Easing Access to Lung Cancer Screening: The Potential Impact of Blood Tests

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics program and co-directing the Cleveland Clinic Sarcoma program. Today I'm very happy to be joined again by Dr. Peter Mazzone, the section leader for thoracic oncology in the pulmonary department. Dr. Mazzone was previously a guest on this podcast to discuss a collaborative solution to management of lung nodules, and that episode is still available. He's here today to discuss a new blood test that may identify an early lung cancer. So welcome Peter.

Peter Mazzone, MD, MPH: Thanks for having me back, Dale.

Dale Shepard, MD, PhD: Remind us again a little bit about what you do here at the Cleveland Clinic.

Peter Mazzone, MD, MPH: So, I work in the pulmonary department as a section leader for thoracic oncology, and that covers programs for everything a lung doctor might do related to a thoracic lung cancer being most of the work. So, we have programs for smoking cessation, for lung cancer screening, lung nodule evaluation, diagnosis and staging, survivorship care, pneumonitis care. So, a broad swath. I get to work with a whole lot of great people across the health system who help to lead all those programs.

Dale Shepard, MD, PhD: Excellent, and you've done a lot of work in pulmonary solitary nodules and screening and things like that.

Peter Mazzone, MD, MPH: Early detection of lung cancer has been a particular interest of mine, both clinically in the types of patients I see, the programs that we've built, but then also from a research perspective as well.

Dale Shepard, MD, PhD: Excellent. So as with most cancers, early detection, hugely important. Tell us a little bit about what's currently in place, like lung cancer screening is relatively new compared to some of the other cancer screenings that are out there. Tell us a little bit about what the world looks like right now from a lung cancer screening standpoint.

Peter Mazzone, MD, MPH: Early lung cancer detection is very, very important. The earlier you identify the lung cancer, the more likely you are to have a good outcome, better chance of cure, less in invasive therapies or less potentially harmful therapies. So, there are really two ways that we detect lung cancer early. The one we all think about is lung cancer screening, and then also evaluation of incidentally detected lung nodules can lead to early lung cancer detection as well. Currently, lung cancer screening with a low radiation dose chest CT scan is considered standard of care for a certain high-risk group that's been deemed to be eligible by the United States Preventative Services Task Force and Medicare. So, individuals age 50 to 80 who've smoked at least 20 pack years and have smoked in the last 15 years are eligible to receive an annual low dose chest CT scan. There is evidence supporting benefit from low dose CT screening, benefit meaning fewer people die of lung cancer if you get screened.

And there's an understanding of the trade-offs, the potential harms of lung cancer screening. That includes mainly finding a lot of lung nodules that aren't cancer and not wanting to over-evaluate those lung nodules. As it stands, despite lung cancer screening being standard of care for the last eight years or so, only around a quarter of everybody diagnosed with lung cancer is diagnosed at an early stage, localized stage. This is in part because of the strict eligibility criteria, but also because of some implementation challenges for lung cancer screening, only around 10 percent of everybody eligible is actually getting screened. Only around 25 percent of everybody who gets screened is coming back for their annual screen, and then there's still some concern about how do we manage all the nodules that are found with some suggestion that the management is more aggressive out in practice than it was in the clinical trials. So, for all those reasons, those challenges, there's an opportunity to try and improve screening. So, there's a lot of work being done to develop easy to use tests, molecular biomarkers, blood tests, and the like.

Dale Shepard, MD, PhD: And we're going to talk about those biomarkers here in a second, but just to double back really quickly, when you think about other types of screening, in some cases it is a blood test, things like PSA, but in other cases it's something invasive like a colonoscopy. Yet it seems like the number of people who get screened for colon cancer with an invasive procedure still higher than you said about 10 percent of people that get lung cancer screening. What are the reasons that drive that?

Peter Mazzone, MD, MPH: It's a really good question and one I'm not sure we have all the answers on. As you mentioned initially, it's relatively new compared to some of the other cancer screening programs and it took those programs a good number of years to really get up to where they are now too. So, part of it is education and awareness, awareness of coverage from insurers. All of that is no doubt influencing uptake a bit. It's also a population of individuals identified by a factor, did you smoke cigarettes, that can lead to stigma and concern from that patient. So, overcoming stigma of smoking is a big part of trying to get people to come in and be screened. There is some fear about the radiation from the scan itself. There's concern from patients about how much am I going to have to pay if not for the screening test, for all the downstream stuff. And then some people that just really don't want to know and we try to encourage them with information about the success of outcomes from lung cancer care now compared to in the past.

