2024 ATS Highlights

Podcast Transcript

2024 ATS Highlights

Host: Kristin Highland, MD

Guests: Peter Mazzone, MD and Vickram Tejwani, MD

Kristin Highland, MD
Hello, I'm Kristin Highland. I'm vice chair of research for the Integrated Hospital Care Institute and I'm delighted to host today's podcast on ATS updates.

We all just returned from a great meeting in San Diego and I have with me Dr. Vickram Tejwani, who is assistant professor of medicine and the Airways investigator, as well as Dr. Peter Mazzone, who is section head of thoracic oncology. Both are in our pulmonary department.

So, I'd like to start off by talking about exposures. Exposures certainly contribute to exacerbations of asthma, exacerbations of COPD and risks for having lung cancer.
So Dr. Tejwani, talk to me a little bit about the biologic link of exposures and people who go on to get COPD.

Vickram Tejwani, MD
Thank you, doctor. Very excited to be reviewing what was the really fantastic meeting and going over some great highlights and updates that we all enjoyed over the last few days.

So I think independently as with COPD patients and lung cancer as well, it's been increasingly recognized that exposure is beyond just tobacco smoke and can promote flares of disease and disease progression. These are things such as particulate matter and O2, both ambient and indoor, and I think what was particularly novel at this year’s ATS, which is the application of omics-based technology, which has been used separately from exposures to identified path of physiology to disease and now merging these two methodologies.

So essentially saying, OK, we appreciate that - O PM 2.5 exposure might worsen asthma/COPD, but can we better understand the mechanisms by which this is happening? Which I think is really exciting, because they're of course efforts both nationally from a public health perspective and what we do inside with air purifiers to eliminate these exposures, but I think they'll appreciate that it's unlikely ever to eliminate 100% of them.

So to be able to better understand the mechanisms by which these exposures or driving diseases really exciting so that we could potentially in addition to trying to minimize our exposures to them, try to abrogate some of the downstream implications in terms of the inflammation that they're causing in airways and lungs,

Kristin Highland, MD

What exposure has your attention right now? So I see the usual tobacco smoke.

Vickram Tejwani, MD
Yeah, that's a great question.

And I think it's probably the exposures in aggregate. So certain particulate matter really seems has probably the most evidence behind it. There was some great data we all experienced in this region and others, a pretty rough summer of 2023 with Canadian wildfire smoke. That was terrible across many fronts, but in a way, it gave us an opportunity to appreciate that wildfire smoke caused disease flares and disease progression, both from pulmonary disease and there is some data on cardiovascular disease flaring at that time as well. So I think at this point the kind of perhaps the leading contender would be particulate matter. But I think that's more a reflection of the data around it as opposed to that potentially the strongest signal per se.

Kristin Highland, MD
Great. And Dr. Mazzone, what have you learned about developments in epidemiology and drivers that are leading to lung cancer?

Peter Mazzone, MD
I think there were some similar messages in lung cancer as well. And, of course, lung cancer's been tied to cigarette tobacco use. So there were some updates on that front, in particular treatment-related trials and in the screening space. And this is still an extremely hard nut to crack, even successful trials are still showing very poor rates of cessation overall. But the main messages out of them were more intense combinations of therapies, including counseling. Just nicotine replacement alone is unlikely to get you far, but combine those other modalities is more likely.

The other message that was different than what the traditional teachings were is, it doesn't matter if your patient is ready or not. It used to be they had to be ready.
Now it's prescribing any way, start the treatment anyway and maybe as they go away there'll be some trigger that makes them start taking those treatments.

Separately, it was recognized that the rates of tobacco smoking and cigarette smoking are at their lowest point in decades, but there's concern that that may be being offset by the increased uptake of vaping nicotine-related products such as flavorants or vaping or dabbing with marijuana combined with these.

And the numbers of people, particularly young people, who have started to use these products, it's somewhat scary, particularly without a known impact over the long term, it hadn't been used long enough to have strong epidemiologic ties with lung cancer risk or development that there certainly are most models and pathophysiologic models that suggest a lot of the same types of changes we’ve seen with chemicals and cigarettes and the use of these products.

