Sorry about that, guys. My name is Rich Schneier, this is K.G. Stanton. I'm an associate professor at the Fred Hutchins Seattle. I have nothing to disclose relevant to this presentation. Our lesson objectives are here. We're gonna start off with defining what a never smoker is and then discuss how never smokers are becoming a prominent population of patients where lung cancer is being detected. We'll talk about some of the risk factors. Patients who don't smoke. I'll talk a little bit about biology as well after that. And then talk about how treatment and prognosis in this patient group is a bit different than those who do smoke. And last, I'll touch on the TALENT study, which is a screening study in patients who don't smoke trying to detect cancers. And Dr. Sears will be talking a little bit more about that coming up. So when we talk about lung cancer in the U.S., it remains a primary cancer detected both in men and women and the leading cause of mortality. You can see here. There you go. Sorry about that, guys. Here, it's the number two cause of cancer in men and women, and then here it's the leading cause of mortality in men and women. When you look at this data over time, you can see that in men, the lung cancer incidence is going down. In women, it's going down as well, but it's kind of plateauing here, you can see, over time. And when we talk about never smoking associated with lung cancer as a separate disease entity, so these are folks who smoke less than 100 cigarettes in their lifetime. We see that this is actually still, as a disease entity, the top 10 common cancers, 7th or 8th most. It accounts for up to a quarter of lung cancers. Fewer in men, but about half of women have this disease, and it has distinct biology, and potentially, this leads to potential treatment and prognosis implications. These are data from a review that's 15 years old, but still remains relevant. You can see here on the top panel that non-smoking lung cancer remains, is a top 10 cause of lung cancer mortality. And then when you look here on the second panels, you can see that in Asian countries, women account for a large proportion of patients who have non-smoking associated lung cancer. Histologically, here on the bottom panel, you can see that in patients who don't smoke, it's predominantly lung adenocarcinoma type, compared to patients who do smoke, where there's a squamous histology predilection. In more contemporary data, here we're looking at patients in different countries, but by men and women, so stratified by gender, we see that there remains a strong predisposition with women having non-smoking related lung cancer. That's really geographically based in Asia, less than Europe and in the U.S. And again, contemporary data is now showing that even in Latin America, we see that women in Latin America are being diagnosed with never-smoking associated lung cancer in large amounts compared to men and compared to U.S. and European countries. These are data from the U.K. showing in men and women the risk of lung cancer. It's gone down. As you can see, men are here in red and women are in blue. When you adjust for age, it actually looks like women are actually having an increased incidence of never-smoking associated lung cancer. When looking at measures of deprivation, so this is basically defined as home ownership, having a vehicle access to those types of things, those who are more deprived have an increased risk of non-smoking related lung cancer, both in women and men. And you see here, more recent data suggests that perhaps we don't see that trend, but this is likely because these cancers take time to develop, and so we'll have to see how that holds up over time. This is a table of risk factors for lung cancer other than smoking. We see here, I've kind of broken it down by clinical characteristics, occupational exposures, and infectious exposures. You see here the relative risk or the odds ratio for cancer for variables other than smoking, and I'll point out that radon and asbestos account for a significant proportion of patients who never smoke and develop lung cancer. So what are the characteristics of lung cancer in never-smokers? The majority are lung adenocarcinoma, a very small proportion are squamous histology, small cell cases are rare, and there's a genetic predisposition which we'll talk about a little bit more in detail. One of the defining characteristics of lung cancer in never-smokers is that there are driver mutations, so alterations that help the tumor grow, that are distinct and unique and can be targeted by drugs. So EGFR is an example that I'm sure most of us have heard of in the room where there are now FDA-approved therapies, so you can target this mutation, the tumor will respond nicely. And because of this, these patients have in their lung cancer, when you profile it molecularly, they have a decreased tumor mutational burden. So what does that mean? That's basically looking at the number of mutations across a megabase of the genomes, that's 1,000 base pairs. And certain tumors that are smoking-associated, for example, I'll show you data coming up, have a very large tumor mutational burden, so there's a lot of mutations in that area. And that usually predicts responsiveness to immunotherapy, because these T cells are out there and they're looking for foreign antigens, and when you have a lot of mutations in that cancer, you'll get a lot of potentially foreign antigens or non-self-antigens that those T cells can attack. And so that also means that these patients, although they have these driver mutations and targeted therapies, they're less likely to respond to immunotherapy. That's really kind of the paradigm for treating these folks. A few definitions on the genetics of lung cancer in nervous smokers. So a gene locus is a position in the genome, as we talk about it in the upcoming slides. Germline means you've inherited a mutation, a somatic mutation, something that you've acquired. So that correlates with a SNP, that's a single nucleotide polymorph, which means you've inherited a mutation in the genome, as opposed to a SNP, which is a single nucleotide variant where you've acquired that mutation over time and you weren't born with it. Looking at studies from Asia, looking at large case control populations, we see that there are multiple gene loci that are associated with lung cancer risk in these patient populations, suggesting that there is a geographic and ancestral origin for nervous smoking-related lung cancer. And each of these areas in the genome, each of these SNPs can be riskier protective with associated odds ratios that you see here on the order of 1.1 to 1.4 magnitude. And conversely, if you're protective, you have an odds ratio less than one, right? So if you're risky, you have an odds ratio more than one. If you're protective, you have an odds ratio less than one. And you can see that some are protective at the 0.8 to 0.9 magnitude. Looking at all lung cancers, you see this is kind of the pie chart of different types of driver mutations with the predominance of EGFR and adenocarcinoma and different ones in SWAMIS. We'll highlight adenocarcinoma because that's really what we see histologically in patients who do not smoke. When we look at this data by geographic region, we see that whether or not you're in Asia, Africa, or Europe, you do see a large predominance of EGFR driven mutations. I'll also note there's a large portion of unknown drivers. But the good news is that a lot of these do have now therapies that we can target. When looking at the tumor mutational burden that I spoke of earlier, this is a nice chart showing cancers that have the highest tumor mutation burden, so things like melanoma, and those that have the lowest, like leukemia, you see smokers who develop lung cancer have a very high tumor mutation burden, whereas those who do not are right here in the middle. And there are actually subtypes within these never-smoking patients who have lung adenocarcinoma showing decreased tumor mutational