Understanding the role of personalized medicine in your cancer journey

Transcript

Elena Michaels, MD (00:00:08):

Hi, everyone. I’m so excited to be here with you all today. Just like Caroline mentioned, we’ll be breaking this talk up into two parts, and I’m excited to talk with you all about some diagnostic tools that can be used to deliver precision-based care in your metastatic breast cancer journey. I have no disclosures to report, and we can get started.

(00:00:29):

Just to give you an outline of what I’ll be talking about today. First we’ll talk about how we break up breast cancer into its three different treatment categories using estrogen, progesterone, HER2, and then also we’ll discuss PD-L1 status particularly for triple-negative breast cancer. Next we’ll talk about methods we use to test for important biomarkers in metastatic breast cancer. This includes germline genetic testing as well as a technology called next-generation sequencing. We’ll talk a little bit about molecular residual disease or minimal residual disease, a non-genomic tool that can be used to personalize cancer care. And then I’ll give a quick summary and if there’s some time, some future directions of where this is going.

(00:01:15):

All right, let’s get started with estrogen, progesterone, HER2, and PD-L1 status. This image here gives us an understanding of how we go about thinking and treating metastatic breast cancer. There are really three main treatment categories that we put different breast cancers into, and this is a vitally important first step when thinking about how we can personalize cancer care for our patients.

(00:01:41):

The first treatment category is hormone receptor-positive breast cancer. This is a breast cancer that feeds and grows using natural hormones that are produced in our bodies. These hormones include estrogen and progesterone, which can be created by the ovaries and other organs and tissues in the body. And the way that those hormones get into the cancer cells is through receptors that sit on the surface of the cancer cells. Once that hormone gets inside the cell, it then uses it almost like food or fuel to grow and divide.

(00:02:19):

We can understand if somebody has a hormone sensitive breast cancer through staining that we perform on tumor tissue, either from a biopsy or a surgical specimen. And what we stain for are those estrogen and progesterone receptors. When we have hormone-sensitive metastatic breast cancer, we know that those breast cancers will be sensitive to antiestrogen therapies, and that’s just one of the ways that we can personalize treatment for that group. Seventy-five percent of all breast cancer cases are hormone-sensitive breast cancers, but let’s move on to this middle category you can see in this image, which is HER2-positive breast cancer.

(00:03:01):

HER2-positive breast cancer is a breast cancer that grows and divides using a special protein called HER2 that sits on the cell surface. Through a very complex mechanism of different signaling pathways, that HER2 protein is what those cancer cells use to grow and proliferate through the body.

(00:03:21):

Similarly to hormone-sensitive breast cancers, we can test for HER2-positive breast cancers looking for staining on the cancer cells of this HER2 protein, and we can grade that staining from a scale of 0 to 3, 0 being what we would consider to be HER2 negative and 3 being what we would consider HER2 positive. Sometimes we will use a second confirmatory test that we call FISH, or fluorescent in situ hybridization, if we have a HER2 positivity that’s in the middle at 1+ or 2+.

(00:03:54):

We know that HER2-positive breast cancers tend to be a bit more aggressive than hormone sensitive breast cancers. They grow and divide faster. However, in the last couple of decades, we have developed anti-HER2 targeted therapies for HER2-positive breast cancer that have really transformed treatment for patients with HER2-positive metastatic breast cancer and importantly changed outcomes and survival for the better. About 15% of all breast cancer cases are HER2 positive.

(00:04:26):

Lastly, there’s triple-negative breast cancer. And rather than triple-negative breast cancer being defined by what it does have on the cell surface, like these last two treatment categories, triple-negative breast cancer is defined by what it doesn’t have. So these are breast cancers that lack estrogen and progesterone receptors on its cell surface. They don’t use those hormones to grow and divide, and they don’t make significant amounts of that HER2 protein either. Similarly to HER2-positive breast cancer, triple-negative breast cancers do tend to be a bit more aggressive and a bit more fast growing. And because of that, they are sensitive to chemotherapy as well as another class of drugs that we’ll get into a litle bit more called antibody-drug conjugates. And in certain cases, metastatic triple-negative breast cancers can be sensitive to immunotherapy, which I’ll talk about as well.

