ERIC EDELL: Hello and good morning and welcome to today's session. I'm Eric Edell. I'm a practicing pulmonary physician at Mayo Clinic, Rochester. And we're honored to be here today to discuss our multidisciplinary approach to lung cancer management. I would like to welcome Dr. Dawn Owen, who is one of our radiation oncology staff here at Mayo Clinic, Rochester.

Dr. Janani Reisenauer is a member of our thoracic surgery department and also a co-appointment to the division of pulmonary doing interventional pulmonary work. And Dr. Mohamed Shanshal from our medical oncology department. All of us have the privilege of caring for lung cancer patients at Mayo Clinic, Rochester, and we approach as many of our patients as possible with a multidisciplinary methodology. We're very fortunate here to actually have one of the most active multidisciplinary tumor board programs, probably in the country.

By that, I mean we meet every day at 1 o'clock for 30 minutes, and we will discuss anywhere from two to 10 patients. In addition to that, once every two weeks, we meet with our pathologists and our physicians outside of Mayo Clinic and our Mayo Clinic Health System to present cases as well. Today, what we'd like to do is first have each one of our panelists share with you their research at a high level in the management of lung cancer patients.

And then we'll discuss a couple of cases that illustrate the complexity but the benefit of the multidisciplinary tumor board in managing those patients. So I'd like to start with Dr. Shanshal. Could you please, Dr. Shanshal, give the audience a brief overview of some of the exciting research that your team is involved in?

MOHAMED SHANSHAL: Thank you, Dr. Edell. I'm Mohamed Shanshal, a medical oncologist that specializes with lung cancer and cancer drug development. And my primary focus is developing new drugs and also sharing the multidisciplinary management of lung cancer. A lot of exciting development in the field of lung cancer management. We have seen a lot of FDA approval over the last year.

We also have a robust clinical trial and research portfolio in the thoracic and the lung cancer field from the phase I all the way to the phase III, including the innovation and inclusion, also, of bispecific and CAR-T therapy for those patients with the different stages of diseases.

And one of the exciting field also as well is the incorporation of the targeted therapy and incorporation of the cellular therapy team as part of the Mayo Clinic platform. So here, we have cellular therapy, we have a dedicated unit to manage and give all of these new treatments, including the CAR-T therapy and bispecific therapy.

ERIC EDELL: Dr. Shanshal, just a quick question. How would a physician get information regarding the clinical trials that are ongoing at Mayo Clinic that they may have a patient to enroll in?

MOHAMED SHANSHAL: Sure. So we have created multiple resources for that, either by checking the website. It has a list of all clinical trials from the early phase, all the way to the stage III phases as well. If they needed some guidance there, we do have also a navigator that can help with the contact information and an online format that they can submit to refer the patient to us.

ERIC EDELL: Excellent. Excellent. Dr. Owen, could you share with our attendees the exciting work that you and your colleagues are doing?

DAWN OWEN: So my research focuses exclusively on a lot of thoracic malignancies, especially non-small cell lung cancer. We certainly have a lot of programs looking at how to mitigate the risk of pneumonitis from radiation. We have an active proton practice as well as, we're looking at potentially opening a trial looking at different doses of steroids for pneumonitis.

We have a unique program featuring spatially fractionated radiation, both stage III and IV unresectable lung cancer, which may boost the immune system, and its interaction with immunotherapy, which is a standard-of-care therapy across several stages of lung cancer.

And we have a very active practice looking at outcomes of different approaches. So we've recently looked, in collaboration with Dr. Shanshal, induction systemic therapy, followed by chemoradiation, which has no prospective data right now and potentially, there could be a prospective trial in this space. So certainly, a lot of technologically-driven as well as outcomes-driven radiation oncology trials. Very, very multidisciplinary across several disciplines.

ERIC EDELL: Dr. Owen, that's very nice that you're sharing what the collaboration within the organization is. Are you also collaborating with other institutions outside of Mayo Clinic in some of these trials?

DAWN OWEN: We do. We have collaborations with MD Anderson. We have also done some other analyses with Moffitt, looking at rarer types of thoracic malignancies. We also participate in large rare disease sites such as ithymic forthymomas and also mesothelioma. So we have a very, very active cross-collaborative within the specialties at Mayo, but also with multiple other institutions that have subspecialties in thoracic radiation oncology.

ERIC EDELL: Well, the weak link of the four of us is my research work. But I've had the privilege of, over the last 25 years, being the principal investigator of a thoracic specimen registry. And what we've started is collecting the surgical tissue from lung cancers and matched blood. And we've been collecting this for, as I said, 25 years.