burden, again, suggesting that these folks won't respond well to immunotherapy, but they have target therapies that we can use. The biology of these patients we're beginning to understand quite clearly. So adenocarcinomas develop in the respiratory unit at the level of the alveolar duct, and the respiratory change unit, whereas small cell carcinomas, squamous cell carcinomas, those develop in the airways based on the cell of origin. There's been work performed at Stanford in the last 10 years showing that the alveolar type 1 and type 2 cells, so the alveolar type 2 cell produces surfactant and helps to maintain the respiratory unit by generating type 1 cells for respiration. Work by Tushar Desai at Stanford showed that if you acquire mutations in these type 2 cells, they're kind of stem cells, and rather than actually generating normal type 1 cells, they'll generate tumor if you introduce EGFR or KRAS mutations. The story has kind of continued and may be completing, in fact, there's one group here in the Cancer Research UK just published this this year. They looked at patients who had EGFR-driven lung cancer and associated with areas in the UK that had increased particulate matter, so environmental pollution, and they found an increased incidence of EGFR-driven lung cancer in these patients, and then went into preclinical models, into animals, and in conditional mice models with EGFR introduced pollution and showed that you could induce more tumor formation, potentially via this mechanism that the Stanford group had shown. And interestingly, when they looked at the lung away from the tumor in these patients, they found that there were a lot of mutations associated with cancer formation that we talked about, so EGFR and KRAS mutations, suggesting that these patients had an acquired risk to developing lung cancer, and there might be a two-hit hypothesis here, which is what people have been thinking about. This is kind of the first evidence of this data showing that patients have an inherited risk, they acquire mutations, and then you have another hit, which might be pollution, to give you a lung cancer. The treatment, as we talked about, is informed by molecular features, lower tumor mutational burden means the patients are less likely to respond to immunotherapy, but there is a higher prevalence of drug-driven mutations. Literature suggests there's an improved survival in these patients. I think it's partly because you have targeted mutations that can actually give you a nice response rather than chemotherapy, that's kind of carte blanche. And as well, patients who don't smoke, they probably don't have a lot of clinical comorbidities and they're probably younger because they do have some inherited risk. We're also seeing, so that's in the advanced stage, in the early stage we're seeing an increased problem with some brown glass lesions in this population, I'm going to touch a little bit on that. And this is important because I think we're probably all dealing with this problem where we're seeing a lot of these lesions on CT scan, we're trying to figure out what to do with them. And the management of these lesions is still being defined, right? So I think all of us can appreciate the CT scan here where we see a brown glass lesion, the question is what do we do about it when you're in nodular clinic? There's no clear data to tell us what to do about this, but we know that only a small minority progress into the more advanced invasive, fully invasive part solid and solid lesions. And so our practice really is to have a multidisciplinary discussion that thoracic surgeons and our radiologists decide what to do. So I think patient preference does play a large role here because we do not know whether a second these patients actually helping the patient and whether the patient's going to live with these lesions or die from them. And I would encourage folks at their local institution to tap into the local expertise as well. We are following these patients for years, potentially decades, and then usually when we move to action, it takes a few surveillance scans to see development of a solid lesion that would make us think about surgery. I'll briefly touch, I know I'm running over time here, I'll briefly touch on screening. There is a screening study in Taiwan looking at patients who are older and have risk factors for lung cancer other than smoking, namely family history. The patients are being enrolled and basically being randomized by family history with a positive finding shown here based on size and solidity of a nodule and preliminary data or initial data from this showing the initial CT scan T0 shows an increased detection rate of 2.6% of lung cancer detection, which were nearly all adenocarcinoma. So this is compared to the NLST, it's a U.S. study showing about a 1% detection rate. So this is increased. And interestingly, when you look at it by family history, you see more patients being detected with lung cancer in those who have a positive family history compared to not. The question here is, are these indolent lesions, right? Are these patients going to actually live with these cancers or die from them? Because we know that many of these don't progress and this patient population is likely to have a large amount of these drawn glass lesions that potentially could be EGFR positive. And I think Dr. Shilts will talk a little bit more about that. So to serve your objectives, a never smoker is somebody who smoked less than 100 cigarettes over the lifetime. Never smoking lung cancer is a top 10 lung cancer in the U.S. It can lead to significant morbidity and mortality. These factors are driven by patient phenotypes of gender, as well as inherited risk, as well as occupational exposures, environmental exposures, and infectious disease to some extent. The biology of these cancers, they tend to have a lower tumor mutation burden, but they have driver mutations that are targetable, EGFR being the prominent example. And they're less responsive to immunotherapy because these patients are non-smokers and they tend to have fewer comorbidities. Because they may have inherited risk, they tend to be a little bit younger, so they may do better overall, but the data are emerging on that. And there are screen studies underway that Dr. Shilts will talk a little bit more about to understand whether or not screening these patients is useful. Thank you. So my name is Vivek Murthy, I'm an assistant professor of medicine at NYU, and I'll be talking about lung cancer in immunosuppressed patients. But though that is the title of the talk, actually it's probably more accurate to say I'll be talking about lung cancer in immune dysregulated patients, because it really is a spectrum in terms of differences in lung cancer presentation in people who have over or active immune systems, and I have no disclosures to report. So I'd like to cover a couple of things in the time that we have. I'd like to talk about immune mechanisms that are involved in prevention of early cancers that don't progress to being clinically significant, and the impact of their dysregulation. I'd like to talk about the specific evidence in connective tissue diseases of how that might impact lung cancer incidence and outcomes. Similarly in the area of infection, chronic inflammation, address lung cancer incidence and outcomes in patients with HIV, and then talk a little bit about the lung transplant population. So I want to spend a few minutes talking about this concept of cancer immunosurveillance. I think it's relevant to everything that we're going to be talking about today. The idea is very old, probably originated in the 1950s, if you see this term appearing in the literature, but experimental evidence for it really only emerged in the 1990s with the development of high-quality immunodeficient mouse models. And so the innate and adaptive immune mechanisms in cancer prevention include protection against viral-induced tumors, limiting inflammation from pathogens with rapid clearance of pathogens we avoid the