Hello everyone. My name is Hannah Went. I’m the founder of Everything Epigenetics.
And today my guest is Dr. Josh Routh.
This is a really interesting episode where we start off talking a little bit
about who Josh is and the problem with cancer burden and late detection.
We cover the current state of cancer diagnostics and the future state of cancer screening tools.
We talk about the current American Cancer Society guidelines and their recommendations for routine screening, and where we hope
to actually be able to start to detect cancer earlier through epigenetics.
Yes, that is correct. We’re looking in discussing at cell free DNA in the bloodstream.
Josh works at Precision Epigenomics that offers one of these tests that can test early cancer signals called EPISEEK.
So we explain more about these tests, the promise that they hold. How does one actually perform this type of test?
What does it actually test for? What’s the sample type? The specificity. The sensitivity.
How do we even define what specificity and sensitivity means in this case of testing?
Who should actually take this test. What do these results look like and what happens if you get a positive signal?
We also talk about the difference between EPISEEK and the Galleri test
by GRAIL, which most people are probably familiar with. Lastly, we end up with other areas that Josh is really excited
about when it comes to epigenetics in cancer diagnostic tools.
A little bit of interest, interesting information about my guest. Josh is a broad background in pathology and laboratory medicine
and specific training and expertise in bioinformatics, in molecular oncology.
He has a lot of broad experience. He oversees a clinical laboratory that performs next gen sequencing,
whole exome, whole transcriptome sequencing of cancer samples for patients with advanced cancer.
He has provided leadership to a broad range of clinical laboratories academic, government, private and public.
He is a jack of all trades, and he received his MD from the University of Arizona, completed a residency in Anatomic
and Clinical Pathology, as well as a fellowship in Molecular Genetic Pathology at the University of New Mexico.
He is now an Associate Professor of Pathology at Midwestern University, with research focusing on molecular diagnostic and precision medicine.
If you don’t know what all that means, don’t worry, we’re going to hop into it. It’s the first question where we learn a little bit more about Josh.
And now for my guest, Dr. Joshua Routh.
Welcome to the Everything Epigenetics podcast. Josh, I’m excited to have you today.
Thanks, and I’m excited to be here. – Yes. So we first met you, work
for Precision Epigenomics and I’m obviously at TruDiagnostic, and we offer your EPISEEK liquid biopsy testing,
which we’ll, we’ll jump into during this podcast episode. But you’re. Yeah, the laboratory medical director there, and you’re an AP board certified
pathologist with additional fellowship training in molecular genetic pathology.
And you serve as medical director for the clinical laboratory. What does that all mean?
Tell us a little bit more about your journey. You know, I’m sure people listening may be interested
in pursuing some type of career like that one day. What got you there as well?
Yeah. Yeah, I had a pretty, pretty weird career path. I actually started out as an electrical engineer,
so I was designing, microprocessors for a company called AMD. They may make the computer chip in your computer that you’re using right now.
Ended up going back to school, going to medical school. And I got there, and I was I was kind of disappointed.
There’s almost no math in medicine, right? Very little math, which none of my classmates were disappointed with.
But I was I found this field of informatics, within medicine and and also pathology.
And I was really attracted to the pathology that the clinical lab is kind of this nexus where
all this information about a patient comes in and all these results come out. There’s a statistic out there that says 80% of medical
decisions are based on a laboratory test result. And that was compelling to me. And it was a good fit for my personality, my experience as well.
So finished up medical school, went and did a fellowship, sorry, a residency in anatomic and clinical pathology,
with a lot of focus on the clinical kind of lab management side there. Around this time to next gen sequencing was really emerging
as, technology and, you know, generates up to 40GB per patient.
And that is that is my sweet spot writing code to analyze that data, to help these patients.
It was just a great marriage of, some of the things I had experience and interest in.
So I did a fellowship in molecular genetics pathology, worked a lot in the kind of bioinformatics side of things.
Got experience as well in the wet chemistry. Came out of training. So excited, to change the world.
I got my first job working for the Department of Veterans Affairs. So the VA was launching
their first kind of next gen sequencing laboratory. They hired me to be the lab director and then awarded the money for the lab
to another state, which only the federal government would do that. So I got to know the people, in both laboratories.
Managed both, you know, manage the the local laboratory there. We were successful with that.
We were doing next gen sequencing, veterans tours to determine what was the best drug to give rights, with their particular mutations.
What should they be getting? From there, I worked for a company called Exact Sciences.
Huge company. They were buying up smaller laboratories at the time,
and I came in to direct some of their next gen sequencing libraries. So I had a great time working with that company.
Really happy there. But I really liked the small companies that they were buying and some of the innovative work that was happening at the smaller companies.
And not as much, you know, that that big corporate structure. So I took, teaching and research position at Midwestern University.
That’s where I am now. I teach medical students to the next generation of doctors here. The de students.
And then I also do clinical work with a few different laboratories. Kind of doing scientific oversight and medical oversight,
making sure the tests are meeting the standards and then using some of that background to the scientist.
Yeah. And you’re loving it, it seems like right? It’s like a marriage of almost all of your skill sets
where you used to have… Yeah. It’s impossible to, you know, how could you have picked this? You know, if I went back in time ten years and said, what do I want my career to look like?
I couldn’t have imagined this piece, but it’s been a really fun journey. Good, good. Yeah. You’re in the lab. You know, you still have that analytical piece of it with Precision
Epigenomics and what you’re involved now. But, I think I was familiar with, with your at your teaching at Midwestern,
what you’ve been doing to. So you still get that, kind of person to person interaction and able to pass off
your, your skill set to your next, the next generation, too? Absolutely. That’s awesome. Well, today we’re really here to talk about cancer and epigenetics.
