[00:00:00.110] - Dr Lemanne

You come to the realization that the more you treat it and the harder you treat it up front, the worse the patient does. Dr. Gatenby recently told me that the main mistake that they and other oncologists make was overtreating these prostate cancer patients. That made them worse because it hastened the development of resistance. Giving testosterone to a patient with prostate cancer, that's a new idea.

[00:00:27.690] - Dr Gordon

That must have driven some oncologists in the world crazy until they read why you were doing it.

[00:00:33.390] - Dr Lemanne

I think so, but it worked. You can't argue with the data. You have found your way to the Lemanne-Gordon podcast where docs talk shop. Happy eavesdropping. I'm Dr. Dawn Lemanne. I treat cancer patients.

[00:00:56.020] - Dr Gordon

I'm Dr. Deborah Gordon. I work with aging patients.

[00:00:59.720] - Dr Lemanne

We've been in practice a long time.

[00:01:01.520] - Dr Gordon

A very long time.

[00:01:03.720] - Dr Lemanne

We learn so much talking to each other.

[00:01:05.860] - Dr Gordon

We do. What if we let people listen in? So we're going to do something a little different today because as we listen back to this conversation, we realize that some of the ideas we discuss are quite different from the way most people, including most physicians, have traditionally thought about cancer. So we've recorded a few short explanations and inserted them throughout the episode. These are clearly marked when they occur. But one important point before we begin: nothing in this episode changes the standard approach to cancers that can be cured. If a cancer can be eliminated with surgery, radiation, chemo, or another proven treatment, That remains the goal. Today's discussion is about a different situation, cancers that have already spread throughout the body and cannot be completely eliminated with current treatments. So the question we explore is whether in some of those cases, a new approach might be merited. The approach of understanding and managing cancer evolution may help us control the disease for longer. Now let's begin. You've been delving into some new territory in terms of cancer treatment, is that right?

[00:02:35.850] - Dr Lemanne

That's right, and I think it's a little bit difficult for people to understand at first because it's so at odds with how people think about and how doctors and oncologists still think about treating cancer.

[00:02:52.410] - Dr Gordon

So we thought a little explanation here might help. Most cancer treatment is based on a simple idea: kill as many cancer cells as possible as quickly as possible.

[00:03:04.470] - Dr Lemanne

And when a cancer can be cured, that's exactly the right thing to do. The challenge comes when a cancer has spread throughout the body and current treatments cannot eliminate every cancer cell no matter what. In, in that situation, a really different problem appears. The treatment may kill the sensitive cancer cells while leaving behind a small population of treatment-resistant cancer cells, and those resistant cancer cells then have the opportunity to grow without any competition from their sensitive brethren.

[00:03:38.500] - Dr Gordon

So the central question of this episode is not whether treatment works, it's whether in some metastatic cancers treating less aggressively at certain times might actually delay resistance and prolong control of the cancer population. People, doctors, and oncologists, sometimes those even overlap. But you're right, sometimes those are separate categories. And it is— I've learned enough from you to be— have a little bit of a calming down influence. But I have patients who want to get tested for every cancer in the book, whatever that wide-ranging test is that you can test for cancer cells anywhere, and I think they probably want to have that part of their body cut out.

[00:04:24.400] - Dr Lemanne

Oh, the pan-cancer screening tests?

[00:04:26.000] - Dr Gordon

Yeah.

[00:04:26.920] - Dr Lemanne

Yeah, I think they're great. Do you? I do. I think that people who are worried about cancer and are open to the psychological implications of this ought to have that test if they want it.

[00:04:39.620] - Dr Gordon

And what kind of cancers, at what kind of stages are they picking up?

[00:04:43.300] - Dr Lemanne

They're picking them up years before current imaging, blood tests, and symptoms pick things up. So if you find something at that particular point, it's much more likely that you can cure it. Even things that aren't curable otherwise, when people usually present, like pancreatic cancer. So yes, if you find pancreatic cancer 3 years before before you would have found it with the usual methods, which are again imaging, blood tests, and usually symptoms for pancreatic cancer. And the disease is very likely to be incurable at that point, whereas it is very curable if it's caught that early. So it's an evolving test. It's not perfect. I think one of the main companies that makes one of these called the GRAIL Galleri test— GRAIL is the lab and Galleri is the test— the pan-cancer screening test. It's a blood test. It looks at cell-free DNA. Looks for little pieces of dead cancer cells, not cancer cells, but just little pieces of the DNA in the blood that might match up with cancer. And it can detect 50 different types of cancer, they claim. It's not perfect. It doesn't pick them all up. The most common direction of the error is to miss a cancer.

[00:05:58.020] - Dr Lemanne

But it can also say there's a cancer, and we look, and we don't find one.

[00:06:02.020] - Dr Gordon

So both false negatives and false positives.

[00:06:04.600] - Dr Lemanne

I think the false positives probably aren't false. They're probably just cancers that are so small, but that the person's body is successfully controlling at that moment. I think that may be at least some of the answers to some of those quote unquote false end quote positives.

[00:06:20.010] - Dr Gordon

So one of my reservations has been alluding to a phrase you just had there, which is, doesn't it happen sometimes too that the body actually successfully manages a cancer incursion?

[00:06:34.270] - Dr Lemanne

We think so, but we don't know that very well. And so if you find something like, "Hey, you have a really early pancreatic cancer," and we can— and we look really hard and we find it, you probably want to have it cut out. Not wait and see what happens, because usually what happens, we think, is that it's going to grow. Certainly we know very little about very early cancer because until now— this is changing, this is one of the things I want to talk about today— but until now, we haven't been able to see cancers until they're a billion cells big. So a CT scan doesn't show a tumor until it consists of a billion cells.

[00:07:08.440] - Dr Gordon

Wow. That's been dividing for some time, replicating or whatever they call themselves. To get to a billion cells, that's been there for a while.

[00:07:17.460] - Dr Lemanne

Yeah, that's about a centimeter in greatest dimension. Yeah. So new tests, new tools allow us to make progress in any field of human endeavor. And there are so many new wonderful tools coming out now that are flooding the cancer-verse. And we oncologists are struggling to keep up, but I think there's a lot of hope in the tools. Until now, we've been— everything is a hammer. Excuse me, everything is a nail. All we have is the hammer of chemotherapy and targeted therapies, drugs. And so everything looks like a nail that you just hit and pound and pound. And now we have some new ideas. We can change the metaphors that we use to think about cancer. And improve the outcome.

[00:08:05.300] - Dr Gordon

Don't you just wanna take a scorched earth, and I know I'm speaking for, I'm speaking out of total lack of information of the brilliance that I know you are beginning to work, are working on, I'm beginning to understand, because there has been, let's just take a scorched earth policy to any approach to cancer, that's still commonly treasured, isn't it? We got, I'm so happy, doctor said all the cancer is completely gone, every cell's gone from my body. Isn't that what the doctor and the patient try to hear and say?

[00:08:36.750] - Dr Lemanne

I think what you're talking about is the idea that we should, if cancer is diagnosed, you want to hit it as hard as you can, as soon as you can. You want to cut it out. You want to give chemotherapy. You want to give radiation therapy. You want to kill as many cancer cells as fast as you can. And you keep doing the treatment until you're sure you've killed as many as you can. Or the patient starts to say, "Hey, you're gonna kill me," and you just keep going. And that is appropriate in a very specific slice of oncology, and that is where current treatments are curative. So, stage 1, 2, or 3 breast cancer, stage 1, 2, or 3 colon cancer, any cancer that is curable in its earlier stages is a candidate for that kind of approach. You want to get rid of all the cancer cells and you wanna do it quickly. Alright? Surgery is not necessarily the best way to do that anymore, but there are a lot of problems with surgery that we're starting to understand, like any operation, not just cancer surgery, but any operation suppresses the anti-cancer part of the immune system for at least 4 weeks and often longer.

[00:09:51.510] - Dr Lemanne

So any cancer cells that are around have a good chance of coming out of any dormancy no matter where they are in the body, they don't have to be near the operation site, they could be far away. You could have an operation on your leg and you have some dormant cancer cells in your lung, and for that 4 weeks while your immune system is recovering from the operation on your leg, those cancer cells in your lungs can get going. They come out of dormancy and start growing because the immune system has been disabled.