downstream effects of chronic infection, and then perhaps most importantly direct elimination of dysplastic and neoplastic cells before they become active. This is an idea where tumor immuno-editing comes up. So what we see is that in mouse models with depletion of normal adaptive immune activity, there's increased susceptibility to developing tumors with carcinogen exposure. So why might that be? Microscopic tumorigenesis is extremely common, but actually those progressing to clinically significant tumors are rare, and that's for a couple of reasons. Tumors release tumor antigen that's recognized as foreign and results in early clearance. This is the so-called elimination phase of cancer immunosurveillance, and this is the phase that happens in the background. This is what we never see or know about, and we only know about it from experimental evidence. These tumor cells also release so-called danger-associated molecular patterns, DAMP, so these are danger signals that indicate that a response from the host is required. And then downstream we have recruitment of innate and adaptive immune mediators. Successful tumors evade all of this, and they enter a phase of equilibrium, again still in the preclinical phase of a tumor being present, but this is where the tumor cells that survive, for whatever reason, have adopted checkpoint proteins on their cell surface. They've adopted physical barriers that prevent easy elimination. And if tumors progress beyond the equilibrium phase, they enter immunologic escape, and this is a tumor that we'll see as clinically evident. This is a nodule that we'll see on a scan. So the three phases of cancer immunosurveillance and tumor immunoediting I think are really important to bear in mind when we're thinking about patients who are non-smokers who present with lung cancer because of how different their presentation is and how much immune activity, whether positive or negative, can impact them. So tumor-host interactions are obviously very important in this, and just getting back to the experimental data for a moment, looking at carcinogenesis in immune-competent versus immunodeficient mice, it's very different. So RAG2 is a protein that's expressed on lymphocytes. Its deficiency is one of the major causes for severe combined immunodeficiency, and so it's a great model when you have a RAG2 knockout mouse for what happens when we don't have a functional immune system. And so in mice that are immunocompetent, exposure to a carcinogen the vast majority of the time, like with humans, will not result in clinically significant tumor development, in a subset it will, of course. In RAG2 mice, they all get cancer of some type or another. And what's interesting is how tumor derived from those mice behaves differently when inoculated into immunocompetent mice. So you would think that tumor is tumor, but we know that in reality that's not true. There's incredible heterogeneity, and this is just an example of how the original host interaction kind of dictates the downstream effects. So an immunocompetent mouse that generates a tumor, if that tumor is inoculated into other immunocompetent mice, that tumor's going to survive. It survived in the host mouse to begin with. That's not necessarily the case with baseline immunodeficient mice, where about half will have normal tumor progression. But half survived in the immunodeficient mouse, but not in the immunocompetent mouse. And that's very, I think, very telling for how early determinants of tumor heterogeneity can have clinical impact down the line. So there's some really interesting work in humans, just pivoting away from the mouse models, generated by Kwok Wong and his group at Dana-Farber, he's now at NYU. But they looked at patients who were undergoing resection of non-small cell lung cancer to try to identify whether immunophenotyping of the tumor microenvironment might be able to point towards this heterogeneity early on. This might help us decide on choices for early therapy, neoadjuvant therapy. And so what they did was they did immunophenotyping and transcriptomic profiling of these tumors and used a technique called TISNE to try to identify whether there were clusters of similarly grouped, similarly phenotypically behaving cells. And they basically identified that there were indeed so-called hot and cold clusters of tumor cells. So even in patients who had a primary lung cancer that was resectable, the tumor was not homogenous throughout. So the hot phenotype was one where there were a lot of CD8 T cell infiltrations, high expression of PD1, high expression of TIM3. The cold were less likely to respond to conventional immunotherapy. There were fewer CD8 T cells, fewer co-stimulatory markers. These were cases where tumor cells were behaving very differently, so it seemed. With higher expression of actionable cell surface targets in the so-called hot clusters. Interestingly, they found that smoking status did not appear to significantly impact expression of T cell exhaustion markers, but we know, as Vish was telling us, that it can significantly impact expression of markers that indicate response to immunotherapy or potential response to immunotherapy. So that is a little bit about tumor host interaction and tumor immuno-editing and the tumor microenvironment, but where does that cellular infiltrate actually generate? Well, it's complex. That's likely a dynamic process that involves, in a significant way, tumor-draining lymph nodes. So this is some work that we published in 2017 looking at the immune microenvironment in tumor-draining lymph nodes rather than primary tumors for patients who are undergoing staging bronchoscopy for non-small cell lung cancer. This is just a schematic kind of describing what that dynamic is like, where the types of immune activation that occur in tumors that have undergone immunologic escape is very different. So whereas normally you'd expect an activated dendritic cell to present tumor antigen at the draining lymph node, generate a robust immune response, that doesn't seem to be the case with tumors that have undergone immunologic escape, because there, there's elaboration of cytokines that favor immature dendritic cells, and the type of interaction that's generated then is tumor-specific Treg, regulatory T cell expansion, and this is an anti-immune response. This is something that prevents normal immune clearance. What we found was that when we compare tumor-draining lymph nodes to non-draining nodes, so contralateral lymph nodes in the same patient, that there was local depletion of CD4-positive T cells, effector CD4-positive T cells, and up-regulation, and more, I should say, regulatory T cells in the draining node. So this is a local process, so it seems subsequent studies have demonstrated similar findings. So my point of all of that was to say that the interaction between the immune system and developing tumors is incredibly important for their subsequent course. And that is true not only for cases where we're talking about immune suppression, which is the majority of what I'll be discussing, but also inflammation, because really these are two sides of the same coin. Only about 10% of cancers are related to recognized germline mutations, that number is changing over time, but we know that inflammation plays a major role in tumorigenesis. Up to 20% of cancers are directly linked to chronic infection, 30% related to inhalational exposures, 35% due to dietary factors. So there's clearly a really important role that we need to understand better about how inflammation leads to development of cancer. But we know that the main mechanisms are likely oxidative stress, increased activation of transcription factors that can increase the likelihood of carcinogenesis, and very importantly, increased angiogenesis and vascular permeability, very important when we're talking about the potential for metastasis. So when we talk about lung cancer, obviously, smoking is the front of our minds. Eighty-five, roughly, percent of patients who smoke, who have