And I’ve spoken about this on the podcast once before with Dr. Christin Burd,
she’s at Ohio State. And that was, you know, a pretty different episode compared to what this one is going to be about.
We’re really going to talk more about how we can, you know, look at new cancer diagnostics tools
through the lens of epigenetics and what epigenetics can really teach us. So I have some statistics here I want to read off
before we really hop into it. The problem is cancer burden, right? And late detection.
I see it everywhere over my social media accounts and the news. There’s this increase
in cancer diagnostics I have health care providers I work with send me articles that, you know, and 50 years or so 90% of the world is
is going to have some type of cancer, you know, by the age of 65.
So just to name off some of those statistics, over 2 million
new cancer cases are expected to be diagnosed in the US in 2024 alone, just this year, with about 600,000 deaths from cancer expected in the US
last year. There’s about 209 billion per year spent on USA cancer related health care cost, which is insane.
And there are only currently four cancers lung, colon, breast, cervix that have routinely
recommended conventional screening tests, which usually underperform. Not in the way that we really want them to reach our standards.
And then lastly, which I think this is crazy to to even talk about as well, you know, over 60%
of cancers are diagnosed in late stage. And, you know, I’ve been lucky enough and my immediate family
to not have a huge history of cancer, but I mean, cancer touches everyone.
My step grandmother, who I loved dearly, passed away from from lung cancer.
And I remember just wishing and this was only a couple years ago, that there was some type of test to diagnose her early.
I mean, it was it was way too late. We really couldn’t do anything about it. So, Josh, I want to throw it over to you.
What do you see wrong with this in your area? Like, what isn’t wrong with this I think is, is the the correct question?
Yeah. I think we definitely know catching cancer early when it can be
kind of completely treated and gotten rid of. We have better outcomes, right? We have decades of information backing that up.
We also have decades of information of of trying different cancer screenings that have been successful, not successful to, to varying degrees.
I, you know, that’s the work that we’re doing, that Precision Epigenomics is trying to detect cancer earlier, trying to get that final diagnosis,
as soon as you can so you can get that earlier treatment. I do think in the next ten years this is going to be standard of
care, right? You’re going to get a blood test for, you know, be one. See to see if you have diabetes, right?
You’re going to get a blood test to say, “Hey, is there any cancer here that’s been detected currently?”
That we could find and treat? Before before it becomes a stage three or stage four
metastasize is required to do surgery. So yeah, I think that’s the goal.
It is troubling seeing the statistics, cancer rates increasing, especially in the younger population.
And trying to understand why that’s happening to we don’t have there’s a bunch of, you know, possible reasons for it.
I think, obesity, diet, lack of exercise are three of the big things
that we’re looking at, looking at environmental contaminants as well. Some of these forever chemicals as possibilities there.
Regardless of what is causing it, right? It’s becoming more of a problem. Right? It’s not like
cancer is an old disease that’s going away is becoming more relevant. We need better tools to do it. Definitely.
And I know I named those, you know, the American Cancer Society guidelines. They have that routine screening for, for cancers, the breast, colorectal,
cervical and lung would, you know, my mom, for example, she just went and got a mammogram.
So would that be considered cancer screening or just more of, like, preventative screening? Totally. Yeah.
So mammograms are a primary cancer screening test, right? You’re looking for, cancer that’s there that isn’t symptomatic yet.
Right? So mammograms again, we’ve got a pretty good success story there where we are catching breast cancers earlier than before that technology existed.
But there’s a lot, issues with that, that screening modality as well.
Right now, no test is perfect. No lab testing, radiology test, is perfect.
So with mammograms, you can have false positives. You know, you can have a lesion that’s found that
causes concern, in a patient like your mom. Right? And then a biopsy,
that’s not nothing. That’s something that’s happening. And so, it’s important, right, to scrutinize
the tools that we have, celebrate the victories that they have. I think there are millions of women probably.
Right, that beat cancer as a result of those screening programs. That doesn’t mean it’s perfect, right?
I think we should keep driving, keep trying to find, earlier things.
I think with prostate cancer, PSA is kind of an interesting talking point, right? Where it’s somewhat controversial.
In if your listeners here, I’m sure a lot of primary care doctors, it’s maybe split 50/50. Who gets PSA all their patients and who does it?
And looking at the data, it makes sense, right, that there’s some controversy there because there can be some positives that come out,
that there can be early detections, but there can also be situations where,
you know, indolent cancer that’s non aggressive is detected and treated.
And I’ve got a story, you know, in my family of somebody that had a prostate cancer that was detected and treated.
But he also had kind of an end stage neurological disease. And so the question in my mind is did this treatment,
was it helpful or did it actually progress this other disease. Right?
And I think, you know, looking at statistics and papers, can you remove some of these human elements from, you know, having a,
recommendation of always do X for patients and insurance companies when we pay for X, remove some of that human element.
In this particular situation, it makes sense to do this test or it doesn’t make sense.
And that’s where the goal of that position, right, that kind of health care advocate comes into play
to look at that situation and scrutinize it and make it work. Yeah, yeah, definitely. Thanks for for sharing that that story as well.
I know my mom wasn’t happy to get her mammogram like, hey, you know, it’s uncomfortable and you have to, you know, get out of your your own house.
You got to be able to, you know, afford it. Make sure you have the insurance, line up all of the logistics and then get yourself to actually go.
