Personalized medicine in MBC: What it means for you

Transcript

Virginia Kaklamani, MD, DSc [00:00:08]

This talk is going to fit into the No One Missed campaign. I think it’ll be nice to see how far we’ve come, but also to see what questions you all need to ask your physicians and make sure that you get the best care you can possibly get.

These are my disclosures. We all have to do that.

This is what breast cancer used to be. Three types: Triple-negative breast cancer, HER2-positive breast cancer, and ER-positive [hormone receptor-positive] breast cancer. We would give chemotherapy for the triple-negative breast cancer. We would give hormone therapy for the ER-positive breast cancer. And we would give antibody therapy for the HER2-positive breast cancer.

Even though we kind of still do that, this is really something that is in the past.

We’ve evolved a lot. We’ve understood a lot. We have realized several things.

First of all, when we have a primary tumor, not all the cells are the same. They’re heterogeneous, which means that if we think that we can treat one tumor and really kill all the cells by just doing one thing, we’re mistaken. This tumor has already evolved. And it evolves over time as well. So the longer that tumor is there, the more it evolves. These cancers are smart, and we have to be smarter than they are.

The original breast lump is comprised of many different cells. Each one of these cells has different properties. And when the breast cancer spreads, these cells evolve even more. And different foci of metastatic disease behave completely differently. So if we are naive enough to think that we’re going to give one treatment and are able to focus on each one of those sites of metastatic disease, we’re mistaken.

And the other thing that happens is once we treat these cancers, these cancers evolve because of the treatment that we give. They accumulate more mutations; changes in their DNA.

This is a way to think about this. We start with a normal cell that somehow becomes the cancer stem cell. But once that cancer stem cell is present, it starts sending out different signals to different cells that come from that stem cell. And you can see the different colors that are on this slide showing you how these cancers change, how they evolve on their own. Because each one of them has a brain of its own. And that’s how we need to approach breast cancer, not just metastatic breast cancer, but even early-stage breast cancer as well.

Once it goes to different places, it really behaves as its own little community, and you have to address all of those communities. This is our present. A little more complicated than the first slide that I showed you. And I can guarantee you the future’s going to be even more complicated.

I’m going to focus on a lot of these things on subsequent slides, but I want to give a little overview on this slide. When we have patients that have triple-negative breast cancer, we’ve realized that triple-negative breast cancer is really five or six different subtypes of these breast cancers. Of course we’re going to give chemotherapy, which we have given in the past, but we’re going to be checking a few other markers. We’re going to be looking at this marker called PD-L1, which is a marker of the immune system. And we’ll go over that in a few slides.

We’re also going to check and see if a patient was born with mutations in a few genes, such as BRCA1 and BRCA2. And I’m hoping that most of you here have had genetic testing. And if you haven’t, you probably should.

And why do we care about all of these different markers? Because we have drugs that target those specific markers.

ER-positive breast cancer. It can also be part of this BRCA syndrome. So we need to know if a patient caries mutations, changes in the BRCA genes. But there’s other genes that play a role in ER-positive breast cancer. ER, the estrogen receptor, can mutate. And those ESR1 mutations behave very differently. And again, we need to target them with specific therapies.

Virginia Kaklamani, MD, DSc [00:05:02]

There’s also mutations in another pathway, the PI3K pathway. And those mutations, we care not only because these cancers tend to be a little bit more aggressive, but because we have treatments that target those specific mutations, those specific molecules.

When we look at HER2-positive breast cancer, we have these new drugs that everybody’s excited about called antibody-drug conjugates. We don’t just have them for breast cancer, we have them for a lot of other diseases. This is probably one of the big advancements in the past 5 years in oncology. And you’re going to be hearing more and more and more about these antibody-drug conjugates.

Something that’s relatively new in oncology is the fact that even though all cancers are different — so breast cancer and lung cancer and colon cancer are different, and we typically treat them differently — they can share specific changes. And those changes could be changes that we can attack with one drug. And we call these drugs tumor agnostic because it doesn’t matter if somebody’s tumor is a colon cancer or breast cancer or a lung cancer, if it has that change, then that drug has a good potential of working. Now, sometimes it may work a little bit better in breast cancer than in colon cancer and so forth, but we still have these approvals for these drugs.

One example is tumors that have these fusions, and fusions is when different parts of the DNA just come together, and it’s called NTRK fusions. For example, in breast cancer, there’s a very rare subtype of breast cancer called secretory breast cancer. Women in their teens can have secretory breast cancer, it’s actually resistant to chemotherapy. It gets big, it’s really hard to treat. But we have specific drugs for these NTRK fusions that can target those breast cancers. And if we know that this breast cancer has these fusions and we give these drugs, you can see the tumors melting away, so much better than chemotherapy would ever do.

All of these things, I hope you can appreciate, are extremely important, because if we didn’t know any of these things and all we knew was what the estrogen status was and if it was a triple-negative breast cancer, HER2-positive breast cancer, we’d just be thinking of three different kinds of therapies. And here I’ve shared another six, seven different therapies and we can combine all of those as well.

So very, very important that we know what our tumor looks like. And how do we know that? Well, we know that by doing biopsies.