non-small cell lung cancer have smoked. But on the other side of that, the effects of smoking, DNA damage and its result, can also be seen with pulmonary inflammation, whether that's from chronic infection, HIV, inflammatory lung diseases. And so let's talk a little bit about inflammation. I'd like to focus on connective tissue diseases to start out, specifically, rheumatoid arthritis. So the data I'm showing you here comes from a review of the Scottish Cancer Registry, encompassed from 1981 to 1996, and what they were looking for was the observed incidence of various cancers in people who presented to the hospital for any reason. So these are all sick patients at the time of their initial presentation. They were followed subsequently. And they were looking at patients with RA who were admitted for any reason, what their observed cancer incidence was at the time of presentation and within six months, and what was expected based on the National Cancer Registry, regardless of RA status. What they found was that, actually, there was a lower standardized incidence ratio for patients with colorectal cancer, so there were fewer colorectal cancers than expected in this cohort, which, considering the data on NSAIDs and anti-inflammatory drugs in that context is kind of curious, but hard to really take anything away from that, but significantly higher risk of hematologic cancers and a higher risk with a standardized incidence ratio of 1.3 in men and 1.4 in women for lung cancer. Additional subsequent analysis found that the excess risk of lung cancer was actually lower five years out from hospitalization, but was highest, 10 times higher in the first three months after hospitalization, suggesting that a lot of these patients are probably presenting with complications of lung cancer at the time of their enrollment. So looking at data from the United States, a retrospective case control study in the VA system, encompassing data from over 8,000 patients, compared those with lung cancer to those without, based on their smoking status. Logistic regression was performed to adjust for age, gender, race, tobacco, and asbestos exposure. So patients with rheumatoid arthritis in this cohort had a significant association with lung cancer, 43% higher adjusted likelihood of developing lung cancer. Even with nonsmokers, the adjusted risk was 1.36. So clearly there's a link between rheumatoid arthritis and lung cancer that is not really explained adequately just by, at least from the data that we have available, environmental exposures. This increased lung cancer risk was not observed as much in people under 55 years of age. Shifting gears a little bit to another inflammatory condition that we all see, lupus. There have been a number of large cohort studies looking at outcomes in patients with lupus and other inflammatory diseases in lung cancer. So the data I'm presenting here comes from a 30 center study, 90% of patients enrolled in this cohort were female, followed for an average of seven and a half years. And what they found was that the cohort of patients under age 40 had the highest relative cancer risk overall with a standardized ratio of 1.5 versus one for those over 60. And the longer they had lupus, there was a lower likelihood of developing cancer, which is a really interesting observation and in contrast to what's been reported in other inflammatory conditions. And in another study, which was a meta-analysis of 48 smaller cohort studies, 247,000 patients enrolled included overall, an overall increased risk of cancer for patients with lupus, including a higher risk of death from cancer. And the lung cancers in this population appear to have a similar distribution to what we see even for non-lupus smoking population. So the histologic subtype didn't seem to differ significantly. The vast majority of these patients I should mention were naive immunosuppressive agents. So primary inflammatory conditions, there seems to be some association, really not well understood at a biologic level, but clearly demonstrated in multiple cohorts. What about infection? So there's been a lot of really interesting work, not so much just in infection, but also just in the role of the microbiome and development of lung cancers and propensity to developing lung cancer. So the graphs at the right that I want to talk about first actually come from NYU. They're from James Tsai and Leo Segal, who do a lot of work in this area. And what they were interested in understanding was whether there were regional changes in the lower respiratory tract microbiome that might predispose to likelihood of developing cancer. So the way this particular study was conducted and was published in 2018 was routine bronchoscopies done for cancer or non-cancer reasons. We obtained airway brushings and compared findings from the nasal epithelium, contralateral lung, and ipsilateral lung related to primary tumors. And those are detailed 16S RNA sequencing performed along with transcriptomic data that was collected, trying to find whether there were signals for enrichment of particular taxa of organisms that might be related to inflammation in the lung. So what they identified, and it's kind of hard to see here, but I'll just describe it to you, was that comparing the groupings of taxa for lung cancer, non-cancer, and control patients was that there was enrichment of lower airway microbiome with V. anella species, which is an oral commensal bacteria usually, with upregulation of precarcinogenic transcriptomic factors that were related, associated, I should say, to development of cancer. But it's not just an association, because when those same cultures were added to an in vitro model, there was upregulation of those factors seen directly. So it seems like a causative link that was observed not just in smokers, but 10% of this population were non-smokers, and a very similar pattern was observed. So there seems to be a smoking-independent, you know Vish mentioned a two-hit phenomenon, there seems to be an independent factor that may predict likelihood of developing lung cancer. Some of the proposed mechanisms for the carcinogenic potential include dysbiosis-related inflammation direct metabolic effects of some bacteria, some bacteria do elaborate known carcinogens like acetaldehyde, and then toxin-mediated genotoxicity, which can be observed. So I talked a little bit about inflammation, what about the HIV population? This is a major concern because we know that there's a lot of overlap between HIV-infected individuals and smoking exposure, but there's also a subset of patients for whom smoking exposure is not a major factor. So there's been a number of large retrospective studies looking at outcomes in this population. So this data comes from a large European study encompassing two databases of HIV-infected individuals and five databases of solid organ transplant recipients, and compared their outcomes to the National Cancer Registry to see whether there were differences between the observed and expected cancer incidence. So the standardized ratio for cancer overall for patients with HIV was nine, so nine times higher likelihood that they would have cancer compared to non-HIV-infected individuals. However, the specific SIR for Kaposi's sarcoma was 451. Once that was removed, as well as non-Hodgkin's lymphoma, the odds ratio, sorry, the SIR was around 1.8, so still higher. And specifically for lung cancer, it was around 1.7 for both patients with HIV and those who received single organ transplant. Similar data out of the U.S. again. So this was a larger study looking at the VA cohort. They evaluated 113,000 patients, and they adjusted for multiple factors, including race, age, sex, and also smoking status. So they found a similar incidence rate ratio of 1.7 for HIV patients versus matched non-infected patients for the development of lung cancer. And the patients with lung cancer, one observation they made was that they were more likely to have pneumonia at the time of their initial diagnosis, so not only did they