Dr. Manish Shah (Host): Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care, and research. I'm your host, Dr. Manish Shah. And today, we have two guests to talk about the latest in lung cancer treatment and care.

Joining us is Dr. Jonathan Villena. Dr. Villena is a cardiothoracic surgeon at NewYork-Presbyterian/Weill Cornell Medicine, treating patients with lung and other thoracic cancers. He is heavily involved in ways to make surgery more minimally invasive, including leveraging new cutting-edge robotic techniques to improve surgery for lung cancer. He was recently elected as a member of the Parker Institute for Cancer Immunotherapy, as well as for recognition of his work on immunotherapy and understanding immune cell education and immunity in lung cancer.

Also with us today is Dr. Christine Garcia. Dr. Garcia is a medical oncologist at Weill Cornell Medicine specializing in caring for patients with lung and thoracic cancers. She's also the Director of the Hematology and Oncology Fellowship Training Program, where she oversees the training of up-and-coming cancer physician scientists committed to moving the field forward. Dr. Garcia serves as the Associate Vice Chair for Quality and Patient Safety for the Department of Medicine.

Together, their work and the work being done here at Weill Cornell really encompasses where the field of lung cancer therapy is moving toward, beginning with minimizing surgical morbidity while also improving care for patients with targeted therapy. Drs. Villena and Garcia, welcome.

Dr. Jonathan Villena-Vargas: Thank you.

Dr. Christine Garcia: Thank you so much for having us.

Dr. Manish Shah: So, just to get us started, in cancer care, we really balance removing the cancer in terms of surgical interventions while preserving the function of the organ, and where the cancer's located, as well as overall quality of life for the patients. The lungs are essential to life. They're essential to breathing, filtering air, everyday living. And keeping as much healthy tissue while removing the cancer is really critical for a lot of the advancements. So, I'll start with you, Dr. Garcia. Tell us a little bit just some background, what is lung cancer, what causes it, the risk factors.

Dr. Christine Garcia: At its core, lung cancer is what happens when cells inside of your lungs start growing out of control. Normally, your body has tight systems for regulating cell growth, but when something damages the DNA inside of a lung cell, then the cell can start multiplying to form a tumor.

So, lung cancer happens when cells in the lungs mutate or change. And this most often happens when people breathe in dangerous or toxic substances. When I think about lung cancer treatment today, we're in a modern era of cancer care, especially for lung cancer, and we're in an era of precision medicine. We're no longer asking what the standard treatment for lung cancer is. We're asking more questions about what is the patient's cancer at the molecular level and what is the right treatment for them.

So, there are really two main types of lung cancer, non-small cell and small cell lung cancer. And small cell tends to grow faster and spread to other sites. As far as causes, it's pretty well-known that smoking remains a dominant risk factor, but it's by far not the only one. Around 80-90% of lung cancer deaths are linked to cigarette smoking. But there are a lot of factors that are coming out more and more; radon exposure, secondhand smoke, air pollution as well as one of the most important insights is that there are a lot of lung cancers that are happening in non-smokers. So, around 10-20% of the lung cancers that we see now are in patients who have never smoked or have smoked very minimally.

Dr. Manish Shah: That's really helpful. So, what I always remember is that most patients with lung cancer will have smoked, but there are a lot more people who smoke who don't get lung cancer. So, it's a risk factor. There's some research that says it is causative, but there are a lot of other factors that lead to lung cancer beyond just tobacco.

Dr. Christine Garcia: Tobacco smoke, it's a mix of a lot of different chemicals. We know there's a lot of poisons within cigarette smoke that can cause cancer, but not every patient who smokes can get cancer. And we have a number of patients now who have never smoked and then developed cancer. So, we are learning more and more at the molecular level of why patients develop cancer, especially outside of smoking history.

Dr. Manish Shah: And you described it very well. So, lung cancer is an abnormal growth caused by DNA damage in the lung. Dr. Villena, tell us how do we diagnose lung cancer? What kinds of tests are typically done, and how does that impact our care?

Dr. Jonathan Villena-Vargas: There's basically two major ways of diagnosing lung cancer. One is if a patient is showing symptoms, meaning that they show up to their doctor already with a chronic cough or coughing some sort of blood or weight loss or chest pain—these are the most common ones.

Or we diagnose it by screening, meaning that the patient has no symptoms. And that is something that we pioneered here back in the 1990s with Dr. Claudia Henschke's work showing that if you are able to identify patients with these risk factors we spoke about, like smoking for a certain period of time, you can get a low-dose CT scan and catch these cancers before they show any symptoms, meaning at a much earlier stage, and the patients actually do better.

