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A prototype blood-based screening test evaluated by Cleveland Clinic researchers and other experts can accurately identify the presence and originating site of 12 high-mortality cancer types, across all stages of progression, with a low false-positive rate, according to the latest results of an ongoing national clinical trial. Eric Klein, MD, Chairman of Cleveland Clinic’s Glickman Urological & Kidney Institute and the co-principal investigator of Cleveland Clinic’s portion of the study joins the Cancer Advances podcast to discuss this trial and the path forward to further validate this multi-cancer detection approach.

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Innovations in Cancer Screening and Accuracy

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 overseeing our Taussig Phase I and Sarcoma programs. I'm happy today to welcome Dr. Eric Klein. Dr. Klein is the chairman of Cleveland Clinic's Glickman Urological and Kidney Institute, and an investigator for the GRAIL trial. And he's here to talk to us about that today.

Welcome Dr. Klein. Good morning, how are you doing?

Eric Klein, MD: I'm great. Thanks. Good morning.

Dale Shepard, MD, PhD: Excellent. Could you tell us maybe just briefly a little bit about your role here at Cleveland Clinic?

Eric Klein, MD: Yeah, I've been on the faculty here for a little over 30 years after completing my training here. And my focus is on urologic oncology, particularly prostate cancer. And my side job is to run the Glickman Urological and Kidney Institute.

Dale Shepard, MD, PhD: So the GRAIL trial, can you tell us a little bit, what is the GRAIL trial?

Eric Klein, MD: Yeah, so the original study that we referred to as the GRAIL study is actually called CCGA, the Circulating Cell Genome Atlas. It was a study we completed a little over a year ago, a multi-site study sponsored by a company called GRAIL using next generation sequencing to find circulating cell free DNA in the blood of patients who had cancer and patients who were free of cancer. And out of that study, which was initially both a discovery and a validation study, we were able to develop a methylation based assay that can detect early stage cancers across a whole variety of malignancies for which there are no established screening paradigms currently.

Dale Shepard, MD, PhD: So from a practical standpoint, what did this look like for patients?

Eric Klein, MD: Very simple. It was a blood test. The initial study was eight tubes of blood in order to be able to do the discovery study. Let me frame the context here. We have established screening paradigms for five cancer, cervical cancer, cervical swabbing and cytology, prostate cancer with PSA, colon cancer with Cologuard and colonoscopy, breast cancer with mammography and lung cancer screening for patients at high risk with CT scanning, although it's underutilized, but there are a whole lot of other cancers that there are no screen paradigms for that tend to present in late stages and are hard to cure. So GRAIL's stated purpose is to find cancer early when it's easier to cure. And that was the point of the study. So the original, the CCGA study, was 15,000 patients across a number of centers in the US. The discovery phase was to take patients who had known cancers of all stages and see if we could see a signal in the blood using this NGS next generation sequencing technology.

And the answer was, we could. We could see, we could find about 70% of stage one to three cancers. And the validation study was then to look at patients both with and without cancer to come up with a final test. Initially, we looked at methylation, we looked at whole genome sequencing, and we also looked at targeted mutation sequencing. And what we found was that methylation had the best sensitivity and specificity. So here's the exciting part of this test that we're going to move forward to in the Pathfinder study, which we'll talk about shortly. It detects 70% of early stage cancers across 50 different malignancies, but for 12 common cancers that account for about 60% of cancer mortality in the United States, and that includes things like liver, GI cancers, ovarian, and pancreatic cancer, plasma cell malignancies, that sort of thing. So it detects a whole set of cancers at an earlier stage than we have currently available paradigms.

So it won't be perfect. It won't detect all of those cancers, but in the cancer screening realm, if we can detect some of these early stage cancers that we're not detecting now, that's going to be a positive. So that was one important finding.

The second important finding really remarkably was that this methylation based assay can predict the tissue of origin or which organ system has the cancer. And if a patient gets a positive signal with more than 90% accuracy. So if you get a positive test back, not only does it suggest you might have cancer, but it can expedite a diagnostic workup by suggesting, hey you may have kidney cancer or you may have colon cancer, do a CT of the abdomen or get a colonoscopy, that sort of thing.