(00:05:19):

Some of you may also have heard of HER2-low and HER2-ultralow disease. You may have looked it up or heard about it from your oncologists. And this is a fairly new concept that we’re using to describe what we would have traditionally called HER2-negative metastatic breast cancer. And it’s a new subcategorization of treatment that we use to describe both hormone-sensitive breast cancers and triple-negative breast cancers that are traditionally HER2 negative, but that we know might be candidates for a treatment called trastuzumab deruxtecan or Enhertu.

(00:05:54):

Enhertu is from a class of drugs I just mentioned before called antibody-drug conjugates, and you can think of antibody drug conjugates almost like a cargo plane carrying explosives. The antibody tells the cargo plane where to go and where to land. And in the case of Enhertu, that antibody is trastuzumab. It tells the cargo plane to go to cells that have that HER2 protein on it. And once that cargo plane gets there, it can release its explosives, which is chemotherapy, into the cells. And so this delivers a very targeted attack of this treatment to those cancer cells.

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Now you can imagine because that antibody trastuzumab is leading the drug to HER2-positive cells, this of course would work in HER2-positive breast cancers, but we’ve learned over the last couple of years that Enhertu actually works very, very well in what we would have traditionally called HER2-negative breast cancers. And that’s because if a cancer even has some HER2 protein on its cell surface, it can lead that drug to those HER2 positive cells and still lead to a very targeted killing of the cancer cells around it. And so we have reclassified some tumors as HER2 low and HER2 ultralow if they even have a slight amount of staining of this HER2 protein so we can consider them for treatments with this drug.

(00:07:23):

And then what about PD-L1 in metastatic triple-negative breast cancer? So I mentioned to you earlier that some metastatic triple-negative breast cancers might respond to a group of drugs called immunotherapy, and PD-L1 is key to understanding who might be sensitive to these immunotherapy drugs. PD-L1 is a protein that sits on the surface of cancer cells and it almost acts like a shield or a mask protecting the cancer from being recognized by the body’s immune system and preventing the immune system from going and attacking that cancer. We know that there are some types of cancer, not just breast cancer, that make lots of this PD-L1 protein, and we’ve learned over the years that cancers that make lots of PD-L1 protein can be susceptible to a group of drugs called immunotherapy.

(00:08:20):

In metastatic triple-negative breast cancer, the immunotherapy drug that is approved for tumors that make lots of PD-L1 protein is called pembrolizumab, or Keytruda. What Keytruda does is it removes that mask, that shield, that the cancer cells created using this protein so that the immune system can recognize and go and attack that cancer. But not all metastatic triple-negative breast cancers make lots of this PD-L1 protein, so it’s vitally important to test our patients. We do this using staining for that PD-L1 protein on tumor tissue from either a biopsy or a surgical specimen.

(00:09:02):

Next, let’s talk more about methods that we can use to test for important biomarkers in metastatic triple-negative breast cancer. Before we do, let’s take a quick step back and talk about what even is a biomarker. I don’t think this is a term that’s used very commonly outside of the medical field. A biomarker is a protein, a hormone, a gene, a genetic mutation, or a molecule that gives a provider additional information about a disease.

(00:09:28):

This is not a term that is necessarily used in breast cancer specifically or even cancer specifically. It’s a term we use in many different diseases, but within breast cancer, we use biomarkers to obtain lots of different information about someone’s cancer. It can help us estimate prognosis, understand cancer biology, what is causing that cancer to grow and spread, to understand breast cancer subtypes. Estrogen, progesterone, HER2, are considered biomarkers. We can use it to consider whether or not someone’s cancer might be sensitive to certain treatments or clinical trials, just like that PD-L1 protein I mentioned earlier, and we can also use it to monitor response to treatments. You can understand that identifying biomarkers in metastatic breast cancer is hugely important. And so how do we go about doing that?

(00:10:21):

Well, one of the ways that we can do this is through germline genetic testing. And germline genetic testing is a blood- or a saliva-based test that we use to assess for genetic mutations in a panel of inherited cancer-related genes that you have in your own body. These are genes that would have been passed down from your parents and their parents before that, and we know that there are certain genetic mutations that we can inherit that might increase the risk of developing breast cancer. You might have heard of some of these mutations like the BRCA1 and the BRCA2 gene, but there are several others that give us a much higher risk of developing breast cancer. That can include mutations like PALB2, PTEN, CDH1, and TP53. And very, very importantly, we have certain treatments available for patients with metastatic breast cancer who have certain germline mutations. So for practically everyone coming through the door with a new diagnosis of metastatic breast cancer, undergoing germline testing is very important if it hasn’t been done before.