So really, the way we diagnose it is through imaging. And then, we see something that's suspicious, that may push us to get a biopsy as doctors to really look at what's going on underneath the microscope and see what type of lung cancer it is and how best to treat it.

Dr. Manish Shah: So, we talked about the risk factors and tobacco use. So, a chronic cough, weight loss, maybe coughing up blood. These are some common symptoms for lung cancer. How long do people typically have symptoms before they end up presenting to get a chest x-ray or to get evaluated? Is it a few weeks or is it many months?

Dr. Jonathan Villena-Vargas: A lot of times, people tend to delay getting diagnosed once they have symptoms because everybody's busy. Especially younger people or people that have a lot of economic burden will tend to put off going to the doctor. They'll have a cough and it won't be unreasonable for them to show up in my office saying, "I've had a cough for two, three months. It just doesn't go away," or "I've had weight loss and I'm not really sure why. I haven't been dieting, et cetera, et cetera, and I smoke." Or there's kind of this fatalistic, if they are heavy smokers, they don't want to know.

So, there's a lot of factors that a lot of times delay diagnosis in patients that have symptoms for a while, and that's something that we're really trying to turn around.

Dr. Manish Shah: Exactly. And we're hopeful that, if people understand that there are good treatments for lung cancer, both surgical and medical treatments that can really improve a patient's care, hopefully that will avoid delays in diagnosis.

And now, you mentioned lung cancer screening. I think for me this was really quite pioneering work. You're talking about the low-dose CT scans that are done, right?

Dr. Jonathan Villena-Vargas: That's exactly what I'm talking about. Prior to that, it was basically x-rays that ruled diagnosis and x-rays can't pick up these smaller lesions. So, it was really Dr. Henschke's work followed up by other people that have led these national trials that showed that you are able to pick up earlier cancers if you do a low-dose screening on patients that meet the risk factor such as smoking.

Dr. Manish Shah: A lot of the work done here at Cornell, it really focuses on minimizing surgery. So, if lung cancer is diagnosed, typically, you do need a tissue, you need a bronchoscopy or a biopsy of some sort after something is seen on a scan. If the cancer is limited to one lobe of the lung or one area, then often you think of involving the surgeon or a radiation oncologist to try to treat that area. But another advance that happened relatively recently was the concept of minimizing the extent of surgery needed. Do you want to talk us through that?

Dr. Jonathan Villena-Vargas: If you were diagnosed with a lung cancer in the past, you would get a lobectomy, which means a large section of the lung would have to be removed. Almost how in the past for breast cancer, they used to do mastectomies for every breast cancer that was noted.

Breast cancer beat us to it in the sense that they showed that you don't have to remove the entire breast in order to treat the patient. And we actually showed that here. So, there was a landmark trial in the New England Journal of Medicine by Dr. Nasser Altorki, that showed that if you have a two centimeter or less peripheral lung nodule, meaning a smaller T1 lesion or a smaller stage I lesion in the lung, you don't have to remove the entire lobe and you can spare a lot of healthy lung. And that randomized trial, which came out only a couple of years ago, really changed the field in how we treat lung cancer and trying to do more of a lung-sparing technique than to remove a lot of healthy lung. And I think that's made a huge advancement throughout the country, if not the world, and really it was led by Cornell.

Dr. Manish Shah: It's remarkable. So historically, what would happen is that you would have a lesion in the lung, a small lesion, maybe the size of a golf ball or something like that. And you want to make sure that you get the tumor out. You would need to have clear margins. You need to also ensure that you get the appropriate lymph nodes removed. At least that's what we thought historically. And so, that would lead to what we call a cancer operation, which was taking out the tumor as well as wide surgical margins, as well as the draining lymph nodes.

And that's where you get to the idea that you need to take out the entire lobe, because it's an oncologically safe and correct procedure to ensure that we have a complete dissection. And this is true in a lot of solid tumors, where you need to take out the tumor, take out the wide margins, and take out the lymph nodes that are along the vascular structures.

But as we learn more about the biology of the cancer, we know that some tumors extend to lymph nodes less often. And so, you can safely take out less of the tumor, maintain the margins that will prevent local recurrence and still achieve an equal oncologic effect, but with less surgery. And this is the idea behind this data that Dr. Villena talked about.

Dr. Jonathan Villena-Vargas: The idea that it's non-inferior, that was shown in the trial, that it basically has the exact same oncologic outcome while sparing healthy lung is critical. And that really has pushed us to things that we'll talk about further down the line and how we do that safely in patients.

