-day Medicare rule? Has your team, or have you in particular, tried to navigate some of those issues, and what are your thoughts on how we can try to improve some of those conversations? 

Dr. Christian Rolfo: Yeah, that's a really good question, because here we are talking about inequities in access to the technology and the results and it's crucial. Several of our patients, specifically in lung cancer, they are coming to our consultations or to the emergency with a very bad situation so they need to be admitted immediately. And as you say, they can be there for one month waiting for results or for recovery or for stabilization of their general condition before we can start. Several of these patients will have some biomarkers that we can target with treatment. So in other words, I will say that this is a stupid rule because we cannot have in 2024 these kinds of limitations to access to treatment when we have on one side, the FDA is doing a terrific job to get drugs approved in a very short time, and on the other side we have payers who are not understanding the concept of molecular or precision oncology. 

So what we are trying to do in these cases, to be honest, is to navigate with the vendors and try to get this done. I generally send the samples because I consider that personally that it is a very crucial information. And in several cases, we have started targeted therapies while the patient is still admitted. So I think it's something that we need to put in a better effort, because already we are not doing enough for our patients, if you look at the data of the MYLUNG Consortium that was presented in ASCO some years ago on the testing performance in the community practice, 50% of the patients with lung cancer were tested there were only some in minority groups, African Americans, 39%. So I think we need to do better in education, but also from the payer side, it's really crucial that they understand this concept. 

Advocacy groups have a lot of say here. They are also doing an important job on that. We are now launching with ISLC, ISLB, Lung Cancer Europe, and Longevity in a survey that is to make also the patients aware what is the importance of molecular profiling, tissue or liquid biopsy, it’s very important that you get something to treat the patient and select the right treatment. And even to say, there’ll be a whole other work in your case so that is really important. 

Dr. Rafeh Naqash: Absolutely, I completely agree. We have made a lot of strides, but there is still a lot of room for improvement in terms of equity, access, and reimbursement.  

Now, one of the things that I noticed in your paper, and you could tell me a little bit more about this, when you looked at the pre-diagnosed liquid biopsies, meaning before tissue diagnosis, 56 individuals there suspected to have lung cancer, community-based testing was identified in 53 individuals versus academic being three. This is very encouraging when you see something like this happening in the community. Did you look at that? Did you try to understand why or how that was the case? Because in a general community setting, I would think that community practices have a more complicated system of reimbursement because they are dependent on direct reimbursement, whereas in bigger academic centers, there’s some leeway here and there. So did you try to understand how they were able to order this before tissue, could you give us some insights there?

Dr. Christian Rolfo: Yes, I think it was not big in this specific question, but it's a very interesting topic. Because we, generally, in academia, will believe that we are doing the things in advance and we are more, compared with the practical and the general practitioners or the general colleagues in the community practice, we have more resources. But sometimes, and it's true, obviously, we have more resources in terms of research and more opportunities in terms of clinical trials in some cases. But I think we understood with this minimal example that there is an important interest among general oncologists in the community practice to get this done. And this is something we need to emphasize, because sometimes we are putting the blame on our colleagues that are outside the academic centers on this lack of testing, and it’s not really true sometimes. So this is a good point to start to work together and try to get more things done for our patients and try to get also the reality.  

I think one of the problems we will have in the future that we can face right now is the lack of new figures in this molecular profiling. I am referring, for example, molecular nurses or personnel that is working and helping to get this done. We need to have more people that are working in this education for the patients in the access to treatment and access to the technology, but also to navigate better these problems with payers that sometimes in some patients that seem to be overwhelming. Because when you talk about the $100 that could be extra, it’s hard for some patients. So we need to be very conscious about that. So having a new figure in the hospitals and the community practices could help to test more patients. 

Dr. Rafeh Naqash: And I think at the end of the day, the payers or the reimbursement mechanisms need to understand that genomics is part of the diagnosis these days. It's not ancillary, it’s not an addition, but it is part of the diagnosis. I'm pretty sure you have had similar instances where you get a confusing pathology result but then a genomic result points in a certain direction. You treat the patient in that direction, and then you see the patient benefiting in the tumor shrinking, which suggests that genomics is complementary to the path diagnosis. It’s not necessarily a surrogate.You can’t replace pathological diagnosis, but you can use genomics as a complementary diagnosis as part of the whole paradigm of treating the entire patient. So I think we definitely need more and more conversations like the ones that you’re having or your liquid biopsy consortium is having and then more education from the FDA. Of course, more legislation, more advocacy.  