(00:11:32):

We have guidelines that you can see listed here on other reasons to test patients with germline testing, but like I said, because we have specific treatments available for patients with metastatic breast cancer, that is a good enough reason for our national cancer guidelines to pretty much test everyone with germline testing.

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And then we’ll talk about another method that we can use to look for genetic mutations and that is next-generation sequencing.

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Next-generation sequencing is a technology that analyzes the genetic makeup, the DNA and RNA, of cancer cells to identify mutations that the cancer cells themselves have that is allowing them to grow and to spread. We know, similarly to what I mentioned with germline genetic testing, that there are certain medications and certain clinical trials that we have available if a cancer possesses specific mutations, and that can allow an oncologist to tailor their treatment to a tumor’s unique genetic profile.

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Testing can be performed either on tumor tissue from a biopsy or a surgical specimen, and we colloquially call this a solid biopsy. Or it can be performed using a blood sample, which we call a liquid biopsy.

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We also know that the genetic mutations that a cancer has is not fixed. It can change over time. As a cancer is exposed to different treatments that we give it and learns to outsmart those treatments, it can develop and acquire new mutations that we can take advantage of with treatments. Oftentimes we will repeat next-generation sequencing over the course of someone’s treatment.

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Let’s talk just a little more about these two different methods, solid versus liquid biopsy. So a solid biopsy, just like I mentioned, is next generation sequencing performed from the tumor tissue, either from a biopsy or a surgical specimen. And because we’re using a biopsy or surgical specimen, we can obtain additional information about the cancer, not just the genetic mutations it has. It gives us an opportunity to repeat testing if we need it, to repeat estrogen, progesterone, HER2, and PD-L1 testing. And because we keep our samples stored for long periods of time, we can even go back and test older samples to see how someone’s cancer has changed genetically over time.

(00:13:58):

We also prefer solid biopsy for a certain type of mutation we see in breast cancer called PTEN loss, which Dr. Wander will talk about in a little bit in more detail. And we also generally prefer solid biopsy right now to assess tumor mutational burden, and tumor mutational burden is just a fancy term for how many mutations the cancer has overall. That is an important thing for us to understand because that same immunotherapy drug I mentioned to you earlier, Keytruda, is approved for patients who have high tumor mutational burdens, which we categorize as greater than or equal to 10. And that is completely separate from that PD-L1 status I mentioned earlier and is an option for treatment for any different breast cancer category.

(00:14:46):

There are of course limitations to solid biopsy. It is invasive. We’re sticking a needle in patients. Sometimes we don’t need to do that. There can be infections, bleeding, we can damage other areas. So we do want to weigh the risks and the benefits carefully of getting a solid biopsy. There are cost and time constraints on behalf of the patient, of course. Sometimes there are anatomical limitations, places that we can’t stick a needle into or it’s not safe to get a needle in. Sometimes we get limited amounts of samples also because of those anatomical limitations. And then solid biopsy can also be difficult to assess tumor heterogeneity.

(00:15:22):

Now what the heck do I mean by tumor heterogeneity? So we know that just because a cancer originated in the same person doesn’t mean that it can’t change in different parts of the body as it learns to grow and spread. And we know that cancer behaves almost like a city that has different neighborhoods within it. You can think of cancer kind of like New York City. There are some neighborhoods that are like Times Square, big, bustling, aggressive, always moving. And then there are other neighborhoods that are much quieter. These different neighborhoods all developed from the same original cancer cell, but they learn to have different behavior over time using genetic mutations. And when we obtain a solid biopsy, we’re just getting a piece of that cancer. We might just be seeing mutations from 1 or 2 or 3 neighborhoods of cancer cells, but we’re not necessarily seeing genetic mutations from cancer cells that live in other parts of the body and so we may not identify all the mutations we can take advantage of with this type of biopsy.