[00:10:16.600] - Dr Gordon

And is it just that surgery is a more powerful intervention than somebody getting a cold or—

[00:10:23.160] - Dr Lemanne

No, so COVID seems to do the same thing.

[00:10:25.890] - Dr Gordon

Oh.

[00:10:26.330] - Dr Lemanne

So COVID seems to suppress the immune system in ways that can allow cancers to suddenly start growing. So you've heard of maybe turbo cancer, and I think that what's going on there, I think there's two things.

[00:10:38.730] - Dr Gordon

And say a little bit about, can you just?

[00:10:40.390] - Dr Lemanne

Turbo cancer. So there was a, some people call it a rumor or a conspiracy theory that COVID or COVID vaccines can turbocharge cancers. It's a little more complicated than that, but not super complicated. What we saw early in the COVID epidemic was that some people would get a really bad case of COVID and they'd finally recover, 2, 3, 4 months, they'd be in the hospital, et cetera, and then a cancer would appear, and it would often be a very aggressive cancer, and so there's possibly two things going on. I'm not making these ideas up myself. I'm passing along things that I think are worth thinking about for all of us, and number one is that yes, the COVID seems to, in some people, very much suppress the immune system. However, another idea that I think is quite brilliant and worth looking into, I'm not saying it's right, but I think it's really interesting, is that patients who had a dormant cancer that their body was— Handling. Handling, but maybe having a little trouble handling, then got COVID, the COVID completely distracted the immune system.

[00:11:47.060] - Dr Gordon

That makes sense.

[00:11:47.740] - Dr Lemanne

And the cancer was able to take off, hence the turbo cancer. So I think that possibly both of those are worth looking into. I don't know which one is correct or if Neither one of those is correct, but those are some ideas that have come along. But back to surgery, radiation, chemotherapy as treatments for cancer, the idea with those is to get rid of the cancer cells, period. And again, that is currently the correct approach if the cancer is curable with those approaches. But when you think about the cancers that are— the cancers of late adulthood, like prostate cancer, breast cancer, colon cancer, pancreatic cancer, when those cancers are out of the cure range of standard therapy, and that is when they're stage 4, and there are other cancers that I'm not mentioning, but—

[00:12:35.220] - Dr Gordon

Okay, I think of glioblastoma.

[00:12:37.460] - Dr Lemanne

Glioblastoma, we should probably put in its own category. It's a very different type of tumor. It's behind the blood-brain barrier, and it doesn't ever metastasize to other parts of the body, but I'm gonna put that in a separate container for now, but for the common, and it's not that common, It's not super rare, but it's not as common as, you know, metastatic breast cancer, metastatic prostate cancer, metastatic lung cancer, metastatic pancreatic cancer, metastatic colon, colorectal cancer. That's a biggie. That's the number one killer, cancer killer of people under 50. Colorectal cancer right now. I don't think people understand that.

[00:13:10.610] - Dr Gordon

Yeah. We can't say that often enough. And it does come up in the news really often. And I don't want to distract completely, but There's some attention as to why that's happening. Listen to our episode on ultra-processed foods. But okay, circling back to in the years, primarily in later years, where those 4 cancers can common— fairly commonly present at a metastatic form.

[00:13:35.930] - Dr Lemanne

Exactly. Those are the places where we're starting to look at, thanks to some new tools that we have, like circulating tumor DNA. And I'll talk a little bit about that later. But we're starting to look at how we treat those cancers and how we, and before that, how we think about those cancers, because how we think about those cancers determines how we treat it. If we think about it like an enemy that must be completely eradicated, or do we think about it in a more environmentally metaphor, an ecology metaphor. So for instance, this cancer is growing in the ecosystem of the body. It wants some of the things that the body produces, glucose and lipids. It wants waste removal. It wants oxygen, and it competes with normal normal cells, normal for those things. And, you know, what's really interesting is that when we think about cancer that way, it changes how we think about treating it. So if you're a farmer, and you have a little farm. Do you garden?

[00:14:34.190] - Dr Gordon

Do you grow? We do a little bit of gardening, and we definitely grow a lot of eggs, and we grow a little bit of meat.

[00:14:39.190] - Dr Lemanne

How do you deal with weeds in your garden?

[00:14:41.130] - Dr Gordon

Pull them.

[00:14:41.970] - Dr Lemanne

Just pull them out, right? And you expect them to come back, right? Yeah. But when they come back, you pull them out again, right?

[00:14:46.730] - Dr Gordon

And sometimes we use Vinegar.

[00:14:49.390] - Dr Lemanne

Okay.

[00:14:50.750] - Dr Gordon

But yeah, somebody gave us, when we moved into that house, every house should have one, a bottle of Roundup, and I think we've used it in the 13 years we've been there once for something, and I can't even remember what it was. But yeah, I think of that as scorched earth land management, which for most land management issues doesn't make sense because you still need the land to be healthy.

[00:15:15.860] - Dr Lemanne

Oncologists have started talking to ecologists. Oh. So one of the foremost, one of the leaders in this field is a gentleman named Dr. Joel Brown, and he is a doctor of ecology, basically, and mathematics, and he studies ecosystems and squirrels, squirrel biology, predator-prey dynamics, and he models, mathematically models, if you have more predators, you're gonna have Less prey, and if the prey gets down too much, then you're gonna have fewer predators, and then the prey is gonna go up in number. I mean, kinds of cycles. He's one of the leaders in defining those kinds of biological cycles. And so he's been recruited by people interested in cancer evolution, especially by someone named Robert Gatenby, who's at Moffitt Cancer Center, to help figure out cancer. And so for our listeners, Everybody has heard about DDT, if you're our age. I think it was developed in 1950, and farmers started putting it on their fields in the South because the cotton boll weevil is a very dangerous predator for the Southern economic system, which is based on cotton, growing of cotton. And so the boll weevil is a pest that destroys cotton crops, and DDT destroys or did, destroyed the boll weevil.

[00:16:37.690] - Dr Lemanne

So farmers got ahold of DDT in the early 1950s and started applying it to their fields. The first year, ah, fantastic. You couldn't find any boll weevils. And in fact, if you could do a CT scan of the cotton crops, the farmers would have come running out of the ecologist's office screaming, "Yay, I'm boll weevil free, I'm boll weevil free." They weren't boll weevil free. Okay, there were still a few boll weevils that had survived the DDT.

[00:17:06.100] - Dr Gordon

Oh, sturdy ones.

[00:17:07.260] - Dr Lemanne

And by, anyway, everybody knows where this story is going. Each year the treatment worked less and less well. And by, I think it was only 1956, it didn't work at all. Farmers were applying this stuff like water and the boll weevils were just chomping away at the cotton. Well, People like Joel Brown and others, Dr. Gatenby, have pointed out that this is exactly what happens in cancer. So we have these advanced cancers, these big problems, we can't cure them, we can't get rid of every single boll weevil. And so if we spray with chemotherapy-type DDT, using the DDT paradigm, over and over, we get pretty quickly to a state where the cancer cells that remain are completely impervious. To our treatments.

[00:17:53.200] - Dr Gordon

So with the analogy of DDT, it's existed in our commercial marketplace for a lot longer than the cotton farmers get— after they gave up on it. And I think where a lot of people our age were exposed to it, where I was exposed to it, is they drove around the Girl Scout camp spraying DDT out of the back of open trucks to kill the mosquitoes. And I think it was used in other locations besides that, and the mosquitoes probably didn't have the same chance to become sturdy and resistant like the boll weevils did. But the people that were subjected to it are part of our cohort of Parkinson's disease, and I think there were toxic effects on the bystanders for whom the spray wasn't intended.

[00:18:43.960] - Dr Lemanne

Exactly, yeah, it was collateral damage.

[00:18:45.460] - Dr Gordon

Collateral damage is the word, yeah.

[00:18:47.100] - Dr Lemanne

Absolutely, so toxins like DDT have lasting damage, off-target damage, we call that. So does chemotherapy, has off-target damage.

[00:18:54.180] - Dr Gordon

Besides just not weeding, killing, really eradicating the cancer, it has other effects too. Absolutely.