And then the last thing that's really important for patients in developing this kind of screening test is to have a very, very low, false positive rate because we cannot be offering a screening test where there are too many false positives. The neat thing about this methylation test is that the false positive rate was less than 1%, 0.7%. So that's about seven out of a thousand patients. So as we move this forward, we're very excited by all of those findings and we'll examine how all of them can be used in clinical practice.

Dale Shepard, MD, PhD: Yeah, this was certainly a big undertaking. And so it's particularly exciting when things like ovarian or pancreatic, which are normally always found at a late stage. So certainly a potential for huge benefits. I mean, simply from a logistic standpoint, this was a huge effort. How did we manage to pull this off?

Eric Klein, MD: We had a great team. I mean, Mikkael Sekeres was the co-investigator. Peter Mazzone was part of it. These are people in our cancer center. And we had a great team that was actually headed by Wilson Tang and Jennifer Owens oversaw the study coordinators. We hired a number of coordinators. We sent them out to various sites across our system. And as patients walked by and potential participants walked by, they were approached nicely and said, hey we're doing this study. Would you be interested in participating and work? The team did a great job. We accrued more than a thousand patients in a relatively short period of time. And we were the number one accruing site in the country.

Dale Shepard, MD, PhD: And we've likely learned some things that we can use moving forward for other trials, I suspect.

Eric Klein, MD: So we have and I'm really excited about the next trial, which is called Pathfinder, not only because of the science involved and what we hope to discover, but the way that we are going to run the trial, which is really novel for the Cleveland Clinic. So let me talk about the science about Pathfinder first.

Dale Shepard, MD, PhD: Sure.

Eric Klein, MD: So Pathfinders, the next study, the follow up to CCGA, it's a, I think a six institution study aimed at accruing 6,200 patients to use this new methylation based assay, which commercially is going to be called Galleri. So we're going to use the Galleri test in patients who have no known active cancer. So this is an intended use population study, where we're going to determine how this methylation assay performs in the real world. The eligibility criteria will be 30% of patients who have no risk factors for prostate cancer, other than being over age 50, and 70% of the patients will have one of the following factors for a increased risk of prostate cancer, a smoking history of at least a hundred cigarettes in their lifetime, a known inherited genetic syndrome, like Lynch Syndrome or BRCA syndrome, or a treatment for an invasive cancer more than three years ago with presumably no evidence of disease currently.

So that's who we're targeting. We aim to learn how the test performs in the general population. We aim to learn how patients react, both in the idea of this new screening test for cancers. We want to learn how participants respond to this. And we're also going to study the diagnostic algorithm that comes out of it. So as I said before, this test predicts tissue of origin or organ system of origin with high accuracy. So in the Pathfinder study, if a patient comes back with a positive signal, the report will say signal detected and it will give us the likely tissue origin, probably the top two or three candidates from that.

And we're going to have an expert panel that includes radiologists pathologists, medical oncologists, primary care physicians, and one of geneticists go over that and come up with what we think is a streamlined diagnostic paradigm to share with the patient's primary care physician, and then help the PCP to get the participant through the workup. So we want to see whether or not using a test like this can streamline the diagnosis of cancer.

And we're also talking about yet another study to follow this one to be used in the primary care setting with patients who have vague symptoms, where the primary care physician might have in the back of her or his mind, hey this patient might have cancer. If I add this blood test to my initial workup, I might get to an answer more quickly. Anyway, that's the scientific substance of the study.

Dale Shepard, MD, PhD: Is there any potential, this could have a role for cancers of unknown primary, for instance? So people we know have a cancer, but we don't know where it's from.

Eric Klein, MD: Yes. I'm sure that it could, although I don't think there were many such cancers in the initial discovery study, but yeah, potentially it could. Absolutely.

Dale Shepard, MD, PhD: Yeah.