Going back to the paper, I did notice another interesting thing, which is, again, very encouraging is patients with lung cancer with a performance status of 2 or about had a decent proportion of testing done. Which, again, points out to the important concept of avoiding these preconceived biases that, “Hey. If somebody is not a great performance status, testing and finding something in that individual could potentially change a lot for the individual.” Do you have any personal examples from patients you have treated or seen in the clinic for our listeners where you identified something and maybe they were not doing as great initially, and then you identified something in liquid biopsy, treated them and it changed the entire course of their illness and whole trajectory for them?

Dr. Christian Rolfo: Being working in lung cancer for years, everyone has this kind of patient that we see that their performance state was very bad. Obviously, as a clinician, we need to identify why the performance is bad and is deteriorating. So we see some patients in lung cancer, some of them, they can have a very important comorbidity packet that is associated with lung cancer. So in patients who have a deterioration for lung cancer, and we find a driver help in some patients that were doing a kind of a weakness, and that is something that we see in several patients, specifically in patients living with leptomeningeal disease. In some cases, when we start to do drivers that have a big impact in the crossing the blood-brain barrier, I have a good response.  I have patients that had an important recovery. So this is something we need to distinguish and sometimes when the patients seem very bad they say, “Okay, we go directly to targeted care or supportive care.” We try to test these patients as well because these patients have an important impact on the quality of life that we are treating. We will not be able to cure patients in this setting with targeted therapies, but we can certainly make an impact in the quality of life and also in our form of survival. 

Dr. Rafeh Naqash: One of the other questions that comes up often when you’re in a multi display team, since most cancers these days are on the multi display decision making opportunities to treat the patient the best possible way is: Who orders the liquid biopsy? I remember from my fellowship several years back, our program director Paul Walker, who is, again, an amazing lung cancer thoracic oncologist, he had advocated that our endoscopic suite folks, the bronchoscopist, whether it was pulmonary, interventional pulmonology or CT surgeons, whoever did the bronchoscopy for the first time in the patient that they would send it whenever they see the patient from the bronchs. This was around six, seven years back. And I think Paul was a little ahead of his time and I didn’t necessarily understand the implications that this would have. 

And now, as I progress in my own little career, I can see the vision that he had, which I think a lot of other sectors have tried to do, and I’m pretty sure you have a certain process, too. Is that something we should try to talk more and more about? Because, of course, when you do the bronch, then you get a diagnosis and the patient sees the oncologist. This whole process takes anywhere from two to three weeks, maybe even more for smaller centers. So, is that something that you’re doing or you see that you’re having more conversations that, “Hey. Whoever sees the patient first should be able to order the liquid biopsy.” It's not necessarily the medical oncologists, it doesn’t mean I love to order sequencing results or  sequential tests, but it could cause a delay in the patient care. So, could you tell us a little bit more of that? 

Dr. Christian Rolfo: So it's really important, this part, because we need to create in our institution flows that will have this very well organized. And ideally, in the ideal world will be that we have reflex tests coming from the pathologist, but it's not happened in several places, because we don't have our NGS at home, or we are sending to vendors, and sometimes we are not sending to them. So that is one of the aspects.

 The second aspect, and that I think is still a problem in some treatment, is that we still have 24:30 cytologists coming out in place of covariances. And in our institution, we were working very hard with our interventional pulmonologists and interventional radiologists to get this quality of tissue appropriate, and we have a very good rate of success and issues in a very minimal quantity of patients. Obviously, some patients are very difficult to get samples, and we need to refer still with cytology. But in some cases, where our surgeons or our pulmonologists have sent in samples for NGS, and I think this is we are coordinating. “I will see this patient next week. Can you please start to order?” And here, our nurse practitioner, our nurses in the team are also playing an important role for the reason I insist in the idea to have new figures that could be these molecular navigators we can call, or molecular nurses that helping coordinate this, not only the coordination, but also in the discussion of molecular tumor boards. We did an experience like that some years ago at Maryland University, and actually it was a very important opportunity to decrease the number of quantities of issues and get the results done very quickly. So I think it's important to come to have conversations with our colleagues, pulmonologists, radiation radiologists, interventional radiologists, pulmonologists and pathologists to get this done very quickly. 

Dr. Rafeh Naqash: I love the idea of molecular navigators. And of course, everybody in the current day and age, we’re having staffing issues, so getting a molecular navigator would be awesome, but I’m not necessarily sure how everybody would be able to implement it. But I think in the bigger picture, whether it’s molecular navigators or multi disciplinary nurse navigators in general, liaisons in general, I think we all can do a better job in trying to coordinate some of these testings. And we have tried to do that through our thoracic oncology group and of course, there’s a lot of progress that needs to be made, one step at a time.