[00:19:01.080] - Dr Lemanne

Old-fashioned chemotherapy, we have targeted treatments that now that have fewer off-target effects, but they still do have many serious off-target effects. But the older chemotherapies have a lot of off-target effects. But in the— I want to be fair— in the early stage scenario, stage 1, 2, or 3, those, even the cruder, older chemotherapies will cure the cancer. And you want to cure that cancer. You don't want to get into the stage 4 situation because then you're unable to eradicate the cancer.

[00:19:30.540] - Dr Gordon

Because the cancer cells are fewer in number, or there's more, a single type of organism, or why are they more eradicable than later stage cancers? Another little brief explanation here. When we say that early cancers are easier to cure, many people assume it's simply because they're smaller.

[00:19:53.070] - Dr Lemanne

Size matters, but evolution matters too. Every time a cancer cell divides, it creates an opportunity for a new mutation or some other type of epigenetic change. A small cancer typically contains relatively few different cell types just because it's small and there are fewer cells. But a large cancer has gone through many more generations and has had many more opportunities to develop treatment-resistant populations. So larger cancers are not only bigger, they're biologically more diverse. And that's one reason why early detection can be so powerful. Oh, because there are fewer of them. Yes. And they're more usually more— the definition of stage 4 is that it's no longer localized. So you can't aim your treatment at one anatomic part of the body, like the breast or the colon or the prostate. The cancer's out of those areas into distant places like lung, bone, breast— excuse me, lung, bone, liver, brain. So the cancer's no longer targetable anatomically.

[00:20:56.940] - Dr Gordon

In the same way. Okay.

[00:20:57.860] - Dr Lemanne

All right. Yeah. So I think that one of the things that we're now starting to admit to, when you go in and you have an advanced cancer, the oncologist will say it's not curable, but it's treatable. It's treatable but not curable. And people hear that and I think they think, that means I'm going to live with it like people live with high blood pressure. They live a normal life and normal lifespan. They take some pills every day and get their blood pressure checked and things are gonna be fine. But that's, I think that's a little misleading to say that it's treatable but not curable.

[00:21:27.850] - Dr Gordon

I must say, yeah, that would be my kind of impression then.

[00:21:31.390] - Dr Lemanne

Yeah, I get it. And I want people to understand that high blood pressure and even diabetes, not the same as cancer in terms of survival in most cases. Sometimes, but usually not. And what usually happens in these, and the reason for that is, now I think it could be that we could treat these cancers maybe indefinitely and keep them under control like we do blood pressure. But what happens right now is that the patient comes in, oh, you have stage 4 prostate cancer, breast cancer, here's your bone scan, look, there's bone metastases all over the body. And for prostate cancer, we're gonna give you a treatment. It's going to wipe out all the cancer cells that we can see, and we're just going to keep giving that to you until it stops working.

[00:22:15.030] - Dr Gordon

Oh, that sounds like DDT.

[00:22:17.070] - Dr Lemanne

Exactly. And I think, so the patient says, I think a lot of times patients don't quite get that it's going to stop working, or that it's hard to think about that. I get that. I'm a big baby myself. I'm quite a hypochondriac. I'm not going to be thinking about, oh, it's going to stop working. I'm going to think, yeah, give me that drug.

[00:22:31.970] - Dr Gordon

But also, it's just going to be, it's going to go everywhere in your body. So they didn't just spray the DDT on the cotton crops. It's like they sprayed it on the whole farm acreage. If you've got cancer all over your body, it can't be a very focused treatment.

[00:22:45.570] - Dr Lemanne

It's not a focused treatment. So let's go dive a little deeper in prostate cancer. Okay. Let's use that as an example.

[00:22:50.930] - Dr Gordon

Very common one.

[00:22:51.950] - Dr Lemanne

Yeah, prostate cancer, when it's metastatic, can be treated with— by depriving the body of testosterone. And why is this? Prostate cancer is made of prostate cells, and prostate cells are part of the male prostate gland. Males have a prostate gland, and to get a prostate gland and get it to grow, you need testosterone. And if you have a cancerous prostate gland cell, it also likes to grow when you give it testosterone. So it needs testosterone, that's its fertilizer. So we can— and when it spreads, when these prostate cancer cells spread to the bone, that's where they like to— they still need testosterone and they're still prostate cancer. Cells. They're not bone cells or generic cancer cells. They are prostate cells, and they are looking for testosterone. In fact, they have little doors on their cell membrane, the outside of their cell— cells, that are just for testosterone to come in, or various forms of male hormone. And those are called androgen receptors. Androgen is an umbrella term for male hormones. So androgen receptors are present in any prostate cancer cell wherever it is in the body, even if it's spread outside the prostate gland to the bones or liver or lungs, anywhere else.

[00:24:06.250] - Dr Lemanne

So we can block the prostate gland, we can block the androgen receptors, we can block those little doors in those cell membranes. We can either put in a medication that looks almost like testosterone and then gets stuck in the membrane so the real testosterone can't get in, that's called competitive inhibition, Or we can turn off testosterone production. Testosterone is produced in the testicles. It's produced, though, the testicles produce testosterone in response to a hormone sent down from the brain and from the pituitary gland. So we can turn off the pituitary gland's production of these hormones. We can even go up higher in the brain and turn off the pituitary gland itself. Ooh.

[00:24:47.650] - Dr Gordon

Wait, it does other things, I think.

[00:24:50.070] - Dr Lemanne

Yeah, yeah. Yeah, but we can just turn that part off and we're pretty good at that. And what happens then? So you've deprived, you're depriving all the prostate cancer cells that care about testosterone, you're depriving them of testosterone. Great. And they are in the majority and they die. The scans start looking better.

[00:25:10.230] - Dr Gordon

They're in the majority. They're not in the unanimity. It's not unanimously those kinds of cells is what you're—

[00:25:17.130] - Dr Lemanne

Yes. Yes.

[00:25:18.400] - Dr Gordon

They're—

[00:25:18.480] - Dr Lemanne

Reference. Not all the prostate cancer cells care about testosterone.

[00:25:22.120] - Dr Gordon

Oh, even though that's where they came from, their motherlode cared about testosterone.

[00:25:27.380] - Dr Lemanne

As they spread around the body, they, a lot of them change a little bit, just like the DDT and the boll weevil. Some of the boll weevils didn't care about DDT. It didn't bother them. It was just something intrinsic in them, in their genetics. They were insensitive to it.

[00:25:40.700] - Dr Gordon

They didn't have little DDT receptors on their bodies.

[00:25:43.360] - Dr Lemanne

Or they could detoxify it quickly.

[00:25:44.780] - Dr Gordon

Or, yeah, okay.

[00:25:45.420] - Dr Lemanne

Or whatever. And so the same is with— it's the same idea with prostate cancer cells. And by analogy, any other type of cancer, whatever the treatment is, you can kill the cancer cells wherever they are in the body by giving a treatment that you think affects most of them. But are you always— are you going to get most— are you going to get all of them? No. And so at that point, you ought to stop that treatment and try something else. Or what we're finding out is that This is a process our astute listeners, our savvy listeners, are going to recognize this as the process of evolution, and I mean that in a Darwinian sense. And I don't mean the survival of the fittest, the strongest. Evolution has nothing to do with strength and survival. It has to do with how well you fit into your environment. That's what the word fitness means. It doesn't mean physical fitness and strength and how many push-ups you can do or how strong this cell is.

[00:26:40.170] - Dr Gordon

You're gonna change the bro world here.

[00:26:42.790] - Dr Lemanne

They'll roll with it. They'll evolve. Yeah, they'll evolve. But anyway, so if your environment requires that you live, for instance, if you're a prostate cancer cell and your environment requires that you live in a place, a neighborhood with no testosterone, if you're good with that, you're good with that. And you then, you can watch your neighbors who've been competing with you. You watch your other fellow prostate cancer cells who do need testosterone. You watch them die off.

[00:27:10.300] - Dr Gordon

And you go, whoa, I dodged a bullet.

