Liquid Biopsies for the Early Detection of Cancers

Liquid Biopsy

[00:00:00]

Don Davis PhD, MBA: In this episode of the life science success podcast, we'll be discussing liquid biopsies for early detection of cancers. I'm joined today by Dr. Sam Hannah Ash from the envy MD Anderson cancer center. And Dr. Dusty . As I said, we're going to cover liquid biopsies and the importance in the field of detection of cancer in early stages when it's most curable and where we stand today with the technology.

Additionally Dr. Hanash has very recently [00:01:00] published a seminal article in the journal of clinical oncology, where the largest blinded study of its kind reviewed a four protein marker panel that informs about the risk of harboring lung cancer and the need for CT screening. For those of you who are new here, my name is Don Davis.

And I'm a consultant in, in life sciences, focused on managing complexity and increasing the performance of organizations. So with that, let me introduce my guests, Dr. Hanash and dusty. Dusty. Did you want to kick us off and go ahead and start with a brief intro.

Dusty Majumdar PhD: Yeah, sure. Uh, you know, I'd like to also mention that we are honored to have Dr. Hanash join us in this conversation. Uh, Sam Hanash has been a pioneer and a leader in the early detection of cancer, and we're really privileged to have him, uh, to, uh, opine [00:02:00] on what's going on in this, uh, space, uh, and on, uh, I've been a. Uh, marketing and strategy executive, uh, now for over two decades, uh, in companies such as IBM, uh, GE healthcare had the honor of working and one of the early cancer detection firms, exact sciences as well.

And, uh, I, uh, work, uh, with, uh, corporate America and, uh, at different capacities of the moment and also advise, uh, different, uh, health tech related startup.

Don Davis PhD, MBA: All

Sam Hanash MD, PhD: right. Well, let me introduce myself. So I'm the McComb's Institute for cancer detection and treatment at MD Anderson. And I've been in the field of cancer early detection for over two decades.

Uh, that goes back to when I was at the university of Michigan, I was taking care of patients and I had a patient who presented with advanced stage. I had to tell the family, unfortunately, there is nothing that we could do. The disease is advanced and, [00:03:00] uh, the family, uh, was, uh, very obviously upset by this and said, well, why did we wait until the disease so advanced?

Why couldn't we catch the disease earlier? And so that was my trigger to want to come up with a better mouse trap that we could catch cancer at an early stage. And that led to my working. Wanting to develop blood tests for cancer or.

Don Davis PhD, MBA: Oh, well, I mean, it's exciting and it's great to have you in this space for sure.

Dr. Hanash. So to get us started, in the topic, um, it seemed like quite often anymore. Uh, anytime I, I checked the news for life sciences or, even, uh, you know, last week, I believe it was. There was a panel discussion at JP Morgan's event where they talked about liquid biopsy to just get us started in the topic.

Can you talk to us a little bit about what liquid biopsy is?

Sam Hanash MD, PhD: Well, [00:04:00] uh, basically the concept of liquid biopsy is that, uh, could you with a biological fluid, which obviously is liquid be informed about cancer? Uh, what could you be informed about cancer? About it could be basically somebody already as a cancer, and they're going to use the blood test to determine the molecular profile of that tumor so that you could decide exactly how you should treat that tumor.

That has been a sort of a debate as to what would be better. Having a tube of blood that tells you about what's going on in the tumor or a biopsy of the tumor itself. So there are advantages and disadvantages. So when you are dealing with a biopsy of the tumor to determine the molecular profile, you're looking at one part, one tiny part of that big tumor, and you may not be looking at what's metastatic.

You're looking only at the primary tumor, whereas the blood can give you a sort of like a, uh, a [00:05:00] broader picture of what the molecular profile of the tumor. Uh, like, uh, you could decide on the treatment and then you could use the liquid biopsy to follow up and see like what sort of response you got and is there any residual disease?

So this is kind of like from how you manage patients, would liquid biopsy, like question then is also, could you possibly, uh, use liquid biopsy to cast cancer even before our set of symptoms? And so that's kind of the use of liquid biopsy for early disease.

Don Davis PhD, MBA: And dusty. Do you have anything that you'd like to add to that?

Dusty Majumdar PhD: Yeah, sure. I just wanted to kind of set the perspective here for folks who might be joining and perhaps not very familiar with this, uh, field, right. Uh, so it's been five decades since, uh, president Nixon declared the war on cancer. Right. And the reality is that after 50 years we are still not winning the war on.

Despite all the advant advances and [00:06:00] therapeutics and screening, we're still finding cancer too late. Um, and, uh, we know that, uh, this year 2022, nearly 2 million new cases of cancers are expected to be diagnosed. And some 610,000 people will likely die from cancer in 2022. And this is actually up from last year, which was 1.8 million new cases that awkward in that.

So we also know because of COVID screenings kind of taken a little bit of a backseat for the first time we see breast cancer, death rates, uh, increasing among American women, uh, under age 40, uh, for sure. And prostate cancer is being detected more and more today at a later stage than ever before. So, and we know the PSA test has largely failed us.

