May 6, 2025 • 48 mins
Would you want to know if cancer is in your health future? In many cases, detecting cancers early before they metastasize and when they are more easily treated is the key to survival and return to good health. Unfortunately, many aggressive cancers are identified in the later stages of progression, making treatment difficult and sometimes ineffective. Today, however, biomedical companies are racing to develop cancer screening technologies that may ultimately change the trajectory of cancer mortality. Leading that effort is GRAIL with its first-to-market Galleri multi-cancer early detection test, which is awaiting FDA approval. In this episode of Healthy Longevity, Dr. Comite discusses this pioneering test with Eric A. Klein, MD, a distinguished scientist at GRAIL and a long-time urologist and surgical oncologist.
You’ll learn…
· Currently, we can screen for only cervical, breast, colon, lung, and prostate cancers.
· Standard screening tests only detect 14 percent of cancers. More than 80 percent of people who die of cancer succumb to cancers for which there is no screening.
· While those current tests reduce mortality, we still lose more than 600,000 patients yearly in the U.S. to cancer.
· Multi-cancer screening tests like Galleri fill an unmet need for finding the deadliest cancers before they become symptomatic.
· Cancers growing in the body shed DNA into the bloodstream. These DNA fragments act like a fingerprint of cancer that the Galleri blood test can detect.
· When a cancer fingerprint is found, the test can predict the typ
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:10):
Would you want to know if cancer is in your future?
It's a question most people think about and understandably a tough one to answer.
But as a precision medicine and longevity physician, I really believe strongly thatknowledge and wisdom can save lives and give us remarkable control over our future health
trajectory and the emergence of cancer and other diseases.
(00:33):
Precision medicine actually looks for diseases and disorders of aging, which cancer is oneof, at the cellular level to identify and predict disease, and even decades before it
manifests and emerges as symptoms.
Identified early, cancer is curable in a lot of ways, and disease can often be reversed sowe can extend our health spans to match long lifespans that we're living today.
(00:58):
Hello and welcome to Healthy Longevity.
I'm Dr.
Florence Cometay, CEO and founder of the Cometay Center for Precision Medicine and HealthyLongevity.
I know that today's podcast guest, Dr.
Eric Klein, shares my passion for predictive, proactive, and preventative medicine, andI'm very happy to welcome you to the show, Eric.
Thanks for joining us.
(01:19):
Thanks for having me.
So Eric Klein, who I just found out is a neighbor here in New York now, is a medicaldoctor and a distinguished scientist at Grail, a biomedical company whose mission is to
develop safe and effective cancer screening technologies to detect cancer early, again,before symptoms actually emerge, when it can be cured and ultimately change the trajectory
(01:42):
of cancer mortality.
Dr.
Klein previously served as the Andrew C.
Novick Distinguished Professor and Chair of the Glickman
Urological and Kidney Institute and Lerner College of Medicine at the Cleveland Clinics,where he was also a member of the Department of Cancer Biology oh at the Cleveland
Clinic's Lerner Institute, Lerner Research Institute, the TauSig Cancer Institute, and theGenitourinary Malignancies Program in the Case Comprehensive Cancer Center.
(02:14):
Dr.
Klein was a fellow in the Distinguished Careers Institute at Stanford University in 2022and ultimately joined GRAIL in 2023.
Dr.
Klein's clinical and research interests focus on prostate cancer with an emphasis ongenomics and trials or clinical trials.
Most recently, his work has centered on the clinical development of cancer screening testslike Grail's Gallery Test, which is a first of its kind multi-cancer early detection test,
(02:45):
a breakthrough test that we have recommended and used since its inception at the CometaCenter.
I had actually been waiting for these tests to come along
I was really reluctant to study a person through radiological techniques like PET scan.
So having a relatively non-invasive way by just drawing some blood and looking for markersthat circulate was a wonderful step in the right direction to predict cancer in the long
(03:12):
term but early in the disease course.
That's just a very brief introduction to Dr.
Klein's very distinguished career and accomplishments.
And I don't know how, Eric, you would fit it all
on a business card, but that was pretty incredible.
um Thank you again for chatting today and let me ask you to start by telling us more aboutGrail and specifically about the Galleria test.
(03:37):
Yes, so Galleri is a blood-based test that measures the presence of what's calledcell-free DNA that is derived from cancer cells.
And we know, we've known for a long time that when cancer cells grow and the cellsmultiply and die, that they release all sorts of biologic substances that can serve as
(03:58):
signals to their presence into the bloodstream.
And so the basis of this test is next generation sequencing, which is what was used tosequence the human genome.
And in the background of all the normal cell-free DNA, our assay can uh detect if a cancersignal is present.
Excellent.
Could you explain a little bit more about GRAIL's methylation platform and what that meansto determine and detect methylation patterns to predict cancer origin?
(04:27):
short.
The way to think about this is in two analogies.
One analogy is light switches turning on and off, and the other analogy is fingerprints.
So, methylation is a normal biologic process where DNA is chemically modified to turngenes on and off.
(04:47):
And a liver cell, for example, will use methylation to turn on all the genes that make ita liver cell and turn off all the genes that would make it some other kind of cell.
And a kidney cell does the same
thing to make it a kidney cell.
Cancers exploit this normal biologic process called methylation and use it in a littledifferent way.
They use it, and all cancers do this, they use it in a way to turn off the genes thatprevent them from growing and turn on the genes that allow them to grow unrestricted.
(05:20):
And that's a fundamental biologic process, what we call a hallmark of cancer.
And so the fingerprint analogy comes in where the number of light switches or the order oflight switches on the wall, if you think of methylation as, let's say, 100 light switches
on the wall, in a normal cell,
is going to be, know, will be on, certain will be off, and in a different cell of adifferent type, different ones will be on and off.
(05:45):
And a different pattern occurs in cancer.
And so we can exploit that.
And we can see the methylation fingerprint of cancer versus non-cancer in the DNA that'sin the bloodstream and using a machine learning algorithm for both of these processes.
If there's a cancer signal present, we can predict with more than 90 % accuracy where thecancer comes from, what kind of cancer it is, and that helps.
(06:07):
diagnostic workup.
And taking a step back for the moment, I'd really like to learn how you first becameinterested in this type of research because you've had a very distinguished career at a
number of institutions and then what led you to follow this particular path in yourjourney.
I've always been interested in biomarkers and did some prior work in my career on prostatecancer biomarkers and I treated urologic cancer patients my whole career.
(06:36):
And I had a relationship with Grail's very first chief medical officer from some work withanother company.
And he came knocking on my door while I was still practicing in 2016 and said, we havethis really interesting technology that I just described.
And would you be interested in helping us accrue patients to our clinical trials?
And being intellectually curious and understanding the vast unmet need in cancerscreening, I was intrigued.
(07:01):
And I said, yes.
So I helped accrue several thousand patients to the first two big clinical
trials that GRAIL did and along the way I became a consultant and then I retired frompractice.
I did a sabbatical at Stanford and Stanford is in the city next door to GRAIL'sheadquarters and so I started at the company's invitation, started spending more time at
(07:23):
GRAIL and I got to understand everything that was going on there and very very excited bythe technology and when the opportunity came and they offered me a job I said yes.
was a little curious because we all have a reason we go into the particular field.
Was there any trigger that led you to become a urologist and then focus predominantly onprostate cancer?
(07:44):
uh
a kidney stone when I was in college and I had surgery for it and being the nerd that Iwas when I got back to school because that happened over spring break.
I missed a whole vacation week because of that.
When I got back to school, I went to the bookstore and I bought a urology text and I readit cover to cover and I got really fascinated by it.
(08:05):
So when I went to medical school, I had the option of doing a urology rotation as anelective, which I did, and I really liked the people and I liked the kind of conditions
that came.
along and I was really attracted to the cancer surgery.
That's really what got me interested in treating cancer in general.
And so that was the career path that I followed.
Wow, that's a long training path because besides training in urology, you have to go on totrain in urological cancers.
(08:32):
It's kind of fun for me looking back in medical school at Yale, there was no separateurology division.
And whenever we studied it, because I did an elective in that as well, they weren't reallytoo inviting of women in the room.
And the men were all very uncomfortable at that time.
At that time, wasn't that many women in medical school.
So it was kind of unusual to be in there.
(08:54):
And now I
I it quite well and then it was difficult.
Since then, Yale had created a urology department and because I do so much work in men andwomen, I've really had immersed myself in urological issues and having two sons and a
father and other.
reasons and learned quite a bit but I remember complaining to the first chair of urologyhow difficult it was for women to learn urology at Yale so it's kind of interesting.
(09:22):
um We work with a fair amount of urologists.
was probably Bob Weiss was the first chair, think.
Wonderful.
Wonderful man.
I'm sure he was welcoming and warm to you.
Right, right, he was wonderful.
And I have referred plenty of men there to be tested back in the day when you discoveredit and you wanted to get beyond, you wanted to market, to do MRI, because they were one of
(09:47):
the first places to offer MRI like Cornell and like NIH.
And it was very hard to get people into these institutions to be tested.
Now we take it for granted, but just a few years ago it was challenging, like a decadeago.
It's really changed what we can do for people who do get diagnosed and how we can do thatearly now.
(10:07):
But that's why Grail is here and it's fantastic.
I'd love to understand a little bit more about what is the opportunity to see whichcancers are most easily noticed and found early on.