[00:27:12.300] - Dr Lemanne

And you say, "Mm, I can move into their house. I can eat their food. I can use their garbage pickup service and their electric wires and their oxygen delivery, and I can really go to town now." And we see this. We see that after a cancer has been run into the ground so that the scans look really beautiful, almost immediately the cancer comes roaring back.

[00:27:38.470] - Dr Gordon

We thought a brief clarification might help here.

[00:27:42.160] - Dr Lemanne

The important principle is broader than prostate cancer. Most, most metastatic cancers contain multiple populations of cells, with some of these populations sensitive to treatment and others being resistant. And an adaptive therapy approach tries to manage the competition between these populations rather than eliminate one population completely, typically the sensitive population by definition.

[00:28:09.900] - Dr Gordon

So this is something I haven't gotten before from what you've talked about is if I had— if somebody has a metastatic breast cancer sitting in location 13 in their right breast, if you wipe that out, if it's— something's going to come back, it's going to be different kinds of cells, even if they move into location 13 again, the same place they take over the same, literally the same place that the treatment—

[00:28:34.130] - Dr Lemanne

No, so exactly. So that's— I'm glad you brought that up. So no, we're not talking about breast cancer that's still in the breast. —can be removed. You can just cut it out, you can radiate it. That's removable, and that's a curable situation. So no, we're talking about cancer cells that have traveled outside of the original area, the primary tumor, and that's again what we call the metastatic process. But they—

[00:28:57.910] - Dr Gordon

and when you eradicate one metastatic locus, that locus is still vulnerable to cells that maybe weren't there to begin with or that you didn't take out?

[00:29:09.920] - Dr Lemanne

It could be that more cancer cells will come from elsewhere and move back into that same locus, but what we usually see is that there are many foci of metastatic deposits. When someone has metastatic disease again, we might see one or two spots on the bone scan, but again, remember, that's a billion cells. Oh. Before we can see it on our scan. Yeah, so is it likely that there are many other places in other parts of the body that we— that our scans just can't pick up? Yes. And I think that's a good— so I think this is a good place to talk about— we have ways now of finding those with something called circulating— something called liquid biopsies. And we talked a little bit about a particular type of liquid biopsy called a pan-cancer screening, where we're looking for something called cell-free DNA and looking for new cancers that haven't been diagnosed and hopefully diagnosing them many years before they would be diagnosed in the usual old-fashioned ways. I'm gonna call them the old-fashioned ways, like scans and symptoms, so that they could have a chance of being curable even if they're not curable if we wait until they're diagnosed the usual way, like pancreatic cancer is the one that I'm really thinking of.

[00:30:20.040] - Dr Lemanne

There are lots of types of liquid biopsies, many different kinds. One of the things that I want to talk about today is something called a circulating tumor DNA liquid biopsy. And there are, even within circulating tumor DNA liquid biopsies, there are two major different kinds. One type of circulating tumor DNA, liquid biopsy, and a liquid biopsy is just a blood test. It comes out of your vein. It sounds like a very— You know, like the crook of your elbow, just like any other blood test. Your patients know that you do blood tests, so they go in, they stick their arm out, somebody sticks a needle in the crook of their elbow, and they get some blood out. That's where a liquid biopsy comes from.

[00:30:56.120] - Dr Gordon

So much easier than numbing something up, cutting it out, and stitching it up. Oh my goodness, yes. Probably easier on your body too, less a mini surgery.

[00:31:05.060] - Dr Lemanne

Exactly. A liquid biopsy circulating tumor DNA can either look at different mutations in the cancer, and we do these over and over again. This is not a one-time thing. In oncology, you get a scan and then you get a scan maybe 3 months later, or maybe you get 4 scans a year. And the doctor's doing that because they want to see how things are changing over time. Is the treatment working? Is the tumor bigger? Is it smaller? Is it in a new place? Is it— Is it gone? Those kinds of things. Should we change the treatment if it's getting bigger? So a liquid biopsy we can do as often as you can do a blood test, theoretically anyway, and we can see whether the— if the tumor genetics is changing. So there are certain genetic changes that we can look for that tell us that the tumor has— is evolving a certain type of resistance, and for lung cancer this is really important. So for patients on things like osimertinib, which is a targeted treatment for certain mutations in non-small cell lung cancer, people generally develop a resistance to that after about 13 months on solid treatment.

[00:32:03.880] - Dr Lemanne

Now, I think that's going to change because there's some work out of Japan that shows that— we'll talk about this— alternating treatment with treatment pauses based on mathematical modeling, not just the calendar. We'll get to that. But— okay. Stopping the treatment intermittently may delay the development of this resistance, but Osimertinib causes a particular gene to arise in the cancer cell population. We can see that if we do a liquid biopsy and we can say, ah, this, after 3 or 4 rounds, looks like maybe it's not working so well, we better change to a different treatment. But in any case, we can use circulating tumor DNA also, and this is what's really exciting. We can count the number of pieces of circulating tumor DNA of DNA in a certain tiny volume of blood, and if that number's going up over time, we know that the cancer's getting worse. There's more cancer debris in the body. If it's going down, the cancer's getting better. There's less cancer debris in the body. It doesn't matter what the treatment is. You could use any treatment. If it's making the cancer better, we can see that with the circulating tumor DNA.

[00:33:09.790] - Dr Lemanne

If it's making the cancer worse, we can see that with the circulating tumor DNA.

[00:33:12.890] - Dr Gordon

And by better and worse, you really just mean volume at the— how either more cancer or less cancer. That's right. Okay. That's right.

[00:33:20.590] - Dr Lemanne

You could have a tiny cancer in a really sensitive spot like the lining of the heart, and that's a very bad news. You can have a tumor the size of a beach ball in the abdomen, which is meant to carry pregnancies and constipation and everything, and you can still be walking around and doing your thing. So again, yeah, it's not always— the placement matters. But in general, for any one particular patient, we can see whether the whole tumor situation is getting better or worse. So DNA, I think most of our listeners will understand this, but DNA is the material, the genetic material, the strings of genes in our cell nucleus that are held inside the chromosomes. So the genes are in the chromosomes, there are 23 of them, are in the nucleus, and that's— pieces of that debris from those long strands of DNA is what we are looking for in the blood test called the circulating tumor DNA. Now there's a lot of other DNA. All of our cells, our normal cells too, are dying and being born, and there's a lot of DNA from the debris from dying normal cells that has to be sorted through to get to the DNA from tumor cells.

[00:34:30.600] - Dr Lemanne

And that's another topic, but I think what's important for our audience to know is that we can tell now when in the blood pieces of— little pieces of nucleic acid, little pieces of DNA, we can tell when they're from a tumor. And we can count up those pieces, and we can tell if, by counting them at any period in time, whether the tumor is getting better or worse.

[00:34:51.910] - Dr Gordon

We thought this would be a good place for a bridge between circulating tumor DNA and adaptive therapy.

[00:35:00.190] - Dr Lemanne

For decades, one of the barriers to adaptive therapy, meaning pulsed therapy, was that we couldn't measure cancer often enough. We might get a scan every 3 months, but that's like trying to steer a car by opening your eyes for 1 second every quarter mile or so.

[00:35:16.870] - Dr Gordon

That's not gonna work very well.

[00:35:18.370] - Dr Lemanne

Not ideal. Not ideal. But a new tool, circulating tumor DNA, which is a blood test that we can get as often as we like, a circulating tumor DNA blood test gives us a much more frequent way to monitor what's happening. And instead of waiting months to learn whether a treatment is working or not, we can often see trends developing much sooner, and we can tell if the treatment is working. And that's what makes adaptive therapy practical. And I promised I'd talk about adaptive therapy. Do you want me to talk about that? This is—

[00:35:53.190] - Dr Gordon

yeah, because this is, okay, now we've learned something about how this is all behaving. What advantage does that give us? What have you learned about how you could manage that?

[00:36:03.150] - Dr Lemanne

Yeah, so this is work done among other places. A lot of it's been done at Moffitt Moffitt Cancer Center, and it's been led by a gentleman named Robert Gatenby, who started, along with Alexander Anderson, they started about 20 years ago the Integrated Mathematical Oncology Department at Moffitt Cancer Center. And what they do there is they look at cancer from an evolutionary perspective. They look at how cancers change over time and how that matters for the way that we treat them.