Eric Klein, MD: It's an interesting idea. So to operationalize and Pathfinder study, we have decided to become very creative in part, because it's a relatively straightforward study. It's not a therapeutic study and it doesn't require multiple visits to campus by participants and then also in part because of the pandemic. So it's probably not the safest thing to do to send study coordinators out to various sites and sit in a public area where there are lots of people walking by some of whom may or may not be masked. Some of them may have may or may not have COVID, that sort of thing. So we decided to do this study virtually. So we have hired fewer coordinators and we're going to keep them on campus.

And we're going to advertise this study through Cleveland Clinic channels and the media to the public and ask people who are interested to sign on to a landing page and express their interests. We're going to give them the opportunity to review the consent form on the webpage, and then we'll have the study coordinators contact them. That is going to keep people safe, first and foremost.

Secondly, it's going to give potential participants the opportunity to look over the consent form in the comfort of their own home, without the usual anxiety that comes with sitting in a medical center in a small room with someone tapping their pencil waiting for them to sign the consent form. It's also, I think, going to be more efficient the way we did CCGA, we approached many potential participants. Most of whom said they were not interested. On the other hand, in this guise of doing it this way, or coordinators are only going to be talking with participants who have expressed interest in the study.

And so my guess is that the amount of work necessary for the coordinators to reach our accrual goal is going to be a lot less. So once that virtual conversation takes place, another new part of doing clinical trials is that we now are accredited to do DocuSign. And so the consent forms will be able to be sent to the patients electronically. They will sign on and sign the consent form electronically, and assuming they meet the eligibility criteria, there's one last part of the study, which is to ask the participant to go to a local Cleveland Clinic, blood draw lab and have the blood drawn.

And that is all that's necessary on the participant's part, other than some follow-up questionnaires, which will also be done electronically. And I'm really excited by this. This is the first time we've tried something like this at the Cleveland Clinic. And while it may not be the best way to do, for example, therapeutic trials that need multiple visits to a center to get treatment and so forth. I think this is going to pave the way for us to be innovative in the way we do clinical trials in the future. So I'm really excited about both the scientific part and the operational parts.

Dale Shepard, MD, PhD: I mean, that operational part sounds great. I mean, even from the standpoint of a therapeutic trial, being able to do similar things to get patients interested, or not necessarily come here thinking about trials we may have here on main campus and somebody in the region may think about participating and want to do everything kind of upfront. That sounds a little, the logistics of what you've set up here, sounds like it could potentially be transferable to many, many trials. So that's excellent.

Eric Klein, MD: I hope that's true, and even for therapeutic trials, as people get comfortable with virtual visits, you might be able to do the safety valuations while someone's on therapy virtually.

Dale Shepard, MD, PhD: Taking a step back, you mentioned that this Galleri test, is that something that's currently available commercially, will be commercially available? Tell us a little bit about that.

Eric Klein, MD: So Galleri is this methylation based essay that detects early stage cancers for a lot of cancers that we don't detect that has a high tissue of origin specificity and a low false positive rate. So it's all the same test. Galleri will be the commercial name for it. It is not yet commercially available. I believe the company has petitioned or is about to petition FDA for approval. And that that process takes some time. So I'm not sure when it will be available. I think we need to get data from Pathfinder to assure ourselves and everybody that it performs as intended in the intended use population in a healthy population that does not have known cancer. I think we need that data before we might see widespread adoption.

Dale Shepard, MD, PhD: What kind of timeframe are we expecting for that?

Eric Klein, MD: So Pathfinder is already open in a couple of sites across the country, and we are very close to opening it for accrual sometime in the next two weeks.

Dale Shepard, MD, PhD: So very, very soon. So we should have some information sooner than later.

Eric Klein, MD: Yes, and the accrual period is very short. We hope to have it completely accrued, 6,200 patients across all the sites by the end of the year. So I would hope that we would have some results by the middle part of next year.

Dale Shepard, MD, PhD: What's next, are there other similar things in terms of tests that are being developed or where do you think this might go next?