(00:16:28):

Next is liquid biopsy, which like I mentioned, comes from a blood sample. This is a distinct test from that germline genetic testing I mentioned earlier because with what this blood test is looking for is the cancer cells themselves. It’s looking to pick up circulating cancer cells and to analyze the DNA and RNA of those cells to assess for genetic mutations. You can imagine that a much quicker and simpler blood test is much less invasive, and because we’re picking up cancer cells from all over the body, all these different neighborhoods, it does reflect tumor heterogeneity. We are picking up mutations from all over the body.

(00:17:07):

Because this is an easier, oftentimes more feasible test for us to perform too, we will typically use liquid biopsy to repeat this testing over time throughout a patient’s treatment course. And then I mentioned to you that in solid biopsy we prefer for assessing PTEN loss, and in liquid biopsy it is generally preferred for assessing a type of mutation called ESR1 mutations, which you guys may have heard about earlier and that Dr. Wander will discuss in more detail next.

(00:17:35):

Some limitations right now of liquid biopsy is that at this point it is not quite as sophisticated as solid biopsy in assessing estrogen, progesterone, HER2, and PD-L1 status, but that is changing even as we speak. These types of liquid biopsies that we are performing from these companies that you can see listed here are getting better and better about giving us this additional information, and in the coming years this will likely be able to provide us with all the same information a solid biopsy can. And because this is a blood test that relies on detecting circulating tumor cells, sometimes we can get false negatives if someone’s cancer simply isn’t shedding as much tumor DNA or tumor cells into the blood. Again, we are getting better and better at this as we speak. These tests are getting more and more sensitive at picking up even low levels of cancer cells and this is becoming even less of a problem.

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You might ask because we have these two different methods to test for next-generation sequencing: Is one better? Is one more accurate? And this is a question that we’ve asked ourselves in several different studies, but here you can see data from one clinical trial that was conducted out of the United Kingdom called the plasmaMATCH trial. This was a phase II clinical trial that’s entire purpose was to see how accurate or how concordant solid and liquid biopsies are. This trial took patients with metastatic breast cancer of all different subtypes and they performed solid and liquid biopsies at the exact same time, which they call contemporaneous samples. They looked to see how accurate they were in detecting some well-known mutations in breast cancer, which you can see listed here AKT1 mutations, HER2, ESR1, and PIK3CA, and they saw that overwhelmingly the two tests were pretty accurate. Depending on the mutation, there was 75% to 100% concordance, or accuracy, between the two tests. But there was a difference, like I mentioned, in that ESR1 mutation, with the liquid biopsy being able to detect ESR1 mutations more frequently than the solid biopsy.

(00:19:48):

Next we’ll talk a little bit about molecular residual disease, or minimal residual disease. This is a different type of blood test that can detect cancer circulating in the blood or circulating tumor DNA, but rather than looking for genetic mutations in the blood, what this test is trying to detect is how much cancer there is. This test is used in both early-stage breast cancer and in metastatic breast cancer, but specifically in metastatic breast cancer, it can be used to monitor how someone is responding to treatment in combination with scans and in combination with tumor markers. As you can see here in the image, if somebody is responding to treatment and the cancer is sensitive, we can watch that MRD level go down, and we can use it to track if someone’s becoming resistant to cancer sometimes before we even pick it up on scans. So this can be a very powerful tool.

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And then lastly, I’ll talk about one non-genomic test that we can use to personalize cancer care, and that is FES-PET.

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FES-PET is a very specific type of PET scan for hormone-sensitive breast cancers. This is a type of PET scan that injects a radiotracer into the blood, but instead of going to areas where there’s lots of glucose uptake, which is what a traditional PET scan does, an FES-PET’s radiotracer goes to areas where there’s lots of estrogen receptors. And so this is a very sensitive scan for picking up hormone-sensitive breast cancers.

(00:21:20):

This PET scan can be very beneficial, especially if a biopsy isn’t feasible or safe; if we’ve had mixed biopsy results in the past, where someone’s breast cancer has been both estrogen sensitive and negative and we’re trying to understand if an estrogen-sensitive breast cancer is really driving their current breast cancer so we can take advantage of it with treatments; if we have lobular breast cancers, which are breast cancers that arise from the milk producing ducts and these can be traditionally very difficult to pick up on our imaging; and then if we have inconclusive imaging results.