[00:36:32.880] - Dr Gordon

And you mean one cancer in one person's body evolving over time. You don't mean sociologically.

[00:36:39.040] - Dr Lemanne

I don't mean sociologically. Mr. Jones or Mrs. Smith with a cancer. Okay. How is their cancer changing over time? Over time. Yeah. And when you look at a cancer that way, if it's metastatic, you come to the realization that the more you treat it and the harder you treat it up front, the worse the patient does. And we have all the statistics to show that. Any doctor can look them up. Say that again, because that's a little counterintuitive. Isn't it? Yeah. So the core hypothesis that Robert Gatenby developed, that what he calls the standard maximum tolerated dose, give the biggest dose as often as you can, the maximum tolerated dose therapy creates a strong selection pressure favoring resistant cancer cells. Subclones. So what does that mean? It means you kill off all of the cancer cells that are sensitive to your treatment, and you leave only the worst ones. The ones that are resistant. Yeah, and if you've ever seen those little ads for the video games when you're like on some place and you haven't bothered to pay the price for an ad-free experience online, and one of these games is these armies of little minions by the thousands marching, and you have a machine gun or some kind of special bow and arrow or something like that.

[00:37:54.780] - Dr Lemanne

And you can just mow down the army, blah, blah, blah, blah. But then some big giant 10-foot-tall monster type with a club comes and wipes you out.

[00:38:03.960] - Dr Gordon

Because they were resistant to your arrows.

[00:38:06.560] - Dr Lemanne

Yes. Yes. That's exactly what's happening.

[00:38:08.800] - Dr Gordon

And so what was that big giant doing before you mowed down all the little ones?

[00:38:13.740] - Dr Lemanne

It was suffering because all of the little ones were eating its food. Aha. It was not able to reproduce very well. There is a cost to being a big, giant, tough cancer cell, person, predator, whatever. You need a lot of resources.

[00:38:30.630] - Dr Gordon

But you have to be different than the minions, so— Yes. The environment—

[00:38:35.070] - Dr Lemanne

There are a lot more deer than there are cougars.

[00:38:37.370] - Dr Gordon

And so, aha, and you'd get rid of all the deer, what happens to the cougars? Yeah, they come after you. Yeah, but if you're not there, pressure on their ability to survive, they have to get stronger and range farther afield if they lose they're dear.

[00:38:54.870] - Dr Lemanne

Exactly. So they have no competition. It's called competitive release. It's a Darwinian studies term. So competitive release means that you kill off all of the sensitive tumor cells, and what you have left are the resistant cells, and what you've given them are all the resources that the sensitive cells would have used up that would have kept them in check.

[00:39:18.270] - Dr Gordon

We thought it might help to define that term one more time.

[00:39:22.140] - Dr Lemanne

Competitive release simply means that when treatment removes the sensitive cancer cell population, the resistant cancer cells suddenly gain complete access to resources that were previously being used by their sensitive brethren. And these resources are nutrients, oxygen, growth signals, physical space. The resistant cells are no longer being held in check by competition, and that allows them to expand. Suddenly and much more rapidly. So the sensitive cancer cells are doing the oncologist's job. They're keeping the insensitive treatment-resistant cells in check in terms of number. So keeping them at a low number. They were being your friend. They were being our friend. The enemy is your friend. And so, all these war metaphors, but it kind of works here. We're mixing our metaphors, ecology, war. Deer and cougar, I don't know how that goes, anyway.

[00:40:19.460] - Dr Gordon

That's 'cause we're in Ashland.

[00:40:20.720] - Dr Lemanne

I heard the mayor told us we're to piss the deer a bit to make them less afraid of humans.

[00:40:26.380] - Dr Gordon

Yes, let's not even get started on that. I have my own opinions about that. Oh, okay, let that one go. I don't really aim for them with my car, but I think of it. Because, okay, just a total aside, there's a wonderful book about the deer and how they invite the cougars into their neighborhood, a book about Boulder, Colorado called "The Beast in the Garden." And even if you don't like nonfiction, I highly recommend it to anyone to read it because it's about the nicer you are to the deer, the more likely you are to have cougar eating your children.

[00:40:58.930] - Dr Lemanne

Anyway, okay, back to Kansas. Wow, okay, well, that's ecology. What is this?

[00:41:03.610] - Dr Gordon

It's an ecology— Yeah, it's a really good book. You would enjoy it.

[00:41:07.570] - Dr Lemanne

You'd find it fascinating. The idea that Gatenby and his Moffitt crew, Dr. Anderson and Dr. Brown, came up with was that maybe we ought to keep some of these sensitive cells around. They're doing our job. Anyway, they did the math, figured out with things like game theory that the math worked. So they tried it in animals, it worked in animals, and they tried it in humans. They did a big, big, in terms of changing our ideas about this, a big pilot trial. It was just 17 patients, that they pulsed the therapy using their PSA dynamics. So they let the PSA go down, but not too much, and then take the drugs away. PSA is prostate-specific antigen. It's a blood test that anyone who's male over 50 is familiar with, and anyone who has prostate cancer is intimately familiar with it in a way they just wish they didn't have to be. But the PSA goes up the more prostate cells, whether they're malignant or not, you have in your body, and it goes down the fewer prostate cells you have in your body, whether they're cancerous prostate cells or not. So if you have prostate cancer, your doctor's following your PSA very assiduously, and these were— they took 17 patients with advanced prostate, metastatic prostate cancer, gonna die, okay, and they compared them with 16 patients who were going to be in the control group, standard of care patients, and they treated these 17 patients with what's called adaptive therapy using very— as little as possible of the androgen deprivation therapy.

[00:42:36.760] - Dr Lemanne

So they just gave them as little as possibly they could to keep their PSA cycling between two points, and each point was a little different for each patient, and each cycle was a different length for each of these 17 patients.

[00:42:49.680] - Dr Gordon

And they could manipulate literally the PSA itself?

[00:42:53.320] - Dr Lemanne

Yes. Yes. So virtually all of the patients in the control group who were taking androgen deprivation therapy just continuously, they all, by the end of 14 months, had run the course of androgen deprivation therapy. It had killed all the prostate cancer cells it was gonna kill, and the resistant ones were there, and they progressed at 14 months, all of them.

[00:43:13.430] - Dr Gordon

So they might have had the best early scores in terms of lowering their PSA, But they had the worst ultimate scores.

[00:43:22.410] - Dr Lemanne

Exactly. Exactly. Anyway, to make a long story short, the— in the adaptive therapy group, I think all but one passed that mark very easily. One patient did not. So it's not perfect, but, you know, 16 out of 17 did very well with that.

[00:43:38.930] - Dr Gordon

I'll take that. Those are good odds.

[00:43:40.730] - Dr Lemanne

Yeah. And they didn't progress until— the median progression for that group was 33 months compared to the 14 months for the first for the control group. And what was really interesting is 4 patients were— continued to remain stably cycling low PSA, high PSA, low PSA, 55 to 70 months without any disease progression. So what they've done is control— Years. Years. 4 to however many months, 70— how many years 70 months is? Yes. 7 or 8 years. Yeah.

[00:44:13.930] - Dr Gordon

Okay, you're gonna— I'm sending you back to math school for that.

[00:44:17.010] - Dr Lemanne

Yeah. Not quite 6 years, but— so I'm curious.

[00:44:19.880] - Dr Gordon

How long— say it again. When you were going to do on and off cycling, you said the periods on and off tended to alternate. So I'm thinking when the patient is off androgen deprivation therapy, I'm thinking on behalf of their muscles, bones, sexual interests and stuff like that, they get their testosterone back.

[00:44:40.870] - Dr Lemanne

They do. And how long? Not always. Not always.

[00:44:44.770] - Dr Gordon

Not always.