I’m sure you’ve all had biopsies, probably more than one, and they’re not pleasant. It’s easy for me to say to somebody, “We’re going to order a liver biopsy on you,” and then I see the patient cringing. Instead of just doing what we call a solid tumor biopsy, where we target the liver or the lung or anywhere the cancer is — that only gives us information for that tiny little piece of tumor that we biopsied. And what did I say in the beginning? That tumor evolves and different sites look different. If I just do one little biopsy of one little site, that’s all the information I get. But if I do a liquid biopsy — which means I draw somebody’s blood, much easier than sending them for an actual biopsy — and I look at the DNA, the cancer DNA in the blood and all of these different sites, shed their DNA into the blood, then I can have a much bigger picture of what this cancer looks like. So this is what we’re all moving toward, and we’re doing a lot more of these liquid biopsies because not only are they easier to do, but we also can get a lot more information from them.

Let’s look at one of the first drugs that I talked about. Let’s say somebody was found to have a BRCA mutation. And what are these mutations? These are mutations that we’re typically born with. Our mom or our dad passed it on to us. Many of these patients may say, “Oh, yeah, my grandmother had breast cancer and my mom had ovarian cancer and I have a sister that also had breast cancer.” But many don’t have a family history of breast cancer, which is why it’s important to do genetic testing regardless of our family history. So most of these mutations are inherited, even though sometimes the cancer gets smart and creates those mutations itself.

What these mutations do is they do not allow the DNA to repair itself. DNA breaks all the time. Mutations happen all the time. But our body is so good at being able to repair all of these different changes so that we can go on. If it didn’t, we’d all get cancer at the age of 6 months and unfortunately die. So our body is very smart. Sometimes it fails. Sometimes it fails because we’re born with something that doesn’t allow that DNA to repair itself.

If it can’t repair itself, over time, it’ll get some kind of cancer. And typically patients that have these mutations have a higher risk of getting breast cancer, ovarian cancer, sometimes pancreatic cancer, prostate cancer, for the men, and so forth.

Virginia Kaklamani, MD, DSc [00:10:28]

And the reason why we don’t get as many of these cancers at a very, very young age is there’s this tiny little particle called PARP. And PARP also repairs the DNA. So when the BRCA is not able to repair the DNA because the BRCA doesn’t work, PARP goes in there and repairs the DNA. So over and over and over again, over years, it does that. At some point it might fail, and patients might get breast cancer.

So BRCA repairs DNA, PARP repairs DNA, if neither of the two work because somebody has a BRCA mutation and then we put an inhibitor for PARP, then the DNA can’t repair itself at all. And what happens when the DNA can’t repair itself at all, the cell dies. It’ll survive when it’s perfect. It’ll survive when it’s almost perfect. It might get some cancer, but it will survive. But if the DNA can’t repair itself at all, the cell dies.

The benefit of knowing that we carry one of these mutations is that we have drugs, PARP inhibitors, that we use specifically for patients that have these BRCA mutations.

And obviously the benefit of us knowing is we can also inform the rest of our family because our whole point is to try to decrease the risk of other people getting cancers. And if we know that they have a higher risk, then we can help decrease that risk.

Let’s look at another kind of revolution in the past 10 years, immunotherapy. I’m sure you guys have all heard of immunotherapy. What is it?

Cancer cells are our own cells that have evolved to never die. But because they are our own cells, they have developed mechanisms for our immune system to see them as our own cells, to recognize them. Because if our immune system doesn’t recognize them as our own cells, it’s going to kill them. Cancer cells don’t want to die. So they have these little receptors on them, and those receptors, on the cancer cells, communicate with similar receptors on the immune cells. And they all talk to each other, and the immune cell looks at it and says, “OK, this is my kind of cell, I don’t need to kill it.” So those two receptors, there’s a bunch of them but the most common ones are PD-1 and PD-L1. And you guys may have heard those names. The cancer cell comes, the immune cell goes there, looks at those receptors and says, “OK, you’re my own cell, I’m not going to kill you.”

Well, some smart people said, “Why should we allow the immune cell to recognize the cancer cell as its own? Why don’t we get rid of that connection?” And so we developed PD-1 and PD-L1 inhibitors. Once you have those inhibitors, the connection between the cancer cell and the immune cell is not there anymore. And so then what happens? The immune cell recognizes the cancer cell as a bad cell, attacks it and kills it. This is what immune therapy is.

Now, immune therapy, we have it for many cancers, not just breast cancer. For breast cancer, especially triple-negative breast cancer, it seems that it works only if those cancers are positive for that PD-L1. It means that they have that marker that the immune system recognizes. That’s why it’s important to be looking at those cancers, looking and seeing if they are PD-L1 positive because that opens up the door for us to use immunotherapy for those cancers.

Virginia Kaklamani, MD, DSc [00:14:18]

Moving on to estrogen positive breast cancer. The estrogen receptor is the big part of why a cancer is called estrogen positive; it has a lot of these estrogen receptors on it. What are these estrogen receptors? Those estrogen receptors are little molecules. Estrogen binds them, and those receptors get activated. They go into the nucleus of the cell and they tell the cell that it needs to grow. And the cell grows.

We’ve had therapies where we take away the estrogen, and so that estrogen receptor doesn’t have food. If it doesn’t have food, it’s not going to do anything into the cell. The cell’s going to die. So aromatase inhibitors, that’s how they work. They work by taking away the food of the estrogen receptor, the estrogen.

