ASCO 2024 Recap: Advancements in Cancer Treatments

The Patient from Hell (00:01.586)
Hi, everyone. This is Samira Daswani, the host of the podcast, The Patient from Hell. I have our chief medical officer here today. You guys have met him before. This is Dr. Doug Blaney, former ASCO president, well-renowned oncologist, who's here today to explain to us what actually happened at ASCO this past year. Dr. Blaney, welcome back.

Douglas Blayney, M.D. (00:21.583)
Thank you, Samira. It's great to be here and I won't object to the title of your Patient from Hell podcast, but we're hoping to make our participants less that and more knowledgeable. So I'm glad. Let's have a great experience.

The Patient from Hell (00:28.466)
Thank you.

The Patient from Hell (00:42.898)
Let's start with what was the big, big, big take away from ASCO this year?

Douglas Blayney, M.D. (00:47.791)
Well, as a doctor who treats breast cancer, I thought it was important that we're having a lot of alternatives to chemotherapy. So even though some of the studies were portrayed as negative because they didn't improve overall survival, I think pushing out the time a patient gets chemotherapy and its associated toxicities is a major advance.

Some of the things I think we'll touch on later include antibody drug conjugates, immunotherapy, and some of the targeted oral therapies that are emerging. So those were, I thought, there were some big hits, there were a lot of base hits and singles.

The Patient from Hell (01:39.314)
We're going to be using baseball metaphors. Okay. All right. We will have to do some one-on-one stuff. Maybe on some baseball terminology for me and then chemo cancer terminology for everybody else. So why don't we, let's start with, let's start with ADC. What is it?

Douglas Blayney, M.D. (01:41.134)
It's baseball season.

Douglas Blayney, M.D. (01:53.935)
Okay.

Douglas Blayney, M.D. (02:00.528)
Okay, ADC stands for antibody drug conjugate. I suspect most of our community is familiar with monoclonal antibodies. Monoclonal antibodies are natural human proteins. So you and I, when we get a cold, we develop antibodies against the virus that is that species of cold.

When we get a tetanus shot, we develop antibodies against the tetanus toxoid or the bacteria that could infect us. So taking that concept a little deeper, monoclonal antibodies are engineered or the antibody producing cells are taken out of the body and grown in petrodysis test tubes, sometimes animals, et cetera.

to produce an antibody that's directed at a very specific antigen or protein or target on a cell. So, Trastuzumab or Herceptin, it is probably the most famous monoclonal antibody. It's directed against the HER2 protein that is on the surface of many breast cancer, of about 25 to 30 % of breast cancer cells. So, Trastuzumab is the prototypic

monoclonal antibody probably known to your listeners. So, Trastuzumab is what I call, and many do, a naked antibody. So, it's just an antibody. It kills cells, and particularly cancer cells, that express the antigen by activating the body's own immune response mechanism.

So it seeks, the Trastuzumab seeks out the HER2-bearing cancer cells and activates the body's immune system around those cancer cells and the body immune system degrades and kills those cancer cells. So that's a naked antibody. The antibody drug conjugates have a, typically a chemotherapy molecule.

The Patient from Hell (04:16.69)
Thank you.

The Patient from Hell (04:20.594)
Thank you.

Douglas Blayney, M.D. (04:25.969)
that's attached to the antibody with a little linker protein or that linker series of amino acids. So it's really a magic bullet, which is the antibody, with a payload, which is a small amount of chemotherapy. The way antibody drug conjugates work is that the monoclonal antibody seeks out the cancer cell.

The Patient from Hell (04:30.834)
Thank you.

The Patient from Hell (04:40.754)
It's a terrible thing to do to assist with other people's health. But any other person who's going through it, they're going to be sick, they're going to be in a lot of pain, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick, they're going to be sick

Douglas Blayney, M.D. (04:55.025)
the monoclonal antibody gloms onto or attaches to the cancer cell. The cancer cell ingests that antibody or tries to get rid of it and brings it internally inside the cell. As it ingests and breaks down the antibody, that linker is removed and then the chemotherapy drug is released inside of the cell.

And it's not typically, it's not released elsewhere in the body. So there are no, there are very few or no HER2 positive cells in the bone marrow. So that chemotherapy drug does not go to the bone marrow and produce some of the damages that chemotherapy produces of white cells, platelets, and red blood cells. So anyway, I'll stop there. You have a question.