[00:44:44.890] - Dr Lemanne

Not quickly enough. And we can talk about that, but let's talk about that, but before I get there, let me tell you that when they first started doing this, they didn't know how much to suppress the PSA and how much— how high to let it go, so they just let it— they decided to use a 50% threshold. We'll treat them until their PSA is 50% of what it was when we started treatment, and then we'll remove the treatment and let it rise back up again, but now they've refined that. I won't get into detail, but each patient has a different formula, and it has to be— it has to keep being adjusted, but it's based on how fast the PSA rises and falls off and on treatment, respectively, and we try to— they're trying to keep the patient asymptomatic, all right, so not letting it go up so high that the patient has symptoms from their prostate cancer, but not letting it go so low that they have symptoms from that. No, that they wipe out the population of sensitive cells, and that was In this study, the study's gone on for about 10 years now, Dr. Gateby recently told me that the main mistake that they and other oncologists make was overtreating these prostate cancer patients.

[00:45:49.420] - Dr Lemanne

That made them worse because it hastened the development of resistance. So now they barely push the PSA down, very little. Of course, each patient is different, and don't do this at home, and don't just stop your— Nobody, nobody stop your androgen deprivation therapy. Dumb, okay? Don't do that. All right, get someone to help you who knows about such things, but because you can make things worse. But yes, overtreatment was the biggest mistake.

[00:46:15.390] - Dr Gordon

So this is a total, and I don't know anything about androgen deprivation therapy reality, but I would imagine that a man, like men feel better if they have low testosterone, if I give them something and they get their testosterone back. Doesn't the chemotherapy portion of this treatment itself, the chemo portion of it, don't they actually— can they feel it? Do those men feel a little worse when they're on, in general, feel a little worse on androgen? Maybe it's not as bad as some of the scorched earth chemos, but— So it's not chemotherapy.

[00:46:51.640] - Dr Lemanne

It's a hormonal modulation, we call it. It's not chemotherapy in that it directly kills cancer cells. So chemotherapy drugs of— by definition, directly kill cancer cells. They go in, they damage the DNA, and they die. Okay. Androgen deprivation therapy is a more targeted therapy. It goes in, it attaches to either the part of the brain that tells the testes to make testosterone or to cells in the outside of the brain that have androgen receptors and blocks those so that real testosterone, real androgens can't get in. So it's not a chemotherapy, it's targeted treatment, but Absolutely, yes. And, and the other thing is that we give these shots. Men will take Lupron shots that supposedly last 3 months. If you check their testosterone level, the testosterone level goes down a few days after that Lupron shot, and it stays down not 3 months, but 5, 6, even longer, months or longer sometimes. So yes, and the patients are unhappy about that. Losing your testosterone, if you're a male, is a very difficult thing. There's hot flashes, there's muscle weakness, there's metabolic issues, there's loss of certain types of motivation. There's certainly loss of sexual function and potency and desire.

[00:47:59.220] - Dr Lemanne

And so all of those things are suboptimal for a great quality of life. Most men feel that it's better than being dead. But another thing that's really interesting is that it doesn't necessarily improve survival very much. That's the real burn. Yeah, it does help with symptoms though. You don't want to go around with broken bones and things like that, so it can be helpful. But yeah, there are a lot of problems with it. So I thought that the work going on at Moffitt was really interesting, so I've been bringing it to some of my patients, and I've worked with Moffitt on a lot of patients now. And we had one patient, and he's given us permission to talk about his case. Oh, good. And in fact, we published a case report on him. It's called Directed Evolution, because we directed the patient's cancer's evolution. We controlled it by alternating, and this is to get to your point, we alternated the androgen deprivation therapy with testosterone therapy. We actually gave him testosterone in between his androgen deprivation therapy sessions. And so that gets rid of a lot of the side effects, at least part of the time, from the testosterone.

[00:49:04.080] - Dr Lemanne

It gets— because the testosterone does not automatically bounce right back when you stop these drugs, it can stay low for months. We actually gave him testosterone to get him back to the normal level, and then in a few rounds, what we call supraphysiologic testosterone— and that's a whole nother topic. I don't want to get too much into that.

[00:49:20.900] - Dr Gordon

But on behalf of his muscles and bones and brain and libido and partner, I thank you. Exactly.

[00:49:27.680] - Dr Lemanne

So yes, so I think that giving testosterone to a patient with prostate cancer, that's a new— that is— I didn't invent it. That was invented by Dr. Denmeade and all at Johns Hopkins, and they called it bipolar androgen therapy. The way that they used it, they gave very large doses of testosterone to prostate cancer patients. That must have driven some oncologists in the world crazy.

[00:49:51.100] - Dr Gordon

Crazy until they read why you were doing it.

[00:49:53.940] - Dr Lemanne

I think so, and but it's, it worked. You can't argue with the data. Can't argue. And it's just one case, is what people are going to say, but that's how cancer is going to be treated, and that's how cancer research is going to proceed in the future. One patient at a time. And large randomized controlled trials have completely failed to cure for all these common advanced metastatic cancers. Worse.

[00:50:22.970] - Dr Gordon

We thought a clarification might help here as well.

[00:50:26.800] - Dr Lemanne

Randomized clinical trials remain one of the most important tools in medicine. They are excellent for determining average outcomes across large groups of people. The challenge in oncology though is that cancers evolve differently in different different patients. So the question adaptive therapy asks is not only what works on average, it asks how can we use measurements from this particular patient to guide this particular patient's treatment over time. We've been trying large randomized controlled trials to, to study and treat, learn how to treat advanced metastatic breast cancer, colon cancer, there's virtually, there's very little progress. We can measure our progress in months of increased survival, like in few months, like 2, 3 months of increased survival in a lot of these cancers over the past 30 years. And in fact, prostate cancer, the drugs we're using to treat prostate cancer now are the same ones we used when I was in medical school, and believe me, that was a long time ago. And the reason that large People will say the gold standard. I chuckle to myself when I hear people, everybody says this, Dr. Lemanne-Gordon podcast, "Large randomized controlled trials are the gold standard." You hear this from podcasters to oncologists to people at the large research institutes.

[00:51:49.530] - Dr Lemanne

First of all, they probably don't even know what the gold standard really is, which we don't use anymore. Has anybody noticed that?

[00:51:54.990] - Dr Gordon

And— That's so funny. You mean gold.

[00:51:58.970] - Dr Lemanne

Yeah. And we don't carry around gold as money anymore. We barely carry around money anymore. Yeah, that's true. Yeah. And the reason that large RCTs don't work, they're the wrong tool. So you wouldn't take a hammer to a screw, or you shouldn't. I've done it, but it doesn't work very well, I found out pretty quickly. And it's because of, there are two problems. It's convergence of fundamental tumor biology, which is that tumors within themselves have a lot of different types of cells and different treatment resistances between those different types of cells. You biopsy a tumor, On one side, you'll get one set of drug sensitivities. You biopsy an inch away, a different part of the tumor, you're gonna get a different set of drug sensitivities. So right at the beginning, tumors have a lot of variation within them, and so that makes it very difficult to determine what treatment might work, especially over a large group of people. And then the large randomized trial itself is just the wrong tool because it looks for average responses, and so we get modest effect sizes. We might have 1,000 people, and maybe 2 people in that group with a new treatment get a good response, but 998 don't, so we say that treatment doesn't work.

[00:53:12.140] - Dr Lemanne

But for that, the ones that it did, it worked great. The new question that I think that we need to be asking is more like, not does this treatment work for the overall group, does the overall group benefit, but But who are the people— in this group benefits?

[00:53:26.830] - Dr Gordon

Yes, and this is analogous to the work in cognitive medicine and hormonal health, which is applying the umbrella term precision medicine with tools that are in the cognitive world, the hormone world, or in your case, the oncology world. You're taking a precise, crowd-driven, your whole crowd has accumulated a lot of information, but you're applying it individually to people in a way that the doctor did some very brave experimentations. You're gonna put me on and off chemotherapy? I'm sure some of the original clinical trial subjects were going, is that really a good idea?

[00:54:14.220] - Dr Lemanne

Yeah, so we don't, We use that with anyone who doesn't understand it very deeply. So a lot of our first patients were doctors. So we treat a lot of— doctors will come to me and say, "We want— I want this." And they understand it, they get it. So a lot of our first patients have been doctors, and we don't do this with anyone unless they really, really get it and are somewhat savvy and intelligent and able to make an informed decision. You're not— we're not doing the standard therapy. We understand standard therapy, and we're not— we don't want that.