But the cell’s smart. It’s realizing that we’re taking away its food. So what does it do? It evolves into not needing that food. It evolves into not needing estrogen. And how does it do that? It mutates. The estrogen receptor mutates, and it becomes activated. Regardless of whether there’s estrogen, regardless of whether there’s food. So you can appreciate the fact that if I give an aromatase inhibitor to somebody’s cancer that has that ESR1 mutation, the aromatase inhibitor’s not going to work, because the estrogen receptor is already activated without the estrogen.

Why do we care? We care because we have specific drugs, that are much better than the drugs that we already had before, that target those cancers that have these ESR1 mutations. They destroy the estrogen receptor. So they don’t wait for the receptor to be activated or not activated. They don’t care if the receptor has estrogen or not. They just degrade it. That’s how these degraders work. And that’s why it’s important for us to know that our cancer has these ESR1 mutations because then we can actually take specific drugs that target those mutations.

The estrogen pathway is much more complicated than that. And you can see on this slide that there’s other molecules that are kind of flying by there. One of them is called PI3K, and the other one is called AKT. I talked about this briefly before, but this is one of the pathways in cancer cells that gets activated quite a bit. Sometimes it gets activated because these cancers have mutations in three parts of that pathway. The PI3K, the mTOR, and the AKT.

You guys are going to say, “Oh goodness, what are all these names? Why do I need to know them?”

You don’t need to know them. What you need to know is that we actually have drugs that target those exact molecules. That’s why we care.

Those drugs work only if this pathway is activated because of these mutations. So if I didn’t know that my cancer had these mutations, I wouldn’t be able to use this drug that may kill my breast cancer cells. So that’s why we need to know.

Then these antibody-drug conjugates. You guys may have heard about these. They call them the Trojan horse. They call them smart chemotherapy. Well, it’s not extremely smart, but it’s smarter than the chemotherapy we have. We’ve still got to do much, much better.

What are these antibody-drug conjugates? They’re antibodies. And we have antibodies in our body anyway. That’s how our immune system, or partly how our immune system, works. But we’ve developed antibodies that can target specific receptors. And the antibody will go to that receptor, it’ll block that receptor. And that’s kind of how it works. But people thought, well, that’s fine, it blocks the receptor and then the cell kind of slows down and eventually dies. But can I do better? What if I put things on that receptor or in that antibody? And what do we usually put on stuff? Chemotherapy.

That helps in two ways. Number one, instead of just giving chemotherapy that goes to the good cells and the bad cells and causes all of these bad problems like hair loss and decreased blood counts, and we feel pretty badly. If I put it on an antibody and that antibody only goes to the cancer cell, then I’m creating a smart drug. It doesn’t just target every fast-growing cell in the body, which is what chemotherapy does. It targets the cancer cell, which is what I want to target.

Virginia Kaklamani, MD, DSc [00:18:58]

People created these antibody-drug conjugates — back in the early 2000s by the way, we’ve had a few out there. But now the technology got so much better that we’re creating them full force. And there’s more than 200 of these antibody-drug conjugates currently in clinical trials all over the world.

How do they work? The antibody-drug conjugate recognizes a receptor, whatever receptor we want it to recognize. If we want it to recognize HER2, then we create an antibody against HER2. And then there’s a few other antibodies that we have for breast cancer. One of them is focusing on another specific receptor called TROP2. And don’t worry about those names, it doesn’t really matter. What matters is the whole concept.

Once the antibody finds that receptor and it binds the receptor, the receptor’s kind of recognizing that something’s happening, it doesn’t like it. And so what it does is it brings that whole antibody into the cell because it says, “This doesn’t look good to me. I need to kill it. How am I going to kill it? I’m going to kill it with my garbage disposal inside the cell.” And that’s called the lysosome.

It brings it into the cell, and then all of these enzymes try to kill the antibody. But the antibody inside of it has chemotherapy. And what the lysosome does, without realizing it, is that it’s releasing this chemotherapy into the cell. And once it releases the chemotherapy into the cell, what does the chemotherapy do? It kills the cell.

That’s why we call it Trojan horse. And since I’m Greek, I love that because that’s one of the things we learned in school. How the Greeks beat the Trojans. The Trojans thought they were getting a nice little horse as a gift. Unbeknownst to them, chemotherapy, Greek soldiers, were inside that horse. At night when everybody was sleeping, the soldiers got out of the horse, opened the gates to the city, and Troy fell. That’s exactly how these antibody-drug conjugates work.

Interestingly, even though this is like an amazing approach, and you’re thinking, “Oh my god, how have we not cured breast cancer already with these awesome drugs?” Only 1% of that chemotherapy actually makes it into the cell. Only 1%. So even though it looks amazing, and we should really be getting it right, we still have so much room to do better. And we will. But even with that 1%, we’re having better results with these antibody-drug conjugates than we’ve had with chemotherapy. They’re still more toxic than we want them to be. So they’re not as targeted as we want, or we thought initially they would be.

But how does the cell figure this out? Because the cell is smarter than Trojans were. It survives. So how does it survive?