So all of these kind of treatment I don’t want to call them treatments cancer screening test. And, you know, you have to think of the availability
to the end user and then, you know, how how likely is it for them to actually go and get the screening, too?
So I think there are ways that these tests can become easy, more easily accessible to people too.
So just just to recap, those cancer screening tests, they really are looking to find cancer before it causes symptoms.
It may be easier to treat that successfully. And usually these effective type of cancer screening test find cancer really early,
reduces the chance that someone who is screened, regularly will actually die from that cancer.
And then hopefully it has more potential benefits and harms. So you mentioned a couple,
but you know, possible harms of screening tests like bleeding, physical damage, false positive, false negative test, overdiagnosis as well.
So, you know, diagnoses of cancers that would have not caused problems and did not need that, that actual treatment like you may have mentioned.
So, Josh, what what do you think? How can we actually detect cancer early or even,
before these types of screening test. Yeah. It it’s a it’s a solid question, you know,
and we’re talking about epigenetics today. Right? And so one of the, one of the things that, the scientists
at Precision Epigenomics, landed on was that, cancer is a pretty diverse set of diseases, right?
We sometimes refer to it as one thing, right? We say 95% of patients will get cancer by 65.
That stat you shared earlier. And that’s not currently the case at some future state. Right?
But really, it’s a lot of difference. Basically every person is different, right?
And every pathway that cells take to become cancer, is different.
And so one of the problems you run into trying to look at at a biomarker test is you may have something that
this for sure means it’s cancer, but it’s only present in 1%. Right?
One of the advantages to using epigenetics is that cancer has, you know, a
lot of things that happen in change and a lot of pathways converge by turning genes on and off with epigenetic switches.
Right? And so what, what the test that pays offering EPISEEK can do is look at some of those common end points
where multiple cancers at multiple sites converge together. So take a really close look at a handful
of methylation sites to be able to detect that cancer. So you mentioned some of the limitations with screening, right?
Having to logistically schedule it. You know, maybe you live in an area where mammograms aren’t
always available, right? If you’re in some rural, this is a blood test, right?
Looking at cell free DNA, circulating cancer DNA, looking for these common endpoints and trying to detect cancer early.
That’s certainly one approach and one that I think is a solid one, obviously. I’ve got my name on those reports, so I think it’s a good one.
But there’s other approaches as well that people are trying where there are new radiology tools coming out.
Right? So I assisted tools that can look at features and images that humans just can’t detect, right?
We can’t a human can’t look pixel by pixel for some sort of granularity that an AI tool can do.
So Radiomics has got kind of field, these advanced,
tools, to try to detect cancer more accurately. There’s protein biomarkers.
There’s a lot of work going on right now. In proteomics, we’ve got new tools coming out that let us look
at more proteins at the same time, at a more sensitive level. And so I’m excited for that work.
And to see that integrated doing some of the tools we have. So I think there’s a lot of tools here. Yeah, I think the important things are how cheaply can we do it,
how accurate can we make it and how easy to make it for patients. Yeah, definitely. And when you talk about the
AI type of tools where they’re at, they’re reading this imaging. Are you familiar with like for Prenuvo and the Cleerly heart scan?
By chance a woman at the Prenuvo is the the MRI or the the body screening and then Cleerly like the the heart screening,
I know some of our health care providers are starting to use those a lot more on top of even these, these cancer screening tests or things like the EPISEEK too.
Yeah, I’m not I’m certainly not an expert on those things. Yeah. I think it’s very cool.
I’m interested in it academically because I think it’s a different type of information, right?
If you if you’re looking at the same types of information, there’s only so much like statistical power you can add to make a test better.
But when you take in and the other domain and put together, right, I think that, you’re able
to really help sensitivity and specificity, right at the same time by putting pieces together right now that happens in in your doctors brains.
Right? They get multiple tests together. Put those things together and make a decision.
And so I’m excited that, you know, it’s not just us in the genomics world trying to solve this problem.
It’s really, you know, across disciplines, across specialties. Right? So, yeah, I’ll, I’ll send those companies to you.
I think you’ll be super interested in them. But I think one of the issues with them is that they’re so new. So whenever I’m asking the providers, hey, are you using this, this new technology
or have you seen this new screening, capability? They’re only in, you know, a couple hotspot locations within the US.
So it’s very rare that providers actually have this technology in their practice. Usually the patient has to have a script for it
and, you know, drive a couple hours or even fly somewhere as well. So although it’s really a cool new tool, scans for a lot of cancers
looks at a lot of different biomarkers from this imaging techniques, you know, it’s still limited in some ways too.
Yeah. So we mentioned you, you’re you know, Precision Epigenomics and you offer this testing called EPISEEK.
That’s right. So this would be called a multi cancer detection test.
Is that correct? – That’s correct. Yeah. Yeah okay. That’s the term that’s floated around there, right?
You there’s some IH workgroups looking at at the CDC as a workgroup looking at it.
We could call it multi cancer early detection. We dropped the early, I’m not totally sure why. I think because we can detect it.
We want to be clear it detects like cancers as well. So gotcha gotcha. That makes sense. Yeah.
Yeah. So that’s that’s this, this domain of multi cancer. Right? Instead of one that’s targeted,
so there are some phenomenal tests out there. You mentioned, you know for those these four cancer types, right?
There are tests that are cancer type specific. That
you know one of the issues with that right is you may have a great test for colon cancer detection.
Right? So garden has, this new test shield that’s out there with some phenomenal data.
It’s a blood based test, for colon cancer, but it is specific right, to that one type of cancer.