We have over 25,000 specimens now, a couple thousand patients. And it's really exciting to see how this idea and this tissue registry has led to a lot of the collaborative work that you hear about. And I'd like to just kind of now pivot to Dr. Reisenauer on how she has utilized some of the tissue registry resource in the work that she's doing here at Mayo Clinic.

JANANI REISENAUER: Thanks, Dr. Edell. Good morning, and thank you for the opportunity this morning to discuss multidisciplinary lung cancer care. As you mentioned, the thoracic specimen registry has really allowed us to leverage exciting and innovative research in the field of early risk detection, interception, and minimally invasive approaches to treatment.

So my specific area of interest and research is in robotic bronchoscopy, which we'll discuss a little bit later on in the program, but obtaining very small lung cancer specimens in patients and utilizing that to not only identify cancer early but identify potential new opportunities to treat those patients as well. Thanks again.

ERIC EDELL: Excellent. Well, I hope you all can see how exciting it is for someone like myself to work here. And how we keep these people working at Mayo Clinic is because of the resources, the patients that we get to see, but the camaraderie and the multidisciplinary approach that we have. I think everybody that's here attending this webinar realized that lung cancer continues to be the leading cause of cancer death in both men and women worldwide, and how we've made great advances, but we need to do more.

What we'd like to do now is pivot to a multidisciplinary discussion of two very frequent clinical scenarios that come to our tumor board and share with you how we work through these issues, and then encourage you to ask for any questions after or during our presentation. So the first case that we want to present is a 64-year-old gentleman that was a previous smoker that presents with cough. Very active. You can see he's got fairly good pulmonary function tests.

And a CT scan was done, and a PET scan was done that shows a clinical stage IIIA lung cancer. The reason that's clinical stage IIIA is there is uptake in the N1 hilar node, and there's a little uptake in that 4R N2 lymph node. What I'd like to do now is ask our panel a few questions for management and therapeutic options. So I'd like to first ask Dr. Reisenauer, what's the standard approach and the tools available to us to adequately diagnose stage and ensure that we get the material needed to optimize the therapeutic options for this patient?

JANANI REISENAUER: Thanks, Dr. Edell. As you stated, this patient, based on imaging, does fit into what we would consider probably a stage IIIA adenocarcinoma. We would obviously need to prove that pathologically. And stage III is a bit of a mixed bag in terms of treatment options, as you'll see. So step one is understanding as much as we can about the biology of the tumor, the diagnosis component, as well as the staging component as well.

If you're diagnosing just the nodule in and of itself, there are multiple options. There's the conventional transthoracic CT-guided biopsy or there's robotic bronchoscopy, which I mentioned earlier. The robotic bronchoscopy is done in a bronchoscopic suite. The patient is brought to the bronchoscopy suite and put under anesthesia. Utilizing a special bronchoscope, we're then able to drive out to the nodule and collect samples from the nodule.

If there's suspicion of nodal disease, we may start by staging the mediastinum first or we might do a combination of biopsying the primary lesion and sampling the lymph nodes, depending upon the clinical indication.

Regardless, with robotic bronchoscopy, we now have shown through the literature and our retrospective reviews that we can obtain enough material sufficient enough to search for specific molecular markers that might be amenable to various therapeutics. And not only are we now able to look for those specific markers, we're also exploring research where we're getting the full RNA and DNA profile of all of these tumors, which might lead to more therapies down the road in the future.

ERIC EDELL: So the approach of endoscopic sampling of either the primary tumor or the nodes-- and in this case, we would want to assess all nodes that were greater than 5 millimeters-- we're able to get an adequate specimen for molecular testing. What do you do at the time of sampling to ensure that you have enough specimen to fulfill the adequacy question for next-gen sequencing?

JANANI REISENAUER: Yeah, that's a fantastic question. So we have a mechanism on site called rapid on-site cytology, where we have our pathology team in the room staining and fixing and preliminarily interpreting the slides for us as we're performing the procedure.

So they can look at the slides, and based on the cellularity of the slide, tell us, you're going to have enough material here for PD-L1 and the other molecular marker analyses. We oftentimes take two or three additional samples just to make sure we do have sufficient amounts. But having that rapid on-site cytology has really helped us direct sufficiency of material at the time of biopsy, hopefully preventing unnecessary multiple procedures for the patient.

ERIC EDELL: Perfect. I'd like to now ask Dr. Shanshal-- we've talked about this molecular testing, the next-gen sequencing, PD-L1. That's new in my career. In fact, we didn't care if it was squamous cell or adenocarcinoma in the past. Why is it so important now for us to have this kind of information as we're looking to treat these patients?