So this is the reason why. Tremendous interest in this field right now. Um, we do have a lot of investor dollars flowing in. Um, as we know, some of the clinical trials that are running right now [00:07:00] that are heavily funded and a part of the unmet need is today. We just have four cancers for which there are screening guidelines from USPSDF the United States preventative services task force at the population level.

So that's breast, colorectal, cervical, and prostate. And if you combine all of these together, we're only catching 15% of the cancers early. So again, there's a huge unmet need here. And, uh, we're going to talk more about some of the different trials that are going on and you know what, they're targeting, going to talk about the multi cancer tests as we go along this conversation.

But I just want to set the stage Don at this point and, uh, you know, let you continue on this. Uh,

Sam Hanash MD, PhD: A huge unmet need. Uh, I can list quite a few, uh, unmet needs. One is obviously better. Three. And so there's an unmet need for that. [00:08:00] Uh, the other one is like you, uh, talked about an unmet need to catch cancer early. That's another unmet need there's yet an even more important unmet need than catching cancer early, namely determining who is at risk of developing the cancer so that you could intervene even before the cancer is, uh, has developed.

And how would you interpret. Altering lifestyle, or it could be that with all of the, uh, excitement about vaccines at the present time. If somebody is at risk for breast colon, lung pancreas over here, and what have you, and you are able to determine that risk through illiquid biopsy or other means. Well, you can intervene.

Here's the vaccine to prevent ovarian cancer that we think based on your profile, you are at risk for. So, uh, to win the war I cancer, we need to move across all of those fronts, better treatment, better [00:09:00] early detection, better risk assessment, better intervention before the cancer, uh, through prevention. So all of those things are going to be variable.

Dusty Majumdar PhD: And Don, I would just add to that, uh, one more better compliance. And Sam knows this right for colorectal cancer. For all these years, the compliance is in the 65% range right now. It actually dropped a little bit last year, um, for lung cancer with low-dose CT screening, um, the compliance rate is around 15.

After a lot of efforts since the, uh, analyst's trial that was held in the mid two thousands. So that's a huge unmet need. So the need for a simple, accurate test that patients can take at their convenience and they can believe in is critical. And that's something that's FDA approved and reimbursed. So we're going to come to all of those things.

Um, as we go along. So Don,

Don Davis PhD, MBA: you know that, I mean, that brings up a good point. Dusty, [00:10:00] the, the cost of cancer care and pharmaceutical drugs, you know, does continue to, to grow every year. Do you believe that early detection will have a huge impact on reducing the economic burden of cancer?

Dusty Majumdar PhD: Well, I do. And you know, Sam is also at a great position to answer this, but I'll just be very brief and I'll let Sam, I think early

Sam Hanash MD, PhD: detection and catching cancer early stage has a tremendous impact on how you would treat the cancer.

When you think about how we are developing drugs at the present time or therapeutics for cancer, uh, you wait until somebody is advanced stage has failed with so many other therapeutics available, and then you try to see you. Drug is going to work. On the other hand, it may fail at that point during the progression of the cancer.

And have you tried your test on early stage cancer, then it would have worked. And so we need to go back to the drawing board. If we are able to catch cancer at an early stage, how would we treat that [00:11:00] cancer or differently and what treatments that would have failed with advanced stage cancer might very well work at an earliest.

So it would change the conundrum completely if we're able to catch cancer better and early stage. But like I said, I'm more of an advocate of trying to prevent the cancer, then having to worry about cancer at an early stage, just net power only.

Don Davis PhD, MBA: Yeah. So, I mean, and certainly being able to know that you're at high risk to, to get cancer similar to, you know, cardiac disease or, or anything else.

Right. You know, it'd be similar in my mind.

Sam Hanash MD, PhD: And we need to have the intervention at that point in time, whether it's the vaccine or whether it's a changing in the lifestyle or some other modality. And, uh, that's absolutely key.

Dusty Majumdar PhD: Yeah. Hey Don, I'm getting a couple of things saying that, uh, we may not be live at the moment. Uh, can I just check or it could be just an individual [00:12:00] issue.

Hopefully we are alive. Uh, are you getting any comments?

Don Davis PhD, MBA: It appears to me that we are alive. Uh, I am not seeing any comments. No.

Dusty Majumdar PhD: Okay. All right. So let's, uh, let's, uh, continue. I'm getting a couple of, couple of things in that direction, but you know, continuing on the team that Sam just said, right. I was just looking at some numbers this morning.

Um, five-year survival rate between early and late diagnosis. 56% versus 5%, if you look across cancers. So for example, when you look at renal cap carcinoma, um, when it's detected, when it's still localized in the kidney five-year survival rate is 93%, but the survival estimate decreases at 12% when the cancer has metastasized.

Similarly for five-year survival rate for female breast cancer drops from 99% when detected. Two 27% of the cancer spread and I can go on for lung cancer and colorectal, but that [00:13:00] guy shows you, there's a huge difference when you shift the detection to the early stages.

Don Davis PhD, MBA: So I, I would like to recognize though, too, that, uh, you know, something that I keep seeing in the news, you know, over and over again, is that, uh, you know, there are different articles that keep coming out.