Is there a difference, for example, between solid cancers and cancers that actually tendto circulate in the blood early on as opposed to later metastasizing?
(10:32):
And whether it matters whether it metastasizes lymphatically or in what way.
I don't have very much knowledge about how cancers begin to deviate.
And I'm particularly curious about prostate cancer because I had a former colleague who
was told that he had an underlying urological infection and he had some pain and he hadsome symptoms but his PSA was low and he ended up having a neuroendocrine prostate cancer
(10:58):
which spread very rapidly and unfortunately led to his early death.
So that was of interest to me because I don't think that was anything we ever studied inschool.
Now let's talk about the unmet need in cancer screening first.
I think that will put everything else in context.
We currently screen for five cancers.
We have high level data for cervical, breast, colon, lung cancer, and smokers, andprostate cancer.
(11:25):
That screening for those cancers reduces mortality, which is terrific.
The challenge is that despite the fact that we screen for those five cancers and despitethe fact that they reduce mortality, we lose more than 600,000 patients a year due to
cancer in the United States.
In fact, the standard of care screening tests only detect 14 % of all cancers.
(11:46):
And more than 80 % of people who die of cancer die from cancers that we don't screen for.
And so that's the big unmet need is to develop a broad-based test that can detect thesecancers that people die from that we don't have good screening tests for.
It would be too inefficient to screen for all of them individually.
(12:06):
oh
because the false positive rate in someone who got five or six or eight or 10 individualscreening tests would be very high.
It would be approached 50 % or greater.
And so the advantage of a multi-cancer early detection approach is that the test iscalibrated to have a very, very low false positive rate while still detecting a broad
(12:29):
array of cancers.
So this technology can detect dozens of different kinds of cancers that we don't screenfor now.
The sensitivity for uh individual cancers varies both across cancer type and biology.
So as I mentioned, the test detects DNA fragments, cell-free DNA in the bloodstream, butnot all cells uh get DNA into the bloodstream.
(12:52):
And we know that the ones that do, we know not all, I should say not all cancers uhsecrete DNA into the bloodstream.
The ones that do,
are ones that we know behave aggressively biologically because the ones that are able toshed cell-free DNA are ones that have high mitotic rates, uh have uh high metabolic
(13:13):
profiles, have necrosis in the tumor and that sort of thing.
So the cancers that are detected by these tests are ones that generally are on theaggressive side and need treatment and we can say that with really good uh solid
scientific evidence behind it.
In terms of sensitivity for specific cancers, it varies.
(13:36):
But for example, I always like to talk about pancreatic and ovarian cancer.
Our current screening paradigm, we detect 0 % of pancreatic and ovarian cancers beforethey're symptomatic.
In the big trials that we did, we can detect 80 % of ovarian and pancreatic cancers and 60% of those at stage one and two.
(13:57):
And that's where the real opportunity is to detect the cancers, not only in asymptomaticpeople, but to detect them when they're before they're metastatic and when they can be
treated and cured and cured at a lower burden.
And that's fascinating, and with ovarian pancreatic cancer um and screening, what othercancers would you say, uh if let's say they run in your family or your best friend,
(14:22):
because obviously that always puts a fear in someone, would be the most likely to bedetected early on in the course.
Yeah, so the ones that the test detects best are head and neck cancer, liver and biliarycancer, uh colon cancer, ovarian, uterine cancer.
(14:43):
uh The kinds of cancers that it doesn't detect almost at all.
are really early stage, low grade indolent cancers like prostate cancer.
And in fact, you asked how I got interested in grail.
When I first had the conversation with the chief medical officer.
I had it in the back of my mind, gee, this sounds like great technology.
(15:04):
Maybe we can replace PSA and screen for prostate cancer better.
And it turns out that low-grade prostate cancer doesn't shed any cell-free DNA to speakof.
And so this is not a good test for low-grade prostate cancer.
The flip side of that is we over-detect too much low-grade prostate cancer with PSA.
And so this test will not make that problem worse.
(15:25):
And cancer is not detected well.
thyroid cancer is not detected well.
And the reason is that those cancers don't shed much cell-free DNA.
And brain cancers are not detected because the DNA can't pass the blood-brain barrier.
But for the major cancers that people die from, the test works very well.
breast cancer also falls into the category for most as like prostate cancer they don't youknow shed early on most of them.
(15:53):
Early stage, so it's interesting, again, these are biologic issues.
It depends on the kind of breast cancer you're talking about.
Early stage hormone receptor positive breast cancer, which is over 90 % curable, doesn'tshed much cell-free DNA.
It's not a very aggressive cancer.
On the other hand, triple negative breast cancer, which is often missed on mammography,sheds lots of cell-free DNA, and the test works very well for that more aggressive form.
(16:19):
So that's triple negative, hers negative as well or hers positive.
No, her negative, triple negative, ER negative and her negative.
And that's the most lethal form of breast cancer.
And the test works very well for that.
As I said, the cancers that shed DNA into the bloodstream that can be detected by the testare aggressive and need treatment.
(16:40):
which makes sense.
A couple of things to follow up on that.
I was always curious about oh Gleason scoring with PSA.
And we are very careful to do PSAs with percent free.
Sometimes we do testing, doing K4 and other ways to approach MRI, as I mentioned, as well.
um And there's always been a debate.
(17:01):
I don't know where it stands now, but I remember the scientific papers I read from Mayoclaiming that you can't really consider, as you alluded to, low-grade prostate cancer.
a Gleason 6 as really an aggressive cancer.
So there are a number of men now in my field.
I come from the hormone field.
I'm an endocrinologist trained in multiple fields of endocrine from PEDs to GYN toandrology and men and women.
(17:26):
And um it's always a debate we have because we do follow up on the change in PSA.
We work with people who actually biopsy and follow.
We use hormonal agents to protect people's health, so they don't get diabetes and heartdisease, heart attack and stroke, far more widespread than prostate cancer that is deadly,
(17:49):
if you will.
And I had a lot of run-ins with urologists at the beginning.
And then slowly they started changing.
I would say
this started about 15, 20 years ago in New York when I was transitioning from Yale and Iwas told, you know, go ahead, you can treat.
But a funny story is one of my patients went to Sloan, could not really describe what wewere doing.
(18:10):
And he met with a researcher there who is going to report me to the morbidity andmortality committee to discuss this.
And I had to present the case and then he came and we met and he understood immediatelywhat I was doing because at the time they were looking to set up
VO2 max tests and exercise and they were recruiting I think someone from Duke because theyfigured out that exercise is a good thing as people age in terms of you know minimizing
(18:37):
disease and since then we've been great buddies and I refer everyone to him so he can growhis panel of people to follow but I've even had people with Gleason 6 which I don't worry
as much about then show up with a no a biopsy that contains a Gleason 7.
How do you think of it given your deep x
expertise as a urologist who focuses in on cancer.
(19:00):
Is there anything we should do differently to manage these guys?
Well, PSA has been shown to reduce mortality in the European screening trial.
And so I'm a believer in PSA and screening people appropriately.
The challenge is that PSA is prostate specific, but it's not prostate cancer specific.
And benign prostate enlargement, BPH, is far more common than prostate cancer.
(19:23):
So on average, most elevated PSA comes from BPH and not from cancer.
A second challenge, as you've alluded to, is that really high-grade glycine
eight and nine prostate cancers and or endocrine cancers don't make much PSA.
So PSA isn't perfect for lot of reasons.
So the way the field has evolved now is there are new tools to distinguish whether or notan elevated PSA indicates the likelihood of cancer and you've mentioned one of them the 4k
(19:53):
score is one there's another one another blood-based test called iso PSA there are someurine-based tests.
And before moving to a decision on biopsy, it's appropriate, I think, to repeat one ofthose tests, do a reflex test.
because they better stratify those who are at risk of cancer.
And then as you mentioned, MRI is a great tool for seeing high-grade cancers and targetingbiopsy and so forth.
(20:19):
It's really revolutionized what we've done.
But even MRI isn't perfect.
It misses about 20 % of high-grade cancers.
So that is the way the field has moved.
Yes, and you know I work with some great urologists.
I'm always very impressed and monitoring with active surveillance is the way we tend togo.
But I worry.
I worry that I don't want to miss anything and yet I do want to treat people metabolicallyso that they don't get diabetes, they don't have a heart attack, because that's far more
(20:47):
likely than the fact that we've all heard probably most men and most women when they dieat autopsy you'd probably find niduses of abnormal cells in the prostate and the breast.
So it's
common probably long you know aging phenomenon as well.
So yeah, no question that it is.
So I think that the evidence isn't great.
(21:10):
We don't have long-term mortality trials for testosterone replacement in men withprostates.
But you think about it this way.
That's how I think about this problem.
Testosterone is at a normal level in the vast, vast, vast majority of men who get prostatecancer.
It's not abnormally high.
It's not that testosterone causes prostate cancer.
(21:31):
It's only in metastatic disease where the testosterone androgen axis is deregulated andtestosterone fuels growth.
So if you get back to the early stage, low-grade prostate cancer, if you have a man who'shypogonadal and who's having symptoms from being hypogonadal,
It's safe, in my view, to give him enough testosterone to make him asymptomatic and gethis testosterone into the normal range.
(21:57):
You're not trying to drive it, you know, into the very high range.
And there really isn't any evidence that that has an adverse effect on low-grade prostatecancer or causing high-grade cancer.
I think there's a bigger controversy here, which is, is there an advantage to takingtestosterone in someone who's not hypogonadal and who has no symptoms?