And my concern, too, is that there are already some pretty solid options out there. You know, calling out Skippy is a great option
if it’s available to you, if you can afford it. Cologuard. You know, I used to work for that company, I think is a phenomenal test
I’ve seen behind the curtain of what’s going on, I think they’re operate… I think those are fantastic results.
So that helped a lot of people. So yeah, I think casting a broader net and being able to detect more cancers,
allows you to really catch, you know, more patients, in the at the same time.
Yeah. And just to recap for the listeners as well. So these multi cancer detection tests there blood based, they’re also called liquid biopsies.
And they’re really designed to try and find more than one cancer at a time at a more treatable stage usually in asymptomatic patients.
So they’re designed to be used alongside of existing screenings,
usually developed and studied by multiple companies, top cancer research institutions and, you know, America, across the world.
They’re not yet approved by FDA, which is okay. A lot of these these new technologies aren’t yet
and, they’re not covered by Medicare or other health insurance plans. But, you know, definitely hopefully in the future they would be too.
So, I think, Josh, we were going back and forth, via email about this and maybe this is like, yeah,
this is a limitation or my ignorance in understanding this. So I’ve also heard, though people call these tests
stage zero liquid biopsy cancer screening tests too. But I think you corrected me there.
So, like, I want to know the difference between just like these early multi cancer detection liquid biopsy tests.
And maybe I even just made it up like the stage zero liquid biopsy cancer test too. Or if that’s an option if that’s a product.
Yeah. Yeah. So I’m a pathologist right? That’s my training. So I’ve got a microscope here in the background.
And it’s not just for show that it’s a real functional microscope. So cancer staging right?
Is part of the job of the pathologist. So you’re looking at clinical information. You’re looking
under the microscope at the extent some of the features of the disease. And you’re giving that stage.
So the stages that are out there, the main stages are one and two. That’s kind of localized disease.
The earlier stage disease three could be regional spread Right? And then four is often metastatic.
And there’s a big thick manual that I’ve got behind me here. With for, you know, every cancer what feature is put in there.
Right? It’s called the AJCC Cancer Staging Manual. So stage zero in that context.
And that’s the context that my brain works in. And marketing professionals like to take the technical terms, right?
And apply them elsewhere. Stage zero is an insight to disease, right? So that means that the cells have changed.
Right? Some of the cancer hallmarks are there. So the malignant potential is there. But it hasn’t crossed through the basement membrane yet, meaning
it’s still in the place that the cells are supposed to be. So the cancer cells have that gamely ability to spread in the body.
Right? Even, you know, to the other part of the breast. Right? So ductal carcinoma in situ, that’s a stage zero.
Is it a cancer is not a cancer. That’s also open for debate, a semantic argument there.
I think that there is definitely a movement to detect cancer even before it’s invasive.
Right? And if you look at some of the controversy around existing tests,
their performance for detecting like, colon polyp. Right? So colon cancer is one of the ones where you can treat the cancer before it’s
even technically cancer. Right? It’s a, it’s an adenomatous polyp. We know it’s on its molecular way to becoming a cancer.
It’s got epigenetic modifications, but it hasn’t yet started invading the breast.
Right? So we either call that pre-cancerous or possibly a stage zero cancer, depending on your terminology.
There’s definitely value to detecting that and treating that early. I think some of the language is coming out and saying, yeah,
we want to catch that early and detect it early. So maybe we’re targeting stage zero before it’s even technically a cancer
to treat designing clinical trials, which is part of my job. It it’s difficult, right?
Because if we don’t have a gold standard for detecting these, so you’re not going to see any graphs from we’ll take you into early
detection saying what’s our stage zero detection rate. Because we don’t again, there’s no gold standard for that metric.
So it’s… I sorry I went down a rabbit hole there but yeah. Yeah that was good.
I think it’s an interesting goal. Certainly like, that’s, that’s where we should be going.
Right? Is before it becomes cancer, can we find it? There are some startups out there who are very early stage looking at ways
to identify cancer by the immune system response to it. Right? And then before it’s even confirmed by a biopsy or anything,
doing a treatment to get that eliminated. Right? So that’s again a difficult thing to study from a clinical trial
because you have to follow the patient for you have to follow a big number of patients and prove they get less cancer than,
you know, the people that that weren’t on that treatment. But I do think we’ll get there. I think that’s one of the one of the pieces
where it will be a pretty cancer, diagnosis and treatment. I do think we’re a few years away.
Yeah, I was selfish. I selfishly was like, wait, I’m gonna I’m gonna ask him about this tomorrow, because, you know, I want to be clear.
And it seems like a semantics things as well. Like. Yeah, pre-cancerous stage zero. You know, what are we really detecting here?
But I can understand how how marketing teams or runner want to run away with that a little bit more and make it sound better.
Yeah. Yeah, it does sound great, right? Stage zero. Even better than stage one. Yeah, yeah. You’re like, yeah, I’m not even, you know, diagnosed yet.
Yeah. Awesome. Yeah. Thanks for that, Josh. So we know a little bit more now about these multi cancer detection tests.
Like I mentioned we have at EPISEEK from Precision Epigenomics. And you mentioned a couple benefits that these tests can hold.
Right? And where we see these in the future hopefully everyone will be doing these and will be able to detect cancer super, super early.
Use them with some of the existing screenings that are available there. Is there anything else you want to mention in terms of the promise that they hold,
or what we can look forward to in these tests become a little bit more mainstream? Yeah, I think I think there’s
some of the excitement I have about it is we’ve got if you look at cancer incidence right now, you can look the National Cancer
Institute puts together this data and they release it every year. And they’re tracking over time, right?