Things like, uh, liquid biopsy being misplaced faith, uh, in early cancer detection. Yup. All this tells me is that people just don't understand really where we are today, uh, in terms of creating a liquid biopsy, uh, a test, you know, that does provide early detection. So, um, so I guess I, you know, I'm, I'm looking to try and get some comments from both of you with regards to the overall goal.

Should it be, you know, Overall looking at detecting early stage cancer today, or should it be that we make some other improvement on getting the cancers that are already present, uh, in people Dr. Hanash? [00:14:00] Why don't I turn for you to you first for that question?

Sam Hanash MD, PhD: Well, that's, uh, obviously, uh, a little bit of a complex question to answer and a sentence or two.

Um, the issue is. Uh, what is the purpose of liquid biopsy for cancer early detection? And so is it to actually detect the cancer or determined that somebody has a risk of having this or that cancer? It's a big difference. That's one issue. The second issue is we do have modalities available today for common cancers.

We have a CT for. Long, uh, we have mammography and other imaging modalities. And so the question becomes, and those are the common cancers, five common cancer for which we have screening modalities. So in the face of those screening modalities, the question becomes what is the [00:15:00] purpose of a liquid biopsy, which in principle, if it's a multi cancer is supposed to detect those cancers when we have, who are smooth realities available.

So that's a big issue. Is the liquid biopsy going to replace those modalities? The answer is no, it's an emphatic. No. And so if liquid biopsy is not going to replace those, then what would it contribute for the common cancers? So we'll talk about common cancers first. Then we talk about the rare cancers next.

And so it would seem to me that, uh, it is going to be very hard at the present time for a liquid biopsy. To be competitive with the current screening modalities that have very high sensitivity at very early stages. And so the way I look at it is the liquid biopsy at the present time for common cancers would be best suited to determine the [00:16:00] risk personalize the risk.

We know that, uh, there's a lot of issues now about screening for breast cancer. Then do women need to be screened every year, every other year? What modality, if the, uh, mammogram is negative, should we have yet another mammogram every year? So the liquid biopsy, as far as I'm concerned would be the one to personalize that woman's risk for breast cancer.

And so if it looks like her risk is high, absolutely. You should get an imaging modality on a very regular. If it turns out that the risk is even below average, then maybe, uh, one could skip the imaging modality. That's an example for breast cancer for lung cancer. As Dustin mentioned, uh, the compliance rate with screening by CT is variable.

On the other hand, if there's a blood test that could tell you a look, your risk is very high, then you should get the CT. Then [00:17:00] compliance would be much better. So in my view, illiquid biopsy for the common cancers should be one that empowers the current modalities available as opposed to competing with them on the other hands for the rare cancers, for which there is no screening available, then that would be very beneficial obviously to have.

Multi, uh, rare cancer pan-cancer sort of liquid biopsy that would pick up even if it were to pick up 10, 20% of those cancers for which there is no screening modality available today, that would be a plus. And so one, it's not like one size fits all the liquid biopsy has to perform the same way across all cancers.

It has to have multiple sites. Performance criteria, depending on the cancers that the multi-campus or pan-cancer liquid biopsy, is it tended to, [00:18:00] uh,

Intro Music: detect

Don Davis PhD, MBA: very good. Dusty. Is there anything additional you'd like to add to that?

Dusty Majumdar PhD: No, I think Sam covered, uh, you know, most of it, uh, you know, I totally agree with them.

In fact, this is something that. Sam. And I both espoused almost a decade ago when we talked about lung cancer screening, as it's still at that time. And unfortunately it has not really progress to LOC since, uh, since then, in terms of compliance, you still are in the 10 to 15% range for heavy smokers complying with this.

So if there was a blood test that actually stratified the risk of, uh, these patients, uh, who are, who are heavy smokers, uh, to go into lung cancer, That obviously would be a tremendous improvement on the current standard of care that exists, uh, today. Uh, Sam mentioned the lung or the rare cancers, right?

And the challenge in the, in the rare cancer space is, uh, the, uh, prevalence in some of [00:19:00] these rare cancers is less than 0.1%. So somehow if you could actually aggregate some of the. Rare cancers and you'll have a higher prevalence. So you'll have to screen less number of patients to find one of these rare cancers.

And if there's a universal kind of a pan cancer test for these rare cancers, uh, by aggravate, uh, the aggregating, the prevalence, you may be able to raise the positive predictive value even for a test. The sensitivity could be quite modest so that those are some of the things that, uh, we you think about.

Uh, and, uh, I totally agree with Sam that, uh, this is, uh, going to be a personalized, it's going to be, uh, targeted, um, in a way that we are actually getting the best outcomes for both the aggressive cancers that are fast moving, as well as some of the rare cancers and some of the indolent cancers, for example, Um, with prostate [00:20:00] cancer, you know, men would probably die before the prostate cancer.

In many cases become, becomes a metastatic metastatic, and we just have to keep in mind all these different new ones.

Don Davis PhD, MBA: And I think you covered this early on, um, Dr. Hanash while in your opening comment. So how do you think the future blood tests are gonna work for cancers? Um, and you know, how do you think there? What about things where there is no screening protocol?