(22:19):
And I think the evidence for that is weaker.
And that's not something that I ever did.
That's not anything I did in my practice.
Well that's interesting because back when I trained, I trained with lot of reallydistinguished people, Ronald Swirdlaw for others, and there is a fair amount of data
showing how testosterone really is effective in terms of metabolic disease because webegin to decline in our 30s, testosterone starts falling in men and women and it
(22:48):
definitely leads to decrease in muscle.
I used to use the fact, as you alluded to, that as men age, their testosterone is actuallylow.
yet to meet a person, one exception, but still the free T was quite low in a man at 70 whowas on DHEA, which can contribute to testosterone and his free T was about 70.
(23:11):
So having taken care of infants through every decade of life, most men, if not all,decline with age.
There's no question about it.
It's just like menopause, it's andropause and diseases, you know, permeate and emerge.
So we have used it
and to our benefit and what, know, years ago and still occasionally people will pop up andsay testosterone causes prostate cancer.
(23:34):
I will point out that testosterone is usually quite low when you get prostate cancer.
There's actually some association that's been alluded to in the papers about estrogen,which also increasingly gets aromatized from testosterone um as men age.
And so those were the arguments I used to use both directly with doctors and withpatients.
(23:57):
It's testicular cancer I'd be concerned about that happens at a younger age with young menwhere their testosterone is generally high.
So it's been an interesting conundrum, but I've been up and down with it.
So I appreciate your input, that's fantastic, and agree that it's still a work, all ofmedicine is still a work in progress, but when it comes down to the individual patient,
(24:21):
you like to be able to give them something to weigh the risk benefit for each of them, soI find that.
There is also data that shows a low grade, oh that using uh a uh low dose of aspirin, itcomes out of Europe, so it's the 100 milligram aspirin for five years or more,
actually reduces the rate of pre-occurring cancer but also prostate cancer, colon cancer,and a couple of other cancers of the midline.
(24:48):
So that's something we tend to be in favor of.
I think the risk of bleeds from a low dose aspirin is far less than the benefit you canexperience with it.
But that's fascinating and I really appreciate it.
Who do you find your typical clients or patients are who do grail?
Is it just about everyone or given the price point maybe a challenge?
(25:11):
is there, you know, do you have one demographic or another that you can point to?
You can't point to any demographic.
Really the common feature of the individuals who do it are people who are concerned aboutthe risk of cancer and want to be screened and who want to know.
That's what it's about and that crosses all demographics.
Okay, I think also you pointed out that the test is fairly sensitive and effective withcertain cancers when they're really malignant and they shed quickly.
(25:41):
I don't think, in my experience, we have not had any false positives.
In fact, we've only had one positive in all the years that we've actually been screening,even though we've diagnosed cancer, the cancers that fall into the less aggressive type,
thyroid and breast that are hormonally positive.
Any false negatives where you find out subsequently if you follow people beyond the grailtest that they in fact had a cancer and it was missed and what would be the percentage of
(26:12):
that?
Yeah, so it's a challenge because we have not seen patients who have had a negativegallery test and who are, let me say this, healthy patients who have no symptoms.
We've not seen patients who have had a negative gallery test and then are diagnosed withan aggressive cancer in the next week or two.
(26:33):
So they might be diagnosed with a cancer six or eight or 10 months later.
And what we don't know, and there's no way of knowing for sure, is that a new cancer thatreally wasn't present when the test was done?
Or did the test actually miss that cancer?
And as I said, or implied earlier, no test like this is going to find every cancer.
(26:55):
cancer that it finds has to shed cell-free DNA into the bloodstream and there has to beenough to be detectable and distinguishable from the background.
So yes, there probably are some false negatives.
I think the number is very small, but it's hard to know exactly because when someone getsa negative gallery test, we don't then recommend that they have a cancer workup.
(27:18):
So we don't know what the ground truth is.
We don't know if they have cancer.
Are there some people who have negative tests and then are diagnosed with cancer withinthe next year?
Yes, there are.
But that's also true of every other screening test that we use.
oh So again, back to the example of breast cancer, triple negative breast cancer, the most
(27:39):
aggressive kind is often missed on mammography because its appearance is a littledifferent than other kinds of cancers.
And it is the most common breast cancer that is detected in what's called an intervalcancer between mammograms.
So let's say you have a woman who has a negative mammogram and is diagnosed with a triplenegative breast cancer six months later.
(28:01):
Did the mammogram miss it?
Was it there in the mammogram?
Did the radiologist miss it?
Or is it a new cancer?
And we just, don't have enough follow-up data since we don't work people up for cancerafter a negative test to know the answer to that.
Yeah, that's a very wise answer and I think maybe we will know in the future given thedata out of AI and objective reading of mammograms which has shown to be very fascinating.
(28:26):
um We all, think we do agree that most cancers grow over years but some of them do not andthe interval cancer that you alluded to, which I've never heard that term, that's an
interesting term, um I think is helpful.
think weighing risk benefit for everybody is an important issue.
So this brings me to the total body MRIs, which I actually did many of them years agobecause they were less invasive.
(28:55):
And when I was working with startup companies that preceded Grail and didn't come to life,they couldn't scale or it didn't work effectively, there were actually several companies
that were quite promising.
And if somebody had a borderline test, I would do an MRI.
And the yield was kind of low.
Nowadays, so many people, because they're targeted by Pranuvo and Ezra, all of which aregreat techniques, um are doing testing and then going on to have additional tests when
(29:22):
some glitches show up and there some issues that can be frightening too.
a lot of folks.
So if you were faced with a family history that was, and this isn't a trick question, I'mgenuinely curious because of who you are, what you would think about a friend or family
member who's facing a risk given family history and other...
(29:44):
indications, would you think that it would be wise to get an MRI um to look at theprostate or the pancreas or would grill suffice given the kind of cancer it is and the
kind of concern?
Yeah.
ah It's a challenging question to answer because there haven't been any head-to-headstudies.
But here's how I think about it.
For an MRI or another imaging technique to detect the cancer, has to be of a certain sizeand location to be visible.
(30:12):
And we don't really know if those are the same sort of cancers that a blood-based test candetect.
And uh we do have some patients who are considered false positives, meaning they have apositive gallery test and a negative diagnostic workup.
And they have a cancer signal origin predicted, let's say, of head and neck cancer.
(30:36):
And a few months go by and the clinician, because of family history or smoking or someother reason, persists in doing the evaluation and reevaluates the patient and they have a
head and neck cancer.
And that's probably a cancer that was detected correctly by a blood-based test, but onethat was so early that it wasn't evident clinically or by imaging and so forth.
(30:58):
And so...
uh
I think they're fundamentally the kinds of cancers that they find are different.
And as I said, you can't on an MRI, if you see a small kidney tumor, for example, youdon't know whether or not that's one that needs to be treated or not.
Whereas with the gallery test, you find a cancer, as I've mentioned, the data are prettystrong that those need to be treated.
(31:23):
Those are biologically aggressive cancers.
So one other thing, I've talked to lot of radiologists about this.
Radiologists don't like whole body imaging.
mean, academic radiologists that I've talked to about it.
They don't like it because there are a lot of little ditzels and incidentalomas on therethat they have to comment on.
And that can lead to unnecessary worry and...
(31:46):
follow up exams and that sort of thing.
So it's a little bit of a dilemma.
Having said that.
We looked at one of our big studies was the Pathfinder study, which was using Galleri in6,600 healthy asymptomatic individuals.
Healthy meaning no suspicion of cancer.
(32:07):
And a subset of those were cancer survivors.
And that's a challenging group that's similar to the very positive family history group.
And the reason that that's challenging is that they're at double risk.
They're at risk for recurrence of the original cancer, and they're at risk for developinga new cancer, a different second primary.
How do you screen for those people when you don't know what cancer they're going to get?
(32:30):
uh And a blood-based test makes a lot of sense.
And if you look at the group at Hopkins published about two and a half years ago in theJournal of Clinical Oncology,
the group that follows high risk, patients at high risk of pancreatic cancer.
So family history, diabetes, cysts in the pancreas, that sort of thing.
(32:50):
And they screened everybody with uh endoscopic ultrasound and uh MRI, I think, of thepancreas.
And they found something really interesting, two things.
One is that screen-detected pancreatic cancer actually has better survival thansymptomatically detected pancreatic cancer, which is no surprise.
But more importantly,
(33:10):
in that trial you were seven times more likely to be diagnosed with a non-pancreaticcancer than a pancreatic cancer.
So it brings me to an observation that one of my colleagues likes to make is that ifyou're unlucky enough to get cancer, you can't pick what cancer you're going to get.
So even if you're adherent with colonoscopy and mammography, you're still more likely tobe diagnosed with a cancer that you're not screened for.
(33:33):
And that's where I think there's another big unmet need that tests like Galleri can fill.
Yeah, I think it's a fascinating recognition of how in many ways we're not very advanced.
People have to live the life and then hope for the best.
In other ways, I think if we can use risk kind of indicators, we can help people makedecisions, good decisions about what would be the best way to go about it.
(34:01):
But I agree, I use GRAIL in that fashion as well.
I will selectively do uh diagnostic tests with MRI, but just in the same way that totalbody CAT scans to me were largely ineffective except for maybe the heart and the lung and
maybe colon, although not my favorite because not only did it introduce air and pain, butyou couldn't biopsy when you looked at the colon.