How many, stage one colon cancers are diagnosed and stage two colon cancer are diagnosed in three and four.
And for every cancer type, right in every stage, they’re tracking it.
My hope here is that these tests become mainstream. And we see a shift in that data from we see less stage
four cancers, we see less stage three cancers. And more early stage cancers. And then we it’s it’s difficult now
to model and predict because we don’t have a… without these tools, we don’t know how many people are walking around with cancer.
Right? How many people we know that how many people this year got diagnosed with stage four cancer,
but we don’t know that they have stage one cancer five years ago or six years ago that we could have detected with this tool.
So I’m excited for some large clinical trials to happen or broad adoption of the test in us to see that shift.
Right? And I think we’ll see that first. And then following that we’ll see changes in the cancer mortality.
So we look at how many deaths from different cancers, by age etc., to correct for some factors.
And I’m really excited to see the needle move on those things. This results. Yeah, it sounds like, you know, there’s just a lot,
a lot more data to be gained and a lot more insights to be gained. I think that’s that’s interesting. And I’m coming back to the example my grandmother with lung cancer,
I have this, you know, chart here that’s looking at cancer types. And you know the five year survival rate if that was detected early
was lung is still the lowest sort of, you know, breast colorectal pancreas
prostate urinary bladder and a but she would have had, you know, a 61%
five year survival rate if that was detected early, but only a 7% five year survival rate if that was detected late.
And, you know, it was obviously detected very late. And I’m wondering, yeah, when did she have, you know, stage one, stage two, stage three?
So like definitely understand what you’re saying and trying to apply it to like these real life situations.
And you know, this is this is real science. This is a real test. This is something that can be done right now.
And my parents haven’t done it yet. I’m definitely going to get them in with a provider and have them do it.
You know, their, mom’s 53? Step dad’s a little bit older than that.
But I want them to take it, you know, once a year, for the rest of their lives or,
we’ll get to some of those logistical questions here at the end on how often you should be testing. And who is this testing really for?
Maybe that’s too frequent, but, I’m super excited about everything you all are bringing to the field and the technology
You have too. – Cool. Thank you. Yeah. Awesome. You hinted a little bit more at this too Josh,
kind of about epigenetics and, you know, obviously, my handle being Everything Epigenetics and this role that it plays in cancer.
And, you know, you can even start with like a broad definition. But do you want to add any other context and maybe how we can use epigenetics
to start looking at more of these cancers in some of the research or just how we can detect,
you know, these early signals from the the epigenetic mechanisms themselves to.
Oh, yeah, totally. Yeah. So epigenetics are a huge part of how cancer works.
And I’m guessing on the previous podcast you had, on the topic, maybe you got into some, some details of that.
But traditionally we thought of cancer as an accumulation of mutations over time.
But really, it’s an accumulation of both mutations and epigenetic alterations. Right?
It can’t exist without both of those things, happening together. One of the pieces that that I’m excited about in the field
is, therapy resistance. Right? So patients that start on a drug and initially the drug works great.
Right? And so this happens in small cell lung cancer, for example. Right? You’ll get a drug. You’ll go on to platinum.
Fantastic response. Cancer may disappear, right? But we know that that doesn’t last.
So some of the cancer cells develop resistance. They come back with a vengeance. They’re more aggressive.
And this time you give the drug again it doesn’t do anything to the cancer. Right? And so we study
resistance mechanisms in bacteria. Right? If you know, in medical school we’ve got probably three months
of classes on resistance mechanisms and antibiotics, in bacteria.
And it’s a good parallel for, for cancer and some of those changes
that happen, those resistance mechanisms or genetic mutations. So differences in the code in the sequence.
But there’s evidence pointing that the majority of them are actually epigenetic changes that happen.
And so there’s some work happening. You know, we’re targeting that. So along with the primary drug, you give another drug that blocks
epigenetic changes from happening, right? So can you give combinations of drugs that kill the cancer
and stop it from being able to respond, in change in response to the therapy?
And I’m very excited about about that piece with epigenetics. Right? It’s not a diagnostic question.
And I think that’s what we’re talking about diagnostics here. But I still think it’s a pretty important, piece of the field.
Right? Yeah. And I that’s, you know, that’s that’s an interesting, point there. So now I’m thinking, okay, well,
you know, again, I, I don’t know, I’m, I don’t know if I have a genetic mutation that predisposes me to an increased rate of, you know, some specific cancer type.
I need to rerun mine. I lost my, like, raw data file for for my genetics, but,
you know, say, for example, someone did. Right? If we use my grandmother’s lung example, who isn’t isn’t blood related to me?
Are you saying then there are, you know, maybe some epigenetic expression levels that could also be related?
It doesn’t necessarily have to be fully genetic. But you mentioned a couple things earlier, like the environment, right?
Kind of weight status or, you know, smoking status as well, like those are all, I think, right, things that can affect
these epigenetic mechanisms. So are the drugs helping on on that side is that does that question kind of make sense.
Yeah, it does make sense. I don’t think we have evidence of that yet. This is in a patient who already has cancer.
Right? And they’re already receiving treatment. I do think what you’re describing is,
epigenetic status as a risk factor for developing cancer and as a targetable modifiable risk factor.
I don’t think we have great data on that yet, but I think it’s only a matter of time. I think we’re going to develop it, right?
We’ve only had these tools for a pretty short amount of time. Right? We’ve been looking at DNA methylation for 40 years now.
But that’s only one component here. We’ve got new tools in the laboratory now looking at histone modification.