First of all, the cell changes the confirmation of the receptor. It says, “Hey, I’m not going to let you latch on. I’m not going to let you inside. I’m just changing the lock to my gate.” That’s one approach, and it works. The second approach is that it won’t allow that whole molecule to go inside the cell. It blocks it. And then the third approach is once that molecule is inside the cell, it’ll do one of two things. Either the DNA of the cancer cell will change, and so the chemotherapy just won’t work. Or the cell’s going to spit out the chemotherapy quickly.

Doesn’t like it, spits it out.

The chemotherapy doesn’t enter the cell and doesn’t have enough time to work. It’s not going to work.

That’s how the cell evolves. And that’s why we need to create even smarter drugs to be able to bypass all of these different mechanisms.

Virginia Kaklamani, MD, DSc [00:23:08]

Let me give you an example of how all of this works in our everyday practice. I have a patient; they have metastatic breast cancer. I need to figure out what the cancer looks like. So what am I going to do? Either a biopsy, which I’m going to typically do anyway to know that the patient has metastatic breast cancer, or I’m going to do a liquid biopsy.

This was one of my patients I did a liquid biopsy on, and I found that her tumor had that PI3K mutation, called the PIK3CA mutation. The minute I find that the patient’s cancer has this mutation, I know that she’s eligible for a specific targeted therapy against that PIK3CA. And the good thing is, even if I didn’t know that, the lab tells me that.

Remember, I have the luxury of only treating breast cancer patients. I pride myself in knowing most of the things about breast cancer. Not everything, nobody can know everything. But imagine the doctor who sees colon cancer and lung cancer and breast cancer and lymphoma and multiple myeloma and leukemia. How can they keep up with all of this stuff that’s happening now? Because remember I showed you on my first slide how easy breast cancer was to treat back 15, 20 years ago. Not anymore. So the lab helps the physician and says, “Hey, just letting you know. Now this patient is a candidate for these specific therapies.” And it also will say, “And by the way, here are all these clinical trials that are going on around the country or close to you that you may talk to your patient about because they might be eligible for that specific clinical trial.” And that’s amazing. If we don’t do clinical trials — and Jean said it so nicely in the beginning — if we don’t do clinical trials, we’re not going to improve our therapies. We’re still going to be struggling treating breast cancer.

Virginia Kaklamani, MD, DSc [00:24:58]

Here’s another example. This patient, I initially treated her for her breast cancer, and then her breast cancer evolved. Initially when I treated her and I did this genomic testing, I found that she had that PIK3CA mutation. But as I treated the breast cancer, it also accumulated mutations in the estrogen receptor, an ESR1 mutation. So now I know that I’m dealing with two mutations. I’m also realizing what’s happening with the cancer, how the cancer is responding to the therapy that I have. And so now again, the lab is very smartly telling me this is what the cancer looks like and this is how you can treat it effectively. It’s helping me out.

What are we looking forward to in the future? How are things going to evolve in the future?

We’re going to be doing a lot of these genomic tests. We’re going to do a genomic test, and then depending on what that test shows, we’re going to give a specific targeted therapy. But what’s probably going to happen, because, what’s happening now, right? We’re giving a therapy and then we’re doing CT scans or a PET scan after 3 or so months. And then finding out if the cancer shrunk, the cancer stayed the same, or the cancer grew. Now we’re realizing that there’s a lot of things happening during those 3 months. Even if the scans are stable, the cancer may be evolving.

We don’t need to wait for what we call a clinical progression, meaning the scans are showing that the cancer’s growing, we are looking for a molecular progression. Any sign that the cancer is evolving and it’s figuring itself out, it’s figuring out how to bypass our treatment. And then instead of waiting until that treatment fails and we need to move on to the new one, we switch sooner than before. So we don’t wait for these scans to look worse. And then we do the same thing over and over again. Hopefully with this sort of approach, we’re going to be able to prolong life expectancy and hopefully at some point cure metastatic breast cancer.

Here’s another way that AI [artificial intelligence] helps us. We all hear about AI, Chat GPT, right? Anybody using it? Lots of hands, yes. Next year, at your 20th you’re going to see all the hands coming up.

What AI is doing is it’s good at processing a lot of data. That’s basically what AI does. It just takes in a lot of data and it organizes it for us. What these guys did, and they presented it at the most recent San Antonio Breast Cancer Symposium, is they took patients that had estrogen-positive breast cancer that were on a CDK 4/6 inhibitor. And those are drugs that we use all the time for metastatic hormone receptor-positive breast cancer. They’ve really revolutionized how we treat metastatic hormone receptor-positive breast cancer. It looked at a bunch of different factors. Some of those factors were things about the patient, how old they were, how many sites of metastatic disease they had, things like that. Some of those were just the molecular changes in the cancer. And it was able to break patients down into four different categories. One category where patients were doing really well with those drugs and then other categories where patients weren’t doing as well. And then the last category were patients where the cancer was just not going to be responsive to these CDK 4/6 inhibitors.

This was after the fact. So all of these patients had received the CDK 4/6 inhibitor. But imagine if I had that information before I gave the drug to my patient, and I knew that I’m giving a drug that’s really not going to be very effective. Then what do I do? I give something different. And that something different can really change how this cancer is going to respond, which is really my key.

This is what’s extremely important about these sort of AI models, and how they can change how we treat metastatic breast cancer.