(34:28):
There's always something to work towards em and I too selectively use what we apply.
But we do test everyone with GRAIL.
We do believe at this point in time it's been helpful and reassuring to some degree.
We have found people who undergo the full body MRIs to find it fascinating, but there havebeen a few people who have found, for example, meningiomas and then it weighs on their
(34:55):
mind to not turn it into a pond.
and they are fearful of what's going on and wonder what to do and gone to manyneurologists and neurosurgeons even though these can just be present and not have a
problem.
So it's a conundrum, I think, in today's world, and the cost can go either way.
(35:16):
I guess one final thing would be great to hear, but is there anything you want to addthere?
Because I'm in agreement with everything you've pointed out.
think it's, progress is fantastic, but we always want more, you know?
And I think patients who can benefit because they, can uncover something very early andcure it as opposed to it continuing to cause disease, death and dying, like ovarian cancer
(35:43):
and pancreatic cancer are certainly life-changing.
know, and sustaining.
uh Are there clinical trials that are currently ongoing in the field that either Grail isinvolved in or you're aware of for prostate cancer and other cancers that will, you know,
also lend itself to reliability, reproducibility, and precision?
(36:05):
Yes, uh Grail has committed to almost 400,000 people in clinical trials, nine clinicaltrials, most of which are completed and have, and we have published, but there are three
big ones uh that I'd like to mention.
One is Pathfinder 2, which is a trial in the U.S.
of 35,000 individuals, including uh more than 20 % of the population that's in the studyqualifies as uh
(36:35):
underrepresented uh minorities or underserved communities and so forth.
And we will have results from that trial later this year.
We have the only ever randomized trial of multi-cancer early detection that was done inthe United Kingdom.
called NHS Gallery, which randomized 70,000 people to standard of care screening versus70,000 standard of care plus gallery.
(36:59):
And we're expecting that readout in a year or so.
And then we have another trial with CMS with Medicare that Medicare is paying for.
That's 50,000 individuals in the Medicare population screened once a year for three years.
And that study is called REACH and that just got going last year and that'll be a fewyears.
(37:19):
We have that.
All of those trials will uh continue to expand the knowledge base that we have aboutthese.
But what we've seen consistently across all the trials that have been done, and even inthe real world, is that the performance of the test is just as we saw in our very first
trial.
The false positive rate is very low.
It's half a percent, meaning one in 200 people has a gallery test as a false positive.
(37:45):
the positive predictive value of the test, the likelihood that someone who has a positivetest actually has cancer in our studies was in the mid 40%.
But there are now two reports, one from the Mayo Clinic and one from Dana Farbersuggesting that the positive predictive value is a lot higher than that as they both
reported over 70 % and some other real world experiences that are in the middle of there.
(38:09):
And our ability to predict if you have a positive test, what kind of cancer it is,
is better than 90 percent.
So those are all encouraging results.
the exception of false positives, when something happens like the individual you spoke ofwith the head and neck cancer that showed up six months later.
So could not be found when the gallery test was done, even though it was positive.
(38:34):
So in a way, it's a warning sign if you want to choose to look at it that way as well.
um
actually have, yes I agree, and we have some data on how to handle that situation.
So the dilemma is you have a positive gallery test, you have a negative diagnosticevaluation, what do you do?
Is that truly a false positive?
(38:55):
What we found in a small cohort of patients, about 150 patients, it seems like the idealthing to do is to repeat the gallery test, which we offer free of charge.
If the repeat test is negative, we have not observed anybody diagnosed with cancer overthe ensuing 18 months.
If the repeat test is positive, about a third of those patients were diagnosed with cancerwithin 10 months.
(39:20):
So we think that's the way now to identify those people that you still need a high degreeof clinical suspicion, as the example I mentioned.
We've actually experienced that and the GRAIL folks were very helpful in the test that wehad seen and it was easy to get follow-up and ask questions.
(39:41):
I was always grateful for that because sometimes it isn't always possible as you and Iknow as clinical investigators to get clear-cut answers or at least guidance and support
along the way.
So think doctors and patients can be reassured.
um I have an interesting question for you that I'd love to bounce off
of you to see your thoughts.
(40:02):
I had one quick one that has to do with other competitors coming out of left field orcoming out because I've heard of other groups, particularly in Europe I think, that are
looking at alternative ways to pick up early cancer.
That was one question.
We can start there.
Yeah, there are lots of competitors in the space, actually.
So uh Exact Sciences is working on a multi-cancer early detection test and have said thatthey're going to have that on the market later this year.
(40:30):
Garden participated in an NCI sponsored trial called Vanguard and just recently postedtheir results.
And the good things about that is that both companies have found results that are veryconsistent with what we have seen.
And in the past, when Grail was the only big player,
in the space there was some whole skepticism about the whole field but I think that's gonenow because you have multiple independent observations there and there are lots of other
(40:58):
companies in Europe and in China and in the US that are looking not only at DNA but atother cancer signals in the bloodstream so yeah there'll be there'll be a plethora of
options we still believe that Galleri will be the first FDA approved test though we arethe farthest along in development.
How much does it cost for an individual?
(41:19):
know they can get the test.
don't know if it's, you need a prescription because we prescribe it for our patients or apatient can elect, a person can elect to just do the test on their own and the cost.
be prescribed by a physician.
The cost is $949.
The cost is $949.
For individuals who do not have a physician who knows about Galleri or is unwilling toprescribe it, they can go online to galleri.com and have a virtual appointment scheduled
(41:52):
with a physician who will go through their understanding of the test and their riskfactors and if they qualify, order it for them.
Fascinating.
Great.
um I guess the little bit of a far out question I wanted to ask and wrap up this part ofit is I had tested people, as I explained before a gallery was available and grail had
(42:13):
come to fruition and found abnormal findings in very reliable reproducible tests.
um And then I would go on to do MRIs to look or specifically do diagnostic workups.
Without exception, most of them were negative and I continued to follow individuals.
But one of the theories I had at the time, and I don't know how realistic this is, iscancer in effect, could it be like an infection where cells can be abnormal, but if you
(42:41):
have a healthy immune system and you do a lot of things good for yourself, that you canclean it up and get rid of it.
Because there's data out of Yale that
shows that most cancers are happening with aging and sort of cells that kind of go awry aswe age.
And I think it applied to breast cancer was one of the trials I read and studies.
(43:02):
Is your feeling that that's possible that we can actually make bad cells but then our bodygets rid of them with good killer T cells and not too many zombie or senescent cells?
Yes, it probably happens every day.
There are billions of cell divisions every day, and that's where cancer comes from, isdisordered cell division at the very start.
(43:22):
And so, yes, an intact immune system can probably scavenger those and suppress them and soforth.
And that probably happens.
I've been afraid to raise that in any meeting or anything, afraid that people would laughme out of the room.
There's a theory and a body of literature around that.
I have to look for it.
I guess I wasn't vigilant enough to because I was just thinking on my own.
(43:44):
The other thing we've just we are going forward with because I experienced it two or threeyears ago is therapeutic plasmapheresis, where the notion that if there are reactive cells
because you've had infections like COVID or a cytomegalic virus and your antibodies arehigh, Epstein-Barr, any of them that you can actually clean up the plasma.
(44:05):
And there's some data.
It's still a growing field.
but I've been impressed with some of the outcomes working on it.
Yeah, I haven't followed the literature on that at all.
It's a good investment of both time and money where you really want to do it more thanonce, at least three times.
When I did it myself, I found that after three treatments, my biological age, to theextent you believe in the data, which I do to an extent, reversed by 15 years, I needed
(44:33):
more energy.
When I stopped sleeping effectively, because I was building an app to be able to deliverthis virtually to people, the work we do, uh it jumped back up again.
So sleep is actually
paramount, you know, you really want that.
It is, it is the most important.
So to wrap up, I'd love to hear, you know, I like to ask people I speak to, if somebodystops you or you're sitting next to someone on the plane, as we invariably do, and they
(45:00):
find out you're a doctor, or they find out what you do for a living, what would be the onemost important thing you might mention, or you think in life would be most important to
share?
Find a way to relieve stress that is uh constructive and leads to other good things andget enough sleep for sure and eat a plant-based diet.
(45:23):
Those are the three big things.
I agree with everything but a plant-based diet in some ways, because I've seen plant-baseddiets really not be effective for a lot of folks.
It's just like looking at genetic variants where some people, I just saw one yesterday,can't fast.
don't have the ability.
Fasting would do nothing.
But absolutely, stress reduction, we look at, you know, even meditation is a fantastic, ifyou can learn to meditate, which has always been elusive for me, but I try, it actually
(45:52):
turns off genes that lead to increased cortisol.
and all sorts of issues with increasing cortisol.
But that's a great answer, I really appreciate it.
Is there anything you want to add to wrap up what we've shared or put a period or anexclamation point on it?
Yeah, this is really exciting technology and there's a huge unmet need here that MSEDtechnology can address.
(46:20):
And I think it's really important that all the related uh fields and constituencies,patients and advocacy groups and academics and industry get behind this and figure out how
to make it work.
And we think that we're doing that.
But I'm really excited because of that.
(46:40):
my, just to get back to my career trajectory, this is how I've thought about it.
As a surgeon, I can help one patient uh at a time.
As an academic that does clinical trials, I can help maybe hundreds or thousands ofpatients if the clinical trial is positive.
With something like screening for cancer like this, the number of people that can behelped is infinite.