Dale Shepard, MD, PhD: When we think about that stigma from a patient standpoint, it is something that certainly not always, but is often linked to a behavior. So, do you think there's maybe some fear or guilt related to maybe with a colonoscopy, people may not have some preconceived notion that they might have it, but it's something they know they should do, but maybe a little more fear you find something?

Peter Mazzone, MD, MPH: I think that that's entirely true. I think there is that guilt that health behavior they may feel was chosen one, and we try to overcome that both by understanding that smoking is an addiction that can be treated and by changing the language that we use in the community. We try hard not to call anybody a smoker or former smoker anymore. We prefer person first language. This is a person who smoked or a person who smokes. You're not identified just by that factor. And we hope that we're able to get rid of some of the stigma in working with these communities. Some of the most vulnerable groups are those who have smoked the most over time too. So, it's that group that we need to bring into the health system and show we care and are sensitive to what they go through.

Dale Shepard, MD, PhD: You mentioned there's some newer things that are being developed, some biomarker-based things. Tell us a little bit about that approach.

Peter Mazzone, MD, MPH: So, the goal of that research, molecular biomarker development, blood test development is to make it easier to get screened, essentially. The target of some of the most recent work is the screen eligible population. So, it's not expanding criteria to others, it's making it easier for those who aren't coming in for their screens or their annual screens to still get tested. So, we've been fortunate to work with a few companies that are developing these blood tests and have recently reported some promising results.

Dale Shepard, MD, PhD: Tell us a little bit about, there was this DELFI study that you participate in. Tell us a little bit about that technology and how that works.

Peter Mazzone, MD, MPH: DELFI is based on an understanding that when cells die, they spill their DNA into the blood and the DNA that gets spilled into the blood, gets digested into fragments. And the way that the DNA is digested is influenced by the structure of the chromatin, genomic and epigenomic changes. So, you will get different fragment lengths and different fragment cut points in a cancer cell that spilled its DNA versus the DNA spilled from a normal healthy cell. So, the assay being developed is looking at fragmentomics, looking at these fragmentation changes. They measure 40 million fragments across the genome with low depth whole genome sequencing and they bundle those fragments into 473 five Megabase pair wide non-overlapping windows. And within those windows they measure a ratio of short to long fragments. When they graph out those ratios across the genome, for individuals without cancer, they're remarkably consistent.

It looks like a single line, whereas when it's graphed out for those with cancer, those ratios are quite variable and so there looks to be a signal there. They did some proof-of-concept studies, a couple of studies. One, a multi cancer early detection study and the second a lung cancer early detection study that showed promising accuracy. But those proof-of-concept studies weren't done in the intended use population, weren't done with the type of data collection and subgroup analysis that you need. So, we were fortunate to recently report the results of a prospective case control study, CLIA lab approval level of evidence where they trained their classifier, locked it down, and then externally validated it. So tested it in an entirely different group to see how accurate it was. Enrolled about 958 individuals, about two thirds of those were used for training the classifier.

The classifier was locked down. Intended use again was screen eligible folks. So, these are 50 to 80 years old, 20 pack years smoking or more. And then after the classifier was locked down, they tested its accuracy in another 300 or so individuals. Bottom line was the overall sensitivity was around 80 percent, so about eight out of 10 cancers were found at a specificity of about 53 percent. Now the choice to weight the results towards sensitivity was made because the intended use is a group who should be getting screened. So, you don't want to miss those cancers. You want a sensitive test, and if you have a few extra false positives, it's okay because that's only leading to the low dose CT scan that the individual should have anyway.

Overall, that population without the blood test, it would require about 140 folks to get screened with a low dose CT to find one lung cancer. With these test results, a positive result, it would be about 80 folks need to be screened to find one lung cancer and a negative result would mean 380 or so folks would have to be screened to find one lung cancer. So quite promising results. The assay is being further validated in a prospective cohort study of about 12,000 individuals already enrolled and just being followed up on now, as well as another validation study being conducted in Europe. And the hope will be that these translate into clinical utility studies in the near future as well.

Dale Shepard, MD, PhD: And then that larger study, is this, again, looking at comparison of patients without cancer, patients with cancer to make sure that we can accurately pick the ones that have the cancer? How are they determining the sensitivity? Are they doing tests and then doing CT scans and seeing which patients have cancer? How are they answering the question of the specificity and sensitivity?

Peter Mazzone, MD, MPH: So, it will be the same lockdown biomarker and it's a prospective cohort study, an FDA level study. So, they will be enrolling individuals who are being screened, so who are getting their low dose CT scan. The number of lung cancers is small compared to the overall population that gets screened. Again, about one in 140 are found to have a cancer, so that large size of 12,000 individuals, they're all getting screened with a low dose CT scan. It's anticipated at least 70 of those will have a lung cancer, and the sensitivity and specificity will be calculated based on those outcomes. So as opposed to a case control where you're enrolling cancers, you're enrolling individuals without cancer who meet that eligibility, here, it's everybody who's being screened and some of those will have a cancer as you follow them prospectively.