[00:54:42.510] - Dr Gordon

We want something individualized to us with understanding of the broad science but I want you to put it into my body.

[00:54:50.330] - Dr Lemanne

And when you think about it, these patients who are doctors and other medically savvy people, they understand that the trials that define the standard therapy likely wouldn't have accepted them as subjects. They might have been too old or too sick or not had quite the right scans or had some— they have a liver problem or a kidney problem too. So the trials that defined standard treatments wouldn't— most patients that come for those standard treatments wouldn't have been eligible for those trials. So those trials really don't exactly fit them either. So it's a mess, oncology research in that regard, and not that there aren't brilliant people working in really sensitive and advanced ways trying to figure this out, but it's a big complex field, and some of the lenses that we've been using, for instance, the antibiotic lens to treat cancer, just aren't the right tools. So for instance, antibiotic therapy You have a bacteria, for instance, you give it an antibiotic. I think it was pneumococcus, pneumococcus, streptococcus pneumoniae, and pneumococcal pneumonia. When penicillin was first tested on that, I think it was something like 92% of patients recovered. Oh, that's a lot. 7% didn't.

[00:56:00.670] - Dr Lemanne

In oncology, it's the opposite. We use treatments. So penicillin's great. You got pneumococcal pneumonia, the group studies show that's perfect.

[00:56:09.050] - Dr Gordon

They don't show that anymore, of course, but anyway, but it did. It saved— countless lives.

[00:56:15.250] - Dr Lemanne

In oncology, we use treatments that help 3% of patients. You just have to be in the right— And are you going to be in the right 3%? Chances are 97% you're not. That's a lot of the breast cancer drug statistics are in the 2, 3, 4% range, and I think people don't quite understand that as well, but doctors do. And so they come and they say, you know, no, I don't want that. I want— I want to try something else. And again, but this is only in very specific cases because cancers that are caught in an early stage, you don't want to mess around with adaptive therapy. You want to get the cancer dealt with immediately.

[00:56:48.660] - Dr Gordon

Absolutely. And then to use this adaptive therapy, you have to have— PSAs are brilliant even for putting off therapy, or that's in that prostate cancer has the PSA. Colon cancer doesn't have a test like that, does it? Does it?

[00:57:06.640] - Dr Lemanne

Oh, yes it does. Oh, okay. Now the circulating tumor DNA, one of the first cancers to be, that was used in was colorectal cancer and Signatera test, the Signatera test by Natera Diagnostics, Natera, N-A-T-E-R-A. The Signatera test was first developed in mainly, I believe, in colon cancer. And it is fantastic for a lot of colon cancer patients. So we get a nice number. If they have circulating tumor DNA, we can measure it, we can get it, we can measure it. And we can follow it over time with blood tests once a month or however often we want to do them to see if the number's going up or down.

[00:57:40.660] - Dr Gordon

Absolutely. So I was understanding it was only a minority of cancers that had tests like these that you could follow with your treatment.

[00:57:49.500] - Dr Lemanne

Yeah, no, now with circulating tumor DNA, more and more cancers are— we can detect them. And the reason that prostate cancer was tested first in this realm, you're right on, you absolutely put your finger on it, is because it had a really nice marker. Almost everybody with prostate cancer— not everyone, but almost everyone with prostate cancer has an elevated PSA. Now, some people can have end-stage prostate cancer and their PSA is 70, and other people can have early prostate cancer and their PSA is 1,500. So it doesn't necessarily mean that everybody's PSA is comparable— comparable in terms of the amount of disease that it represents, but the direction of change— was it going up? Is it going down? That's what we look for and that's what we use. And how fast is it going up and how fast is it going down? So men who are dealing with prostate cancer understand the concept of PSA doubling, which is different and it's much more important than the actual PSA number. So how fast is it doubling? Is it doubling every month? Is it doubling every 2 years? That's different.

[00:58:47.500] - Dr Gordon

So thinking more of the— of something like breast cancer where there are So many different kinds of breast cancer with different hormone— does each kind of breast cancer have a different circulating DNA test that they can monitor or only some?

[00:59:05.280] - Dr Lemanne

So the way the circulating tumor DNA test— I think what you're getting at is how do we know what we're measuring? We send in a piece of the tumor. So the patient has had a biopsy passed and there's— this is something that patients want to know, need to know. Listen carefully. If you don't get anything else out of this podcast, understand that your tumor, your pathology specimen, is kept in the laboratory for 7 to 10 years. And should be. And that 7 is certain states and 10 is other states. It's state law. All states mandate that pathology departments keep your specimen around, and that's just for this purpose, so we can test it if something new comes around. So we send a piece of that tumor in to, say, maybe Natera, so they can do their Signatera test. They go in and look for the markers that they want to find in your blood, in that tumor. And then they set up a special test just for you. It is so personalized. It is so personalized. You can't use Mrs. Smith's down the street. Even though you both had ER receptor. Nope, nope. It's your tumor.

[01:00:04.760] - Dr Lemanne

And they will set up that test for you. And then once it's set up, that takes about 6 weeks or so. So that's a long time. Once that's set up, then you send in the blood tests and they can test your blood against the setup that they have and see if there's a match, if they can find this circulating tumor DNA that they know is in your prostate cancer tumor.

[01:00:24.300] - Dr Gordon

Oh, that inspires a lot of confidence. Okay, you know how to measure my cancer that I can't see, feel, or touch, but you can tell the way you can with the PSA whether it's growing or not growing.

[01:00:38.950] - Dr Lemanne

Now, if you have a needle biopsy, which a lot of people do these days, if you have just a needle biopsy, sometimes there's not enough tissue.

[01:00:45.930] - Dr Gordon

An excisional biopsy is really better for that.

[01:00:48.270] - Dr Lemanne

If you want that kind of a testing possibility. However, there are— they're called non-tumor-informed circulating tumor DNAs that are generic, like what you're talking about, breast cancer. They're not very good, but they're better than nothing. And if you do happen to match what is just set up in the lab, just generically for some other person, You lucked out. You lucked out and you can follow that possibly over time, but it's better to have your own tumor-informed— it's called circulating tumor DNA test— set up.

[01:01:20.460] - Dr Gordon

Wow, that's brilliant to have that range of opportunities. Lucky me, I got it without having to have a solid tumor biopsy, but if that didn't work, go in and pick out a piece and get me my blood markers that enable you to stratify the effects of the therapy. Ah, that's great. So are people beating down your door for this? A little bit.

[01:01:44.950] - Dr Lemanne

People are hearing about this and they're— people who are savvy want this. Now, we can't do it for everyone, so you have to have a tumor that fits certain parameters. It has to have a good marker. We have— we do have to have ctDNA or a PSA or something similar. Sometimes you can use other tumor markers like CEA or CA125, those are much, much less sensitive than circulating tumor DNA.

[01:02:06.500] - Dr Gordon

Because they're much more—

[01:02:06.500] - Dr Lemanne

I imagine they're less individualized. And a lot of tumors don't make them, even if they're ovarian cancer. Some ovarian cancers don't make CA125. Oh, interesting. And so, yeah, we can try, but you have to have a marker. We have to be able to find a marker, and we usually do that with circulating tumor DNA. And you have to have a disease that has a treatment that can shrink the tumor somewhat, but that we can cycle. So, for instance, I don't use Lupron shots when I'm doing this with men with prostate cancer. I use a pill, and there's a new pill called Relugolix, and they can just take it every day, and instead of me giving them a shot that's supposed to last 3 months and actually lasts 5 or more, we can, when it's time, when the mathematics, when the mathematicians say, hey, stop this this drug, we can just have him stop taking the pill.

[01:02:56.270] - Dr Gordon

And the effect goes away with it. Oh.

[01:02:58.810] - Dr Lemanne

Yeah. If it doesn't, we can replenish the testosterone. Now we can get some testosterone going exogenously to get the testosterone level up to normal. And I do see that with my older gentlemen that once they're in their 70s, even the 60s, the testosterone doesn't pop back up once you stop these anti-inflammation drugs, the ones that affect the brain.

[01:03:17.630] - Dr Gordon

And the idea that you're giving exogenous testosterone therapy to a patient with prostate cancer, you go, what are you crazy?