MOHAMED SHANSHAL: Thank you. Excellent question there. One thing is to assess the future resectability of disease. The other thing is also, these molecular markers can help to define what would be the optimal upfront neoadjuvant for an adjuvant therapy. And the reason behind that is that it's very important to know, for example, if there is an EGFR mutation to define if this patient will benefit from an adjuvant therapy utilizing a drug like osimertinib.

On the other hand, if there is no targetable mutation, then one of the options, and one of the good options, is to consider a neoadjuvant approach utilizing chemoimmunotherapy. There have been multiple trials that have been launched, for example, the CheckMate 816, which we have a four-year survival update, four-year data update there. The pathologic complete response by incorporating immunotherapy increases to around 24%.

I think what is also important in this case is that the four-year update showed the median event-free survival really had increased tremendously from 18 months to 43 months, awaiting a final overall survival benefit there. So there have been an FDA approval for immunotherapy in the upfront setting. There is also an FDA approval for a targeted therapy. I mentioned the EGFR in this case, in the adjuvant setting. And for the ALK mutation, we have the alectinib-- have been approved there.

One additional advantage here we have at Mayo is that we have created a good clinical trial that capture all of these rare mutation, targetable mutation. For example, we have a trial that include the use of targeted therapy for different type of mutation in the upfront setting for those patients, including, for example, the ROS1, RET mutation, BRAF mutation. We know from the previous experiences in the metastatic setting that they tend to respond better to targeted therapy rather than the chemoimmunotherapy here.

So I think having an idea about the biology of disease is very important in this case. The other thing that we consider when we do the multidisciplinary evaluation there-- we still look into the tumor histology. So the regular adenocarcinoma, squamous cell carcinoma, we have very good data from all the KEYNOTE study, CheckMate.

But we also often see rare cancers like sarcomatoid or mucinous. And we put that into our decision-making if that specific patient would be a candidate for upfront therapy, systemic therapy versus, we would rather treat with a definitive approach in this case.

ERIC EDELL: Excellent. So as I said earlier, this patient has very good performance status. Pulmonary function tests are good. Dr. Reisenauer based upon that, do you see any reason why we wouldn't think, even though it's stage IIIA-- and I know a lot of our clinicians are thinking, that's a later-stage cancer than what we're used to for surgery. But is there anything here that would say this patient would not be a potential surgical patient?

JANANI REISENAUER: Yeah, that's a good question. Definitely, we would assess candidacy based on comorbidities, which it sounds like this patient has relatively none, and pulmonary function testing, which sounds relatively sufficient, to be tolerant of a lobectomy.

Many of the clinical trials that Dr. Shanshal have alluded to does appear to show a benefit for patients that undergo surgery as part of a multidisciplinary approach for patients with stage III disease if we feel we can confine surgery to more or less a lobectomy and not an extensive operation, and we feel like we can get good control of the disease with either neoadjuvant or adjuvant therapy.

So this is a perfect example of a case that we would bring to multidisciplinary tumor board, make sure everybody is aligned on the team and on the plan, and offer surgery if the patient is open and willing to do it and eyeballs to be a sufficient candidate and surgically, would be tolerant of a lobectomy, both from a patient factor standpoint and a tumor factor standpoint.

ERIC EDELL: So, Dr. Owen, I've heard what Dr. Shanshal talks about with some of the CheckMate 816 and the ENDURO trial, and we get this next-gen sequencing. And there's lots of drugs out there that thank goodness, you guys keep track of. If this patient comes right now, we're talking about him here at the tumor board, The material is out there waiting, what can you tell us about the difference in your mind when the evidence based upon the studies that are out there-- the advantage of either chemo-rads and then surgery versus neoadjuvant chemo-immuno and then surgery? And would protons ever be brought into the discussion of that situation?

DAWN OWEN: This is a great question. There are no randomized trials comparing these new perioperative approaches to chemoradiation. However, about 10% of patients on the trials-- and actually, when you look at some of the new retrospective data looking at implementation of this approach-- don't make it to surgery. Either there's some progression or the patients are debilitated after some neoadjuvant therapy, and they come our way for potentially resectable candidate. And certainly, chemoradiation is the standard of care for unresectable lung cancer.

And so it's very difficult to directly compare to outcomes. But if you look at the overall survival in the perioperative trials as well as those compared to PACIFIC, they're fairly comparable, and I think that either approach is good. I think the way that I view it is, surgery and chemoradiation are both local control treatments. The surgeon is going in and resecting the cancer, and there still needs to be some systemic therapy on board to prevent distant metastasis.