Dale Shepard, MD, PhD: Are there other biomarker approaches being studied as well?

Peter Mazzone, MD, MPH: It's a very exciting time to be in this field because there's a lot of good work being done, both academic and in industry. The science is sound and the funding that's available to conduct high quality studies has been there. There are other single cancer early detection tests like the DELFI test, and then there are also multi cancer early detection tests looking to detect one of 50 types of cancer. We recently, at the same time of the DELFI study, reported another study very similar in design to the DELFI study and this one from a company called Nucleix that looks for methylation markers in the blood. The company has a unique way to look at the methylome, traditional methylation assays used by sulfite sequencing that has a fair amount of noise, so it's difficult to detect very low levels of these methylation changes.

The science behind this assay uses something called the restriction endonucleases to find these methylation markers and can do so with a lot less noise, so a lot more sensitive. They developed an atlas in individuals with early-stage cancer who meet lung cancer screening eligibility to find methylation markers unique to that group, 89 percent of which had not been identified previously. And using that assay, they recently reported a prospective case control study, the training an internal validation as opposed to external validation from the DELFI study. At least at this point, they were reporting sensitivities of about 90 percent and specificities of around 55 percent. So, another very promising result. Further validation, a prospective cohort study, then clinical utility studies are all planned with that particular assay as well.

Dale Shepard, MD, PhD: And then since this is a blood test, if one or both of these approaches, this approach in general is approved, logistically it would be quite simple because people could just get a blood test that's sent off and wouldn't have to have procedures and things like that.

Peter Mazzone, MD, MPH: I think that's really the hope. These are screen eligible individuals, so we don't want to replace low-dose CT for those who have access to it, who are willing to have it done and come back annually. But even in our program, well-supported across the health system, there are many people who get referred for screening who never come. Many others who are eligible who don't get referred in. So, there's a large group who could be benefited potentially by a very easy to employ blood test. So, it's that group that this would be targeting, those who are eligible, but they're just avoiding the scan for whatever reason, and the blood test may help to guide them better.

Dale Shepard, MD, PhD: So really this would be a standalone test. We're not necessarily thinking that everyone would get a blood test and then only those we were worried about get a CT. We'd really rather have people get that CT scan, but this is an alternative?

Peter Mazzone, MD, MPH: I think that's the exact right way to think of it now. Now, if a different test gets developed and its 95 percent sensitive and very specific as well, the holy grail of tests that we just don't have right now, that thought process may change if though that test then has evidence of clinical utility and so on. But right now, with these good results, the thought is that it supplements current low-dose CT screening. It doesn't replace it.

Dale Shepard, MD, PhD: So in some ways this really does become a lot like colon cancer screening where you have DNA tests and you have fecal blood tests and you have colonoscopies, and we'd all love to have someone get the colonoscopy, but if someone says, "Which is the best test?" I always say, "The one people will get." And so maybe it'd be an alternative to those people.

Peter Mazzone, MD, MPH: I think that that's a good way to see it. We would like to see some of the clinical utility work being done. We'd hate for people who would've otherwise got the low dose CT to not get it. We worry a little bit about, it's not that specific a test, so if it's positive and then I find a little nodule on the low dose CT, am I going to evaluate that more aggressively than I otherwise would've and lead to more harm? There are still many questions, but the hope and the promise is there and it's much as you've described for colon cancer screening.

Dale Shepard, MD, PhD: Interesting. And then next steps, this looks like a promising approach. Are there other things that are very much still in the developmental stage or are probably figuring out these blood tests and how we use them really going to be the next thing to deal with initially?

Peter Mazzone, MD, MPH: I think it's both. I think it's with the currently developed blood tests, how might they be implemented in a way that can help our patients? And in parallel to that, it's improving on those tests, next generation, next iteration, and its other tests being developed by other academic and industry partners as well. Looking at other either omics or combination of omics, we have to keep in mind that these have to be affordable and easy to use in a screening setting. But I think that we're finally reaching the point where things are accurate enough to be thinking about implementing them while some of the other work to improve them is ongoing.

Dale Shepard, MD, PhD: It's fantastic. Really, really important area to be studying. Looks like some good things coming in the future. Appreciate you coming and giving us the insight.

Peter Mazzone, MD, MPH: All right. Thanks again, Dale. Thanks for having me. Appreciate it.

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