have HIV, but pneumonia was a consideration in their initial presentation as well. There was a subsequent study looking at not only at their HIV status, but also CD4 counts, so degree of immunosuppression that was done out of the Kaiser Permanente system. And so they looked at 21,000 patients with HIV compared to 215,000 uninfected patients in their database, and found that the relative risk of developing lung cancer was 2.2 if the CD4 count of the patient was under 200, which was not observed with a normal CD4 count over 500. So this seems to be almost like a dose-dependent effect where the degree of immunosuppression and the severity of AIDS really seems to correlate with the likelihood of developing lung cancer. This was corroborated, by the way, by an HIV cohort study done in France with 52,000 patients with very similar outcomes. So what about lung transplantation? This is obviously an area of major concern. Many of our patients with transplant have had chronic inflammation for years, that's why they're having a transplant, or they've smoked and they're getting their transplant for COPD. So we know that there are multiple risk factors for de novo malignancy in patients who've undergone lung transplantation, and these include, this is data from a retrospective cohort study encompassing multiple centers that are all enrolled in the UNOS database, but predictors for developing malignancy in this cohort include age, male gender, and then really importantly, single lung transplant, with particular emphasis on development of cancers in the native lung, where the hazard ratio for developing lung cancer for those who underwent single lung transplant only was 1.6. With increased morbidality attributable to cancer, really noted around the four years after transplant mark, so it wasn't immediate, and these patients do have very close surveillance and obviously very careful screening before their transplants, but the timing of this seems to be about four years after transplantation. And risks for worse survival include poor pre-transplant functional status, having only had a single lung transplanted, and then advanced donor age. So Maddy Triplett with a group of other lung cancer researchers in the U.S. looked at their outcomes for patients who underwent lung transplantation as well, and similarly found a median time to lung cancer diagnosis of around four years after transplant, with a significantly higher likelihood of developing lung cancer of 13 for patients who underwent single lung transplantation, so corroborating the findings of the prior study. In patients undergoing double lung transplant, there was no higher cancer risk when correcting for recipient-specific factors, so, you know, if you smoked for 50 years, you got a lung transplant, the likelihood of getting cancer wasn't higher, but if you compare to the donor what you'd expect from someone who's presumably younger and healthier, the risk was five-fold higher of developing cancer, so again, we're talking about host-specific factors that seem to be playing a really important role in the development of lung cancer. So in summary, normal, innate, and adaptive immunosurveillance pathways, they play an important role in the development of lung cancer. When these are dysregulated, either through inflammation or immunosuppression, there are changes in immuno-editing and immunosurveillance that can result in clinically significant disease. There seems to be a strong link between chronic inflection and inflammation and the development of cancer, but it's still really incompletely understood, and then the higher risk of de novo lung cancer in lung transplant patients, particularly in single lung transplant patients, needs to be acknowledged. Thanks so much. Morning, everyone. So I'm going to talk quickly on lung cancer in the younger patient. First thing I'll say is that the definition of what a younger patient is varies within the literature, so I'll try and keep the discussion to the most common definition, which is patients less than 40 years of age. I don't have any disclosures. In terms of objectives, I want to talk about the epidemiological trends. There's quite a global differences here. Describe the typical clinical characteristics of diagnosis. Outline some of the patterns in the tumor biology, which are similar to some of the NeverSmoker data that you saw a bit earlier, and then discuss survival compared to older cohorts. But what I first wanted to do was to talk about all cancers in the young to give us some context. What we're seeing in the US, this is data from JAMA Open from earlier this year, 560,000 cancers over 10 years, 65% of these were females. And you're seeing that it's being driven by an annual percentage change of 1% per year in the 30 to 39 cohort in the first table. And you can see that this age group, it's being driven by females in the second table below. You can see that in males, annual percentage change is in the negative, and in females, it's positive, which much of that change coming in Asians and Hispanic patients. When we look at Asia, there are six countries that have had a positive difference in terms of annual change in all cancers, less than 40 years of age. These are countries with large populations, which are really driving increased incidence of cancer in the young. And that's true also in Europe, a paper just published in ESMO, adolescents and young adults, age standardized ratios are also increasing in Europe, particularly in France and Eastern Europe. So if we look at lung cancer, this is 20 years of data published in scientific reports of this year. You can see there's been a decline in all lung cancers, more marked in men, and the female to male ratio is narrowing, but males are still ahead. If we look at the less than 40 population, you can see some interesting differences. There's been a slower decline in terms of lung cancer, and it started to level off in the last couple of years and may actually be increasing. And over the course of those 20 years, female to male ratio has been greater than one. So females predominate in this age group for lung cancer. So in total over those 20 years, there was over 4 million lung cancers. Less than 40 accounted for 0.6% of these lung cancers, and you can see that females were nearly 52% of the proportion of that population. And that's different, as I said, to all the other age categories, with greater than 80 coming closest in terms of the male-female equality. More recent data from SEER 2016 to 2020, a bit difficult here because they have cut it at 35 to 44 and 20 to 34, but you are getting a sense that there may be an increased incidence of lung cancer in patients less than 40 in the U.S. And this female to male inversion in the young has been seen in six countries. This is data from 40 countries over five continents published in the International Journal of Cancer from 2020. You can see there's been steep declines in the older age groups, and nearer the bottom you can see that it's been kind of leveling out or plateauing, and maybe increases in the female to male incidence in these countries. So what about China? It's a huge country, over a billion people. You can see on the top right that in males, in young patients, it's stabilized or maybe declining, but in females there's been increases in all age groups, but particularly in those less than 40, there's been a 5% change over the course of this 10-year period in terms of lung cancer incidence in young women. And the majority of that change is actually being driven by rural rather than urban, which I thought was quite surprising. It may be due to better access to healthcare in rural China than there has been previously, but it's still to be determined as to why that is the case. But this Chinese data is really contributing to the increased numbers of lung cancers in young women in particular. So this is a paper from the New England Journal in 2018 where they sought to look at the U.S. data and try and understand why this female to male ratio is as it is. And