This, for example, is a new drug. It’s a PI3K inhibitor. It’s in clinical trials, and it’s shown that if I give it in combination with that CDK 4/6 inhibitor, the overall survival goes up to 77 months. Now I’m not very good at math, so I actually had to divide it by 12, 6.4 years.

Do I need to give that drug upfront? If somebody’s going to do really well on my CDK 4/6 inhibitor, probably not. I can give it after the cancer progresses. But if I know the cancer is not going to do well with the CDK 4/6 inhibitor and it’s just going to progress very quickly, then I can give that upfront. So those are all things that we do to be able to bypass how resistance happens in those cancer cells. Because that’s the big issue, resistance.

Virginia Kaklamani, MD, DSc [00:30:15]

We also know that these CDK 4/6 inhibitors, the cancers become resistant to them because of certain mechanisms. We’ve done a lot of work on that because we’ve had them out now for 10 years. And we’ve established that some of these mechanisms have to do with PI3K. Some of them have to do with other molecules in that little path. And again, I don’t need you guys to be looking at all that and trying to memorize it, but just the concept.

We know for example, that one of these ways that a cancer cell bypasses these CDK 4/6 inhibitors is by this other molecule called CDK2. Why do I care? Guess why? Because we have CDK2 inhibitors. If I put somebody on a CDK 4/6 inhibitor and then the cancer progresses, and I’m able to see that the reason it progressed was because of that CDK2, what do I do? I give a CDK2 inhibitor. Or if I know ahead of time that the cancer is really not going to do much with that CDK 4/6 inhibitor because that CDK 2 is also active, then I can give a combination of a CDK4 and CDK2 inhibitor. And now what we’re doing is we’re looking after the fact. What we’re going to be doing in the future is looking in real time. And so we’re going to be able to be smarter in how we treat our breast cancer patients.

Here’s one way of how we can treat our breast cancer patients. This is a really cool trial that was initially a small trial, and we just had a press release on the larger trial which was positive. So you guys are going to be hearing a little bit more about this in June at one of our national meetings. As I mentioned, when we treat estrogen positive breast cancer, we give a CDK 4/6 inhibitor together with some endocrine therapy, typically an aromatase inhibitor. And typically this treatment works for a couple of years, might work for more, might work for less, but it’s usually around a couple of years. But what happens, and one of the ways that the cell figures things out, is by creating those mutations in the estrogen receptor, those ESR1 mutations. We’re actually getting pretty good at detecting these mutations in the blood.

These women were put all on the same therapy, and then they were having liquid biopsies every few months. And once the investigators were seeing that the rates of these ESR1 mutations were increasing, they were realizing that this tumor is having a molecular progression. The scans were looking fine, but it was just a matter of time that the scans would not look fine.

Once that molecular progression was happening, they switched the hormone therapy around. They took away the aromatase inhibitor, which was not going to work in patients who have cancers with ESR1 mutations. And they gave another drug called fulvestrant, which actually is a degrader. So it’s a lot more active. What happened when they did that? They showed that the cancers were progressing much later.

This is the sort of approach that I think we’re going to be using, looking at these molecular markers and looking at molecular progression instead of clinical progression.

So what have we learned? We are all unique and our cancers are also unique. So if we think that we’re going to treat every triple-negative breast cancer the same way, we’re going to fail. If we think we’re going to treat every single ER-positive breast cancer the same way, we are going to fail. We need to get smarter.

Now you guys are all here, and Jean said, get to know each other, right? Talk to each other. We got to do the same thing with our cancers. We got to get to know our cancers and the only way to get to know them is by looking at the makeup of our cancer. So that’s why we have to do biopsies and liquid biopsies and so forth. We have to get better at getting to know our cancers. That’s the first step to be able to treat them effectively.

But we also have to remember that the same way we change and we evolve — for the better, always. Our cancers evolve for the worse when it comes to us, but for the better when it comes to them. And so we have to keep up. We can’t just take one picture in time and think that that picture is going to be accurate in 6 months. It’s not. It’s changing.

What really this all comes down to, so far we’ve been playing catch up. We’ve been playing catch up with our cancers. We need to be one step ahead, not one step behind. And once we do that, then we are going to cure metastatic breast cancer.

Jean Sachs, MSS, MLSP [00:35:04]

I think it would be good to just start with genomic biomarker testing 101. There’s just a lot of questions. How often should I get a liquid biopsy? At what point? A lot of people are confused. Is FoundationOne the same thing? Is Caris?

Virginia Kaklamani, MD, DSc [00:35:23]

Absolutely, yes. Those are all great questions. So again, it’s individualized. You can’t just have a roadmap that will apply for every single patient and every single patient’s cancer.

I always do a genomic testing at the time of diagnosis of metastatic disease. And there’s genomic testing for early-stage breast cancer too, by the way. They’re just different. So every single time I think a cancer has spread, and I’m going to do a biopsy to prove that, I’m also going to send that biopsy to whatever lab it is. It could be FoundationOne, it could be Caris, it could be Tempus, it doesn’t matter. All of these labs are reputable labs. Some of our institutions do their own testing as well. Whatever it is, as long as we get a picture of what the cancer looks like.

As the cancer evolves, I also need to make sure that I understand what’s happening with that cancer. For estrogen-positive breast cancer, I will typically do a liquid biopsy another couple times. Typically every time I see the cancer growing — but again, I’m hoping that we get smarter enough to do it sooner — because these mutations change.