Dr. Manish Shah: It's a concept that's important to understand—at least in solid tumors—is that, if the tumor is localized to the organ that the tumor originated in, so lung cancer or breast cancer or prostate cancer, then generally the best approach involves some kind of surgery to remove the tumor in its entirety.

And over the last 30, 40 years, our ability to do surgery in a way that is more refined, take out the tumor, make sure the margins are appropriate, but not take out too much tissue, those advancements have happened throughout surgical oncology, throughout many different organ systems.

And I think that leads us really nicely to the idea of robotic surgery, minimally invasive surgery, and then something that you've been working on, which is single-port robotic surgery. So, walk us through that.

Dr. Jonathan Villena-Vargas: Historically, surgeries in the chest cavity, so barring the last 20 years, it was basically done through a thoracotomy incision, meaning that we'd have to go in between the ribs, do these large incisions that were very painful for patients, and were actually very traumatic, because you'd have to do a lot of tissue division in order to access the lung. And then, the advent of minimally invasive surgery came, which is thoracoscopic or VATs. And then, further down the line, robotic surgery in which you actually just need a camera and go between the ribs.

But that surgery, which is basically the same surgery for the lung, it's just a different approach to actually get at the lung, still had a lot of pain associated with it. Going between the ribs, it's a very small space. And as you can imagine, there's a lot of nerves running through that space. And patients would have something called a post thoracotomy syndrome, even with minimally invasive approaches, meaning they have this prolonged pain from going between the ribs.

So, the newest thing is actually to avoid the ribs. It's something that we are pioneering here at Cornell called single-port surgery, which we make one-and-a-half-inch incision right below the ribs, and we can do the exact same oncologic surgery and avoid the ribs.

We've done the most in the country. People come from all over. And we're publishing on how much better it is for patients. So in general, everything goes hand in hand. Less healthy lung tissue can also lead to us refining our approach to getting the tumor and sparing the healthy lung tissue and as well as making sure that the patient recovers very quickly. So, this is something that we've started here. It just got FDA approved last year.

Dr. Manish Shah: That's incredible. For any of our listeners that have broken a rib, you understand how if you can avoid that, you're better off. I think I saw that you recently did a hundred of these so far. Is that right?

Dr. Jonathan Villena-Vargas: So, we did our first hundred right on New Year's Eve. We kind of had a nice little celebration for that. But in general, it makes sense and the patients do better, so we're very happy about it.

Dr. Manish Shah: We've talked a lot about how we've advanced surgery to reduce the amount of normal lung that's taken out, to use minimally invasive techniques to reduce surgical morbidity, and now even doing a minimally invasive procedure through a small incision below the ribs to avoid ripping the ribs apart. So, that's really fantastic.

Let's shift a little bit to the advances in medical care instead of using chemotherapy, which is still critical. But there truly has been a shift to using targeted therapies in lung cancer. Christine, do you want to talk to us about biomarkers and the targeted therapies?

Dr. Christine Garcia: So, not too long ago, a lung cancer diagnosis meant that you got one of a handful of chemotherapy regimens, and that was largely it. And the type of chemo really didn't change that much based on the tumor. But over the last two decades, there's been a major shift in how we start to approach lung cancer.

And really, the foundation of everything that we do now is comprehensive biomarker testing. And I really cannot stress this enough. Before any treatment decision is made, we need to understand the molecular footprint of that tumor. Biomarkers are essential in giving you the cancer's instruction manual. It tells us what's driving the disease, how it's likely to behave and, most importantly, what the cancer will respond to.

I say over and over again to my patients, we need to wait for the molecular testing because I want to give you the right treatment, not the fastest treatment. And I think this is also a good place where our multidisciplinary team is so essential. There are a lot of different types of biomarkers that we're looking for. So, you really need comprehensive next generation sequencing.

One of the most compelling examples is EGFR mutations. This is a mutation that we see, largely, in never smokers, and patients often look very different than your typical lung cancer patient. They tend to be non-smokers, women and of Asian descent. This is very critical, because this type of cancer is responsive to targeted therapies. But unless you test, we won't know what to treat you with.

So, I think that's why it's so important that we spend some time to learn more about the cancer itself before we jump right into treatment.

Dr. Manish Shah: On CancerCast, we've talked about biomarkers in other diseases, and one thing that we've come to is that if you identify a biomarker, the earlier you target that biomarker, the better off you are.

So, I use the analogy in colon cancer, BRAF is a biomarker. And only recently was there a drug, encorafenib, that was used for BRAF treatment. It was originally approved in a later line setting where the improvement in survival was modest. But then, if you use it in the first-line setting, you have dramatic effects.