[01:03:26.140] - Dr Lemanne

No, actually we're not. No, we're not. We've got the data and we're publishing it. And yeah, so it's, it's coming. But these things take a lot of time and they should. We should be very careful. These are lives. And the idea that, oh, we are experimenting on people. Every patient who comes for any, to any doctor for any treatment is an experiment. You've heard, you're the doctor, you've heard that this treatment works. You don't know that it's going to work on this patient. You try it. That in its heart is an experiment. Yeah. So I don't have a problem with that part of things, although people could— and I think I listen to that criticism, but I also am careful to just remember that every patient is an experiment, even if you're using standard therapy. And especially when we get that criticism, I remember that, well, we're using standard therapy that will benefit 3 out of 100 patients that we actually use this therapy on. So 100 patients are going to be exposed to the side effects for no benefit. Excuse me, 97 patients are going to be exposed to the side effects for no benefit, and 3 of them will get exposed to the side effect and will benefit.

[01:04:28.850] - Dr Lemanne

Yeah, it's a sobering place to be. I'm glad I'm a doctor. It's the right job for me. That does make me think, and people like you keep me on track.

[01:04:37.590] - Dr Gordon

Yeah, yeah, but it's fascinating that I have, I have patients fairly frequently pursuing me for one of these injectable weight loss drugs. And I have a few patients on them. And the data— I was going to say this about vitamin D, but it's more pertinent about the shots because I have a pertinent recent example. Oh, do these shots, they'll help you lose weight. Oh wow, it might reduce your risk of Alzheimer's. Oh wow, it might do other really good things for you. Oh, it might have some side effects. So the side effect— or the one of the findings that a recent trial on these weight loss drugs showed was that only the people who stayed on the full dose for a long term kept the weight off. And that's very interesting. And for some people, that would not be a deal breaker. And each individual is different. It doesn't make the therapy itself good or bad. It's just you have to know the accessories that come with every drug outfit you're choosing to to put on and match them to the patient and to, you know, my own expertise. If somebody wants intense peptide therapy, I can't do that.

[01:05:49.420] - Dr Gordon

There's probably even some chemotherapies that, you know, other people are better at than you are. But it's having therapies where you feel adept and you know they're complicated and the patient you're giving them to is complicated and you have to keep gaging that interaction. I just think it's fascinating that cancer is— because I used to think of, you find the drug, you give the drug, you kill the cancer, the patient lives, but—

[01:06:14.650] - Dr Lemanne

And that was the antibiotic model. That was the antibiotic model. And that hasn't panned out in cancer. It's failed completely. I think maybe we can close with this, is that we have new tools now, and so we can do different— we can practice medicine differently. We don't have to rely on large randomized controlled trials that only, they have their place, but relying on a large randomized controlled trial, 1,000 people, half get this, half get the other, and then we do a scan every 3 months, something like that, because that's the tool we have, that's the kind, you can only do a bunch of averages with that. So you can get an average treatment effect, and nobody's average, so it just doesn't work very well in these very complex diseases with a lot of heterogeneity. So if you take into account, which we are now doing, if you take into account that tumor heterogeneity is a real thing that we oncologists must deal with, and that resistance is something that we as oncologists ought to deal with. Right now we just accept it and say, yep, we know that it's gonna stop working, and that's the way it is.

[01:07:20.310] - Dr Lemanne

So that's gotta change. And now we have the tools. That will allow that, and we can do continuous monitoring. I envision soon we're gonna have, like we have continuous glucose monitors, we're gonna have continuous tumor DNA monitors.

[01:07:32.040] - Dr Gordon

Wait, can we have continuous ketone monitors first, please?

[01:07:34.440] - Dr Lemanne

Yeah, that would be nice too. So continuous monitoring, okay? It's wearable. Wow. The patient carries around. We're gonna have, we have FNAE, that's a new technology, and we'll probably have even better tests than that very soon. We can mathematically model the therapy dose schedules, how often When do we pause? When do we restart based on the tumor marker that we've chosen? And we do that with each patient. And what's really interesting, and we're starting to work with this in another patient who's very public about it, a male with metastatic male breast cancer. He has two tumor populations. One makes CEA and one makes CA-15-3. Those are different— Wow. —tumor markers, and they grow at different rates, and they shrink at different rates with different treatments. One set of— he has bone metastases and liver and lymph node metastases, and one will grow with one treatment while the other shrinks, and vice versa. So in the past, we wouldn't really deal with that. We'd just say, "Ugh." Too bad. Throw our hands up, and that's the way cancer is. Sorry, you're gonna do badly, and let's get you in palliative care. And now we have so many more tools that we can actually look at those things.

[01:08:39.630] - Dr Lemanne

We don't have to just cover our eyes and scream and run out of the room. We can actually look at those things and think about, okay, can we actually give this patient two different drugs or toggle them, or those kinds of things. So cancer is going to become less killing off all the little minions in the video game until the big giant goon comes with his club and kills you. And it's going to be more like a farmer managing an ecosystem. You don't, you might use a little bit of DDT in this one corner and then you plant some plants over here that discourage this particular pest and/or encourage their predator, whatever eats them. Those kinds of things. You manage the whole picture rather than just aiming at the cancer cells trying to kill them, because that doesn't work.

[01:09:24.180] - Dr Gordon

Doesn't work for actual complex— For patients with— Individualized human beings.

[01:09:28.840] - Dr Lemanne

For patients with advanced metastatic cancer. Right. Again, this is only in that one setting. Again, I can't say that enough. If you have early-stage cancer, please please go get it treated, get it treated briskly and immediately. But if it's an advanced cancer and your doctor's saying we can treat it but we can't cure it, then you might want to start asking your oncology to look at it a little bit differently.

[01:09:49.510] - Dr Gordon

Brilliant, but cognitively challenging to grasp what this new paradigm is, as I'm sure it is to manage it, but the excitement overwhelms the challenge. It's, it's very optimistic. It's great work. I can't wait to keep following it. Before we finish, let's summarize the central idea.

[01:10:13.160] - Dr Lemanne

The goal of this episode is not to suggest that less treatment is always better. For cancers that can be cured, eliminating the cancer remains the goal, but for many metastatic cancers, We are facing an evolving ecosystem rather than a problem that can be eradicated outright. And that's a fancy way of saying we are facing a cancer that cannot be cured when we are in the metastatic situation many times. And new tools such as circulating tumor DNA can allow us to observe that evolution in real time, and the hope is that by understanding and steering Taking charge of cancer evolution, the oncologist can prolong the disease control and preserve the quality of life, and eventually actually improve outcomes, meaning increasing the length of survival.

[01:11:07.320] - Dr Gordon

So in other words, we're not just chasing cancer from behind and taking familiar swings at it, but we're actually learning how it behaves well enough to get ahead of it.

[01:11:19.020] - Dr Lemanne

Exactly. Nice talking to you, Deborah.

[01:11:20.950] - Dr Gordon

Good talking to you as always. See you around. Okay. Bye-bye.

[01:11:24.890] - Dr Lemanne

Bye. If you haven't already, please take a moment to subscribe. Your simple click is not abstract. It's not anonymous. To us, it's very real. It helps us reach more patients and physicians to challenge the old ways of thinking about health and to keep these evidence-based Conversations going. Hitting that subscribe button actually makes a huge difference. And thank you.

[01:11:54.090] - Dr Gordon

You have been listening to the Lemanne-Gordon podcast, where docs talk shop.

[01:11:59.890] - Dr Lemanne

For podcast transcripts, episode notes and links, and more, please visit the podcast website at docstalkshop.com. Happy eavesdropping. Lemanne-Gordon podcast. Everything presented in this podcast is for educational and informational purposes only and should not be construed as medical advice. No doctor-patient relationship is established or implied. If you have a health or a medical concern, see a qualified professional promptly.

[01:12:34.130] - Dr Gordon

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[01:12:46.120] - Dr Lemanne

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[01:13:00.580] - Dr Gordon

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[01:13:07.460] - Dr Lemanne

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[01:13:24.780] - Dr Gordon

Doc's Talk Shop is recorded at Freeman Sound Studio in Ashland, Oregon.