The Patient from Hell (05:52.626)
I have a few questions. You know me well by now. Let's actually go all the way back. Why is chemotherapy so toxic to the full body?

Douglas Blayney, M.D. (06:02.641)
Well, it's not toxic to the full body. Chemotherapy drugs are developed to have toxicity or poison to the cancer cell and sometimes there's bystander effects to the other normal parts of the cells. Typically, chemotherapy damages fast-growing cells. So when you...

you take an oral chemotherapy drug or have it put into the vein, the chemotherapy goes all through the body. And if there are fast growing cells, those cells can be damaged by the chemotherapy. One of the fast growing cells in the body is the cancer cell, and that's why we use it. But other fast growing cells are those in the bone marrow that make red blood cells, white cells, and platelets. And...

the damage to those cells, those precursor or producing cells is temporary. Similarly, other fast growing cells align the GI tract from the mouth on down. And that's why some of the chemotherapy causes mucositis or stomatitis or sores in the mouth and other kinds of sores.

And also, some of us have fast-growing cells in our hair, and that's why chemotherapy can damage the hair cell precursors. Our body has developed compensatory or compensating mechanisms, so that damage is only temporary. Hair regrows, mucositis heals up, and the white blood cells heal up. So...

And there are other toxicity of chemotherapy, including on the nerves sometimes, et cetera. But that's sort of a general introduction to the toxicities of what we call cytotoxic chemotherapy or CITO is cell, toxic is poison. So poison chemotherapy.

The Patient from Hell (08:16.69)
So it's fair to say that the ADC won't cause the same cytotoxicity profile as a general chemotherapy drug.

Douglas Blayney, M.D. (08:27.541)
As a first pass, what are called first generation antibody drug conjugates or ADC like TDM1 was developed so that the chemotherapy payload was kept inside of the cancer cell,

and there was very little leakage outside of the cancer cell. There's some, but it's very small. The second and third generation antibody drug conjugates were designed so that there's a small amount of leakage outside of the cancer cell. So for instance, in HER2 or Trastudumab -Deroxetan,

has a little different characteristic. It's still Trastuzumab, or still herceptin, as the seeker or the magic bullet. But the payload leaks out of the cell and damages the surrounding cells. So that's why it's called a bystander effect. So the TD in HER2 has some leakage.

And if not all of the cells, the cancer cells in the tumor deposit are HER2 positive, that bystander effect can kill nearby cells that are not HER2 positive. So that bystander effect is now the next thing that is being explored and tried to be taken advantage of.

So there, you know, women who, the patients who have been on TDM-1, the first generation antibody, sometimes after months will have their hair thin, so there is some leakage of a payload. But the bystander effect antibodies, that is a designed or built-in effect of the...

Douglas Blayney, M.D. (10:52.566)
designed of the antibody drug conjugate. It may, just one last note, that may be important to understand the toxicity of these antibody drug conjugates in HER2, for instance, as pulmonary or lung toxicity, or there may be some lung damage associated with N-HER2.

The Patient from Hell (11:20.082)
Thanks.

Douglas Blayney, M.D. (11:21.879)
Probably, maybe, because the antibody gets trapped in the circulation or in some way and leaks out. Again, it's rare, it's treatable if caught early, but it's something that gives us hesitation or pause to bring it to the so -called adjuvant setting. We can talk about adjuvant treatment, but

adjuvant treatment means after surgery. So women or men with other kinds of cancers who have had their tumor completely resected and may very well be cured and live a very long time, we want to be careful about bringing these antibody drug conjugates which have side effects which may be long-standing and may be permanent.

to somebody who's gonna live another 30 or 40 years, or 50.

The Patient from Hell (12:23.474)
I have lots of questions, which should not surprise you.

Douglas Blayney, M.D. (12:27.094)
Okay.

The Patient from Hell (12:29.362)
Let's go first with, I think you said something about the bystander effect is designed.

Douglas Blayney, M.D. (12:37.591)
The bystander effect, yes. So it's like dropping a bomb in the middle of a targeted bomb that may be directed toward brick buildings. But the explosion on that brick building may also damage the surrounding log cabins and concrete buildings and parking lots. So that's an illustration of the bystander effect.