And the same is true with chemoradiation. And certainly, the standard of care is to have consolidative immunotherapy. So our treatments for the local control portion also need to make sure that the patient will be well enough to receive any sort of adjuvant therapy or neoadjuvant therapy, because it's a combination of multidisciplinary approach that really results in that survival benefit for a good, long-term survival for these stage III lung cancer patients.

In terms of proton therapy, I think that the way I view when to use protons-- and certainly, not all cases require it-- would be patients who have-- it's usually more of an unresectable setting, where patients have much larger tumors, where we have difficulty meeting our standard lung and heart constraints. But also in patients who have a lot of debility, where we're concerned that excess doses to the heart or the lungs could be very, very morbid, and we can certainly minimize the risk of that with proton radiation.

And then the other thing is pneumonitis. That's something that can happen in up to a quarter or a third of patients of chemoradiation. And we know that the adjuvant therapies, whether they have an EGFR mutation using osimertinib or whether they receive durvalumab as their consolidative therapy, increases the risk of this pneumonitis. And using protons in select settings, where we can minimize that risk, we enhance the success of these patients going on to those systemic therapies which have the survival benefit.

ERIC EDELL: Excellent review. Excellent. And I really liked the nuance. I think it's important in the art of medicine and the power of the multidisciplinary tumor board, the knowledge that Dr. Owen brought to remind us that there are no clinical trials comparing chemo-rads to neoadjuvant chemo-immuno that we're starting to do. It just shows the breadth of information we still have to obtain in the future.

So here we are. We've got this patient. The sample has been collected. It is an adenocarcinoma. PD-L1 is 12%. And Dr. Shanshal, we're sending it off for next-gen sequencing.

Now, I don't care what panel people are doing. A lot of people have panels within their organization. Some send them out to other places in the country. But frankly, it's going to take maybe two to three weeks for this patient to know whether they're going to have a targetable mutation or not.

What do we do as clinicians when we're working together in the multidisciplinary tumor board or counseling the patients? What do we do? Is it better to wait and get the results of that next-gen sequencing? Should we start chemotherapy now? How do we manage that in that setting? And I know that's-- I may have thrown you a curveball. I don't know if I told you I was going to ask you this. You're muted.

MOHAMED SHANSHAL: Thank you very much. That's a common scenario and oftentimes create a lot of anxiety for the patients. I think, depending on the case here-- so a patient-- for example, this gentleman. If I see a patient, non-smoker, young and healthy, there is an up to 50% chance in non-smoking patient that we might find a targetable mutation that could potentially change the course of treatment through either an upfront standard of care versus targeting it through a clinical trial approach there.

One advantage about seeing a patient here also is that we do have a very rapid turnover of this testing through the Mayo panel that we have available, including testing for those rapid EGFR testing and ALK mutation testing. Usually, we get an answer within a week.

Sometimes, we also incorporate the ctDNA that has a good correlate with the treatment. I think in this case, in this specific case, if a patient is never a smoker, it will be important to know at least, what's the EGFR here before we make our final decision, since we have good trials there that we think the patient might benefit from.

ERIC EDELL: Excellent. I'm glad you brought up the point of the rapid testing because that is something potentially that referring physicians could take advantage of here at Mayo Clinic. Secondly, thank you for mentioning the serum testing for next-gen sequencing, the liquid biopsy, we sometimes refer it to, because I think we're seeing advances in that, and we're doing a lot of work here at Mayo Clinic in evaluating that as well.

Well, I do believe in shared decision-making and true informed consent. So this patient was counseled, after the multidisciplinary tumor board discussion, that he has a low likelihood of a targetable mutation, that it will take anywhere from a week to two weeks, even with sometimes the rapid. He was very comfortable waiting for the next-gen sequencing. And he had no targetable mutation.

So he went on. He had chemoimmunotherapy as neoadjuvant treatment. He went on and had resection and had a complete pathologic response, and he's now being monitored in our postprocedure lung cancer group for recurrence. I'd like to ask the final question to Dr. Reisenauer. We now have a patient who's NED, at least at complete pathologic response at surgery. What is the monitoring for this patient as we go forward?

JANANI REISENAUER: That's a great question. So typically, we see those patients back at about a month after surgery, usually just with a conventional chest X-ray to make sure that healing has gone appropriately and they don't have any side effects from the surgery. I will just add that in 2024, committing a patient, there's some myths out there about, rendering a patient for chemotherapy up front doesn't allow them to be a candidate for minimally invasive surgery thereafter.