you can see in the younger patients, 30 to 34, 35 to 39 at the bottom of these graphs, in most races females predominate over males except in black patients. And I'll just draw your attention to the Hispanic population in the 30 to 34 age group where females are very clearly greater than males in terms of lung cancer incidence. And when they looked at the smoking data, they could see that as you got younger, the curves started to join together, but still males smoking more than females. But in the Hispanic population, the difference between males and females was quite stark, which led them to conclude that smoking behaviors weren't all of the story in terms of why young women were getting more lung cancer than men, and maybe some environmental exposures or germline DNA repair deficiencies that may be more common in women than men. So another way to look at the U.S. data is to compare those with lung cancer less than 40 to those who are older than 40. I'll just draw your attention to three big things. Young lung cancer is less white, it's more adenocarcinoma, nearly 60% of cases compared to 40% in the older cohorts, and more presentation with distant disease, 68% of these younger patients are presenting with stage 4 or stage 3B disease. This is an interesting abstract from World Lung that I came across, and they looked at the age groupings of stage 4 presentation from the SEER data. And what you can see in the 20 to 29 cohorts in 2010, 80% of those populations who had stage 4 disease were presenting much higher than in the 70 to 79 cohort, which was 40%. And with the advent of increasing use of cross-sectional imaging and lung cancer screening in the 2018 data, you can see that there's been a decline in the presentation of stage 4 disease in the older population greater than 50, but no such change in the younger cohort, leading them to conclude that lung cancer screening is in some way widening disparity in terms of early stage detection. In terms of how patients present, it's quite nonspecific, which is part of the problem. The most common symptom is irritative airway symptoms, such as cough, shortness of breath, fever. About 65% of these patients were diagnosed with pneumonia. Average age of these patients was 36, so you can understand as to why that may be the clinician's first thought when seeing these patients. I just put two images to the right. You can see a young male, never smoker, with a dominant lesion in the lower lobe with some pretty diffuse ground glass changes, and that was a ROS1 rearrangement. And then a 28-year-old male, again never smoker, with a dominant mass in the right lower lobe with this millery-type pattern with bone metastasis, which was a mutant EGFR-positive lung cancer. So this is data from New York. When they compared this to data from Taiwan, 144 patients, the clinical characteristics were very similar. In terms of the molecular phenotyping, this is really key in patients less than 40 with lung cancer. This is data from Dana-Farber, over 2,000 patients over a 10-year period. This cohort were 90% white, 87% had adenocarcinoma, 64% were stage 3b and stage 4, so quite a advanced disease. You can see that 81 patients, or 3.6% of the cohort, were less than 40. And you can see a definite change in EGFR and ALK as the proportion of targetable mutations in the younger cohort, and then as you get older, the proportion of those mutations changes. Conversely, BRAFB600E and KRAS were more common in the older cohorts. So if you were less than 50 years old in this cohort, you had more than a 59% chance of having a targetable mutation. And if you were less than 40, you were more likely to be female, a never-smoker, and Asian race. So that EGFR data was quite interesting, so then I compared it to a similar-sized study in Japan of 1,746 patients, and they showed similar findings in the ALK-positive group, but they showed that EGFR-positive patients were actually more common in the older cohort. So just a bit of a caveat, when you look at these single centers, albeit with very large numbers, that you can get divergent results. And I would point out that the PIONEER study, which was a multinational Asian study from 2010, a prospective study looking at the characteristics of EGFR positivity, did not show any association with age. This is another paper from Geoffrey Oxnard with Dr. Gitlitz. This was funded with the GoTo Foundation, published a couple of years ago. Prospective study, 133 patients over five continents, 20% of these patients were Asians as opposed to 10% in the Dana-Farber cohort. What they found was that ALK and EGFR mutations were more common in non-smokers, that smoking habit and marijuana smoking seemed to match very well and we need to ask about marijuana smoking in these younger patient populations. They also found that there was a higher proportion of Asian patients in the ROS1 cohort in the bottom left and they also found that family history was not an important factor in terms of the presence of a molecular target. When they looked at the EGFR mutations and looked at the subfamily of mutations, they found that the vast majority were exon 19 deletions and a very small proportion were L858R substitutions, which is also seen in all other age groups, but the proportions here were much higher. So you would expect about 20 to 40% of your EGFR mutations to be L858R positive and in this study it was much less than that for the younger patient population. They also had an increased proportion of exon 20 insertions in the younger patient population and I bring that up because Mobocertinib, one of the targeted therapies for that mutation is being removed from the market after the negative exclaim 2 trial. This is data from China over 7,800 patients and again they showed that ALK, ROS1 and RET rearrangements in this study were more common in the younger patient population and similar to the Japanese data, they showed that EGFR mutations were slightly more common in the older age group. What they did show though was that the exon 19 deletion and L858R pattern that had been seen in the prior studies were also present in this study. In terms of genomics, this is a study from HUETAL looking at the presence of germline variants in those less than 40 compared to those who were greater than 60 and they found a statistically significant difference in terms of detection of germline variants in the younger patient population and similar to the never smoker patients that you heard about earlier, tumor mutation burden was lower in these patients. They typically have higher proportions of never smokers and if they do smoke then they have a lower pack year history. So this is quite a busy heat map but I'll draw your attention to the genes on the right patients of the columns. You can see that in this more than 60 year old cohort that the total number of mutations on the top is much higher just by visual inspection compared to the less than 40 cohort. You can see that EGFR mutations, exon 19 deletions are more common in this younger cohort. You can also see down the bottom that ALK mutations more common in the less than 40 cohort and just below that BCL2 more common in the younger cohort too and that's a mutation that's associated with EGFR TKI resistance. And I bring that up because there's a slight discrepancy in terms of survival in some of the studies that I'll talk to you about in a short while. In terms of the pattern of the mutations detected in those younger than 40 and those more than 60, missense mutations predominate, C to T transitions are the most common in both cohorts as you would expect. But you can see in the older cohort that C to G and C to A transversions are more common in the older cohort which is in keeping with the SBS4 pattern that you see in lung cancer in smokers. In terms of treatment, there isn't really much to say other than young patients get surgery, chemotherapy as often if not a bit more often than older patient populations as you would expect given they have less comorbidities. In terms of survival, it's