The Patient from Hell (13:05.618)
So why, so the thing that I'm sitting with is in the first generation, the M1, the bystander effect is happening but not designed.

Douglas Blayney, M.D. (13:17.144)
No, it's very small and TDM1, there's 20 or 30 years of development and a lot of companies came and went because that linker that they had that linked the monoclonal antibody to the poison wasn't effective. So there's been a lot of design energy and time in making sure that, and picking the

payload or poison so it doesn't leak out. So in the first generation, again, when we were new at this, we didn't want to cause a lot of toxicity. The first generation did not have the bystander effect. I can remember the first time I heard about and heard to, I thought that was crazy. Why would they, you know, this bystander effect, that's going to cause a lot of toxicity. It just goes against everything. And like,

And I was wrong. So, and fortunately I was.

The Patient from Hell (14:20.69)
So back to where I was going with this. What about the bystander effect is actually helpful? Because there is some benefit.

Douglas Blayney, M.D. (14:30.169)
Yes. So, again, to come back in the HER2 world, if you look at, if you take out a tumor deposit and you look at it under the microscope, there's a broad range of cells that express the HER2 on their surface. And it's unusual to have every cell in a tumor express HER2. And...

And once you see it, it's something you can't unsee. But there in many tumors, there'll be a sparse or very few or scattered cells that express HER2. One of the ways this may be familiar is that the grading system or the IHC, many tumors are graded.

3 plus, 2 plus, 1 plus, 0. That's a very subjective measurement. I may look at the pictures in your background and say, I see a bunch of orange pictures. And you may say, no, those are peach. And I see a yellow one. No, that's sunrise or something. So again, two people may judge a 2 plus and a 1 plus,

very differently. So that's one problem with the IHC measure. It's fairly subjective. So I don't know how deep you want to go into the IHC because it has a lot to do with some of the new drugs that are being, new and existing antibody drug conjugates that are being tested.

The Patient from Hell (16:24.05)
We should talk about IHC but before we talk about IHC, I just want to close out the previous conversation. If I understand right, The first generation

was like a sniper rifle.

Douglas Blayney, M.D. (16:41.913)
Yes.

The Patient from Hell (16:42.386)
And the second generation is like a targeted bomb. And the advantage...

Douglas Blayney, M.D. (16:46.33)
yeah, it's more like a bomb. Yes. It's hard and a targeted bomb is it damages, adjacent structures rather than exactly where you aim that magic bullet.

The Patient from Hell (17:00.786)
And the advantage of the targeted bomb is that because not all cells are expressing or showing the HER2 protein, but they are tumor cells, the targeted bomb actually is a good thing because you're capturing more of the tumor. Huh, fascinating. The nerd in me is very happy right now. The patient in me is not at all happy, but we'll put that aside.

Douglas Blayney, M.D. (17:18.713)
Yes.

Douglas Blayney, M.D. (17:22.649)
Yeah.

The Patient from Hell (17:30.546)
Bye.

Douglas Blayney, M.D. (17:31.643)
Well, okay, but let's talk about that because that goes to the a lot of the work that's being done on antibody drug conjugates is exploring how rare is the target and how rare, even if you have a rare target, the drugs can be effective. So now, as we talked about a minute ago, IHC has since

The Patient from Hell (17:33.074)
Can we?

Douglas Blayney, M.D. (18:01.531)
It's been since HER2 was, since Trastuzumab and HER2 expression was discovered. IHC has been part of the picture and classically the naked antibody was only useful in HER2 3 plus or IHC 3 plus tumors. Because probably, and because every cell, every cancer cell had to have that

antibody on it to activate the body's immune system. Again, the body's immune system is like a sniper to use your sniper rifle, to use your analogy. And only because the immune system, as we're discovering, when it goes awry, it can cause widespread damage. Anyway, the 3 Plus. It was noticed with the...

second and third generation and ADCs that had this bystander effect. It was noticed they were effective in 1 plus and 2 plus tumors. So it turns out not in zero tumors, but in 1 and 2 plus tumors. So that's why in HER2 has been widely, or one of the reasons in HER2 has been widely used as a set of

for metastatic cancer is that even conventionally HER2 negative tumors can respond because of this bystander effect to and HER2.

The Patient from Hell (19:44.146)
Okay, so dumb question, HER2 low? What is that?