(47:01):
And that makes me feel very personally powerful, and that's why I have really embraced thefield.
Well, welcome to New York.
I love everything you said and I hope we can continue the relationship.
Please feel free to come visit.
It was a very interesting relationship.
I felt brave enough to ask you some of the questions that have been percolating in mymind.
(47:22):
And you've been very informative.
I think this is going to be very helpful to so many people, men, women, children, and whoneed this kind of screen.
And I completely agree.
The area I suffered the most with when I started my work at Yale to look at predictive
and proactive ways to keep people healthy was cancer.
(47:43):
And I struggled with it because it's so ubiquitous and so GRAIL has offered a solutionfirst to market that really made a difference to all of us.
Would you want to know if cancer is in your future?
It's a question most people think about and understandably a tough one to answer.
But as a precision medicine and longevity physician, I really believe strongly thatknowledge and wisdom can save lives and give us remarkable control over our future health
trajectory and the emergence of cancer and other diseases.
(00:33):
Precision medicine actually looks for diseases and disorders of aging, which cancer is oneof, at the cellular level to identify and predict disease, and even decades before it
manifests and emerges as symptoms.
Identified early, cancer is curable in a lot of ways, and disease can often be reversed sowe can extend our health spans to match long lifespans that we're living today.
(00:58):
Hello and welcome to Healthy Longevity.
I'm Dr.
Florence Cometay, CEO and founder of the Cometay Center for Precision Medicine and HealthyLongevity.
I know that today's podcast guest, Dr.
Eric Klein, shares my passion for predictive, proactive, and preventative medicine, andI'm very happy to welcome you to the show, Eric.
Thanks for joining us.
(01:19):
Thanks for having me.
So Eric Klein, who I just found out is a neighbor here in New York now, is a medicaldoctor and a distinguished scientist at Grail, a biomedical company whose mission is to
develop safe and effective cancer screening technologies to detect cancer early, again,before symptoms actually emerge, when it can be cured and ultimately change the trajectory
(01:42):
of cancer mortality.
Dr.
Klein previously served as the Andrew C.
Novick Distinguished Professor and Chair of the Glickman
Urological and Kidney Institute and Lerner College of Medicine at the Cleveland Clinics,where he was also a member of the Department of Cancer Biology oh at the Cleveland
Clinic's Lerner Institute, Lerner Research Institute, the TauSig Cancer Institute, and theGenitourinary Malignancies Program in the Case Comprehensive Cancer Center.
(02:14):
Dr.
Klein was a fellow in the Distinguished Careers Institute at Stanford University in 2022and ultimately joined GRAIL in 2023.
Dr.
Klein's clinical and research interests focus on prostate cancer with an emphasis ongenomics and trials or clinical trials.
Most recently, his work has centered on the clinical development of cancer screening testslike Grail's Gallery Test, which is a first of its kind multi-cancer early detection test,
(02:45):
a breakthrough test that we have recommended and used since its inception at the CometaCenter.
I had actually been waiting for these tests to come along
I was really reluctant to study a person through radiological techniques like PET scan.
So having a relatively non-invasive way by just drawing some blood and looking for markersthat circulate was a wonderful step in the right direction to predict cancer in the long
(03:12):
term but early in the disease course.
That's just a very brief introduction to Dr.
Klein's very distinguished career and accomplishments.
And I don't know how, Eric, you would fit it all
on a business card, but that was pretty incredible.
um Thank you again for chatting today and let me ask you to start by telling us more aboutGrail and specifically about the Galleria test.
(03:37):
Yes, so Galleri is a blood-based test that measures the presence of what's calledcell-free DNA that is derived from cancer cells.
And we know, we've known for a long time that when cancer cells grow and the cellsmultiply and die, that they release all sorts of biologic substances that can serve as
(03:58):
signals to their presence into the bloodstream.
And so the basis of this test is next generation sequencing, which is what was used tosequence the human genome.
And in the background of all the normal cell-free DNA, our assay can uh detect if a cancersignal is present.
Excellent.
Could you explain a little bit more about GRAIL's methylation platform and what that meansto determine and detect methylation patterns to predict cancer origin?
(04:27):
short.
The way to think about this is in two analogies.
One analogy is light switches turning on and off, and the other analogy is fingerprints.
So, methylation is a normal biologic process where DNA is chemically modified to turngenes on and off.
(04:47):
And a liver cell, for example, will use methylation to turn on all the genes that make ita liver cell and turn off all the genes that would make it some other kind of cell.
And a kidney cell does the same
thing to make it a kidney cell.
Cancers exploit this normal biologic process called methylation and use it in a littledifferent way.
They use it, and all cancers do this, they use it in a way to turn off the genes thatprevent them from growing and turn on the genes that allow them to grow unrestricted.
(05:20):
And that's a fundamental biologic process, what we call a hallmark of cancer.
And so the fingerprint analogy comes in where the number of light switches or the order oflight switches on the wall, if you think of methylation as, let's say, 100 light switches
on the wall, in a normal cell,
is going to be, know, will be on, certain will be off, and in a different cell of adifferent type, different ones will be on and off.
(05:45):
And a different pattern occurs in cancer.
And so we can exploit that.
And we can see the methylation fingerprint of cancer versus non-cancer in the DNA that'sin the bloodstream and using a machine learning algorithm for both of these processes.
If there's a cancer signal present, we can predict with more than 90 % accuracy where thecancer comes from, what kind of cancer it is, and that helps.
(06:07):
diagnostic workup.
And taking a step back for the moment, I'd really like to learn how you first becameinterested in this type of research because you've had a very distinguished career at a
number of institutions and then what led you to follow this particular path in yourjourney.
I've always been interested in biomarkers and did some prior work in my career on prostatecancer biomarkers and I treated urologic cancer patients my whole career.
(06:36):
And I had a relationship with Grail's very first chief medical officer from some work withanother company.
And he came knocking on my door while I was still practicing in 2016 and said, we havethis really interesting technology that I just described.
And would you be interested in helping us accrue patients to our clinical trials?
And being intellectually curious and understanding the vast unmet need in cancerscreening, I was intrigued.
(07:01):
And I said, yes.
So I helped accrue several thousand patients to the first two big clinical
trials that GRAIL did and along the way I became a consultant and then I retired frompractice.
I did a sabbatical at Stanford and Stanford is in the city next door to GRAIL'sheadquarters and so I started at the company's invitation, started spending more time at
(07:23):
GRAIL and I got to understand everything that was going on there and very very excited bythe technology and when the opportunity came and they offered me a job I said yes.
was a little curious because we all have a reason we go into the particular field.
Was there any trigger that led you to become a urologist and then focus predominantly onprostate cancer?
(07:44):
uh
a kidney stone when I was in college and I had surgery for it and being the nerd that Iwas when I got back to school because that happened over spring break.
I missed a whole vacation week because of that.
When I got back to school, I went to the bookstore and I bought a urology text and I readit cover to cover and I got really fascinated by it.
(08:05):
So when I went to medical school, I had the option of doing a urology rotation as anelective, which I did, and I really liked the people and I liked the kind of conditions
that came.
along and I was really attracted to the cancer surgery.
That's really what got me interested in treating cancer in general.
And so that was the career path that I followed.
Wow, that's a long training path because besides training in urology, you have to go on totrain in urological cancers.
(08:32):
It's kind of fun for me looking back in medical school at Yale, there was no separateurology division.
And whenever we studied it, because I did an elective in that as well, they weren't reallytoo inviting of women in the room.
And the men were all very uncomfortable at that time.
At that time, wasn't that many women in medical school.
So it was kind of unusual to be in there.
(08:54):
And now I
I it quite well and then it was difficult.
Since then, Yale had created a urology department and because I do so much work in men andwomen, I've really had immersed myself in urological issues and having two sons and a
father and other.
reasons and learned quite a bit but I remember complaining to the first chair of urologyhow difficult it was for women to learn urology at Yale so it's kind of interesting.
(09:22):
um We work with a fair amount of urologists.
was probably Bob Weiss was the first chair, think.
Wonderful.
Wonderful man.
I'm sure he was welcoming and warm to you.
Right, right, he was wonderful.
And I have referred plenty of men there to be tested back in the day when you discoveredit and you wanted to get beyond, you wanted to market, to do MRI, because they were one of
(09:47):
the first places to offer MRI like Cornell and like NIH.
And it was very hard to get people into these institutions to be tested.
Now we take it for granted, but just a few years ago it was challenging, like a decadeago.
It's really changed what we can do for people who do get diagnosed and how we can do thatearly now.
(10:07):
But that's why Grail is here and it's fantastic.
I'd love to understand a little bit more about what is the opportunity to see whichcancers are most easily noticed and found early on.
Is there a difference, for example, between solid cancers and cancers that actually tendto circulate in the blood early on as opposed to later metastasizing?
(10:32):
And whether it matters whether it metastasizes lymphatically or in what way.
I don't have very much knowledge about how cancers begin to deviate.
And I'm particularly curious about prostate cancer because I had a former colleague who
was told that he had an underlying urological infection and he had some pain and he hadsome symptoms but his PSA was low and he ended up having a neuroendocrine prostate cancer
(10:58):
which spread very rapidly and unfortunately led to his early death.
So that was of interest to me because I don't think that was anything we ever studied inschool.
Now let's talk about the unmet need in cancer screening first.
I think that will put everything else in context.
We currently screen for five cancers.