There’s sequencing techniques that look at methylation and also look at open reading frame, and then also RNA expression, where
I think we’re learning more and more about some of those risk factors that go in. So I think some of the basic science is looking at what you’re describing.
And it usually takes a few years to get from there, right, to, to the clinic. For us to,
to figure it out, if you know any papers, let you know, I’d look to the notebooks to figure it out. – Yeah, yeah.
No, that that makes sense. Yeah. My previous episode with Doctor Bird, which I’ll, I’ll send you her information too,
We are kind of talking about like, the importance of biomarkers and epigenetic clocks for older adults
with cancer and how epigenetic clocks and just epigenetic markers, kind of like the question I asked, you are just not trained on cancer
populations or people who already have cancer. So they developed a really cool P16 epigenetic clock.
So that’s a mutation. You know, for those listening that’s been associated with more commonly,
subsets and types of cancers. So yeah, it’s interesting I see what you’re saying though.
It’s still too early. There are a lot of epigenetic kind of factors that, that we can talk about. But I mean, I’m excited to see how this plays out soon.
Yeah. All Right? Let’s get a little bit more into the logistics of this testing.
So the EPISEEK multi cancer detection test that Precision Epigenomics currently offers,
how does one test for this? Like, what does it actually test for? Give us some information about sample type.
And then I’ll, stop there and ask a couple more, okay? Yeah. So the test is looking at we talked about this
a little bit earlier in the episode, right? Some of these common endpoints where different cancers
converge together and have the same epigenetic changes. The test is composed in ten of those common endpoints.
In some cancers, express hypermethylation more in some of them than others.
So those are that’s the biomarker we’re looking at. We’re looking for the biomarker in circulating DNA and cell free DNA.
So one of the principles here is that cancer is very vascular, right? It needs a blood supply.
It has a high turnover rate, a high use of glucose. And so, the cells also die more often than other cells
in some of the DNA leaks into the bloodstream. We’re able to collect that DNA in a tube, stabilize it,
look at the methylation signatures and say cancer, no cancer based on that. So that’s the basic principles of the test.
To get the test, we need a couple of, tubes of blood. And we use these special tubes called stretched tubes.
It’s a, way to stabilize cells, but we don’t want to happen with the white blood cells to die,
and then their DNA to cover up all the cancer DNA. We won’t be able to detect it. The stretch teams have a special system, typically the cells intact
and also stabilize the cancer DNA. We get those in the lab, we separate out the plasma.
We perform the test in the first. Yeah. And one, question.
I think a lot of researchers, health care providers who who are hopefully listening in on this, they want to know about the specificity and sensitivity.
Right? That’s the million dollar question. And for those who maybe aren’t as familiar with those terms as well,
if you could define those and then talk a little bit about how the PCR test performs, that’d be great.
Absolutely, yeah. So specificity, let’s talk about that one first. That’s of the the ability for us to call a negative sample,
negative and not call a negative sample positive. So it’s expressed in a percentage, 100% would be the best
meaning to have zero false positive results. Right? So none of your negatives are reported as positive.
The specificity for EPISEEK is over 98%. We have some new numbers coming out.
I wish I had them ready for you, today here, and, but we’ll get them out pretty soon here. So 98% is the current number.
They’re a little bit higher than 98% there, which means, we test 100 patients. Right?
We would only have a few in there. False positives, actually. Difficult.
I’m glad we’re on a podcast because I can talk at length. It’s, it’s difficult to, to measure, specificity in these tests
because we don’t know the truth about these patients unless we follow them for five years and see if they get cancer.
Right? So what we can do is say, hey, do you have a history of cancer?
Do you have symptoms of cancer right now? But if you look at that’s who the test is designed to detect cancer in.
Right? And so in that the cohort that we had these are, you know, consented patients as part of a clinical trial,
that we did, we had one that looks very much like cancer, right? It’s not at borderline
in one of the markers, it is, several markers, very elevated, where I,
as a physician, believe this person has undetected cancer. But I don’t know this person in any other clinical follow up data.
So it’s it gets murky, right? And that’s true for all the competitors as well, right? There’s the source of truth here is that’s the question mark.
So I do believe it’s going to be we’re going to have larger data coming out with a better number. But our goal was to set that
very high as the specificity because we don’t want false positives. We talked about some of the negative outcomes that can happen as a, you
know, false positive result where the patient’s concerned. They may get unnecessary treatments.
Exposure to radiation maybe, you know, for follow up testing or something like that.
We want to minimize that. That’s specificity sensitivities. The other big statistic for these things.
And that’s of the people with cancer, what percentage can we detect. And the number there is 65%.
We’ve got some new numbers coming out that are going to say at different cancer stages,
what the percentage is, and kind of also correcting it for the cancers that are out there in the world, right?
So not just if we have 100 cancers that we do really well detecting.
Right? We could kind of game those numbers. We have not attempted to do that. That’s not the case at all.
So we’re getting some new numbers out there. But right now the number is 65% for sensitivity.
And you can look at that and say who you’re missing. You know, 35% of cancers.
I would turn it over and say, we are detecting over half of cancers earlier right before they can be detected.
And if you look at it through that lens, I think it’s a very positive. Right? Half of cancers detected early.
That’s a big plus for me. So that’s some of the numbers that… Yeah.
Awesome. Cool. Sounds great. I’m excited to get that new data too. And we you mentioned that to me a week, a week or so ago.
And by the time this episode’s out, we can link it and have the white paper and have all the data here.