Douglas Blayney, M.D. (19:49.404)
That's a good question. And one of the emerging issues is what is HER2 low? Today, as we sit here today, HER2 low is probably one or two plus, IHC one or two plus. There was talk at this meeting last week of, gee whiz, what is HER2 ultra low? What is HER2 ultra low?

And you know how low there's a whole session on how low can you go? I think the conclusion is that the IHC was not really designed to predict who's going to benefit from these monoclonal from these antibody drug conjugates and that that's turning out to be true not only for her Trastuzumab or Herceptin based antibodies HER2,

but also for other targets like Trope 2, etc., that are coming along. So we need, I think most people in this field think we need better assays to predict who's going to respond to these ADCs, which again, we're learning that they're here to stay. We're learning a lot about them. We're learning a lot about them.

And they're a boon, a great benefit to a lot of people with breast cancer and other cancers that we're learning about.

The Patient from Hell (21:28.786)
What is an assay?

Douglas Blayney, M.D. (21:31.07)
An assay is a test. So in the sense that we use it is if you take a tumor or a bunch of cells, and remember a tumor is a collection of cells, cancer cells and also what are called stromal cells, which support, provide structure to the tumor mass,

and blood cells and other kinds of cells that form that tumor and you do some kind of test. It's a general term for test. What we've been talking about is IHC. So what that is, is you take a tumor, the pathologist takes a tumor, slices it very thinly. So attempting to see just one layer of cells and remember,

a cell is about six or eight microns thick, and micron is a thousandth of a millimeter. So again, very, very thin. You have a single layer of cells, and then you put some kind of stain on the cells. You fix it, or essentially pickle it, so it doesn't rot or deteriorate. And then you stain it with, then one stains it with various stains. And the.

What we talked about IHC is immunohistochemistry. Immuno refers to use a monoclonal antibody essentially, or a protein in the immune system. Histo means cell, and chemistry is you add a stain that lights up when you shine light on it to that.

cocktail or that staining solution. So an assay is basically a test.

The Patient from Hell (23:30.642)
So I want to actually, I'm going to deviate from my script a little bit. Sorry. You know your point in the image behind me, right? If two people look at it, they're going to see different things. So today, the way pathologists are reading an IHC slide is you have basically eye reading, right? There's a human reading it. So you're naturally prone to human error. So now my question is in the world of AI,

Douglas Blayney, M.D. (23:54.974)
Yes.

The Patient from Hell (23:58.418)
Why in the world is a pathologist reading a slide? Why are we not making this all machine read?

Douglas Blayney, M.D. (24:06.048)
Well, there have been fortunes spent and lost answering that question. We will get there. I guess the issue is that, you know, looking, and this is fun, I spent a whole month in medical school looking at slides and it was fun. I mean, it was fun. But it's like looking at a city

from 10,000 feet and saying, I want to find where the Starbucks are. How do you do that? Well, maybe the Starbucks are all on the first floor of the buildings, but what about if they're in the third floor and you can magically see through the buildings? But what if they're on the fourth floor? And what if they're on the rooftop? You're going to miss some of those if you only look at ground level. And when you use a microscope, you have to, you,

focus up and down to see what's on the top floor and what's on the middle floors and what's on the ground floors. So that third dimension, if you will, adds complexity to the AI. In medicine, in general, AI has been applied to chest x-rays and to mammograms. And it's probably as good or maybe

can be a little better than radiologists. But again, both of those are two dimensional. A mammogram pathology slide, even though it's very thin, is three dimensional. That's just one issue. Remember, a mammogram looks at one part of the body, and a chest x-ray looks at another one part of the body. It's the pathology thing is more like looking at a

10 people all together trying to find, I guess the Starbucks analogy is a little better, you know, because you're looking at a broad field and trying to focus in on stuff. That's part of it. And part of it also is that there's a huge amount of data just in a small tumor. Even now, when you do it by hand, by eye or hand, there can be 30 slides.

Douglas Blayney, M.D. (26:31.84)
from one breast cancer tissue. So that's another issue as far as I can understand. Again, I'm not an expert on this, but as a first pass, those are the two things that spring to mind.

The Patient from Hell (26:47.634)
So, everybody, let's do this side as a transition into what is the assay for PBL 1.