kind of large registry data from SEER and UK which are both in agreement showing that if you're less than 40 then you have better five year survival for all stages of disease in the US data and the UK audit data of 146,000 cases in total showed a hazard ratio of 0.43 in those less than 40. But I do just want to bring up this paper again from Dana-Farber because it got a lot of press at the time and they basically showed that in patients less than 40, with or without a targetable mutation being present, that their overall survival was no different than patients greater than 70 years of age and they postulated this was due to just the intrinsic aggressiveness of the tumor. So just something to bear in mind when you are looking at this data, it was a single site and it does seem to be different to the larger prospective data sets. So in summary, lung cancer in young people has a female preponderance, it tends to be adenocarcinoma and metastatic disease at presentation. They have more targetable mutations, they have a lower tumor mutational burden and I would argue that on the data that's available they have better survival. In terms of adverse prognostic factors, things I didn't show but male adenosquamous or undifferentiated histology and black race were all associated with adverse prognosis within the less than 40 cohort. Thank you. Well, we are running a little bit over, so I understand if somebody needs to stand up and leave in the middle of this, but I am hoping to give you some information on where we are with lung cancer screening and never smokers. So, this is me. I do have disclosures that I'm very interested in lung cancer screening and get some funding for research and work for some organizations, but I think you'll see it has, being from the United States, little to do with screening and never smokers at this point. So, just to go through what we know about lung cancer screening as far as what I think about when I think about lung cancer screening, it's typically major studies like the NLST and the Nelson study, very large randomized studies that showed us that screening for lung cancer can improve mortality, but of course, what you'll notice is that the major risk factors and what we look at as far as enrolling for lung cancer screening is advanced age and cigarette smoking, right? And if you look at the recommendations, they basically follow along the lines of the lung cancer screening studies that we have that showed an improvement in mortality, which makes sense, right? We do a study and it shows positive results and we know that that population benefits and that's who we screen. I will point out that there is an additional consideration in the NCCN to discuss additional risk factors, including, and as a part of the shared decision making through lung cancer screening, but how to incorporate this into lung cancer screening is really not clear and it's not defined, right? And so, in preparing for this, I kind of thought about how to approach this and I think there are a couple of big, I put them as problems, but I think they're big, maybe flashing lights to consider when you're looking at lung cancer screening and never smokers. And the first is that this is not the same disease as I think everybody up here has talked and while there are a number of risk factors for lung cancer that we know of, only two of those are currently included in most of the lung cancer screening guidelines and I had to beat Vish, so I had to put even more risk factors up here than he did on his list and even included one while I was here because I went to a talk two days ago where they talked about lung transplant and that lung cancer is actually the second leading cause of death in lung transplant patients, right? So, I would argue that we don't really know how to incorporate these into lung cancer screening. And the second is that lung cancer is different depending on where you are and so, just like in real estate, location matters, right? You've seen this graph on the left, I think Vish showed you this at the beginning, that depending on where you are, lung cancer and never smokers is more or less of a problem and this is likely related to differences in contributing risk factors, including everything from diet to pollution to probably inherent factors. I just wanted to give you an example of how this can differ over time. This was a study that came out of Taiwan where they were seeing a rise in lung adenocarcinomas and they had done quite a bit of effort there to address cigarette smoking. So, on the right here in the blue is male data and in the red is female data. The hashed lines are their cigarette smoking status, which you can see were declining in men and pretty stable for women. But what they saw in both of these populations was a continued increase in lung cancer and in particularly lung adenocarcinoma development over this period of time. And there was a very high rate in never smokers, 53%. They also saw that this differed depending on the location within Taiwan, right? What they show here is a proposal that this may be due to differences in pollution over time. You can see here on the left that what they saw was an increase in, this is a graph of visibility. So, in the green color you see northern Taiwan where the visibility was actually getting better with a subsequent decrease in pollution. In the red, southern Taiwan, where they were seeing a decrease in visibility associated with an increase in pollution. And you can see over here on the right, the trends where there was a stability in the lung cancer diagnosis there in the green where we saw improvements in visibility. In southern Taiwan, they saw an increase over the same period of time, suggesting, of course not proving, but suggesting that in this population, air pollution rather than cigarette smoking was a greater risk for lung cancer. Quite a bit of data is coming out over China most recently. This was just a study out of the Minhang District, which is where Shanghai is. You can see that they took more than 11,000 individuals that they would consider high risk. And they described high risk a little bit differently than us. You can see that the age range is very similar to what you saw from our lung cancer screening data. And their cigarette smoking history they included is pretty similar, a little different cutoff for years quit. They also included those that had a heavy passive smoking history, and then they included never smokers that had another risk factor. And in particular, they pointed out family history, exposure to kitchen fumes, and dust exposure, all of which have been associated with lung cancer risk. You can see that their detection rate is not insignificant, both in the cigarette smoking and non-smoking. While not significant in their cohort, these actually found more cancers in their high risk non-smoking group. And you can see here that they made a couple graphs comparing what they saw to very well-known lung cancer screening studies, the NLST, NELSEN, and then the observation study through IL-CAP. And you can see as expected there in this top left large area that there's an increase in lung adenocarcinomas, which we would expect. And you can see here on the bottom that compared to those studies, there's an increase in stage zero and stage one disease, suggesting that they're going to find those earlier. And that screening that population may end up in improved survival. The National Lung Cancer Screening Program in China has also looked at this. You can see that they included those aged 40 to 75. And you can see that they broke these into what they considered a low risk group and then a high risk group. And note that their high risk group included 78% of that population that were non-smokers. So still a pretty high population. You can see that about 79,000 of that high risk group ended up getting screened and then over a million were not screened and then they compared basically lung cancer diagnosis in those two groups. A little bit busy, but what I'm gonna