Sam Hanash MD, PhD: Well, I think the expectation of a liquid biopsy tests for cancers, for which there is screening available today versus cancers for which no screening, the expectations are radically different.

And, and we cannot treat both the same way. And so how are the different now if you're dealing with a rare cancer. [00:21:00] Then your ability to detect that cancer has to have tremendous specificity otherwise, because it's such a rare cancer. You're going to have a lot of false positives. And so as a result of having very high specificity, that's going to reduce the sensitivity of your test, but one could argue, and this is an argument that grail has made.

For example, That those cancers were rich. There's no tests available today. If we can pick up 5%, 10%, 20%, even that percentage is small, it's still better than zero. And so I buy into that argument at the present time. Hopefully, eventually, maybe tests will become available that have much higher sensitivity at a high specificity, but for other cancers, This should not be a requirement that you [00:22:00] have 99% or 99.9, 9% a specificity.

And, uh, I can give a reason for that right now. What does it take for somebody to be eligible for CT screening? It does not require that you have a hundred percent risk of lung cancer that requires that you have a maybe 0.5 or one person. Risk of lung cancer, that's enough to trigger a CT modality. So we need to look at the liquid biopsy for common cancers, for which there is a, another screening modality very differently in terms of sensitivity and specificity

Don Davis PhD, MBA: and dusty, anything additional you'd like to add.

Dusty Majumdar PhD: Well, I think, uh, you know what Sam said resonates with me, uh, do we really need a specificity of 99.5% across the board for all the cancers? The [00:23:00] answer is probably no. Uh, if you work in conjunction with some of the, uh, screening methods, which are already available and at least in the short term, try to bolster those with, uh, uh, a compliment.

Liquid biopsy test. Um, I would also, uh, agree with Sam that for some of the other cancers, perhaps we could buy into the argument that, you know, we need a higher specificity. Um, and then the, then the issue really becomes at such high specificities for stage one and stage two. Are you really going to be able to detect anything with a reasonable sensitivity?

And there are some mathematical arguments to, uh, to that as well. Uh, There are people who have shown, uh, in their work, uh, where the tumor is smaller than six millimeters or so it's unlikely that a, um, one would detect by, by the techniques currently available, uh, circulating DNA. Right. Um, [00:24:00] because they probably would be, uh, in 10 mils of blood, less than one genome.

And, uh, that goes up as the tumor goes to 10 millimeters and 15 millimeters where, uh, you can, uh, with reasonable certainty, detect some kind of DNA. Um, so I think there are there it's, it's very nuanced and, and if you're only depending on circulating tumor DNA, then your chances of success are even lower at the early stages of cancer.

So when you start combining. With, uh, when he, when he, when he combine mutation and methylation and circulating tumor DNA with proteomics and fragment tonics, and perhaps even apply some kind of AI methodology to it, you probably could go up higher. It's good to see that this is going on right now. There are people who are seriously looking at this and, uh, hopefully we'll, uh, we'll see the advances coming.

Well,

Sam Hanash MD, PhD: I have to say that I don't buy into [00:25:00] those theoretical calculations that if your DNA with the term are less than one centimeter or six millimeter, or what have you, then it's unlikely that you're going to have one copy of DNA in the blood. I just not buy into those. There's no, uh, evidence to that effect.

It also totally ignores the fact that cancer doesn't happen overnight. It goes through progression from early stages, even before, uh, what we are now calling stage one cancer. It goes through an evolution from pre-malignancy to malignancy. And so at the pre-malignant stage, there could be a lot of, uh, changes at the DNA level, including mutations.

What have you. And so if you have now, let's say through artificial intelligence, the ability to look at a wide spectrum of potential alterations in the blood that may not necessarily. Come out of that 0.5 mil, a centimeter tumor, they could be [00:26:00] coming out of the points that are hero tumor, also coming about the pre malignant tissue surrounding the tumor.

And it could very well be that you're going to have an increment in mutations and that would kind of empower whatever test you're using, whether it's a protein or whether it's a DNA or whether it's a mutation or methylation or what have you. So the argument that okay. Point five centimeter tumor have only so many cells and therefore you're going to have so many copies of DNA.

I do not buy into that.

Dusty Majumdar PhD: And if you go back to Sam's work in the past, uh, there are studies where Sam has actually been able to show that even before radiologically, you see anything, uh, in terms of a tumor, uh, I believe it was a study in the lung, uh, Sanford recall correctly. Uh, they were seeing signals with proteomics.

Uh, which clearly shows that, uh, there's a lot of things going on in the microenvironment of the tumor that you might be able to catch even before radiologically, you can actually see anything, [00:27:00]

Intro Music: correct.

Don Davis PhD, MBA: Yeah. I mean, that kind of brings up a good point. So, you know, the overall, there are a few tests with blood being used for testing reoccurance and, uh, minimal residual disease.

Um, why is it so hard to get early detection with liquid biopsy?

Sam Hanash MD, PhD: Well, uh, I'm not sure by so hard, if you are referring to the technology, are you referring to the implementation or referring to the cost effectiveness? There are many, many different factors that go into, uh, whether something works or not does not work for me. Kind of like public health point of view from a technology point of view.