Douglas Blayney, M.D. (26:53.248)
Well, that's another problem. There's not just one assay. Your viewers, our community may know that the FDA, the Food and Drug Administration, which approves drugs for marketing, has attempted to say, okay, if you have a targeted therapy or you have a monoclonal antibody,

which has a target, a sponsor or a pharma company also has to develop a companion diagnostic assay with that drug. So that's added some complexity and some necessary complexity for the targeted therapies, which I think is a good thing for patients, but it makes.

drug development, it has several dimensions of complexity, which means time and which means expense to drug development. So having said that, PD-L1 has been noted and it's, I forget what PD -L stands for, but the L stands for ligand. So there's a protein again, which activates the immune system.

And the ligand is the protein that either circulates or is on the cell and ligate and is ligated or joins ligand to the target on the immune cell. So anyway, early on when many of these drugs were developed, the companion diagnostic was a guess. You know, we thought we knew what, how to measure PD -L1, it turns out, and PD -B1.

It turns out that sometimes you find it on the tumor cell, sometimes you find it in the surrounding stroma, we call it, or the cells that live around the cancer cell and support its growth, provided, you know, nutrients and blood and stuff like that. So that's a long way around saying there are several different assays. Atesolizumab.

Douglas Blayney, M.D. (29:20.771)
which was a drug developed by Genentech in breast cancer, had its specific companion diagnostic, and atezolizumab was shown not to be effective. Pembrolizumab has a different companion diagnostic. Turns out, Pembrolizumab is effective in triple negative and preventing recurrence of triple negative breast cancer after surgery, and it has a different

a companion diagnostic or a different assay in use. So six or eight years ago when we were at Stanford where I was practicing, we had to specify which drug we wanted to use because atezolizumab we were participating in the clinical trial. If a patient was going potentially to be on that clinical trial, we had to specify one assay

or another assay and now Pembro is the only, so far, is the only drug approved for use in breast cancer. So that sort of makes the default assay important. Okay, so that's first generation thinking, to use the analogy we talked about earlier. Second generation, gee whiz, it may not matter what the PD-L1 expression or PD expression on the tumor is

or what it is on the stroma, and that's being explored. So some of these, it's called, it's PD agnostic clinical trials are underway. Agnostic meaning we don't know or we don't care what the expression is.

The Patient from Hell (31:07.186)
So dumb question, if I'm a cell, I can express HER2 and PD-L1?

Douglas Blayney, M.D. (31:14.179)
let's see, you can, yes, I think so. Yes. But it's, it's, it's possible, but it's a little unusual. Most hurt, most trip.

The Patient from Hell (31:19.026)
So in that case,

Douglas Blayney, M.D. (31:26.661)
So as we sit here today, triple negative breast cancer, meaning HER2 negative, many of those are treated with the PDO, anti -PD, you know, some immune checkpoint inhibitor treatment. Again, not as successfully as HER2. And again, we're early in our understanding of this. And I think I represent,

the fields thinking in this. I don't hold myself out as an expert. I think even the experts are n– uncertain of what all this means.

The Patient from Hell (32:09.714)
So the reason I ask you that is I'm gonna go all the way back to our Moab.

Douglas Blayney, M.D. (32:16.452)
Okay, the monoclonal antibody.

The Patient from Hell (32:19.314)
The monoclonal antibody is sitting under the broad umbrella of the immune system. Of our immune system. The reason it's active is because it's an antibody which from a biological perspective is coming from our immune system. Correct?

Douglas Blayney, M.D. (32:26.628)
Which.

Douglas Blayney, M.D. (32:38.726)
Well, yeah, the immune system is engineered to produce those antibodies, those monoclonal antibodies. Some of the monoclonal antibodies, well, stepping back, monoclonal antibodies have what's called a fragment of antibody or FAB, and then they have a fragment.

C or FC fragment constant and the the FAB is the specific that binds the antigen whether it's HER2 or TR2 or the tetanus Protein or whatever, the FC fragment. There's several FC fragments some of them activate the immune system and some don't Some of the FCs don't I think there's five or six again, I don't know the exact number but the

But when they design, when Genentech or whoever it is designs these antibodies, they design the FC fragment on it. And some of the, there was an anti-HER2 treatment that had, that was a naked anti-HER2 monoclonal that was more immune activating than Herceptin. And it,

that turned out not to be clinically important. I forget the name of the company, but it's not one that most people recognize these days. Anyway, so yes, the naked antibody has a small immune activating mechanism of action.