And I think that this is probably true in lung cancer as well. And that's kind of what you're saying: if you have a biomarker, don't start chemotherapy—target the disease that's driving it, which is the biomarker. Let's talk about what are the key biomarkers that we should check for beyond EGFR.

Dr. Christine Garcia: Beyond EGFR, I think every patient with lung cancer should have testing that includes an ALK fusion, ROS1, PD-L1, and several others, since we now have targets that are moving into the frontline setting, meaning these patients are able to skip chemotherapy as their first-line of treatment and stay on targeted therapy, which is often a pill, to treat advanced lung cancer.

So, imagine how quickly we've advanced from everyone getting chemotherapy, 20 years later, to most of the patients with targetable mutations getting a pill to treat their cancer. It's been pretty incredible to see.

Dr. Manish Shah: How many patients with lung cancer have a targetable mutation roughly?

Dr. Christine Garcia: So, it depends on the actual mutation. EGFR tends to be in around 10-15% of patients in Western populations. However, it's much higher in Asian patients. ALK mutations or ALK fusions are actually around 3-5% of the cases. And then, less common are ROS1 and BRAF, MET, NTRK. There's a few other ones that are single-digit percentages.

Dr. Manish Shah: But PD-L1 is more than half.

Dr. Christine Garcia: Oh, yes, PD-L1 is something that we are checking on all of our samples. I don't want to put that in the target category. We also see a lot of patients with KRAS mutations, which is the most common oncogenic driver of lung cancer, as well as other cancer types. But we now have targets for some of the KRAS mutations in lung cancer too.

Dr. Manish Shah: If you see 10 new patients with lung cancer, you would expect maybe three or four of them to have a target or six or seven?

Dr. Christine Garcia: I would probably expect around three or four to have a target like EGFR or ALK or KRAS. They're definitely a smaller proportion of the group, but it is worth testing because it does help guide how you start your first treatment approach.

Dr. Manish Shah: Exactly. And also to avoid chemotherapy, you're able to use a pill instead of chemotherapy. And the other thing about these targets that I've learned is that they work so well that even in the context where the cancer may be very advanced, even if it's spread to the brain or something like that, the targeted therapy can really be quite effective. And you could even avoid radiation sometimes.

Dr. Christine Garcia: We see that especially in our patients with EGFR-mutated lung cancer, where they may have brain disease at diagnosis. But because some of the targeted therapies for EGFR mutations are so effective, we can avoid radiation. So, that also goes into a discussion with our multidisciplinary brain met tumor board, where we get to discuss some of these cases together.

Dr. Manish Shah: We talked about the earlier you use the target, the better. I think there are some recent data of using osimertinib, but maybe other targets in the adjuvant or neoadjuvant setting as well. Do you want to talk about that data? This is pretty recent.

Dr. Christine Garcia: We've been using targeted therapy especially for patients with advanced lung cancer. But now, some of these agents have been moving into the adjuvant space as well as the neoadjuvant space. So, osimertinib as well as alectinib, they’re two of the medications for EGFR and ALK fusions, which are being used after the patient has surgery. So, they'll see Dr. Villena, he'll take the tumor out. And then, we will give them a medication to help reduce their risk of recurrence.

There's also studies looking at giving osimertinib before you have surgery to try to extend that effectiveness prior to the surgery itself.

Dr. Manish Shah: Terrific. So, if you have a new diagnosis of lung cancer, you should check the tumor for a biomarker target. There's a significant chance 30-40% that you'll have some target that will change how treatment's given. And then, you've mentioned a couple times, Dr. Garcia, about the key aspect of multidisciplinary care. How often do you guys speak every week? And then, let's talk about this lung cancer tumor board that is the mainstay of this multidisciplinary care.

Dr. Christine Garcia: Officially, we meet every single week. How often we speak? It is probably every day. You really need a multidisciplinary approach for lung cancer because not one single specialist will have the full picture on their own.

And I really think the best outcomes can happen when every expert is at the same table looking at the same patient from day one or even before you get to the biopsy or surgery. So, we meet every single week in-person and we review patients together. And it makes it easier for the patient because, one, it's faster; two, they're not seeing one person then having to wait two weeks, see another person. It's like a one-stop shop when you do it in a tumor board.

Dr. Manish Shah: And the care is coordinated. Everybody's on the same team, working toward the same goal. And along this line of multidisciplinary care, in patients who are surgical candidates, let's talk about the neoadjuvant immunotherapy program that we've developed here and where that might be going.