(00:21:56):

However, there’s limitations for these scans right now. For anyone who is on an estrogen-modifying treatment like tamoxifen or fulvestrant, there can be very long washout periods before this test can be obtained because it’s not sensitive if people are on these treatments. And we also can’t reliably assess liver lesions right now with FES-PET. As you can see here in the image, that big area that’s lit up is the liver, and that’s because this radiotracer is metabolized through the liver. And then also right now FES-PET is not widely available. Most places that have an FES-PET scanner are very large academic institutions in major cities, and so smaller community practices and even smaller academic sites may not have these tests widely available. But we’re probably going to see that change over the next few years as we get a better understanding of how advantageous this scan really is.

(00:22:53):

Just to give you guys a summary of everything that we’ve discussed so far. From the time of your metastatic breast cancer diagnosis, we should always be rebiopsying to reassess estrogen, progesterone, and HER2 status. All patients with metastatic triple-negative breast cancer should undergo PD-L1 testing to see if they’re a candidate for immunotherapy, which can be combined with chemotherapy. And then germline genetic testing should be performed for practically everyone with metastatic breast cancer if it wasn’t performed previously.

(00:23:26):

FES-PET is a very useful tool for patients with hormone sensitive breast cancers. And everyone should also get baseline next-generation sequencing, either with a solid or a liquid biopsy or both if we want all of that information.

(00:23:40):

After someone is started on treatment, we can repeat next-generation sequencing, particularly any time we see resistance develop on treatment to see if there are new genetic mutations that might explain why this happened and if we can take advantage of those mutations with treatment. And then MRD testing can be considered in combination with imaging and tumor markers as a treatment monitoring tool.

(00:24:02):

Thank you very much. I’ll skip through these last slides, and it was a pleasure.

Seth Wander, MD, PhD (00:24:14):

All right, tough act to follow. I think we should have let her do the second half too. Great to be with everybody. Thanks so much to the organizing committee for the invitation. It’s raining and cold in Boston, so I’m hoping this weather’s moving up toward us.

(00:24:30):

What we’re going to do for the second half, and then we’re going to try to leave hopefully about 20 minutes or so for discussion and questions, is take the tools that Elena was teaching us about and think about how they’re actually altering our clinical approach. We have many new therapies in breast cancer that are based on specific molecular and genetic changes in the tumor, and we need to think about what is the best tool to deploy to choose those drugs in a timely way and in an accurate way.

(00:25:00):

We talked about new technologies. And these are rapidly evolving, and there’s a number of newer ones that are still not yet ready for prime time. I think we’re rapidly getting to a place where we’re going to move away from solid tumor biopsies entirely and start to do things like receptor testing off of the blood. So in a couple of years, we’ll probably be talking about that. What I want to do in the second half here is think about biomarker based treatment options for metastatic breast cancer.

(00:25:27):

Here are my disclosures.

(00:25:31):

In 2025, not that long ago, a little less than a year ago, I gave a talk at ASCO, and the title of the session was Optimizing Targeted Therapies with Molecular Markers. This was the slide I used when we were starting that conversation. We want to think about how to deliver upon the promise of personalized medicine and precision oncology. Well, what does that really mean? It means to me, finding the right drug for the right patient at the right time.

(00:25:59):

Now, if I had given this talk in 2014 when I was in Elena’s shoes and I was a fellow, it would have been a very, very quick talk, probably about 30 seconds and this is what it would have looked like. Almost everybody with estrogen receptor-positive, HER2-negative breast cancer, which we heard is the majority, about 70% to 75%, would have gone from an aromatase inhibitor to fulvestrant to chemotherapy. There was absolutely no degree of personalization in the mix at that time.

(00:26:26):

And this is an incomplete list of how far we’ve really come just in the last few years. This is really focusing on hormone receptor-positive disease. We’re going to talk a little bit about some of the other disease types, but a lot of our research happens to be in hormone receptor-positive. And in the interest of time, I wanted to make the demonstration by looking at this most common type of breast cancer. Although we’re making progress in all types of breast cancer.

(00:26:48):

But just looking at hormone receptor positive, we had tamoxifen in the 1970s, the aromatase inhibitors in the 1990s. We have the CDK inhibitors, palbo-, ribo-, and abemaciclib beginning in 2015. And now on the far right, everything that I have a little asterisk on, these are new FDA approvals just in ER-positive, HER2-negative disease over the last few years that require specific molecular genetic changes for patients to be eligible. And in another year or 2, I’m probably going to have to double that list. We have a lot of phase III data, some of which we’ll talk about today, that we’re awaiting FDA approval on.