The Patient from Hell (34:10.962)
Interesting.

Douglas Blayney, M.D. (34:33.222)
the what I think you're where I think you're going is the checkpoint inhibitors really rely on a set the activation of the immune system, of the immune native bodies and native immune system to get rid of the tumor.

Douglas Blayney, M.D. (34:58.118)
And, and they, well, so it's thought, that you and that normal, that people without known cancer develop one or two, cancers a day, small little bitty ones and our body's immune system recognizes that as foreign and eats them up and the cancer doesn't grow and proliferate.

The Patient from Hell (34:58.322)
How?

Douglas Blayney, M.D. (35:28.231)
One of the ways cancer grows, especially in adults, is immune escape. So somehow the brakes are put on the immune system at some point when that cancer develops. The IO checkpoint inhibitors are thought to work by taking off those brakes.

The Patient from Hell (35:56.818)
Interesting. Interesting. Okay. I'm gonna go do something that it's not exactly the cleanest transition, but we're gonna make it. Something you said is a normal person is every day you're making these like one or two cancer cells and your body's immune system is going after it and basically eliminating it.

Douglas Blayney, M.D. (36:08.742)
Hahaha.

The Patient from Hell (36:28.082)
So today, the vast majority of solid tumors, we are using imaging modalities to identify that the cancer exists. Right, so mammogram, low-dose.

Douglas Blayney, M.D. (36:38.984)
and physical exam or symptoms. You know, if a tumor, I feel something in my breast, okay, we got to check it out. Or I'm coughing and it's going longer than my normal cold cough, we need to do a chest x-ray. So, symptom and physical exam. Yeah.

The Patient from Hell (37:03.314)
Symptom, physical exam, imaging. Now we have this whole new field around liquid biopsy and ctDNA and exosomes and CFDNA and magical things that are floating in my blood that again, the nerd in me is really excited about the patient in me. I really don't know. So if your body is already creating these cancer cells all the time.

Douglas Blayney, M.D. (37:05.447)
imaging.

Douglas Blayney, M.D. (37:11.783)
Yes.

The Patient from Hell (37:32.082)
And you have these, at least what is being marketed as these ultra sensitive tests. How do we reconcile those two things?

Douglas Blayney, M.D. (37:42.023)
Again, an armchair expert like me and real experts are engaging in a lot of controversy about this. So if you think about, I think what I think about being over 50 and having screening colonoscopies. So it's been known probably for 30 years or so, Burt Vogelstein at Hopkins mapped out the progression

from a polyp which is– looks, a polyp in the colon which looks like a wart and as time goes by that polyp accumulates more DNA damage and damage and damage and those damage occurs on certain cells then that polyp turns into an adenoma then it turns into a malignant adenoma.

And then it turns into a full-on cancer in the colon, and then that cancer that's in the colon spreads. At each stage of that development, there are DNA abnormalities, and they accumulate in that development. So it's been known for a while that if you, that DNA, or the cells of that polyp,

that slough off and put that DNA in the stool. And then when those adenomas develop, they also slough, die, and put that DNA in the stool. And that is the basis of what's now marketed as the Cologuard test. So, Cologuard, you send in a sample of stool. That comes from the laboratory two or three weeks later. there's no, the DNA is all normal,

or there's some suspicious DNA mutations that we've detected, you need to go for a colonoscopy or something like that. So that's in the stool where the polyp dies and sloughs off and puts DNA in the stool. It was thought and probably is correct and it certainly is correct that there are.

Douglas Blayney, M.D. (40:04.97)
The same thing happens with cancer cells that might arise in the breast and the pancreas and the colon and the lung, etc. And those DNA fragments can sometimes break off and circulate in the blood and be detected by assays. So, assays tests, again. So, if you...

You know, so when you, well, I, as a kid growing up in California, went out in the sun a lot and I got a lot of sunburn. And sunburn damages the DNA in skin cells. And so how do you, you know, so part of the thing is with the circulating DNA tests is that picking up damage from my skin cells from a sunburn I got when I was 10 years old.