Peter Mazzone, MD

A thing particularly interesting in individuals who have not smoked cigarettes, there's more and more a look at the combination of both germline and somatic mutations in their lungs with some of these environmental exposures. So even in healthy lungs of people who have not smoked, they are finding very low levels of EGFR mutants,
K Ras mutants. And, at least in the lab, when those are then exposed to particulate matter, other environmental exposures that have been connected to lung cancer, we're seeing higher levels, increased frequencies of these mutations driven by those exposures. So it's a combination of some susceptibility, even without tobacco smoke and these exposures that are being uncovered.

Kristin Highland, MD
And I'll ask you the same question I asked Doctor Tejwani, is there a particular exposure beyond tobacco that has your attention right now?

Peter Mazzone, MD

I don't think so. You know, and the question would be answered differently around the world. You know, here we talk a lot about air pollution, PM 2.5 and these sorts of things. In other parts, it's indoor cooking and burning of biomass fuels that really dominate the exposures in those parts of the world. Radon is still talked about in the lung cancer context.

Kristin Highland, MD

So both of you have, I know, have your own personal interest in screening and identifying patients very, very early. Doctor Mazzone talk to me about what's happening in screening for lung cancer and doing the blood biopsies and maybe even how artificial intelligence is helping with that process.

Peter Mazzone, MD

Yes, there was a lot of nice presentations about screening, on cancer screening at the meeting. And I divide them into two sort of areas. One is what you've asked, and this is the cool- it’s AI, it's biomarkers, it's risk prediction and these sorts of things.

And the other is kind of the blocking and tackling. It's: We know what we know and yet it's not implemented nearly as well as it could be and there can be a huge impact. We're just getting the right people to be screened, making sure that you have high quality reads of their scans, following those related findings, making sure there's adherence and trying to overcome disparities and access to, you know, this, this life saving tool.

So when we talk about the exciting stuff, I always get nervous that we're gonna forget about really the bread and butter, the stuff we just need to do well and we'd have maybe an even bigger impact. That said, there was a lot of talk about how do we expand eligibility and a study out of Taiwan that enrolled individuals who never smoked to have another risk factor, particularly family history, showed a pretty high incidence of lung cancer, as high as the other studies in smokers. And it didn't though look to see are we saving these people's lives or we just over-diagnosing the bunch of cancers.

So yeah, how to find the right group in all of this? There's a lot of tools being developed, so circulating tumor DNA methylation-based tools, mutation-based tools, proteins, combinations of all these things in blood. There are some studies looking at breath volatile organic compounds, all looking to assign either risk or early diagnosis to an individual. They may help to overcome some of those barriers. Easier to use casts than getting somebody to miss work and get a CT scan. One blood prick of a finger and might be able to be done at home. They may help to overcome some of the disparities, period eligibility criteria as well. I would say some of them are getting close but still have a couple of phases of development before we can be confident, they're going to.

Vickram Tejwani, MD

And perhaps I could add to what Dr. Mazzone said. I think from the asthma/COPD perspective, the perhaps most interesting finding was more on the blocking and tackling or implementation aspect of it, which is by our colleagues from Canada U CAP investigators.

So they actually, this was published in the journal during the time of the conference and presented, which is really an elegant study where they reached out to the community and perhaps individuals that otherwise would not be seeking care and just in asthma or COPD questionnaire, a fairly short telephone questionnaire and I think this there were really two important findings, one in number of these individuals were found to have undiagnosed asthma or COPD. So just kind of underscoring the role for screening, and we're fortunate in a way that we don't necessarily need to do a chest CT, but just simplest spirometry tends to be diagnostic for these individuals.

But I think what was quite compelling and I think really can impact practice is that they were then randomized to early referral to a pulmonologist and an asthma or COPD educator or just usual care with their primary care physician as those of us practicing pulmonology know by the time these patients come to us, they're often quite advanced and they've kind of bailed on first or second line therapies, and in fact those that were referred earlier had better improvement in FEV1, better improvement in SGRQ and in other patient reported outcomes. So I think there were two kinds of practical implementation takeaways from this one, which has been highlighted and in prior tools which is just that we're not diagnosing these diseases very well in the community.

And this really is likely multifactorial. And in Part 2, the disparity issues that Dr. Mazzone talked about, access to healthcare and to some degree on asthma, the complexity of diagnosis where they can often have normal spirometry and presentation.