(00:27:28):

This is what I wanted to talk about, and I chose these not as an exhaustive list but just to demonstrate how some of the sequencing technology that we just learned about can be deployed to help decide what therapies to give to patients. We’ll talk about BRCA mutations and PARP inhibitors. We’ll talk about ESR1 mutations and next generation antiestrogens. We’ll talk about PI3K pathway inhibition. We’ll talk briefly about HER2-low disease and how we’re using trastuzumab deruxtecan in that setting. And I’ll end with summary and some future directions.

(00:28:01):

I’m going to frame this mostly around hormone receptor-positive disease, but there are examples that are relevant to other types of breast cancer.

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Now, BRCA, as we heard about, is a relatively common alteration. It is typically inherited from parent to child. Genetic causes of breast cancer we think account for probably about less than 10% of the overall cases, but BRCA is the most important gene amongst the number of genes that we’ve identified in the mix there.

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And this is an overly complicated diagram. But it’s showing you that in normal cells throughout the body damage can occur to the DNA. And we have mechanisms within all of our cells to help repair that damage. BRCA is one of the pathways, one of the proteins that’s critically important for identifying and fixing damage to DNA in cells. And so when you have an alteration in BRCA, damage to DNA can accumulate and that can eventually lead to different types of cancer, including breast cancer.

(00:29:00):

PARP is an important protein that plays a separate role in DNA damage repair. And what we discovered a number of years ago is that in patients who have BRCA, and in tumors where there’s alterations in BRCA, there’s DNA damage happening but not enough DNA damage to cause the cell to die and that’s what leads to cancer. But if you then block PARP, which is a separate DNA repair pathway, the two of them together causes enough DNA damage that the cancer cell can no longer survive. And that’s the reason that PARP inhibitors are uniquely effective in tumors that have this already some degree of DNA damage going on.

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And that’s what you’re seeing in that diagram there in the middle. If the patient has both BRCA and gets the PARP inhibitor, the amount of DNA damage is too much for the cancer cell to overcome.

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That led to this study by my colleague at Memorial Sloan Kettering, Mark Robson, published in the New England Journal in 2017. This was the OlympiAD study. There have been a number of studies looking at these PARP inhibitors, which are widely used, for example, in ovarian cancer and breast cancer. This was for patients with both triple-negative and hormone receptor-positive, HER2-negative breast cancer. They had to have a germline, as Elena taught us, meaning inherited BRCA1 or BRCA2 mutation. They were allowed to have had up to two prior lines of chemotherapy. They must have had at least one endocrine or estrogen based therapy if they had hormone receptor-positive disease.

(00:30:25):

Over 300 patients were randomized 2 to 1 to get chemotherapy of clinician’s choice, you can see the drugs they used there, or olaparib. Many of you who’ve been seeing some of these other talks and have been looking at this data are used to seeing curves like this. I don’t always think that this is the best way to visualize it, but unfortunately this is the way that it’s typically presented in the journals. These are progression-free survival curves. So what we’re looking at here starting at 100% as it goes down are what fraction of patients are having a progression event, meaning the cancer is growing or the clinician feels that there’s evidence of some sort of progression. And whenever that curve shifts up and to the right, that’s a good thing. That means progression is happening less frequently and more slowly. So that’s one way to think about these curves.

(00:31:11):

In the blue line, you see chemotherapy. In the red line, you see olaparib.

(00:31:15):

We also think about median progression-free survival, meaning what is a rough estimate of the average amount of time it takes for progression to occur. It’s a bit of an unfair estimate because there’s a mixture of a large amount of different types of patients here. There are patients who’ve had multiple prior lines of therapy. There are patients who’ve had fewer lines of therapy. There are patients who have more sites of disease. There are patients who’ve had fewer sites of disease. So when you look at a median, or an average, estimate of progression-free survival, there’s a huge range around that. There are some patients who unfortunately don’t have sensitivity to the drug in the near term. There are other patients who might stay on the drug for years and years. So we’re getting a rough estimate.