It's, uh, certainly very hard. Um, And, uh, because you are going to be located if you're dealing with a pan-cancer test as so many different variables in there, and it's, uh, like catching a tiger [00:28:00] by the tail type of thing. And so for the longest time that we have been working on wanting to develop a liquid biopsy test for cancer, uh, our sort of.

Vision was a lot more modest than the multi cancer test. Let's first demonstrate that we can work for one cancer in an effective way. And then we can see, well, what about two cancers, three cancer. What have you? And so it certainly created a lot of shock. Uh, when this notion came out that we can have a test that could look.

X number of cancers at the same time, uh, for us Canada in the academic scientific, uh, low budget sort of, uh, uh, mindset, then let's kind of move one step at a time and we're still cannot take, uh, A big jump into pan-cancer, but I have to command whoever is working on pan-cancer, but they were able to attract the funding, attract the interest and the resources to be able to do that.

Um, [00:29:00] the other thing is when people are bashing log, the pan-cancer, they are expecting perfection. And the way I look at it, it's kind of like, uh, basically, uh, the spirit of. St. Louis crossing the Atlantic for the first time. I mean, don't expect a jumbo jet to be crossing the Atlantic. You're the first time I think one has to look at it from the point of view of the promise.

And you're going to have, let's say, uh, an evolution of those tests progressively. So I think it's commendable that there's interest and pan-cancer, uh, that's kinda like how I look at it as opposed to wanting to bash it.

Don Davis PhD, MBA: Yeah. And I, I mean, I, I certainly can see that as well. I mean, and that's, that's where I, I definitely give credit to a lot of people in this space, right.

Is that, you know, it's not like we're waiting until everything's perfect. Before we, before we get to that, you know, end point of having a pan-cancer test, their Mo most likely is going to be [00:30:00] sort of an evolution to your, to your point, Dr. Hanash.

Sam Hanash MD, PhD: Well, I was involved in the cancer seek and, uh, made a contribution to the proteomics part of cancer C and on the paper came out in science.

I was flooded with emails and calls from people statistician and other. What do you think that you really can't detect cancer pancakes? So this way, this is not going to work. I told him, look, this is the first step. This is a proof of principle that may be adding protein to DNA can have a significant contribution to cancer, early detection.

Not that we are ready today to launch a test of that sort.

Don Davis PhD, MBA: And I think that's what a lot of the news articles that I'm seeing at least that, that they're, they're at least indicating that look, it's not going to be tomorrow. Um, we don't know when, how far out it is, but it's not going to be tomorrow that we have that we have this test.

Sam Hanash MD, PhD: Well, I wouldn't say it's not going to be tomorrow. Uh, the first kind of model T that's going to come out. It's not going to [00:31:00] be the same as what you're going to have a few years down the road. Uh, that's kinda like how I look at it. We may end up with model these at the start, but that's still a good start to have a model T right.

So

Don Davis PhD, MBA: how would a liquid biopsy test be integrated into the clinical pathway?

Sam Hanash MD, PhD: That's a very good question. At the present time, the question is going to be how much buy in, uh, one would have for a pant cancer liquid biopsy tests. There remains to be determined.

Intro Music: Um,

you are believers

Sam Hanash MD, PhD: and not so believers at the present time. As we all know, uh, uh, I've been impressed in the past. As the physician scientists as to what it takes for something to be adopted, I think, uh, uh, marketing, publicity shock and [00:32:00] awe have a big, big impact on whether something gets, uh, adopted or not.

Uh, we have, for example, knowing about hemoglobin A1C from a science point of view for a long, long, long time, and nobody was using amyloid A1C. Uh, monitoring diabetes until somebody decided to kind of publicize it, market it and go ask for it. And then all of a sudden it became a standard. And so, uh, what it takes for something to be adopted, uh, requires a kind of, sort of, uh, uh, a way to get, uh, people, uh, to buy into it.

Dusty Majumdar PhD: I would add too to that two things. One is understanding the clinical workflow right now for at least the cancer. Which, uh, you know, we have screening for the four cancers that we mentioned previously. Uh, so how do you integrate a blood test for example, into the clinical workflow for low-dose CT, for [00:33:00] high-risk lung cancer, uh, patients, right.

I mean, are people who we suspect may have lung. I think that is a, that is something that's very important integrating in the workflow. Um, similarly, you know, of colorectal scans cancer, the, uh, compliance rate is around 65% right now. So we have Cologuard the stool tests. There are blood tests that are proudly coming out.

Um, how do you, again, integrate that into an annual physical, or, you know, do at home test and do it effectively and compliantly. The other thing that, uh, is going to become more and more important as these multi cancer tests come up is that today we don't have any legislation that actually is going to provide coverage for pan-cancer or multi cancer screening.

There's a bill in the Congress right now. It has bi-partisan support for multi cancer, diagnostics and innovation in cancer, diagnostic development. And that is going to go through the. [00:34:00] Set it on the house, hopefully in the next few years, uh, or men off. So there's still some uncertainty, uh, with that. Uh, so I think the government angle of this is, uh, it's still up in the air, whether it's going to be a multi cancer test is going to be truly covered on.