So it’ll be great for the listeners. So I obviously wanted to ask my parents and all my loved ones like once a year,
but what is the retest window? How old should you be?
What about, you know, I think we have. Would it be called recurrence monitoring? Right?
The retesting or might that might be something different as well. Yeah. So the kind of testing interval and we’re recommending once a year.
So again you’ve got sensitivity and specificity here. And the more frequent you test,
right, the more likely you’re going to catch the cancer early. And so some cancers are aggressive, right?
And they go from stage zero to stage three very quickly. And some are more indolent, right?
And take you know, some prostate cancers, for example. They might just hang out for 15 years and not really do much.
And so we want to be able to catch the aggressive cancers. So that annual screening window, is our recommendation.
As far as what population to screening, we’re recommending, patients 40 and over.
If you look at the incidence of cancer, right? That’s the group that has an increased risk of cancer.
15 over could be a traditional screening. You know, that was the recommendation for colonoscopy is Right?
Let’s move back now to 45 and older, although I’m inclined not skippy’s. So it’s really, you know, a personal decision,
you know, up to the position and patients together to make that decision, when to test and health. And so those are the current recommendations.
We will accept samples from patients under 40. There’s it’s not like anything.
The test won’t work if you’re younger. It’s just kind of a, you know, positive predictive value, negative predictive value game
where once cancer is less likely in you, the chances, you know, the probability
of a positive result being a false positive versus a true positive. Right? That kind of seesaw favors
false positive more, the younger you test. But as long as you understand that, you know, a position doctor
put together, we will accept in test. You want to test children? That’s good for, right?
Well, being validated in that that. Sure, sure. So what… what happens if you get a positive result, right?
This testing come back, comes back. You know, maybe people don’t want to test because they’re nervous
or they’re scared, but the goal of this testing is to not find cancer, right? And if you do have a positive result to find it super, super early.
So what are the recommendations after getting that type of result? Yeah. Well, so the majority of patients get a result back.
That’s a negative result, right? And that that is good. That is good news. You know, that’s we’ve got a high negative predictive value.
So the likelihood that there’s an undetected cancer there is is low, you know, positive result, right?
We’ve already mentioned there’s a possibility for any test of a false positive, right? That’s true for mammograms, for pap smears…
…for this test. Cologard for everything that’s out there. So let the follow up on that
is really going to be based on the patient’s clinical situation. We’ve had a few positives on the test to date.
So the test just launched in April. We’re still very early in, you know, the clinical use, of the test.
And so, you know, the patients, what I do when we have a positive result is I try to get the doctor on the top, do that.
Next steps. It’s part of my job as a medical director of the lab to offer that support. So if you’re watching, that’s thinking about ordering,
you will get a phone call from me. Your office will, and I’ll hand you until you call me back.
We can talk about it. What do you tell me? That one of the supports, that we offer.
I’m very interested in how people are using the test and what happens next. The two cases we had,
the cases that we’ve had so far that are positives, there have been situations where
without a bunch of additional testing, we were able to determine what was happening. Right? And get to an answer, in those patients.
So those were we observed some true positives, and we didn’t have to go chasing down a rabbit hole.
Our general recommendation, based on talking to oncologists, radiologists, different specialists, is if there’s
no symptoms, if there’s nothing else filling on in the patient, to do what’s called a PET-CT scan. It’s a scan that,
looks for increased, embolism of glucose in the body. So it’s something that is somewhat cancer specific
and also localizes where the cancer is. It’s a test that would only only happen
in those positive where we think something’s happening. We think it’s a real signal. We’re confident that something’s going there.
And then based on that results, the patient would have the normal workout, right? That’s a normal finding that exists in the healthcare system…
…would. Also, and, I yeah.
And last question, kind of maybe about more of the, the logistics here. What about people who’ve had cancer in the past.
So I think that’s what would be defined as recurrence monitoring. Right? So if you’ve it’s a way to detect when cancer returns
after a period of remission. Would you recommend this for people who had cancer in the past or maybe not?
What are the difficulties there? Yeah. So we,
I think this test could be valuable in that population. We just haven’t done the
the clinical evidence building right to make a claim on that. And so there’s a few possibilities, right?
So it’s possible. We’ve got some preliminary data from a research setting.
Where these biomarkers and that’s a patient is receiving therapy.
They go down, right? And they stay down afterwards. We don’t have clinical evidence of them coming back up.
And what that means for a cancer. So there’s a few possibilities, right? Or during the test in that situation, one of them is
it would work great in this patient, right? And would be useful, for, for that recurrence detection.
It’s also possible that but so epigenetic changes can have something called a field effect, right?
So it could be the cancer itself has these changes but also some of the surrounding tissue
could also have the changes their earlier events. And so I would just want I would caution anyone, right, that again
until we’ve kind of validated this for that, for that use case, a positive result right after cancer therapy may just be a result of field effect.
Right? So it we don’t really have the data to say, hey, this is a recurrence. This is a therapy resistance.
Yet with this particular test we are definitely collecting that data. We are writing grants to try to get that information.
I do think this test will be valuable setting, but it’s just not the right use case for it yet.
Got it, got it. Awesome. We’re getting close to the end here.
Josh, just a couple more questions, okay? I think I like all these questions I’ve been really excited about to ask,
but I think the one most people are interested in and one we get a lot, is the difference between EPISEEK by you all.
Why should someone you do EPISEEK versus the Galleri by GRAIL, which is maybe, I think obviously was a little bit sooner to to market?
I know that because is much newer and was just released back in back in April. But, I know a lot of health care providers who are using EPISEEK
as well, even though it’s just been, super early in terms of that, the launch.