We have high level data for cervical, breast, colon, lung cancer, and smokers, andprostate cancer.
(11:25):
That screening for those cancers reduces mortality, which is terrific.
The challenge is that despite the fact that we screen for those five cancers and despitethe fact that they reduce mortality, we lose more than 600,000 patients a year due to
cancer in the United States.
In fact, the standard of care screening tests only detect 14 % of all cancers.
(11:46):
And more than 80 % of people who die of cancer die from cancers that we don't screen for.
And so that's the big unmet need is to develop a broad-based test that can detect thesecancers that people die from that we don't have good screening tests for.
It would be too inefficient to screen for all of them individually.
(12:06):
oh
because the false positive rate in someone who got five or six or eight or 10 individualscreening tests would be very high.
It would be approached 50 % or greater.
And so the advantage of a multi-cancer early detection approach is that the test iscalibrated to have a very, very low false positive rate while still detecting a broad
(12:29):
array of cancers.
So this technology can detect dozens of different kinds of cancers that we don't screenfor now.
The sensitivity for uh individual cancers varies both across cancer type and biology.
So as I mentioned, the test detects DNA fragments, cell-free DNA in the bloodstream, butnot all cells uh get DNA into the bloodstream.
(12:52):
And we know that the ones that do, we know not all, I should say not all cancers uhsecrete DNA into the bloodstream.
The ones that do,
are ones that we know behave aggressively biologically because the ones that are able toshed cell-free DNA are ones that have high mitotic rates, uh have uh high metabolic
(13:13):
profiles, have necrosis in the tumor and that sort of thing.
So the cancers that are detected by these tests are ones that generally are on theaggressive side and need treatment and we can say that with really good uh solid
scientific evidence behind it.
In terms of sensitivity for specific cancers, it varies.
(13:36):
But for example, I always like to talk about pancreatic and ovarian cancer.
Our current screening paradigm, we detect 0 % of pancreatic and ovarian cancers beforethey're symptomatic.
In the big trials that we did, we can detect 80 % of ovarian and pancreatic cancers and 60% of those at stage one and two.
(13:57):
And that's where the real opportunity is to detect the cancers, not only in asymptomaticpeople, but to detect them when they're before they're metastatic and when they can be
treated and cured and cured at a lower burden.
And that's fascinating, and with ovarian pancreatic cancer um and screening, what othercancers would you say, uh if let's say they run in your family or your best friend,
(14:22):
because obviously that always puts a fear in someone, would be the most likely to bedetected early on in the course.
Yeah, so the ones that the test detects best are head and neck cancer, liver and biliarycancer, uh colon cancer, ovarian, uterine cancer.
(14:43):
uh The kinds of cancers that it doesn't detect almost at all.
are really early stage, low grade indolent cancers like prostate cancer.
And in fact, you asked how I got interested in grail.
When I first had the conversation with the chief medical officer.
I had it in the back of my mind, gee, this sounds like great technology.
(15:04):
Maybe we can replace PSA and screen for prostate cancer better.
And it turns out that low-grade prostate cancer doesn't shed any cell-free DNA to speakof.
And so this is not a good test for low-grade prostate cancer.
The flip side of that is we over-detect too much low-grade prostate cancer with PSA.
And so this test will not make that problem worse.
(15:25):
And cancer is not detected well.
thyroid cancer is not detected well.
And the reason is that those cancers don't shed much cell-free DNA.
And brain cancers are not detected because the DNA can't pass the blood-brain barrier.
But for the major cancers that people die from, the test works very well.
breast cancer also falls into the category for most as like prostate cancer they don't youknow shed early on most of them.
(15:53):
Early stage, so it's interesting, again, these are biologic issues.
It depends on the kind of breast cancer you're talking about.
Early stage hormone receptor positive breast cancer, which is over 90 % curable, doesn'tshed much cell-free DNA.
It's not a very aggressive cancer.
On the other hand, triple negative breast cancer, which is often missed on mammography,sheds lots of cell-free DNA, and the test works very well for that more aggressive form.
(16:19):
So that's triple negative, hers negative as well or hers positive.
No, her negative, triple negative, ER negative and her negative.
And that's the most lethal form of breast cancer.
And the test works very well for that.
As I said, the cancers that shed DNA into the bloodstream that can be detected by the testare aggressive and need treatment.
(16:40):
which makes sense.
A couple of things to follow up on that.
I was always curious about oh Gleason scoring with PSA.
And we are very careful to do PSAs with percent free.
Sometimes we do testing, doing K4 and other ways to approach MRI, as I mentioned, as well.
um And there's always been a debate.
(17:01):
I don't know where it stands now, but I remember the scientific papers I read from Mayoclaiming that you can't really consider, as you alluded to, low-grade prostate cancer.
a Gleason 6 as really an aggressive cancer.
So there are a number of men now in my field.
I come from the hormone field.
I'm an endocrinologist trained in multiple fields of endocrine from PEDs to GYN toandrology and men and women.
(17:26):
And um it's always a debate we have because we do follow up on the change in PSA.
We work with people who actually biopsy and follow.
We use hormonal agents to protect people's health, so they don't get diabetes and heartdisease, heart attack and stroke, far more widespread than prostate cancer that is deadly,
(17:49):
if you will.
And I had a lot of run-ins with urologists at the beginning.
And then slowly they started changing.
I would say
this started about 15, 20 years ago in New York when I was transitioning from Yale and Iwas told, you know, go ahead, you can treat.
But a funny story is one of my patients went to Sloan, could not really describe what wewere doing.
(18:10):
And he met with a researcher there who is going to report me to the morbidity andmortality committee to discuss this.
And I had to present the case and then he came and we met and he understood immediatelywhat I was doing because at the time they were looking to set up
VO2 max tests and exercise and they were recruiting I think someone from Duke because theyfigured out that exercise is a good thing as people age in terms of you know minimizing
(18:37):
disease and since then we've been great buddies and I refer everyone to him so he can growhis panel of people to follow but I've even had people with Gleason 6 which I don't worry
as much about then show up with a no a biopsy that contains a Gleason 7.
How do you think of it given your deep x
expertise as a urologist who focuses in on cancer.
(19:00):
Is there anything we should do differently to manage these guys?
Well, PSA has been shown to reduce mortality in the European screening trial.
And so I'm a believer in PSA and screening people appropriately.
The challenge is that PSA is prostate specific, but it's not prostate cancer specific.
And benign prostate enlargement, BPH, is far more common than prostate cancer.
(19:23):
So on average, most elevated PSA comes from BPH and not from cancer.
A second challenge, as you've alluded to, is that really high-grade glycine
eight and nine prostate cancers and or endocrine cancers don't make much PSA.
So PSA isn't perfect for lot of reasons.
So the way the field has evolved now is there are new tools to distinguish whether or notan elevated PSA indicates the likelihood of cancer and you've mentioned one of them the 4k
(19:53):
score is one there's another one another blood-based test called iso PSA there are someurine-based tests.
And before moving to a decision on biopsy, it's appropriate, I think, to repeat one ofthose tests, do a reflex test.
because they better stratify those who are at risk of cancer.
And then as you mentioned, MRI is a great tool for seeing high-grade cancers and targetingbiopsy and so forth.
(20:19):
It's really revolutionized what we've done.
But even MRI isn't perfect.
It misses about 20 % of high-grade cancers.
So that is the way the field has moved.
Yes, and you know I work with some great urologists.
I'm always very impressed and monitoring with active surveillance is the way we tend togo.
But I worry.
I worry that I don't want to miss anything and yet I do want to treat people metabolicallyso that they don't get diabetes, they don't have a heart attack, because that's far more
(20:47):
likely than the fact that we've all heard probably most men and most women when they dieat autopsy you'd probably find niduses of abnormal cells in the prostate and the breast.
So it's
common probably long you know aging phenomenon as well.
So yeah, no question that it is.
So I think that the evidence isn't great.
(21:10):
We don't have long-term mortality trials for testosterone replacement in men withprostates.
But you think about it this way.
That's how I think about this problem.
Testosterone is at a normal level in the vast, vast, vast majority of men who get prostatecancer.
It's not abnormally high.
It's not that testosterone causes prostate cancer.
(21:31):
It's only in metastatic disease where the testosterone androgen axis is deregulated andtestosterone fuels growth.
So if you get back to the early stage, low-grade prostate cancer, if you have a man who'shypogonadal and who's having symptoms from being hypogonadal,
It's safe, in my view, to give him enough testosterone to make him asymptomatic and gethis testosterone into the normal range.
(21:57):
You're not trying to drive it, you know, into the very high range.
And there really isn't any evidence that that has an adverse effect on low-grade prostatecancer or causing high-grade cancer.
I think there's a bigger controversy here, which is, is there an advantage to takingtestosterone in someone who's not hypogonadal and who has no symptoms?
(22:19):
And I think the evidence for that is weaker.
And that's not something that I ever did.
That's not anything I did in my practice.
Well that's interesting because back when I trained, I trained with lot of reallydistinguished people, Ronald Swirdlaw for others, and there is a fair amount of data
showing how testosterone really is effective in terms of metabolic disease because webegin to decline in our 30s, testosterone starts falling in men and women and it
(22:48):
definitely leads to decrease in muscle.
I used to use the fact, as you alluded to, that as men age, their testosterone is actuallylow.
yet to meet a person, one exception, but still the free T was quite low in a man at 70 whowas on DHEA, which can contribute to testosterone and his free T was about 70.