Vickram Tejwani, MD

And then too, perhaps as a community, we need to be more proactive about encouraging referrals for “mild” disease, which is not to say our colleagues in the primary care setting are not doing a fantastic job. But we do have a little bit more in terms of resources as far as education on inhaler use, education on what's a rescue inhaler, maintenance inhalers, things of that nature. And I think all of those in aggregate are really shown within this study that early implementation of these things will better influence outcomes both from a patient reported symptom perspective for the FEV1 which has a number of downstream implications in terms of fatality. So that was, I think, highlight a kind of very mediate practice changing take away from the conference - that was certainly one of them.

Kristin Highland, MD

Fantastic, something we can probably all do better.

So you both talked about reaching out to the communities, people that maybe don't have the same access to healthcare and also sometimes have worse, you know morbidity and mortality.

Can you, Dr. Tejwani, start and then Dr. Mazzone follow up with kind of talking a little bit about the social, now what was discussed about social determinants of health, not only in how it influences their disease, but maybe linking it to the biology as well.

Vickram Tejwani, MD

So yeah, I think that's a great question.

I think it's been, I think progressively more appreciate how, say, every year we've been at the ATS, there's been more and more awareness around this, which I think is fantastic.

This, I wouldn't say any biologic pathways stood out to me per se, but I would say this is the first year where at least I've seen that there were studies where they looked at proximity to factory exposure, for example in rural Pennsylvania and then actually did link that. We've kind of appreciated that the closer you are to these factories and exposures or the further you are from a tertiary coronary healthcare center or the lower your ADI or area deprivation index is, the worst your morbidity and mortality can be from this disease. And if you're even diagnosed to begin with, which is a whole separate conversation.

But I think this was the first time that there had been looks at methylation DNA in relation to this, they've been looking at RNA sequencing different proteomics.
So I think there wasn't a biologic pathway per se that stands out at this point.
I think the fact that the field is now moving, now I say OK, we recognize this.
There are certainly public health policies that need to be implemented to try to address this structurally, but also is there something unique about how this drives disease. And I think that's fantastic because we're really addressing it on both fronts, both the underlying etiology and then downstream potentially unique mechanisms among these exposures and populations.

Peter Mazzone, MD
Yeah, I think there were some similar messages in the lung cancer space. You know, if you focus on screening itself the eligibility criteria, identify a group that may not have access to care at the same level as the general population.

So by including smoking histories and looking to see who's smokes. It tends to be a higher percentage of individuals in areas without great access to care or without, who are under or uninsured, who have higher smoking histories at this time, making it harder for them, harder for us to find the individuals to bring into the screening programs.

Umm, there was a nice study that suggested a that high quality screening could help to overcome some of those barriers. So in a decentralized screening program, the uptake amongst black individuals was lower than white individuals, and in centralized program that disparity was mitigated.

So by identifying a way that we can help to overcome these, not just simply someone’s uninsured, what the heck am I gonna do? I think it helps to, you know, motivate us to attack that issue.

There was similar messages in lung nodule evaluation. The challenge of getting people to come back through their scans is real and there's evidence to suggest if you score poorest in the Social Vulnerability Index or any index of social isolation, you're less likely to come back for your follow up scans. So by identifying those individuals and putting in place tools, navigators, outreach programs directed at that, yeah, we may help to save some lines.

Kristin Highland, MD

So I think I'll maybe finish with some questions regarding what's new in treatment.
And so there was some exciting stuff discussed in the COPD world. Would you like to talk about what you think is really cool?

Vickram Tejwani, MD

Yes. Yeah, absolutely.

So I think I guess starting in terms of the theme and I think for both asthma and COPD, I think it's been increasingly recognized that these are heterogeneous diseases that were kind of using umbrella definitions for and that has kind of evolved into phenotypes.

And I'll focus on COPD because as you point out, Dr. Highland, there’s really some exciting data that's come out actually both last year and this year in eosinophilic COPD, but kind of broader idea is that just using this FE1 to FEC less than .7 criteria.
we've had inhaler therapy in some world therapies, but therapies largely for decades have been fairly stagnant.

And as we've increasingly recognized that there's different phenotypes in terms of presentation potential mechanisms, that's then led to, OK, can these be treated and respond to treatments differentially and perhaps, you know, medication that might not be beneficial in all comers that we can identify the [unknown]. And of course, the best example of this is the endotype Alpha-1 Antitrypsin Deficiency, or in visuals, respond to augmentation therapy.