That's not true. We oftentimes offer minimally invasive surgery up front for these patients, regardless of what their neoadjuvant or adjuvant status might be. And most of us attempt at least a minimally invasive operation, regardless of what sort of neoadjuvant treatment the patient has had up front. So in that setting, we anticipate a fairly quick recovery after surgery. We typically see them back at about a month, four to six weeks afterwards, to ensure that healing has gone appropriately and there's no post-operative concerns.

We typically then see them back in conjunction with medical oncology because at that time, the pathology report is finalized, and we can get a sense of, did we really see sterilization of the mediastinum, meaning, was there residual disease in the lymph nodes or not, what was the control of the primary tumor, did we see any shrinkage. And that's the other benefit of sometimes neoadjuvant treatment up front, is that you can compare what you have pathologically from the diagnosis and staging up front to what you're seeing on the surgical specimen after treatment.

And it gives you some sense of how this tumor behaves biologically in response to systemic therapy. So we typically see these patients back in conjunction with medical oncology, and then based upon review of the final pathology report, make a decision in terms of whether adjuvant treatment is then potentially warranted by means of immunotherapy versus just ongoing observation. And typically, for a patient like this, you're looking at a surveillance imaging probably on the order of every three to four months.

ERIC EDELL: Excellent. Now, you led into the next question for both Dr. Shanshal and Dr. Owen. Is there a standard of care that would tell us what this patient needs going into the future? In other words, do we keep going with his immunotherapy? Is there a need for any radiation adjuvantly in this setting? Dr. Shanshal, could you go first?

MOHAMED SHANSHAL: Yeah, very good question again. This is always a debate. And I think the data comes from the 77T trial, where they looked, actually, at the patients specifically who achieved a complete pathologic response in the CheckMate 77T. And the benefit that we see so far now is that there is an event-free survival benefit, even for patients with complete pathologic response.

This is an area of very active investigation that we really need to continue based on that, on the adjuvant therapy, versus, there is a research going on now about utilizing ctDNA and decide the treatment for those patients would require further adjuvant therapy or not.

What I would say so far-- I make a discussion of the data with the patient present, the risk and the benefit here, that we do have an event-free survival benefit. But really, the main thing is here also, we want to see a long-term survival benefits for those patients. One thing we put also in our consideration is the financial toxicity and the risk of toxicity from the immunotherapy.

So that part will be more of a shared decision-making with the patients when it comes to the patient. Obviously, not all patients achieve pathologic complete response. This was reported in around 24% of the patients. So it's a good discussion or a good question here to answer is, do we continue or not?

ERIC EDELL: Dr. Owen what about the role of adjuvant radiation in this setting?

DAWN OWEN: The short answer is no. There have been two recent randomized trials, LungART and PORT-C, and these were pre-immunotherapy era trials, and so pre-perioperative approach. And there was detriment with the LungART trial. And I think that trial did terrible radiation. But that's an aside. And then the PORT-C trial, where there was no survival benefit but also no detriment.

And I think that that's where our zero resection. For anyone who has microscopically positive margins or R2 or gross residual disease, there's definitely a role for adjuvant radiation and possibly even adjuvant chemoradiation for R2 resection. There's a lot of surgical literature that shows significant increased risk of local regional relapse as well as distant relapse if there's residual disease. So I do think that if there's any concern about that, then they should see a radiation oncologist.

The great controversy is in multistation N2 disease. We just don't know. We certainly know patients who have a lot of N2 nodes kind of surprise. Or there is certainly trying to define the parameters of resectability that multistation N2 nodes, even by ASCO, certainly in a multidisciplinary discussion, was hotly debated, that these patients might still be considered surgical candidates after neoadjuvant chemoimmunotherapy.

Those patients remain at risk of regional relapse. And there are some subgroup analyses that show potentially some benefit. But again, they're in a pre-perioperative period.

So I think that if there's any question, call up-- we're happy to see them or to talk about it. I do think there's definitely a role for protons and adjuvant radiation. The toxicity that came from adjuvant radiation was from 3D conformal, so very old-school radiation. Or IMRT in some cases also could cause excess toxicity.

In protons, we can treat a very, very small strip, where there's minimal dose to the contralateral lung, the remaining lung, and to the heart. And so that's a very important consideration if there's thought to offer a port or postoperative radiation. Again, these types of cases require a lot of multidisciplinary discussion about the appropriateness of consideration of radiation.