Dr. Jonathan Villena-Vargas: So, how we were discussing earlier, a lot of the therapies start out on the advanced setting. That's where most of them get FDA approval and that's where they really start most of the trials. But as they showed, both targeted therapy and immunotherapy, these amazing results, they started kind of transferring into earlier stages, including resectable disease as Christine was just saying.

Immune checkpoint blockade is a little bit different than targeted therapy in the sense that there is no specific target—actually all patients don't have targets. So, that seven out of 10 as opposed to that three or four out of 10 will actually probably get immunotherapy if they're locally advanced or not just the earlier stage of lung cancer. So, it's a lot of patients.

Immunotherapy actually is distinctly different in that it doesn't work directly on the tumor. It actually works on the immune system. And then, the immune system attacks the tumor. And it was something developed here. One of our directors, Dr. Jedd Wolchok is very well-known for leading some of these paradigm-shifting trials in melanoma, which then went on into lung cancer.

The neoadjuvant approach, which means that you give the immunotherapy before surgery, actually came after the adjuvant approach, which is usually given after surgery. And they're both FDA approved. But why we think neoadjuvant might be a little bit better, is the sense that the tumor's already there. And then, in my lab, we study the lymph nodes that are already there. And therefore, the immune system understands the tumor before you completely remove it. But that hasn't been proven whether giving it before or after surgery is better. This is something that we're actively studying here at Cornell.

Dr. Manish Shah: So, on previous episodes, we've talked about immunotherapy and activating the patient's own immune system against the cancer. This concept of trying to educate the immune system while the cancer is there and the draining lymph nodes are there, I think is really emerging as an important approach. In melanoma, that approach led to a survival advantage. Even a short course of immunotherapy while the melanoma was still intact improved survival compared to adjuvant therapy. Maybe you could talk about your research as well and what we're learning from the draining lymph nodes and the T-cell education.

Dr. Jonathan Villena-Vargas: Basically, the last a hundred years in surgery, the draining lymph and the benign draining lymph nodes were really used for staging. They would take out the lymph node and if it was benign and meaning that had no cancer in place, they would basically throw them away. But that mindset has changed now with the advent of immunotherapy where we're actually seeing that the lymph node is a reservoir or a niche of these very powerful immune cells. And that immunotherapy not only works at the level of the tumor, but actually works at the level of benign draining lymph node.

And that's critically important, because these nodes are removed for staging. So, you want to have them in place while you're giving the treatment as opposed to removing them and then treating the patient. In the lab, we studied this extensively in lung cancer patients. And we're showing very discreet things, meaning that they might be uncoupled, sometimes the tumor response, sometimes the lymph node response. But irrespectively, we're trying to figure out ways of using the lymph nodes in order to treat resistant patients, which I think will be critical moving forward.

Dr. Manish Shah: That's terrific. Well, we've covered a lot of ground today from surgery and novel techniques to minimizing surgery to improve morbidity as well as targeted therapy. And targeted therapy does reduce the morbidity of chemotherapy. What are you guys most excited about moving forward the next five or ten years in lung cancer research and care?

Dr. Christine Garcia: I'm most excited about a lot of the targets that we're seeing. And we're now getting medications that are pretty effective for targets that we've had but didn't have medications for. There's interesting stuff happening in the HER2 space now. We have antibody drug conjugates.

There's just a lot of really exciting stuff in lung cancer. And really, for patients that are being diagnosed now, it can be a very shocking diagnosis, but the science is moving in our favor. And our patients will have way more options than they have ever had before. So really, I think it's important that you get a care team that fully understands your cancer before you make any treatment decisions, and getting biomarker testing. A lot is happening in every part of lung cancer care.

Dr. Jonathan Villena-Vargas: I couldn't agree more. I think we're actually right at the point where technology is leading us to these major discoveries. And being in the lab and studying actual patients that we operate on, we are getting—and I'm not exaggerating—millions of data points per patient. And we actually now have the tools to analyze it, and you could imagine then you're studying millions of data points per patient. And you could potentially do that to hundreds, if not thousands of patients. And it's going to really drive how exactly to treat that one patient, not just this group of patients, but that one patient. And I think that's not that far off.

Dr. Manish Shah: That's incredible. So, this is a mantra that we want to get to. I think we really excel at providing personalized patient care from world-class knowledgeable physicians. I can't thank you both enough. This was terrific.

You can download, subscribe, rate, and review CancerCast on Apple Podcast, Spotify, YouTube, or online at weillcornell.org. We also encourage you to write to us at CancerCast at med.cornell.edu with questions, comments, and topics you'd like to hear us cover in the future. That's it for CancerCast, conversations about new developments in medicine, cancer care, and research. I'm Dr. Manish Shah. Thanks for listening.

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