Don Davis PhD, MBA: And it looks like we've gotten a couple of a couple of comments back on the YouTube stream now. So I do know for sure that people are watching there as well. Uh, Dr. Hanash and dusty, um, one of the latest comments that came through, even, even during your comment, uh, dusty was that, you know, we'll start to see this whenever, uh, insurances start to pay as well, you know, for the test in the clinical.

Dusty Majumdar PhD: Yeah. And, and just that everyone understands, this is not an easy process. So some of the companies that Sam and I mentioned, gray and free gnome, um, and got, and gardened are in the middle of clinical trials. These typically would take three to [00:35:00] five years, depending on what kind of, uh, end point you decide on off of that, it could be a year til you get FDA approval.

And then there's a CMS reimbursement that comes sometimes. Along with the FDA approval. If you go through a special path, otherwise it could take another year for that. Once you have CMS reimbursement, Medicare would pay for it. But then the private insurance depends on the ratings that you get from USP, STF, United States, preventive services, task force, which only meets every five years.

So if you, you got to really be at the right cycle at the time that the USPSDF has current. To show all of your results and get their blessings for our ARB rating, uh, for private insurance to start paying for a screening tests. So we're looking at a long journey here, and we can just sit on our hands between now and then, and not have some of these single organ tests moving forward in terms of [00:36:00] integrating with the clinical workflow, improving the performance and improving the compliance.

Don Davis PhD, MBA: So one, one argument that's been made for cancers for which there is no screening today, is that any test that sends people to other tests would be. What kind of performance do you feel the FDA will demand for these types of cancers? Um, also, are there downsides that you believe that are here and, you know, in my mind as well, you know, false positives that could flood the healthcare system, uh, might be another, another concern, uh, you know, for these tests doctor

Sam Hanash MD, PhD: for any tests.

I will imagine what the FDA would consider is what's the consequence of that test being positive. What's the consequences of that test being negative. Now, if a test has a lot of false positivity, but if you are [00:37:00] a positive, you're going to go through surgery. That is a substantial, obviously concern. Now, on the other hand, if your test could have false positives, But as a result of that test, you're going to have some kind of imaging modality.

And that's not as a severe consequence as having to go and get an exploratory surgery of some sort. So I think those are things that I'm sure the FDA will take into account the consequences of false positive and the consequences of the false negative. The FDA is not going to care about how much the test costs or what have you, but those are the two most important issues to.

Don Davis PhD, MBA: Dusty. Anything else to add there? If not, I've got an AI question for you that I know is right up your alley.

Dusty Majumdar PhD: Well, I would agree completely with, uh, with Sam and again, looking at some of the, um, results that are coming out in various publications, [00:38:00] especially for early stage cancer stages, one and two. Um, where for very high specificities, we are seeing sensitivities across the board of around 20 to 30.

I think the thing to worry about there is the positive predictive value for, uh, some of these individual cancers. Now, the advantage of, uh, aggregating some of these, uh, rare cancers and cancers with low prevalence is that, you know, you get an overall blended number of high prevalence, which is going to improve the, uh, positive, predictive value.

Um, so I think that's the advantage of. Multi cancer test and the other way to improve the positive, predictive value or lower lower, the chances of false positives is to target the right populations. Right? We know cancer is a disease of older people. So, you know, you test people over 50, over 60. We know that, uh, uh, patients, you know, who have a family history of [00:39:00] certain types of cancer at a high risk of cancer, we know smoking.

Are the high risk of cancer, not just lung cancer, but across the board bladder cancer, in some cases, pancreatic cancer. Um, so, you know, in some cases we have seen that, uh, transplant, uh, organ transplant recipients are at a high risk of cancer. So targeting those populations with the right kind of tests with the right performance would be.

Don Davis PhD, MBA: Yeah, absolutely. I'm going to stay with you for just for a second. Uh, dusty. Cause uh, this next question I think is, is something that you could start with and then maybe come back to Dr. Hanash on. Um, so we hear some, some companies are now starting to talk about more and more using artificial intelligence to integrate part of the effort for liquid biopsies in detecting early cancer.

Um, what are your views on this and this.

Dusty Majumdar PhD: Uh, increasingly I think you see companies talking about that, and I think it's inevitable [00:40:00] as you move into the multi omics arena that you may need AI to, uh, to help you, um, really get to the answers quicker in a more efficient way. Um, Great talks about using AI, uh, in their, uh, in their gallery test, uh, uh, from what I've heard, freedom, uh, has been promoting AI and their testing quite aggressively, but one of the discussion that Sam and I have had on this as, okay.

So even if you have AI, um, helping you to predict, uh, or to detect cancer early with higher specificity, Um, how are we going to create an assay based on an AI algorithm? And I'll let Sam talk about this because he has put some talk to touch into it. Sam, go ahead.

Sam Hanash MD, PhD: Yeah. I mean, when we are talking about AI for any application, one has to, December-ish the use of AI for discovery.[00:41:00]

Versus the use of AI for implementing the test. And so if you're looking for example, at DNA methylation, and you have millions of sites of DNA methylation, and you have so many variables, the age of the patient or the subject, or what they had the day before or medication they are on, it becomes a very complex undertaking to want to determine what would be the best indicator for this particular case.