The other thing is we may be moving into an era of using circulating tumor DNA after perioperative therapy to define, do we need local therapy at this point. If they look like they've had a complete metabolic response, do we need radiation? Do we need surgery? Do we watch these patients? And so that may be coming in the future that lung cancer will start to use circulating tumor DNA to decide on local therapies or additional adjuvant therapies before or after any local therapy.

ERIC EDELL: Excellent summary. Excellent. I'm just looking at the chat box. I don't see any questions from our participants, our audience. I think we've used this case as a very good example of what I would say is one of the more frequent stages of lung cancer that the multidisciplinary tumor board struggles with, and that's the stage III lung cancer. So I hope that the audience is resonating with the challenges and the benefit of having this multidisciplinary discussion surrounding a patient such as this.

So now let's flip to another-- what I would describe as a frequent occurrence at the multidisciplinary tumor board. And it's probably occurring because of the biology change of lung cancer, but also because of our screening strategies nationally. And this is a case of a 65-year-old, again, previous smoker, that underwent a CT scan for screening because of the age and the tobacco history.

And I'm showing you a couple of scans that illustrate the multicentric adenocarcinoma spectrum-suspicious patient. So as we look at this, I'd like to start with Dr. Reisenauer. Can you review for the audience some of the tools that are available to help determine not only the pretest probability of malignancy but even some of the newer tests that are saying the likelihood of this thing-- we think it's a cancer, that it could be a cancer at resection? Can you comment on those tools that we were using?

JANANI REISENAUER: Sure. Absolutely. Thanks for the question. So there's a couple of different ways to look at how we look at what we call an indeterminate pulmonary nodule or something that got incidentally diagnosed on a CT scan. And do we pursue it? Because just so the audience is aware, there are many times that things show up on a CT scan that look like a cancer that are not cancer. So how can you, based on just imaging alone, make that distinction and make that differentiation?

At Mayo Clinic, we have developed a Mayo Clinic scoring calculator. It's the solitary pulmonary nodule malignancy risk score, which takes into account multiple factors such as the patient's age, size of the nodule, smoking history, prior history of cancer, and location of the tumor and morphology, meaning is it spiculated or solid. And that gives you some sense of the probability of malignancy. We also then clinically look back if the patient's had any prior CT scans to look and see if there's been evidence of growth or change.

Now, at Mayo, we have developed a more sophisticated way of doing the latter, which we affectionately call radiomics. We've been able to take a patient's historical imaging that's been conducted and actually scientifically measure patterns of growth or change based on various radiomic variables. That has actually been developed internally, labeled CANARY analysis. It's been published and validated through multiple internal and external populations and gives some sense of an aggressivity of a nodule.

So particularly in a patient that has multiple nodules, and the multidisciplinary team here is coming together, just because there's a nodule on CT, we don't decide that we want to treat all of them all at the same time. Some of them might make sense to wait because they're not as aggressive.

Some may never progress to the point of being something that we need to worry about. And that's where this radiomic analysis, this radiomic tool, can give us a sense of, what is the most serious or the most aggressive lesion here. And based upon that severity score, so to speak, we can then decide, does it make sense to treat it with one therapeutic modality versus another.

ERIC EDELL: Excellent. So I've put on the screen-- the first slide that we showed was illustrating a couple of nodules that-- I think there were three, two in the left upper lobe, one in the right upper lobe. And then the next slide that I'm showing the audience is the CANARY analysis, which stands for Computer-Aided Nodule Assessment and Risk Yield. And as Dr. Reisenauer stated, over thousands of CT scans, they've evaluated nodule density and then looked at pathologic specimens to correlate whether or not the density of this has anywhere from good to worrisome for malignancy.

And you'll see on this slide the characterization of that predominant nodule in the left upper lobe. And the next slide shows that there were actually six nodules on this patient that were evaluated with the CANARY analysis. Now, it's a bad presentation when you apologize for your slides, but I'll walk you through it. Those top three with all the colors illustrate a more dense, complex, and likely malignant at the time of resection.

The bottom three show a much more benign profile for the density of the nodule and the radiomics that Dr. Reisenauer was talking about. So we have a patient, multicentric adenocarcinoma, very concerned that the nodules, particularly in those top three, have been labeled as likely malignant, and they're interested now in what the multidisciplinary tumor board would say about management. So it comes to us. And the first thing that I would ask is, Dr. Owen and Dr. Shanshal, how badly do you need to know that this is cancer or not?