I’m also going to do another biopsy when things don’t make sense to me. I give a treatment. I think that treatment should work well based on my initial genomic testing, and something’s happening, it’s just not working as well. I’m missing something. If I think I’m missing something, I’m going to do more testing.

Jean Sachs, MSS, MLSP [00:36:54]

There are a lot of questions. Are insurance companies going to cover these tests at every change?

What Dr. Kaklamani is saying is every progression you should be having this test. So is insurance going to cover it?

And then also for people who are being treated in community cancer centers, some of them are saying they go to MD Anderson, they get their tests, they bring it back, and they don’t know what to do with it. So advice for them as well.

Virginia Kaklamani, MD, DSc [00:37:23]

So far we have been lucky, either insurance companies or the companies that provide these tests cover the cost of the tests. All of these companies might send letters saying, you owe this much money, and after three letters they write it off.

Is this going to continue? I don’t know. And obviously beforehand there’s a process to get pre-authorization, but this is becoming more and more common because of the drugs that we have, so we’re typically able to justify them to our insurance companies. And we’re talking about expensive tests, we’re talking about $6,000 tests.

As our healthcare system evolves, and we know that we have the most expensive healthcare system in the world, things may change. In Europe, things are not the same way. Insurance companies don’t pay for these tests. So the drug companies will sponsor the tests but only for their marker.

If I, for example, want to see if the tumor has an ESR1 mutation, I as a physician will go to Menarini, which has the drug, and I’ll say, can you please do the test for that patient? And Menarini will send me the result to say, yes, it’s positive for ESR1 or no. It’s not going to give me a PIK3CA response. It’s not going to give me an NTRK response, nothing else. So this is what’s happening in the rest of the world. And that’s showing me how, in many ways, privileged we are.

Jean Sachs, MSS, MLSP [00:39:00]

Yeah. And just a quick show of hands, since we’re here. Has anyone had trouble with insurance companies paying for these tests?

Caroline Koffke, RN, BSN, OCN [00:39:10]

We have some individuals here who have no evidence of disease, and they are wondering if this could also be something useful for them. If so, how frequently would you recommend that?

Virginia Kaklamani, MD, DSc [00:39:21]

We typically do these tests because we try to select therapies. If we’re not trying to select therapies, we don’t do tests. I don’t want to do a test that’s not going to help me change how I treat my patient.

For patients that don’t have any evidence of disease, right now, we don’t do these tests. There are other tests that we do, typically for early-stage breast cancer — and again, they’re not recommended but people are asking about them — to see if there is what we call minimal residual disease. And, and those tests are even more precise because they look at tiny little pieces of cancer DNA.

They’re telling us, is there even a little bit of cancer left even though it hasn’t metastasized. Sometimes in patients that don’t have any evidence of disease, where we struggle to say, should we continue the medicine or should we just stop because the medicine is just giving us a lot of toxicity. Some people are thinking about whether they can incorporate those tests. Because if they do those tests and there’s no cancer in the blood, then it’s an easier decision to just stop the therapy. But if there is some cancer in the blood, then they might continue the therapy. But this is not considered standard by any means.

Felicia Johnson [00:40:38]:

You’ve mentioned the BRCA mutation and the different treatments for those mutations. However, is there anything in the works for CHEK2 or BARD mutations?

Virginia Kaklamani, MD, DSc [00:40:51]

So CHEK2 and BARD are in the same pathway as BRCA. And we’ve done work looking at these PARP inhibitors in patients that have CHEK2 mutations and BARD mutations. And they seem to be active, not as active as with BRCA mutations, but they seem to be active. The hope is that we create better PARP inhibitors so that they can be more effective in patients that have these mutations in other genes.

Jean Sachs, MSS, MLSP [00:41:19]

Just so you know, I can’t see the questions anymore, but I did read a lot of them.

I just wanted to circle back for people that are not at an academic center.

Virginia Kaklamani, MD, DSc [00:41:29]

Oh, that was your question.

Jean Sachs, MSS, MLSP [00:41:31]

Yeah, is there a way for them to get counseled?

Virginia Kaklamani, MD, DSc [00:41:33]

Absolutely. One of the good things that happened with COVID is telemedicine. Anybody taking advantage of it?

Telemedicine can’t happen out of state. All of our societies are giving us licenses to practice only in our state. If a patient says to me, “Oh, I live in Illinois, can I do a telemedicine visit with you?” Unfortunately you can’t. But if you live in Texas, you can. Thankfully, we have academic centers in all of the 50 states, and you can have a telemedicine consultation without having to go to that doctor’s office.

I would encourage you, if your physician at any point says, “I don’t know,” “I don’t know what this means,” “I don’t know what to do,” that you ask other people. And typically you ask your doctor to find out. Right? If I don’t know something, I’m going to call a friend and get their opinion. I do this all the time. There’s no shame in asking other people what their opinion is. This is the power of us being a community, not just you being a community, but us being a community too.

So it’s extremely important that that you do get a second opinion whenever you have a doubt. It doesn’t matter what the doubt is. Whenever you have a doubt, don’t let that fester. Get a second opinion, make sure that you’re very clear with what you’re doing. It helps us as well. If I’m treating a patient who doesn’t really believe in what I’m treating them with, that’s not a good communication.