But once you have come up with the signature, then the AI goes out the window. You already have 1, 2, 3, 5, 10 particular features associated with that cancer. So let's not mix AI for discovery versus use AI to determine if that person is positive or negative. You're not going to use AI to determine if they are positive or negative.

They're going to use AI to detect. The signature that would make that person positive or negative. But once you have that signature, [00:42:00] AI goes out the window.

Don Davis PhD, MBA: And so what would the fallback be then? So what would happen? What would happen after, after you're furnished using AI? How would, how would that work?

Sam Hanash MD, PhD: Well, let's say that, uh, for a person who certainly characteristics, for example, age sex and what happened. Then this particular signature that we found, if it's related to methylation, meaning those CPG sites that are methylated indicate the presence of this cancer, uh, then, uh, basically you have come up with that signature that you would implement when you're using the test to screen for this cancer or multi cancer topic.

And so it's very valuable. Uh, I can give you the example of back maybe more than 10 years ago. One of the, uh, there are so many different things in the blood that can tell you about cancer and a laundry list. You could look at DNA, multiple features of the [00:43:00] DNA. You could look at RNA, you look at protein, you could look at metabolites, you can look at the immune response and back, uh, more than 10 years ago, I led the project that was supposed to be looking at DNA methylation.

And it became so complex that I would think without AI, you will not be able to come up with a signature. So we gave up on this and to the credit of grail that basically they went a full-blown, uh, approach to look at all those millions of sites and be able to come up with signature that not only tell you that.

Uh, the presence of cancer, but where the issue is. And so I'm very envious of what they have been able to do at the DNA methylation, which we could not do without, obviously not only the AI, but all the massive resources that went into that particular, uh, endeavor.

Don Davis PhD, MBA: Very good. And doctor had Hanash. I'm going to stay with you for a second.

So, um, in your, in your most recent paper, [00:44:00] On a blood-based biomarker panel for risk assessment for lung cancer. It demonstrated how to identify individuals with a high risk of lung cancer. Can you tell us more about your key findings? Yeah. Uh,

Sam Hanash MD, PhD: the premise of our study, which, uh, that pepper is the last in a series of papers that were published.

And like I said, we are the academic, we move very slowly incrementally. If you finish one study, you learn from it. You go to. And you go to the next, but the premise has been that as of today, not even 10% of subjects destined to die of lung cancer are being basically are going through screening for lung cancer.

And the question is, can we come up with a blood test that would determine somebody's. Uh, having a lung cancer or basically over a period of time would be [00:45:00] diagnosed with lung cancer. And so that's what we tried to accomplish. And that study, namely going through the multitude, like I mentioned, the laundry list of different markets.

We look at all of them just about, and then at the end came up with a simple test for protein marker panel that would determine somebody's risk of having long-term. So the concept is that if you are a smoker for now, the test is only applicable. Uh, the data that we have is only related to smokers. So if you are a smoker and you go to see your doctor and, uh, the, uh, the, the division is that okay, we have a test that could determine your risk of having lung cancer.

And if the risk is high and through shared decision-making, then you can decide whether you want to go through screening. And the major reason is that compliance with lung cancer screening at the present time is very, very low. Number one. And number two, there are smokers who don't meet the criteria that may be destined to develop lung [00:46:00] cancer.

So if you have a blood test that could determine your risk, it may sort of persuade you to go through screening with CT. So the implementation, the screening and the compliance could go up considerably and we would save more lives.

Don Davis PhD, MBA: And so, I mean, I I'm taking then from that, that the overall premise being that if you did the protein panel, you have a high indication, uh, that you just need to be screened for lung cancer.

Then you believe that that people will go for the lung cancer or for the CT screening,

Sam Hanash MD, PhD: if you are eligible. But. Having your personalized risk as opposed to some kind of a yes or no risk based on the criteria today, a personalized risk would be more persuasive. Wanting to get the CT screening. Number one, number two, if you are less than a 20 pack year smoker, you're not eligible for screening.

And yet [00:47:00] we know quite a few lung cancer cases are among subjects who are not 20 pack year smoker. So if the blood test can say, even though you are a smoker, you have smoked only 10 pack years. You are just as much as the risk of lung cancer as a 30 pack year smoker, then you should get the CTS.

Don Davis PhD, MBA: Yeah, that's a, it's a call-out for all of my, uh, all of my followers that, uh, that are in this sort of group of people that, that carry around those white ribbons.

Right. I know that, uh, you know, kind of the, the one guy that's that started all. Um, more or less wound up with lung cancer without being a smoker. And so he's just said, you know, look, I, I wound up with this. I, it wasn't something that I felt like I could publicly even talk about. So if there was a way to, to screen people and at least say, you know, to people like him, that, you know, Hey, you're a high prevalence of, of needing at least to be screened.

Um, you know, additionally, just to make sure that you don't have lung cancer would be, would be. [00:48:00]

Sam Hanash MD, PhD: Well, we also have to keep in mind that in most countries there is no adoption of low dose CT screening for lung cancer. On the other hand, if a blood test says you are positive, then that could be a clinical indication to get the CT screening.