MOHAMED SHANSHAL: Yes, thank you. I think one of the important things that we face is, is this part of a unique, multicenter, black, solitary cancer arising there versus, is that part of a metastatic disease that we're dealing with? And I think one of the major thing is to try to attempt to resect the one that was the highest yield.

And this is an area where the expert of the pathologist and the next-generation sequencing also help us to decide if this is a spectrum of disease where the separate primary cancer is arising there versus metastatic lesions there to help us to decide what will be the subsequent therapy there.

Multicentric lung adenocarcinoma is a spectrum of disease, and it can present with different ways there, meaning either as solitary, primary cancers in one side versus metastatic lesions there. So those factors that-- as a medical oncologist, this is what I'm looking for to help make a decision about systemic therapy.

ERIC EDELL: Excellent. Dr. Owen?

DAWN OWEN: So I think multifocal primary lung cancer, multicentric lung cancer is very challenging. First of all, I think you need to individualize care. What's the patient's performance status? What are the patient's expectations? And what is the rate of growth or solidification of some of these ground glass nodules?

Many times, it is not an emergency. But any time you bring up the concern that this is an adenocarcinoma spectrum or a cancer, patients are, get it out, I need to deal with it right now. Meanwhile, they may have multiple comorbidities that are more likely to be the terminal event than this.

So this is where our multidisciplinary tumor board and collaboration shines because the question is-- let's say the patient's really, really fit. The patient is a great candidate for any treatment. And we talk about local treatment often first and reserve systemic therapy for if there's multifocal, synchronous, rapid progression, and as Dr. Shanshal mentioned, looking for certain mutations.

And there are some patients who have EGFR mutations, for example. Sometimes observation is the best thing to do if the lesion is growing very slowly, the patient has a lot of other things going on.

So the question that Dr. [INAUDIBLE] always asks me is, do you need a biopsy? I do think a biopsy is important if possible. So if the patient is very fit, I certainly hope, and will throw the question to Dr. Reisenauer at some point, that we can get a good surgical specimen for both NGS and then also just for pathologic confirmation. I think that's important for any future systemic therapy, and I think it's reassuring to say, well, I'm treating a cancer.

But we do run into scenarios where patients are very frail. They may be smokers for many years, they're on oxygen. And we're asked to see them, and we're concerned that if they have any sort of biopsy, they're very high risk with anesthesia. If we do navigational bronchoscopy or robot, they're very high risk of a pneumothorax where that could be nearly fatal or require ICU admission if they have a transthoracic biopsy.

And in that case, this is where CANARY is very helpful because we have this validated, rad-path correlation showing that this might be a poor outcome or very aggressive-looking lesion where we would be comfortable treating empirically with serial growth and potential FDG avidity when we're very, very concerned about a cancer.

And sometimes I'll say, well, we're afraid to biopsy this patient. What does the radiologist think? If our whole panel is very concerned this is a malignancy, I would be, I can treat it empirically with stereotactic radiation. And we also have a discussion with the patient about the stereotactic radiation that we would offer because certainly, there's a very minimal risk of pneumonitis. But for a patient, for example, that it's an FEV1 under leader, we have to be very concerned if that happens.

So again, it's very individual to the patient, to the pace of the disease, their comorbidities, as to when we treat and if we treat. And I think it's very important for us to be comfortable managing expectations and uncertainty. And that's Dr. Edell's favorite term. We have to manage uncertainty and be comfortable with sometimes watching things that are not going to evolve very quickly.

ERIC EDELL: Excellent review. So you can see how much fun it is when we have these discussions at our multidisciplinary tumor board regularly and why we keep coming back. So this patient, we did the CANARY. High likelihood of at least three that if at resection, they're going to be malignant. This performance status is excellent. The patient wants to proceed.

Dr. Reisenauer, could you describe the program that we have here, what we call single-stage, and how this patient might be a candidate for that? Because theoretically, this would be in order to get both of these cancers a lobectomy-- and the importance of tissue confirmation before a patient were to undergo a lobectomy.

JANANI REISENAUER: Yeah, it's a great question. So the NCCN guidelines would suggest obtaining some sort of tissue confirmation of malignancy in a patient prior to going to lobectomy when and if at all possible.

As Dr. Owen so eloquently mentioned, in some situations, doing a biopsy beforehand is not really necessary. In other circumstances, the NCCN guidelines do allow for biopsy at the same time as resection, whether that's a diagnostic wedge resection as a part of the initial surgery or what we have started to introduce in a situation where a wedge may not be feasible is a bronchoscopic biopsy at the time of the resection.