Eric Klein, MD: Well there are some other companies that are working on similar kinds of tests. There's a group that started at Johns Hopkins that has marketed test called, or is about to market a test, called Thrive, which does something similar, uses slightly different technology that includes some protein essays as well as some genomic essays. And there was just a very interesting study from China called PanSeer, where they used a methylation based test, same technology and same kind of underlying biology as the CCGA and Galleri and so forth. And what they were able to find remarkably in a kind of a retrospective cohort was that they could detect using this methylation assay, the presence of cell free circulating DNA up to four years prior to clinical presentation of cancer. And most of those were GI cancers. And that's pretty remarkable. It tells you what the time predictive value of a test like this is.

So one of the interesting things out of CCGA was that we had, I think in the initial pass, I think we had eight patients who were not known to have cancer. Eight participants rather, who were not known to have cancer who had a positive signal. And within a couple of months, five of them actually were diagnosed with invasive cancers of various organ systems and the predictive tissue of origin I think was correct in all five. So there's a lot to be learned about this sort of technology.

And one of the interesting questions that we haven't answered yet is if you have a negative test, no signal detected, how long does that mean that you're cancer free, right? How certain are you that you're cancer free on the day you have the test, but is there some time prediction there, some negative predictive value that says you're going to be fine for the next year or two or three? We don't know the answer to that yet.

In the CCGA study, we're following all the participants for five years to help determine that. At Pathfinder, we will follow everybody for a year to help determine that. But here's a big important message, is that this test is not meant to replace the standard screening tests that I talked about at the very beginning. This is going to supplement our existing cancer screening armamentarium. This will not replace them. So one clear message that we want to get to everybody who might be listening and to our participants is that even if you have a negative test, if you participate in Pathfinder, that does not mean you should skip your colonoscopy or your mammography or whatever else, your primary care physician recommends.

Dale Shepard, MD, PhD: I mean we can certainly do a lot better in terms of getting screening rates to a higher level. Do you think that maybe tests like this, that sort of capture people's imagination, might help with other screening efforts?

Eric Klein, MD: I certainly hope so. I mean, a blood test is far as simpler than a colonoscopy prep and pleasant-er then some of the other things that we do. So, yeah I hope so. I think the field is going to evolve in an interesting way over the next five to 10 years. And it's possible that blood-based or other liquid biopsy tests will displace some of the more standard screening protocols that we use. Having said that, again I want to be very clear that we are not suggesting that this test replaces any current screening tests. That's really important for people to understand. We just need more information and more long term follow-up before we could even consider something like that.

Dale Shepard, MD, PhD: And it sounds like part of the long term follow-up you mentioned, you don't know how long this is sort of predictive for. So maybe we can imagine that every two or five years or something people might need to do this test?

Eric Klein, MD: Correct. Something like that. And that remains to be determined what the correct interval is and really what the time related negative predictive value of a test like this. Just because you're negative today, doesn't mean you could not get a cancer in two or three years.

Dale Shepard, MD, PhD: Well this has all been really fascinating. And it really points to some important work that's going on for screening. And we spend so much time and energy trying to treat late stage disease, but certainly we can make a big impact by finding it early. So this is a really important step toward that. Any last comments?

Eric Klein, MD: Just to again reiterate the team's excitement for this, not only from the scientific standpoint, but I hope we're going to establish a new operational paradigm that can be rolled out to doing other trials. Let me just say also that this approach is isn't unique to us. There are other centers who have done something similar with similar sorts of technology. So I don't have any doubt that this will be successful, but I'm excited about it, nonetheless.

Dale Shepard, MD, PhD: Well, thank you very much for joining me today.

Eric Klein, MD: All right. A pleasure. Thank you, Dale.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google play, Spotify SoundCloud, or wherever you listen to podcasts. And don't forget you can access real time updates from Cleveland Clinic's Cancer Center experts on our Consult QD website at consultQD.clevelandclinic.org/cancer.

Thank you for listening. Please join us again soon.

 

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