Don Davis PhD, MBA: Yeah, absolutely. And do you see a greater number of academic industry partnerships coming in this space, you know, for liquid bio.

Sam Hanash MD, PhD: Uh, yeah, absolutely. I mean, there's a lot that we bring into it. Uh, uh, like I said, I'm not the only one has been in this field for a long time. I've gained a lot of experience. And, uh, so we have three, we have been preaching about all the different applications, the nuances of what one would do. And at times I feel that a one size fits all in terms of.

What you need in a multi cancer panel for long versus colon versus [00:49:00] breast versus a rare tumor, you cannot treat them all the same way in terms of having a requirement for the same sensitivity, the same specificity. So there's a lot of experience that we have had that would help, uh, in terms of how to sort of finesse a pan cancer screening tests.

Don Davis PhD, MBA: Very good. Dusty. Do you have anything additional you'd like to add?

Dusty Majumdar PhD: No, I think, uh, I think we covered most of it. Uh, I'll just add one more thing. So why do we have all these companies that are jumping into it and why are investors pouring in so much money into it? Right. So it obviously has to do with, uh, the market size that, uh, people see in some of these, uh, uh, early cancer detection opportunities.

So for example, in colorectal scan, Um, if you take patients are off, you take individuals, uh, between 45 to 84 years of [00:50:00] age, there is, uh, a $20 billion market just in colorectal cancer, um, in lung cancer, if you, uh, uh, and as you know, in colorectal cancer, now, you know, there are trials going on, uh, in blood from Darden, Dan Freenode, uh, I believe exact sciences is also developing the next generation.

Cologuard as well as looking at blood, um, you do have a similar kind of, uh, situation with, uh, lung cancer. If you just take the high risk population, people who have smoked over 20 or 30 pack years, uh, um, so that's, uh, smoked, uh, at least a pack for 30 years or two packs for 15 years. That's 30 pack years.

Uh, you can easily see a market of 30 to 35 billion and this doesn't. Um, folks, uh, who are the nonsmoking population at you? Women who have never been smokers non-smokers [00:51:00] are increasingly getting lung cancer now. So you could also imagine a test coming, uh, to that arena. Um, you also see a. Uh, in pan-cancer.

If you look at what's going on across the board, if you look at all these different cancers, you could easily see a, a market opportunity of around 50 to $80 billion, depending on whose calculation you really believe. So there's obviously a very attractive space across the board, and that's why you see a lot of the, uh, major players jumping in, um, like grail and Illumina and.

Gardened and exact sciences, uh, and free. No. And there are probably a list of around 20 other players that we are not mentioning here.

Intro Music: Yeah.

Don Davis PhD, MBA: Very good. So one of my favorite things to talk about as well as what's next. So, uh, dusty, why don't we start with you since the camera's on you? Um, where do you think we'll see the next advances, common and liquid, uh, liquid by.[00:52:00]

Dusty Majumdar PhD: Well, I think that really depends on how the clinical trials, which are underway, uh, pan out. Right. I think that's a, that is the key. And, uh, you know, uh, um, you know, if you want, I can talk a little bit about, uh, you know, what we are seeing in that space. Uh, but I think we are seeing all the right things happening in terms of the combination of.

Mutations and methylation and proteomics coming together in some of these tests that are being developed or at least being talked about. And then the advent of AI, you know, may be able to help in some way to deal with the complexity of data. And the grail has been pretty public about leveraging AI and so has free.

No, man, I'm sure the other players are working behind the scenes to, uh, leverage AI in a way to really, uh, figure out the. The way you can detect cancer, especially at the early stages when, uh, you know, it is most, uh, treatable and curable. [00:53:00] So I see that, uh, continually happening and I sincerely hope that we don't wait for a pan-cancer or universal cancer test to become perfect, but continue the journey that we have with some of the, uh, tests that are already available and compliment them with a blood test so that the overall compliance goes up.

Uh, the. Accuracy of screening goes up. And, uh, we reduced the mortality of, uh, some of these very lethal cancers that, uh, are still taking a lot of lives every year.

Don Davis PhD, MBA: Very good. And Dr. Hanash what do you think is coming next?

Sam Hanash MD, PhD: Basically, the way I look at it is there's going to be one or two or three or four pan-cancer tests out there.

And I can guarantee you if company X is working on their first cancer pan-cancer tests, as soon as they put it out, they're already working on version 2.1 or that cancer test and 3.1 down [00:54:00] the road, or what have you. So there's going to be an evolution of tests out there, uh, with, uh, improved performance, uh, over time.

Don Davis PhD, MBA: And essentially that's what I have for today. It, I'm glad that both of you joined me for this, uh, liquid biopsy panel discussion. So thank you very much for your time. And, uh, as always I will, um, Essentially released the audio version of this on a, on a audio recording as well, so that people can watch, uh, this, if they'd like to on, on YouTube or LinkedIn, but also go to their favorite podcast platform to understand more.

If you want to connect with any of the guests here, uh, you could see them on my website at www.Lifesciencesuccess.com. Thank you so much for watching.[00:55:00]