(23:11):
So having taken care of infants through every decade of life, most men, if not all,decline with age.
There's no question about it.
It's just like menopause, it's andropause and diseases, you know, permeate and emerge.
So we have used it
and to our benefit and what, know, years ago and still occasionally people will pop up andsay testosterone causes prostate cancer.
(23:34):
I will point out that testosterone is usually quite low when you get prostate cancer.
There's actually some association that's been alluded to in the papers about estrogen,which also increasingly gets aromatized from testosterone um as men age.
And so those were the arguments I used to use both directly with doctors and withpatients.
(23:57):
It's testicular cancer I'd be concerned about that happens at a younger age with young menwhere their testosterone is generally high.
So it's been an interesting conundrum, but I've been up and down with it.
So I appreciate your input, that's fantastic, and agree that it's still a work, all ofmedicine is still a work in progress, but when it comes down to the individual patient,
(24:21):
you like to be able to give them something to weigh the risk benefit for each of them, soI find that.
There is also data that shows a low grade, oh that using uh a uh low dose of aspirin, itcomes out of Europe, so it's the 100 milligram aspirin for five years or more,
actually reduces the rate of pre-occurring cancer but also prostate cancer, colon cancer,and a couple of other cancers of the midline.
(24:48):
So that's something we tend to be in favor of.
I think the risk of bleeds from a low dose aspirin is far less than the benefit you canexperience with it.
But that's fascinating and I really appreciate it.
Who do you find your typical clients or patients are who do grail?
Is it just about everyone or given the price point maybe a challenge?
(25:11):
is there, you know, do you have one demographic or another that you can point to?
You can't point to any demographic.
Really the common feature of the individuals who do it are people who are concerned aboutthe risk of cancer and want to be screened and who want to know.
That's what it's about and that crosses all demographics.
Okay, I think also you pointed out that the test is fairly sensitive and effective withcertain cancers when they're really malignant and they shed quickly.
(25:41):
I don't think, in my experience, we have not had any false positives.
In fact, we've only had one positive in all the years that we've actually been screening,even though we've diagnosed cancer, the cancers that fall into the less aggressive type,
thyroid and breast that are hormonally positive.
Any false negatives where you find out subsequently if you follow people beyond the grailtest that they in fact had a cancer and it was missed and what would be the percentage of
(26:12):
that?
Yeah, so it's a challenge because we have not seen patients who have had a negativegallery test and who are, let me say this, healthy patients who have no symptoms.
We've not seen patients who have had a negative gallery test and then are diagnosed withan aggressive cancer in the next week or two.
(26:33):
So they might be diagnosed with a cancer six or eight or 10 months later.
And what we don't know, and there's no way of knowing for sure, is that a new cancer thatreally wasn't present when the test was done?
Or did the test actually miss that cancer?
And as I said, or implied earlier, no test like this is going to find every cancer.
(26:55):
cancer that it finds has to shed cell-free DNA into the bloodstream and there has to beenough to be detectable and distinguishable from the background.
So yes, there probably are some false negatives.
I think the number is very small, but it's hard to know exactly because when someone getsa negative gallery test, we don't then recommend that they have a cancer workup.
(27:18):
So we don't know what the ground truth is.
We don't know if they have cancer.
Are there some people who have negative tests and then are diagnosed with cancer withinthe next year?
Yes, there are.
But that's also true of every other screening test that we use.
oh So again, back to the example of breast cancer, triple negative breast cancer, the most
(27:39):
aggressive kind is often missed on mammography because its appearance is a littledifferent than other kinds of cancers.
And it is the most common breast cancer that is detected in what's called an intervalcancer between mammograms.
So let's say you have a woman who has a negative mammogram and is diagnosed with a triplenegative breast cancer six months later.
(28:01):
Did the mammogram miss it?
Was it there in the mammogram?
Did the radiologist miss it?
Or is it a new cancer?
And we just, don't have enough follow-up data since we don't work people up for cancerafter a negative test to know the answer to that.
Yeah, that's a very wise answer and I think maybe we will know in the future given thedata out of AI and objective reading of mammograms which has shown to be very fascinating.
(28:26):
um We all, think we do agree that most cancers grow over years but some of them do not andthe interval cancer that you alluded to, which I've never heard that term, that's an
interesting term, um I think is helpful.
think weighing risk benefit for everybody is an important issue.
So this brings me to the total body MRIs, which I actually did many of them years agobecause they were less invasive.
(28:55):
And when I was working with startup companies that preceded Grail and didn't come to life,they couldn't scale or it didn't work effectively, there were actually several companies
that were quite promising.
And if somebody had a borderline test, I would do an MRI.
And the yield was kind of low.
Nowadays, so many people, because they're targeted by Pranuvo and Ezra, all of which aregreat techniques, um are doing testing and then going on to have additional tests when
(29:22):
some glitches show up and there some issues that can be frightening too.
a lot of folks.
So if you were faced with a family history that was, and this isn't a trick question, I'mgenuinely curious because of who you are, what you would think about a friend or family
member who's facing a risk given family history and other...
(29:44):
indications, would you think that it would be wise to get an MRI um to look at theprostate or the pancreas or would grill suffice given the kind of cancer it is and the
kind of concern?
Yeah.
ah It's a challenging question to answer because there haven't been any head-to-headstudies.
But here's how I think about it.
For an MRI or another imaging technique to detect the cancer, has to be of a certain sizeand location to be visible.
(30:12):
And we don't really know if those are the same sort of cancers that a blood-based test candetect.
And uh we do have some patients who are considered false positives, meaning they have apositive gallery test and a negative diagnostic workup.
And they have a cancer signal origin predicted, let's say, of head and neck cancer.
(30:36):
And a few months go by and the clinician, because of family history or smoking or someother reason, persists in doing the evaluation and reevaluates the patient and they have a
head and neck cancer.
And that's probably a cancer that was detected correctly by a blood-based test, but onethat was so early that it wasn't evident clinically or by imaging and so forth.
(30:58):
And so...
uh
I think they're fundamentally the kinds of cancers that they find are different.
And as I said, you can't on an MRI, if you see a small kidney tumor, for example, youdon't know whether or not that's one that needs to be treated or not.
Whereas with the gallery test, you find a cancer, as I've mentioned, the data are prettystrong that those need to be treated.
(31:23):
Those are biologically aggressive cancers.
So one other thing, I've talked to lot of radiologists about this.
Radiologists don't like whole body imaging.
mean, academic radiologists that I've talked to about it.
They don't like it because there are a lot of little ditzels and incidentalomas on therethat they have to comment on.
And that can lead to unnecessary worry and...
(31:46):
follow up exams and that sort of thing.
So it's a little bit of a dilemma.
Having said that.
We looked at one of our big studies was the Pathfinder study, which was using Galleri in6,600 healthy asymptomatic individuals.
Healthy meaning no suspicion of cancer.
(32:07):
And a subset of those were cancer survivors.
And that's a challenging group that's similar to the very positive family history group.
And the reason that that's challenging is that they're at double risk.
They're at risk for recurrence of the original cancer, and they're at risk for developinga new cancer, a different second primary.
How do you screen for those people when you don't know what cancer they're going to get?
(32:30):
uh And a blood-based test makes a lot of sense.
And if you look at the group at Hopkins published about two and a half years ago in theJournal of Clinical Oncology,
the group that follows high risk, patients at high risk of pancreatic cancer.
So family history, diabetes, cysts in the pancreas, that sort of thing.
(32:50):
And they screened everybody with uh endoscopic ultrasound and uh MRI, I think, of thepancreas.
And they found something really interesting, two things.
One is that screen-detected pancreatic cancer actually has better survival thansymptomatically detected pancreatic cancer, which is no surprise.
But more importantly,
(33:10):
in that trial you were seven times more likely to be diagnosed with a non-pancreaticcancer than a pancreatic cancer.
So it brings me to an observation that one of my colleagues likes to make is that ifyou're unlucky enough to get cancer, you can't pick what cancer you're going to get.
So even if you're adherent with colonoscopy and mammography, you're still more likely tobe diagnosed with a cancer that you're not screened for.
(33:33):
And that's where I think there's another big unmet need that tests like Galleri can fill.
Yeah, I think it's a fascinating recognition of how in many ways we're not very advanced.
People have to live the life and then hope for the best.
In other ways, I think if we can use risk kind of indicators, we can help people makedecisions, good decisions about what would be the best way to go about it.
(34:01):
But I agree, I use GRAIL in that fashion as well.
I will selectively do uh diagnostic tests with MRI, but just in the same way that totalbody CAT scans to me were largely ineffective except for maybe the heart and the lung and
maybe colon, although not my favorite because not only did it introduce air and pain, butyou couldn't biopsy when you looked at the colon.
(34:28):
There's always something to work towards em and I too selectively use what we apply.
But we do test everyone with GRAIL.
We do believe at this point in time it's been helpful and reassuring to some degree.
We have found people who undergo the full body MRIs to find it fascinating, but there havebeen a few people who have found, for example, meningiomas and then it weighs on their
(34:55):
mind to not turn it into a pond.
and they are fearful of what's going on and wonder what to do and gone to manyneurologists and neurosurgeons even though these can just be present and not have a
problem.
So it's a conundrum, I think, in today's world, and the cost can go either way.
(35:16):
I guess one final thing would be great to hear, but is there anything you want to addthere?