Or is it picking up damage from a tumor that's maybe starting in my pancreas? So that's one issue with these tests. The second issue is how sensitive is this? So it's much like the volume control on an old fashioned radio.

when you turn up the volume to hear, you know, to try and hear very weak stations, you may get a station from Pittsburgh, you may get a station, and a station from San Francisco, depending on, you know, the atmospheric conditions, the noise, all of that. So, again, the sensitivity of the test is an issue of how many times you.

try and amplify those DNA things. Each amplification induces errors and those errors accumulate. So if you do 30 amplifications, there's going to be more errors in it than if you do 20 amplifications. But 20 amplifications may not pick up that one or two or five or 30 cells that are

Douglas Blayney, M.D. (42:31.499)
going to lead to a cancer in the breast or pancreas or wherever it is. So that, I don't know if you want to go into screening or if you, because these tests are used for screening. I think there's issues with that because there's a lot of false positives and you know, you hear the testimonials of the cancer that was discovered. Okay.

The Patient from Hell (42:35.442)
Have fun.

Douglas Blayney, M.D. (43:01.133)
you know, I think that's being sorted. That's valuable, but there's a lot of, biopsies and stuff that were unnecessarily because of that. And I, we're going to get there, but we're not there yet. More important, perhaps more of interest to our listeners or community is, for people with known cancers, do they slough?

DNA or when the cells die, do they slough or shed DNA into the blood? And for many cancers, the answers are really they also they all shed DNA into the blood. But is that DNA normal or is it tumor DNA? And I think for most cancers, if you look hard enough, there is DNA that's tumor DNA.

that's shared into the blood.

The Patient from Hell (44:00.402)
Interesting. Dr. Blayney, I'm gonna try and wrap up our podcast, because as usual, we're almost out of time. I know you and I can keep talking about this stuff basically for hours. But if we had to summarize the sort of like key highlights for the metastatic breast cancer community that happened last weekend at ASCO 2024, what are they and why do they matter?

Douglas Blayney, M.D. (44:26.7)
Okay, so we talked earlier about the monoclonal antibodies. I think we're getting understanding how to use them and we're understanding how to use them to put off and defer the use of chemotherapy with its toxicities. So that's the monoclonal antibodies. Secondly, we're understanding more and more about the immune checkpoint inhibitors.

the Pembrolizumabs and others of the world and how they're making steps in triple negative breast cancer, which has been a real problematic cancer to treat. We're also learning how to combine monoclonal antibodies with the IO inhibitors. Many, you know, the IO inhibitors have, IO checkpoint inhibitors have toxicities.

some of those toxicities add to the monoclonal antibodies. So we're learning how to combine them again to put off cytotoxic chemotherapy. And what we were just talking about, the circulating tumor DNA, we know if you have a metastatic cancer and the circulating tumor DNA goes down, that's a good thing. If it doesn't go down or...

If it comes back up, we don't know what precisely what to do with that information. So we can't, we know that going down is evidence of a good prognosis, but either not going down or coming back, we can't predict what treatment is going to be useful in that setting.

And finally, we're learning more about the assays, looking at targeted tumor assays, which for ESR1, which is an estrogen receptor mutation, and PI3 kinase or PIC3 kinase, which can help with a targeted therapy.

Douglas Blayney, M.D. (46:47.182)
The patient should have those assays at various steps in their treatment. It's not just one and done. It's something that needs to be, is more important to be done as time goes by.

The Patient from Hell (47:04.306)
Amazing. That feels like a lot of progress in the last year.

Douglas Blayney, M.D. (47:07.758)
it's exciting. Yes. Again as, as we've talked, I think in other venues, it's like drinking from a fire hose. even, you know, some of the ex, yeah, a lot of the experts, don't agree on the precise, what this precisely means, but, but again, we have options and we, for some, for some, you know, young women are going to be treated differently and we have a lot more options than perhaps older women or women with, and men with,

comorbidity. So we have a lot of options and I think that's as exciting as anything.

The Patient from Hell (47:44.658)
I love that, such an optimistic note. So thank you. Thank you for joining us on this podcast again. Thank you for sharing your wisdom with us. Thank you for teaching us. As usual, this was always fun, Dr. Blayney.

Douglas Blayney, M.D. (47:47.198)
Yes.

Douglas Blayney, M.D. (47:54.19)
Okay.

Okay, thanks Samira. It was great to engage with you and your audience and our community.