So, I think one interesting emerging phenotype is a perhaps individuals with one gene variant of Alpha-1 Antitrypsin that may represent a population for therapy in the future and then in relevance to this year's ATS we had this study [unknown] which was [unknown] eosinophilic COPD. So importantly to contrast this from some of the asthma studies, this was an eosinophil count of over 300 with frequent exacerbation, so this was the kind of sequel if you will to the [unknown] study which was presented in published at last year's ATS.

So I think for those of us in this space to who have been treating asthma individuals and have had these, this expansion of our armamentarium, we're very much looking forward to the prospect of potentially using Dupilumab for those with COPD that are flaring and having used to fill kind over 300. So Dupilumab will formally in the context of the [unknown] study published last year, and the [unknown] study which was presented at this year's ATS and published then a couple of days ago and journal, will go to the FDA later this year and hopefully we'll have something else in our armamentarium for these individuals with severe disease.

Kristin Highland, MD

And I think of cancer as the ultimate space where they're thinking about precision therapies, and what is exciting right now in the therapeutic space for lung cancer?

Peter Mazzone, MD

Yeah. Not to be too competitive, but I have to do better, they have to, you know, make sure that everyone knows lung cancer therapy is right up there with COPD therapy.

I think the quote that a surgeon who presented at the President's Session said, you know, highlights all of that. It's lung cancer is a family of diseases now. It's no longer just one disease and options for how we treat surgery and systemic therapies and radiation, have [unknown] and give us a lot of flexibility.

In the surgical space within the last year or two there's evidence that sub lobar reception is equivalent to lobectomy for individuals with less than two centimeter tuners and clear lymph nodes. So now the surgeons have some flexibility in choosing what type of reception to use. There was the blocking and tackling quality measures being developed for surgeries clearly showing separation and survival. The higher the quality of the surgery is for the same stage of disease.

In the systemic treatment space, targeted therapies and immune therapies have moved towards earlier stage disease. So you reset someone with an EGFR mutant lung cancer early stage. Now, adjuvant treatment is shown to increase overall survival. Same for health positive cancers. Immunotherapy combined with chemotherapy and the neoadjuvant setting for stage two and three disease shown a substantial improvements in overall survival. So those therapies have moved down to earlier stages, while new targets continue to be identified and studied for later stage disease.

Not to leave the radiation talks out, I thought one of the more interesting studies that resulted this last year, and it was talked about, was treatment of [unknown] progressive disease with stereotactic radiotherapy. So these are individuals with stage 4 metastatic disease. Some of the areas are responding to treatment, but given the heterogeneity of these static sites, some aren't - some are growing. By continuing on those therapies that are working for some sites that radiating those other sites, up to five, in this study, survival. So exciting times individualizing how we treat each and every one of our lung cancer patients.

Kristin Highland, MD

And one last question on the lung cancer front. You know, there's a lot of amazing techniques that are happening in our bronchoscopy labs these days. You know what's new in that space as, you know, as it pertains to lung cancer?

Peter Mazzone MD
Yeah, I'm afraid that the meeting was just a couple days ago and I may already be out of date. The bronchoscopy field is evolving so quickly. The movement to being able to more precisely drive, to fix the scope, identify that your target, your biopsy instrument is in the target.

All of those areas have improved so much that now we're very competitive in terms of the diagnostic yield, needle biopsy and able to do much more at the same time than any [unknown]. So a lot of the conversation, there's a beautiful debate session about things like cone beam CT or digital total synthesis to identify that you're in the lesion. Do you need rapid on-site evaluation or not? Debates in each of these areas just show how far that field has come. With robotic bronchoscopy, it’s starting to supplant, you know, traditional navigation bronchoscopy, the yields are extremely high.

All of this put together is getting them to the point where they're talking more and more about being a way to treat an early-stage cancer. To send an ablation tool through the bronchoscope during the same setting, an ablate tool. That's definitely not standard of care at this time, some Phase I studies are [unknown] talked about just because of how advanced the bronch teams are.

Kristin Highland, MD
Well, I think I will wrap up with that last question and I appreciate both of you coming in today to share your thoughts and impressions and I'm certainly taken aback by all the developments both in COPD and in lung cancer and at the overlap between the two I think is quite interesting as well. And so to all of you that are listening, thanks for joining us and wish everybody a great rest of their day.