Because I'm in agreement with everything you've pointed out.
think it's, progress is fantastic, but we always want more, you know?
And I think patients who can benefit because they, can uncover something very early andcure it as opposed to it continuing to cause disease, death and dying, like ovarian cancer
(35:43):
and pancreatic cancer are certainly life-changing.
know, and sustaining.
uh Are there clinical trials that are currently ongoing in the field that either Grail isinvolved in or you're aware of for prostate cancer and other cancers that will, you know,
also lend itself to reliability, reproducibility, and precision?
(36:05):
Yes, uh Grail has committed to almost 400,000 people in clinical trials, nine clinicaltrials, most of which are completed and have, and we have published, but there are three
big ones uh that I'd like to mention.
One is Pathfinder 2, which is a trial in the U.S.
of 35,000 individuals, including uh more than 20 % of the population that's in the studyqualifies as uh
(36:35):
underrepresented uh minorities or underserved communities and so forth.
And we will have results from that trial later this year.
We have the only ever randomized trial of multi-cancer early detection that was done inthe United Kingdom.
called NHS Gallery, which randomized 70,000 people to standard of care screening versus70,000 standard of care plus gallery.
(36:59):
And we're expecting that readout in a year or so.
And then we have another trial with CMS with Medicare that Medicare is paying for.
That's 50,000 individuals in the Medicare population screened once a year for three years.
And that study is called REACH and that just got going last year and that'll be a fewyears.
(37:19):
We have that.
All of those trials will uh continue to expand the knowledge base that we have aboutthese.
But what we've seen consistently across all the trials that have been done, and even inthe real world, is that the performance of the test is just as we saw in our very first
trial.
The false positive rate is very low.
It's half a percent, meaning one in 200 people has a gallery test as a false positive.
(37:45):
the positive predictive value of the test, the likelihood that someone who has a positivetest actually has cancer in our studies was in the mid 40%.
But there are now two reports, one from the Mayo Clinic and one from Dana Farbersuggesting that the positive predictive value is a lot higher than that as they both
reported over 70 % and some other real world experiences that are in the middle of there.
(38:09):
And our ability to predict if you have a positive test, what kind of cancer it is,
is better than 90 percent.
So those are all encouraging results.
the exception of false positives, when something happens like the individual you spoke ofwith the head and neck cancer that showed up six months later.
So could not be found when the gallery test was done, even though it was positive.
(38:34):
So in a way, it's a warning sign if you want to choose to look at it that way as well.
um
actually have, yes I agree, and we have some data on how to handle that situation.
So the dilemma is you have a positive gallery test, you have a negative diagnosticevaluation, what do you do?
Is that truly a false positive?
(38:55):
What we found in a small cohort of patients, about 150 patients, it seems like the idealthing to do is to repeat the gallery test, which we offer free of charge.
If the repeat test is negative, we have not observed anybody diagnosed with cancer overthe ensuing 18 months.
If the repeat test is positive, about a third of those patients were diagnosed with cancerwithin 10 months.
(39:20):
So we think that's the way now to identify those people that you still need a high degreeof clinical suspicion, as the example I mentioned.
We've actually experienced that and the GRAIL folks were very helpful in the test that wehad seen and it was easy to get follow-up and ask questions.
(39:41):
I was always grateful for that because sometimes it isn't always possible as you and Iknow as clinical investigators to get clear-cut answers or at least guidance and support
along the way.
So think doctors and patients can be reassured.
um I have an interesting question for you that I'd love to bounce off
of you to see your thoughts.
(40:02):
I had one quick one that has to do with other competitors coming out of left field orcoming out because I've heard of other groups, particularly in Europe I think, that are
looking at alternative ways to pick up early cancer.
That was one question.
We can start there.
Yeah, there are lots of competitors in the space, actually.
So uh Exact Sciences is working on a multi-cancer early detection test and have said thatthey're going to have that on the market later this year.
(40:30):
Garden participated in an NCI sponsored trial called Vanguard and just recently postedtheir results.
And the good things about that is that both companies have found results that are veryconsistent with what we have seen.
And in the past, when Grail was the only big player,
in the space there was some whole skepticism about the whole field but I think that's gonenow because you have multiple independent observations there and there are lots of other
(40:58):
companies in Europe and in China and in the US that are looking not only at DNA but atother cancer signals in the bloodstream so yeah there'll be there'll be a plethora of
options we still believe that Galleri will be the first FDA approved test though we arethe farthest along in development.
How much does it cost for an individual?
(41:19):
know they can get the test.
don't know if it's, you need a prescription because we prescribe it for our patients or apatient can elect, a person can elect to just do the test on their own and the cost.
be prescribed by a physician.
The cost is $949.
The cost is $949.
For individuals who do not have a physician who knows about Galleri or is unwilling toprescribe it, they can go online to galleri.com and have a virtual appointment scheduled
(41:52):
with a physician who will go through their understanding of the test and their riskfactors and if they qualify, order it for them.
Fascinating.
Great.
um I guess the little bit of a far out question I wanted to ask and wrap up this part ofit is I had tested people, as I explained before a gallery was available and grail had
(42:13):
come to fruition and found abnormal findings in very reliable reproducible tests.
um And then I would go on to do MRIs to look or specifically do diagnostic workups.
Without exception, most of them were negative and I continued to follow individuals.
But one of the theories I had at the time, and I don't know how realistic this is, iscancer in effect, could it be like an infection where cells can be abnormal, but if you
(42:41):
have a healthy immune system and you do a lot of things good for yourself, that you canclean it up and get rid of it.
Because there's data out of Yale that
shows that most cancers are happening with aging and sort of cells that kind of go awry aswe age.
And I think it applied to breast cancer was one of the trials I read and studies.
(43:02):
Is your feeling that that's possible that we can actually make bad cells but then our bodygets rid of them with good killer T cells and not too many zombie or senescent cells?
Yes, it probably happens every day.
There are billions of cell divisions every day, and that's where cancer comes from, isdisordered cell division at the very start.
(43:22):
And so, yes, an intact immune system can probably scavenger those and suppress them and soforth.
And that probably happens.
I've been afraid to raise that in any meeting or anything, afraid that people would laughme out of the room.
There's a theory and a body of literature around that.
I have to look for it.
I guess I wasn't vigilant enough to because I was just thinking on my own.
(43:44):
The other thing we've just we are going forward with because I experienced it two or threeyears ago is therapeutic plasmapheresis, where the notion that if there are reactive cells
because you've had infections like COVID or a cytomegalic virus and your antibodies arehigh, Epstein-Barr, any of them that you can actually clean up the plasma.
(44:05):
And there's some data.
It's still a growing field.
but I've been impressed with some of the outcomes working on it.
Yeah, I haven't followed the literature on that at all.
It's a good investment of both time and money where you really want to do it more thanonce, at least three times.
When I did it myself, I found that after three treatments, my biological age, to theextent you believe in the data, which I do to an extent, reversed by 15 years, I needed
(44:33):
more energy.
When I stopped sleeping effectively, because I was building an app to be able to deliverthis virtually to people, the work we do, uh it jumped back up again.
So sleep is actually
paramount, you know, you really want that.
It is, it is the most important.
So to wrap up, I'd love to hear, you know, I like to ask people I speak to, if somebodystops you or you're sitting next to someone on the plane, as we invariably do, and they
(45:00):
find out you're a doctor, or they find out what you do for a living, what would be the onemost important thing you might mention, or you think in life would be most important to
share?
Find a way to relieve stress that is uh constructive and leads to other good things andget enough sleep for sure and eat a plant-based diet.
(45:23):
Those are the three big things.
I agree with everything but a plant-based diet in some ways, because I've seen plant-baseddiets really not be effective for a lot of folks.
It's just like looking at genetic variants where some people, I just saw one yesterday,can't fast.
don't have the ability.
Fasting would do nothing.
But absolutely, stress reduction, we look at, you know, even meditation is a fantastic, ifyou can learn to meditate, which has always been elusive for me, but I try, it actually
(45:52):
turns off genes that lead to increased cortisol.
and all sorts of issues with increasing cortisol.
But that's a great answer, I really appreciate it.
Is there anything you want to add to wrap up what we've shared or put a period or anexclamation point on it?
Yeah, this is really exciting technology and there's a huge unmet need here that MSEDtechnology can address.
(46:20):
And I think it's really important that all the related uh fields and constituencies,patients and advocacy groups and academics and industry get behind this and figure out how
to make it work.
And we think that we're doing that.
But I'm really excited because of that.
(46:40):
my, just to get back to my career trajectory, this is how I've thought about it.
As a surgeon, I can help one patient uh at a time.
As an academic that does clinical trials, I can help maybe hundreds or thousands ofpatients if the clinical trial is positive.
With something like screening for cancer like this, the number of people that can behelped is infinite.
(47:01):
And that makes me feel very personally powerful, and that's why I have really embraced thefield.
Well, welcome to New York.
I love everything you said and I hope we can continue the relationship.
Please feel free to come visit.
It was a very interesting relationship.
I felt brave enough to ask you some of the questions that have been percolating in mymind.
(47:22):
And you've been very informative.
I think this is going to be very helpful to so many people, men, women, children, and whoneed this kind of screen.
And I completely agree.
The area I suffered the most with when I started my work at Yale to look at predictive
and proactive ways to keep people healthy was cancer.
(47:43):
And I struggled with it because it's so ubiquitous and so GRAIL has offered a solutionfirst to market that really made a difference to all of us.
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