Dr. Christian Rolfo: If somebody is interested in this topic on the International Society of Liquid Biopsy, we started with a project that is called a Certificate for Advanced Studies in Precision Oncology. So we are educating the healthcare team for all this process and trying to get practical insights to have this career later. Because I think it will be something that’s interesting for nurses or pharmacists to get this kind of career later or get another approach in their career. 

Dr. Rafeh Naqash: Thank you so much, Christian. 

Now, going to not the scientific part, which I think is the most interesting part of this conversation is to talk about you and your personal journey. Could you tell us a little bit about where you started, what your career has been like, how did you progress? Because you have a lot of junior faculty that listen to this and it's always good to take inspiration from people like yourself. 

Dr. Christian Rolfo: Thank you. As you can hear my accent, it’s not from here. So I was born in Argentina, I did my medical degree there. And then I had the opportunity to get a scholarship in Italy. I went to Italy and I stayed there for seven years. I did my fellowship there again, and I started to know there precision oncologists. My journey started in sarcoma. And actually I was working in the group of Dr. Casali's group, a very well known sarcoma expert. And at that time we were running phase I trials for imatinib, I remember, known as GIST. I saw this kind of response and awakening of patients that were really in very bad condition, with only through this imatinib. Very little to treat that disease at that moment, a median overall survival of two months. So I started to be interested in that. Then I moved from there to Spain and met Dr. Rafael Rossell, who was my mentor. In Italy, I have also a mentor in breast cancer, Dr. Luca Gianni, one of the pioneers in breast cancer treatment. So knowing all these people and having the support of them, was really crucial. 

So I think this is the first advice for junior faculty: try to choose your mentor, even if your mentor is not in your center. Like the case, for example, Rafael Rossell was not in my hospital, but he was my mentor. So having this kind of discussion, I did my PhD in EGFR mutation, at that time was the fashion, not immunotherapy, of the moment. And then from there, after eight years in Spain, I moved to Belgium. I have a short period of completing my training at MD Anderson and I went to Belgium to Antwerp University and that was the opportunity to become the Director of the phase I program in the Early Clinical Trials Unit. It was really exciting to see growing a unit, and now they continue  at the center in Belgium. My colleagues that stayed there, they are doing a terrific job of continuing this idea. And from there I went to Baltimore, three years working at Maryland University being the Director of Thoracic Oncology and early clinical trials as well. Three years after, I moved to New York, and here doing this journey in clinical research, also being the Director of Clinical Research at the Center for Thoracic Oncology. 

Life has put me in different places, different cultures, different opportunities. For me it was a really good journey to be in different countries, knowing different ways to see oncology as well, and immediately to work, because it was a shock coming from Belgium to the area of Baltimore where I had the reality to discuss peer to peer conversations and things that are not usually discussed in Europe. So it was really a very nice journey to learn, to have the capacity to adapt. 

That is the other thing, my second advice, if I can give advice, but if you have the opportunity to go to some place, adaptation is the most important. So try to enjoy what you’re doing and try to enjoy and learn from the patients, hopefully, and contribute your knowledge as well.

Dr. Rafeh Naqash: Thank you so much, Christian. Two last questions. For all the places that you visited, what is your favorite place? And what is your favorite food?

Dr. Christian Rolfo: My favorite place to live, I have Italy in my heart. Obviously, Argentina is my place, family. But Italy is in my heart. And then Spain, Spain gave me my wife and my son. So I have very good memories there and it’s a very nice place. Obviously, I’m Argentinian, so for me it means meat in some places, Asado, that is a typical Argentinean one. But also, I am very eager to enjoy the pasta and paella, so we have several things. Anyway, here in New York, the pizza of New York is great. It is not Italian. This new way to make pizza from New York is fantastic. 

Dr. Rafeh Naqash: I can try to see you’re trying to keep everybody happy in a politically correct way.

Dr. Christian Rolfo: I didn't mention Belgium, but we have chocolates there. 

Dr. Rafeh Naqash: That is true. Every place is special and unique in different ways. 

Christian, thank you so much. This was very entertaining and very informative for me and hopefully for the audience. Thank you so much for being a part of this conversation. And thank you so much for submitting your work to JCO PO. We hope you consider JCO PO for future research in this exciting area as well. 

Dr. Christian Rolfo: Thank you. Thank you very much, Rafeh, for the opportunity. And JCO Precision Oncology is a really great forum to discuss precision medicine. Congratulations for all your work. The last, if you allow me to give an advertisement here. We have our Liquid Biopsy Congress, the ISLB, the annual conference will be in Denver from 20 to 25 November, so just before Thanksgiving day. So if you are able to go there, we will have a lot of discussion on liquid biopsy like we did today. Thank you very much. 

Dr. Rafeh Naqash: Thank you so much for highlighting that, and hopefully, our listeners will try to register and be part of that meeting. 

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