Felicia Johnson [00:43:13]:

I often hear that NBC patients should ride out the treatment plan as long as possible and change the treatment only if there is progression on the scans. If we are more proactive and change treatments before progression, couldn’t that lead to running out of treatment options quickly?

Virginia Kaklamani, MD, DSc [00:43:33]

So far this has been correct. We looked at that approach with chemotherapy at the point where we were looking at circulating tumor cells.

You may not remember the era of circulating tumor cells, but it was circulating tumor cells. When we would see the circulating tumor cell numbers rise, even though the scans would be stable, we would change chemotherapy. Then we did a trial to see is that approach really useful. And the answer is no. It’s not useful because we would switch chemotherapy every 3 weeks or every 6 weeks and then we would expose our patients to more and more and more toxicities from our chemotherapy, and they’d live as long, they would just live with a worse quality of life.

This is different because these are smart therapies. These are therapies that target the exact mechanism of how the cancer is slowly growing. So our hope is that this approach is going to work. We’re not sure yet, this is how we’re doing the trials. Our first indication from a few weeks ago is that this approach may actually work for specific changes, but we still have a long way to go.

Caroline Koffke, RN, BSN, OCN [00:44:41]

We have some questions for folks who are wondering the differences or your recommendation on liquid versus solid biopsies. I know you had said you use liquid frequently. Is that something that can always be used? What’s your opinion?

Virginia Kaklamani, MD, DSc [00:44:55]

As I mentioned, I’ll typically do a solid biopsy at the time of diagnosis because I need to prove to myself and to my patient that this cancer has gone somewhere.

After that, it’s not very easy to do these solid biopsies. It’s easier to do liquid biopsies. Now if the patient doesn’t have what we call a large burden of disease, if they just have a couple of spots here and there, those liquid biopsies may be negative because not a lot of DNA is shedding. Then we may need to do another solid biopsy because the liquid biopsy is negative. But in many of the cases, the liquid biopsy is really the way to go because of how much easier it is, but also because of the information it gets from all of the different sites.

Jean Sachs, MSS, MLSP [00:45:40]

I know there was also a question about HER2-low and giving more treatment options. So I think if you could just explain what HER2-low is and what that means for patients.

Virginia Kaklamani, MD, DSc [00:45:56]

Yeah, so we talked about these antibody-drug conjugates, right? There’s an antibody, it has a little drug on it, and the antibody just looks for the receptor. Now, in the old days, when we had HER2-positive versus HER2-negative breast cancer, we knew that Herceptin [trastuzumab], which is the first antibody we use for breast cancer, is very effective in cancers that are HER2-positive. But these antibody-drug conjugates are so much better than Herceptin that they don’t need HER2 to be that much expressed. They just need a little bit of HER2. They just need a little bit of that receptor so that they can latch on, go into the cell, and kill the cancer.

Now we’re able to use these antibody-drug conjugates, not just for HER2-positive breast cancer, but any breast cancer that expresses any level of HER2. And so we call that any level of HER2, HER2-low— so not HER2 zero, not HER2 absent, but HER2-low.

Interestingly, even in the HER2 zero, we can have up to 20,000 receptors on a single cell. So even HER2 zero is not really HER2 zero, but it’s probably a little too low.

Jean Sachs, MSS, MLSP [00:47:10]

How often should you be getting that test? At every progression?

Virginia Kaklamani, MD, DSc [00:47:14]

Every time we do a biopsy, we check for ER, PR, and HER2, and we should be checking for ER, PR, and HER2. So we have this result for every biopsy. Now the liquid biopsy doesn’t usually capture that. There’s new methods that are looking at capturing cancer cells. So not just DNA but cells. And once that you capture the cells, then you can do a HER2 on those cells. So these assays are coming out.

Felicia Johnson [00:47:42]:

What can I do if my liquid biopsy shows nothing to target?

Virginia Kaklamani, MD, DSc [00:47:48]

Yeah, so then we do have other drugs that are not necessarily targeted drugs but are drugs that we can use to treat breast cancer. In those cases we use those drugs and sometimes we’ll fall back to chemotherapy because that’s really something that can work in a lot of different cancers without specific changes.

Caroline Koffke, RN, BSN, OCN [00:48:10]

You mentioned tumor heterogeneity. How do molecular tests work if multiple mutations are expressed? And how does that impact your treatment choices?

Virginia Kaklamani, MD, DSc [00:48:20]

This is where the art of medicine comes. We do a lot of studies, and we have studies where we take patients whose tumors have a few different mutations and we give them one drug or another drug and we see what works. So we typically know that those drugs can work and we can sometimes combine them as well. Which one we target first and which one we target second really depends on what kind of mutation it is. So it’s very, very variable, but we try to target all the mutations at some point.

Jean Sachs, MSS, MLSP [00:48:49]

I know in one of the slides you talked about targeting the CDK2. Are there actually therapies out? Are they in trials?

Virginia Kaklamani, MD, DSc [00:48:58]

There’s a lot of CDK2 inhibitors that are currently in clinical trials. There’s also CDK7 inhibitors. There are specific CDK4 inhibitors, CDK9 inhibitors. So there’s really an explosion. There’s an explosion of these drugs, and I’m sure not all of them will come to market, but I think many of them will and they’ll change 180 degrees how we treat metastatic breast cancer.