So the way that we do that is to bring a patient into the operating room. We consent the patient ahead of time that we'll start with a biopsy, and then based upon the results of the biopsy, if they're confirmatory or not for malignancy, then have a plan set up to go ahead straight to surgery.

We bring the patient to the OR. We put them to sleep under anesthesia. We then introduce the robotic bronchoscope, which is a very slim, ultra slim, 2 to 3 millimeter remote-controlled catheter that can be steered to within 99% of any and all pulmonary nodules through the airway.

We use a hybrid operating room, so we have advanced imaging applicable and available to us if we need to better direct exactly how to get into the nodule and the proximity of our robotic bronchoscope to the nodule. We then obtain a biopsy with the pathologists in the room that can give us a quick overread to confirm, yes, this is, in fact, cancer.

And in that setting, if they're able to do that, we're then conveniently positioned in an operating room with the patient already intubated. We then turn the patient on their side and then perform a minimally invasive resection, a lobectomy, in this case, with mediastinal sampling.

We also have the capability to do EBUS and mediastinal staging if and when clinically appropriate, as it would potentially be in this scenario with bilateral lesions. We have shown that that program has reduced delays in getting a patient to potentially surgery or at least through the diagnostic and workup phase of a patient's care journey, and have in some circumstances also avoided surgery when we have definitive confirmation of benign disease on the biopsy.

ERIC EDELL: Excellent. Excellent. Well, the patient was very interested, and he underwent the single-stage management strategy. We'd proven for adenocarcinoma prior to resection. The lobe was resected, and these were both invasive adenocarcinoma in the left upper lobe, both lesions. OK, now, Dr. Shanshal, does this patient need systemic therapy?

MOHAMED SHANSHAL: So going back to the same, it's really to define, is this part of the same biology? Does all those nodes, you have the same biology? It's to help us to know if this is metastatic lesion versus a separate, primary lesion that is more of a pT1a, each one of them.

So those multicentric, they can evolve at a different time point and sometimes, they can evolve at the same time point. So it's not necessarily those always present a metastatic disease, meaning spread of those nodules to different sites that represent a different biologic disease.

ERIC EDELL: And how do we determine that?

MOHAMED SHANSHAL: Yeah, excellent question. And that's when it come to-- I was mentioning of the pathologist's role in this case. I oftentimes call the pathologist and discuss with them, what do you think? Is this a separate, primary tumor there? Or do you think this is all part of the same disease? And oftentimes, our pathologists are very good at telling us that most of the time, this is a separate, evolving, primary cancer.

Sometimes, where we face where it's not clear to them-- and this is where the role of the NGS comes to help us-- is to see what's the mutational panel there, are those similar or not. So these factors that I put into consideration before I decide to give an adjuvant therapy versus an observation.

And it's important to tell the patient that multifocal disease, multicentric disease can evolve in the future, meaning you can develop a future cancer, and those usually present as ground-glass opacity that continue to evolve over time.

So surveillance is very important for those group of patients. Here at Mayo, we have done a very good retrospective analysis of all of those tissue. One of our colleagues and Dr. Roden also had looked into those. And a minority of them actually can express certain mutations like the VEGFR, which can drive the growth of those cancers.

It's not implemented if the size is less than 4 centimeters, so there is no role for a TGFR therapy there. But it's good to know that some certain subsets can evolve because of an underlying oncogenic mutation.

ERIC EDELL: Excellent. Excellent. I'm glad you mentioned the pathology colleagues, too, because here's a perfect example to me that a comprehensive cancer center that deals with cancer on a regular basis, like Mayo Clinic and other places in the country-- the specialist of lung pathologists are so critical. A general pathologist does a lot of great work, but it's very hard for them to know the nuances of these different histologic features, morphologic features that they might see to be able to say, these are separate primaries.

So you're correct. We went back to our pathologist. They were very confident that these are unique, separate primaries within the right upper lobe, based upon their histologic and morphologic features. And they were very comfortable calling this multicentric adenocarcinoma spectrum. I think the reason I'm bringing this up is that when colleagues outside of Mayo are confronted with something like this, we also have a consultative pathology service that reviews pathology from outside regularly.

So now we have, the patient's very happy. They have taken care of two lung cancers. But they have a third that's in that right upper lobe. Dr. Owen, we're going to refer that third. After our discussion at the multidisciplinary tumor board, you volunteered to see him the next day-- or her. You were very accommodating, as you always are. And she's coming to you to discuss the role of radiation here. She did OK with surgery, but she'd like to try and avoid surgery if that's a possibility. What kind of conversation, information would you give her?