show you here is that as I showed before, there was a shift change. So they showed more stage zero and stage one lung cancers in the high risk group that was screened compared to that group that was not screened, which had a higher proportion of later stages. You can also see here on the right in red is the screened group of that high risk group. They found more lung cancers within that group. And you can also see a lower all cause mortality and lung cancer specific mortality that they reported within this study. So in China, their national lung cancer screening guidelines were initially put out in 2018 and they've been revised twice since in 2021 and then after that study most recently in 2023. And you can see that currently in lung cancer, they are recommending screening for those aged 50 to 80 years old with one of the following criteria, either very similar to what we have seen in our Western studies, at least 20 pack your smoking history or even a higher risk group quit within the last five years if they have quit smoking, or if they could have a passive or secondhand cigarette smoking for at least 20 years, a long-term occupational exposure, and you can see what is listed here as meeting that criteria in the Chinese recommendations, a family history of either a first or second degree relative and having some smoking history, either at least 15 pack your smoking history themselves or that same smoking history as secondhand smoke exposure. And then they include other important diseases in certain high incidence areas. So they leave kind of this open area, which I suspect is trying to address things such as what we saw in Taiwan, right? That there may be some areas that have more environmental exposures or have other occupational exposures. There are a number of attempts to improve lung cancer screening, including the development of risk assessment models. I think many of you in this room have seen these, and these are really well-known risk assessment models to try to predict the risk of lung cancer within the subsequent three, five, or, can we close the door, please, for just a moment? Thank you. Within the subsequent years. But I will point out that these are largely based on cigarette smoking history and age as the two major risk factors. There's been an attempt to look at this in Never Smokers. Dr. Tamamagi and his group used Western data in the PLCO in 2014. You can see a couple using European and Taiwanese perspective studies to try to develop these. A recent publication out of China used the data that I'd shown you before through the China National Lung Cancer Screening Cohort. And you can see they used either Never Smokers or Ever Smokers, aged 40 to 74. And they performed this in two validation cohorts afterwards. You can see that these are the risk factors they used. They used different risk factors for those that have never smoked cigarettes compared to those who have ever smoked cigarettes, including the use of female gender, BMI, family history, and chronic respiratory disease in addition to age. This is complicated, and I'm not going to go through it, but what they showed was that they could basically graph the predicted risk and try to figure out a risk at which they should screen Never Smokers using this model. And what they found is that using a three-year lung cancer risk cutoff of greater than 0.47%, they would have to screen 11% of their Chinese Never Smoking Cohort, but pick up 27% of incident lung cancers within that population. And if they applied both the cutoffs for the Never Smokers and the Cigarette Smokers, they would pick up about 44% of their incident lung cancers. The Talent Study has been covered a bit already, so you've seen some of these. This is a study out of Taiwan, and they have published at least an abstract form, their preliminary feasibility data, the ages of 55 to 74 Never Smokers, but they have to have at least one risk factor, which includes family history, passive cigarette smoke exposure, history of TB or COPD, and a cooking index greater than or equal to 110, or no ventilation within their cooking area. You can see here the data, but in particular, I wanted to point out something that Vish pointed out earlier, which is that the percentage who develop lung cancer is quite high, higher than NLST and other studies. And I will also point out that about 18% of this, they actually broke out stage 0 from stage 1, which in most of these studies are grouped together. Eighteen percent of these ended up having stage 0 lung cancer, which does potentially raise the risk of over-diagnosis. So we're still waiting on some of the survival data from this cohort to be published, to see if this actually ends up in survival. I only have a couple more slides, but I want to point out some of the efforts here locally. This is one of the FANS study, F-A-N-S-S, which is out of New York, where they are recruiting as a feasibility study a thousand female patients of Asian descent, you can see ages 40 to 74, who are considered Never Smokers by the criteria we heard earlier. You can see they're looking at outcomes, and as of yet, they presented their data just this past year in the World Conference of Lung Cancer, and you can see that they've already screened 201 patients and diagnosed three patients. This is 1.5% of their cohort. All were EGFR positive. You can see that these were actually interestingly stage 2B and stage 3C, so we're going to have to see as they go forward. This obviously is not powered to look at stage or survival, but we'll have to see what those numbers end up being. I just want to put in here that there is desperately a need to better identify those, I showed you risk factors for lung cancer, who have risk factors for lung cancer and would benefit from smoking, and I think this is an area where biomarkers may be able to really make quite a bit of difference. There are several efforts going on in this. There's another FANS study on the other side of the United States, this one out of UCSF and other areas in California, or other institutions in California, where they are recruiting 600 Asian females. You can see a larger age range, 21 to 90, with lung cancer, and then another 600 matched controls. They are collecting survey data, saliva, and lung tissue. The FANS study out of NYU is also collecting circulating free DNA, and then the talent study that I showed you before is collecting specimens for consideration of biomarker development, given the interest in this area. And finally, we've heard a lot about the biology of lung cancers and never smokers, and I think this goes well beyond EGFR, as we've heard, and I think there definitely is a role for using this exploding information that we're getting about lung cancers and never smoker compared to lung cancers and smokers, and their genomic, transcriptomic, and proteomic characteristics to try to see if we can develop from kind of the top down some biomarkers to better predict lung cancer development in this population. There's a number of areas, particularly I put Sherlock lung, but others here that have a great interest in developing this within the never smoker population. And so in conclusion, I'd like to point out that there are major risk factors for lung cancer, but how to incorporate these into lung cancer screening I think really have not been well developed. I think that there is clearly some data going on particularly in Asia in incorporating lung cancer screening within this population, and you know, I think there is a large area for looking at specific populations and how to personalize lung cancer screening within those populations, as well as leveraging biomarkers in the future to better select for those populations that might benefit from screening. So I'm going to end there, and thank you for sticking with me. Thank you.

lung cancer

specific patient populations

never smokers

immune dysregulated patients

chronic infections

HIV

lung transplant patients

younger individuals

driver mutations

tumor mutational burden

immunotherapy