Yeah. So, there are a lot of similarities between the test. Certainly. So both are looking at cancer specific epigenetic changes.
I think GRAIL’s a great company and I think it’s a great test. So I want to make sure that I’m clear on that.
And that there, there are definitely differences, though, in the approaches that we take. So Galleri is using a next generation sequencing approach.
I talked earlier in this call about how much I love that as an approach. Our test EPISEEK is not using next gen sequencing.
We’re using quantitative PCR. So the difference between those modalities, Galleri is able
to look at more targets at the same time, but it can’t look as deep. So it can only look at you know,
a few hundred copies of that. We are looking at a smaller number of targets,
but the depth that we’re looking to is much deeper. And so in late stage patients
where there’s lots of cancer DNA, both tests performed very well, where I suspect
there may be a difference in performance is at the earlier stage. So early stage cancers have lower turnover, they’re less vascular.
And so there might be less cell free DNA that’s out there. And so for able to detect but smaller amount of hyperventilated DNA
in the sample, that’s where we could have a better performance. I wish we had head to head data.
I wish, if any anyone watching this, contact us if you know that order both tests on your patients and we can we can compare the results.
I’d be more than happy to do that. It’s really hard to do those type of studies, right? We’re competitors. GRAIL, you know,
basically none of the, none of the business people want that kind of data, out there at all.
But, I think both tests are great options. I do think that early stage performance, is where EPISEEK is going to have
an advantage. And I think that’s where we want the advantage as well. Right? So if you diagnose a cancer in late stage, is that really early detection.
Right? It’s really those earlier cancers that were catching and that’s
why we’ve optimized the tests the way we did use the technology that we did go.
Awesome. Thank you for that. Alright. Second last question here.
You mentioned a little bit about what you were excited, about earlier, which are all of really I think it goes back
to gathering the data, doing some comparative analysis, seeing how, you know, we can we can start to
look at more like epigenetic factors with, with the drugs you mentioned earlier. But what are other areas of discovery that just excite you in this space?
You know, what do you wake up every morning just, you know, running to work and working on?
Yeah, I’m really interested in, so we’ve done a lot of work in cancer for Precision Medicine, for personalized medicine,
which, you know, this is part of that, that field, we’re starting to find other diseases, right?
Where genetic acquired, genetic mutations, acquired epigenetic changes are an important part of it.
And the work you guys at Tru is part of that, right? Is some of these acquired methylation changes…
…I think we’re going to see we’ve seen an explosion of tests emerge and be useful in improvements in cancer.
I think we’re going to start seeing that in other diseases as well. And so some of the work I do on the research side of things is looking at heart attack and stroke
and some epigenetic changes involved there that I think is very interesting.
Also really excited about, I think a neurological disease. We’re going to see some really cool, diagnostic tools
and then treatments come out, epigenetics and Precision Medicine. So that’s what energizes me is we’ve accomplished a lot in cancer.
We’re going to continue, to do that work that really taking some of the lessons we’ve learned.
And the success we’ve had there in taking it to non-cancer kind of chronic diseases that are also a huge burden on the population.
That’s… Yeah, that’s super exciting. No, I didn’t know that. Yeah. That you’re excited about that or that’s on the horizon.
I think you said a keyword to which was, okay, these different diseases and you know, detection of like neurological even, but
also the treatment like, okay, you have this result, you may have a higher chance
of getting it, but it’s like, what do you do for for the treatment then. So it kind of goes goes hand in hand.
I know that’s a missing piece a lot of time, a lot of times with, you know, I think I’ve given this example before, but Alzheimer’s runs in my family.
I have the ApoE 3/4 variant. You know, okay, I know I have that there are
some epigenetic modifications and some papers out there too, showing some things that may work, but I mean, I still have that genetic variant.
So you know. Well, yeah. What can you do about it at that point I think is is what we want to know next.
Yeah. Yeah, that’s part of the work. I’m ready to do. Yeah. I’m excited about that.
Well, Josh, I ask everyone this at the end of my podcast. I don’t know if you’ve listened all the way to the end.
Previously, but it’s just a fun question. If you could be any animal in the world, what would you be and why?
I think I’d like to be a bird. I think flying would be such a free experience.
And bird is so generic. Let’s say a peregrine falcon, right? Okay, I can do that. Okay. One thing, they they’re, you know, the fastest animal.
I think that would be an interesting, you know, visceral experience to fly through the air like that.
I like it, I like it. You’re specific. Yeah, that would be. That would be cool. Cool. Awesome. Yeah.
I think some previous guests have said, like, bird because of flying and stuff, but like, like the exact, the exact example there.
My four year old is really into peregrine falcons too. So there’s, there’s that. Yeah. You would be excited if I be the falcon.
Like good good. You can show them this later. – I’ll show him the video. There you go. Awesome.
Well we’ve come to the end of this awesome podcast. For anyone who wants to connect with you or,
you know, see a lot of research I mentioned, I’ll link the research below. But how can researchers, health care providers, you know, general public,
how can they get Ahold of you or learn a little bit more? Yeah, absolutely. So, Precision Epigenomics, we’ve got contact information there.
We’ve got a feed of some of the stuff that’s coming out. And then I publish work that as well.
So check me out on Google Scholar. I’ve got a page there. Feel free to ping me on there if you want to collaborate on that.
Awesome. Thanks so much, Josh. Thanks for everyone joining us at the Everything Epigenetics podcast.
Remember you have control over your epigenetics. So tune in next time to learn more about how.