Jean Sachs, MSS, MLSP [00:49:27]

This is so important for all of you to be asking those questions because it’s the first time I heard about CDK2. So, great. Go ahead, Felicia.

Felicia Johnson [00:49:38]:

Do liquid biopsies represent mets in the brain as well as the body?

Virginia Kaklamani, MD, DSc [00:49:45]

That’s a great question. We think so. Every tumor will shed. In the brain, we always talk about the blood-brain barrier. That’s a little membrane around the brain. It protects the brain from all the toxins. It helps us think clearly and not expose the brain to a lot of bad stuff. But cancer cells are big cells, and for them to go into the brain, they’ve been able to bypass the blood-brain barrier. So now the barrier is very leaky, doesn’t work.

So once it doesn’t work ...

Caroline Koffke, RN, BSN, OCN [00:50:17]

What resources do you share with patients that you are treating to help them stay up to date with this and find clinical trials, especially if they’re working with a doctor who may not have as much knowledge as you do?

Virginia Kaklamani, MD, DSc [00:50:32]

I’ve learned, also from personal experience, that our patients are very overwhelmed. It’s easy for me to talk about this, and it’s easier for you to listen to it than it is when you’re in your doctor’s office and when you’re getting a result from a scan and everything shuts down because you got bad news.

Imagine at that point if I say, “Well these are our options, what would you like to do?” And you’re thinking, How am I supposed to know I’m not the expert? So I try to guide my patients more than just saying, well, here are these options, you get to decide.

It happened to me in a totally different situation, when somebody called me on something that I was a pretty good expert in and said, “What would you like to do?” And I froze and I said, “I don’t know. What do you think I should do?” So if I say that, how’s my patient that doesn’t have the knowledge that I do make that decision?

There are websites. ClinicalTrials.gov. I love that website. And there’s a patient-friendly website. Hopefully it hasn’t been shut down.

Jean Sachs, MSS, MLSP [00:51:46]

No, it’s there.

Virginia Kaklamani, MD, DSc [00:51:48]

That talks about all the trials. You can put in your geographic location, you can put in how many miles you’re willing to travel. It’ll give you all the different trials.

It won’t help you as much in your specific cancer. You have to put a couple different things, but you’re not going to be able to put everything in there. But take that list and take it to your physician and say, “Which ones of these trials do you think are a good idea?”

I’ll typically do that as well. I typically know the trials that are happening in my city and surrounding cities, so I’ll be able to say, “Hey, why don’t you go into this place? Because they have a really good trial.” Or “This is a trial that we have that I think is a good idea.” But the important thing is ask your physician about clinical trials.

We always think that we have to bring it up and we’re always afraid that if we bring clinical trials up, patients will think, Oh, I’m dying. And that’s not true. We bring clinical trials up because research has shown that patients that participate in clinical trials live longer than patients that don’t participate in clinical trials. And so it’s extremely important that you are exposed, at least you get the idea that there is something out there for me. It doesn’t mean that I don’t have any other options. It means that these trials might be a better option than my standard of care. So make sure that you ask

Jean Sachs, MSS, MLSP [00:53:11]

Yeah, and talk to each other. Because I know there’s a lot of people here today, online, in the LBBC community who have participated in trials. So we can connect you together. I think it’s important.

I know there was a question, and we only have few minutes left. How do you think this new administration will be impacting funding for clinical trials and research? And what can we all do to help make our voices heard?

Virginia Kaklamani, MD, DSc [00:53:44]

I’m not going to lie to you, it doesn’t look promising.

Actually, Dr. Foti is here, she is the CEO of the American Association for Cancer Research. If there’s something that you can do, it’s work with associations such as AACR. That’s their job. They’re there not just to advocate for the physicians, they’re there to advocate for the patients, they’re there to raise funds. I think we’re going to be relying more and more on ASCO and AACR and Komen and LBBC for funding, and that’s the power that we all have, to give the resources to these foundations and associations so that we can continue our research.

Jean Sachs, MSS, MLSP [00:54:37]

Thank you. And talk to everybody here.

I think we can do one more question.

Felicia Johnson [00:54:45]:

When cancer cells are shedding during stability would this lead a biopsy result to show no target?

Virginia Kaklamani, MD, DSc [00:55:00]

I’m hoping I understand the question. So cancer cells are shedding from everywhere. And when we do that liquid biopsy, we look at all of these changes. But when we do an actual biopsy of a piece of cancer, we get tons of information from that biopsy as well. So both of them are useful, and both of them have different utility.

For example, those PIK3CA mutations I mentioned, those are mutations that are present the minute the cancer’s born. So I can find these mutations by doing a breast biopsy. I can find these mutations in a patient that had initial breast cancer 10 years ago, and now unfortunately has metastatic breast cancer. I can look at that tissue 10 years ago and find that PIK3CA mutation if it’s present. An ESR1 mutation is a mutation that develops over time as the cancer is exposed to endocrine therapy, to hormone therapy. So if I look for that mutation in that initial cancer, I’m not going to find it. So that’s where I need to do a liquid biopsy to find that ESR1 mutation.

You can imagine, these are relatively complicated things. These are not things that it’s a one-size-fits-all. That’s why we have to individualize care.