(00:31:56):

You can see here there was an improvement from about 4 to 7 months on the average. But most importantly to me is the response rate. So the response rate was 60%, meaning 60% of patients who had BRCA mutations if they got a PARP inhibitor, olaparib, had a response, meaning the tumors were shrinking by at least 20% on the scans. That’s a very high response rate for ER-positive breast cancer and that doesn’t include the patients who had stability, meaning the tumors didn’t shrink, but they didn’t grow and they stayed stable for long periods of time. So the clinical benefit rate, which is the response rate plus the rate of longer-term stability is much higher, probably on the order of 80% to 90% in this population.

(00:32:37):

This led to the FDA approval of PARP inhibitors for BRCA mutations.

(00:32:43):

I’m just going to show you some of these toxicity tables. Again, this is an imperfect way to measure this. This is quantifying different toxicities on the clinical trial showing you any grade, meaning kind of mild to moderate, grade 1 to 2, or more severe, grade 3 to higher. With PARP inhibitors, we tend to see fatigue. We can see reductions in the blood count. We can see some GI toxicities.

(00:33:06):

In my experience, it’s a generally tolerable pill. We need to keep a close eye on the labs, and it’s oral so the patients aren’t tied to chemotherapy.

(00:33:16):

Let’s move on to talk about ESR1 mutations. This is a really nice paper that was published a couple of years ago showing you all the different mechanisms of the antiestrogen drugs. And we are very much in a renaissance period right now for antiestrogen drugs. There are all kinds of new agents coming online.

(00:33:33):

I sort of joke when I see patients in clinic and say, “Well, about every 30 years we’re due for new class of antiestrogens.” We had tamoxifen in the 1970s. We had the aromatase inhibitors in the late 1990s. It’s been exactly 20 to 30 years and we are now seeing our first FDA approvals for what I would call third and fourth generation antiestrogens.

(00:33:54):

Most of the development recently has been in that middle column there with a drug called a SERD. This is a selective estrogen receptor degrader. These are drugs that bind to the estrogen receptor and tell the cancer cell to destroy it. And that’s important because many of these cancer cells are addicted to estrogen. So by destroying that receptor, you’re actually taking away the stimulant that the cancer cell needs to survive. And many of you are aware that we’ve had a drug called fulvestrant, which is a selective estrogen receptor degrader, for about 15 to 20 years, but fulvestrant is a difficult drug to give. It’s an intramuscular injection. You have to come into clinic every month. It can be painful. It took about 10 to 15 years for our friends at Stemline and other companies to crack the pharmacology here and actually convert from an intramuscular shot to a pill, which makes things a lot easier for patients.

(00:34:46):

And so ESR1, as Elena was alluding to, this is the gene that encodes the estrogen receptor. It’s present in breast, ovary, uterus tissue, and it’s a transcription factor, meaning when it binds to estrogen, it goes into the nucleus, hooks onto the DNA and turns on a bunch of different genes that tell the cell to survive, to grow, to move to other areas. That’s why it’s so important in those 70% of patients who are dependent on estrogen. And there’s complex genomic regulation that impacts metabolism and survival.

(00:35:19):

Interestingly, these mutations in the gene are extremely rare if you look at primary breast cancer or untreated metastatic breast cancer, less than 2% to 3%. But if you look at patients or situations where they’ve been on an aromatase inhibitor for at least 1, 2, plus years, you start to see the frequency of ESR1 climb up to about 40%. Almost half of the patients will develop this mutation, and that’s an adaptation where you put pressure on the tumor. You take away estrogen, the mutation develops and allows some of the cancer cells to continue to grow. And so we need to innovate alongside and develop better drugs as we understand these mechanisms. And that’s exactly what we’re doing.

(00:35:58):

Here’s the EMERALD trial. This is a phase III, prospective study. Now 20% to 25% of these patients had had chemotherapy. Almost half of them had a mutation in that ESR1 gene. Almost half of them had had at least two prior lines of endocrine therapy. So there was a lot of fulvestrant use actually in this population.

(00:36:17):

Patients were randomized. Half of them got endocrine therapy of clinician choice, either fulvestrant or another aromatase inhibitor, and half of them got elacestrant, which is the first oral SERD. Took about 15 years after we had fulvestrant to develop that. And here are those curves.

(00:36:34):

What you notice here is a pattern, and I’m going to come back to this at the very end. You see about 20% to 30% plus, the patients kind of progress very quickly within the first few weeks. That suggests that there are some patients who really don’t have sensitivity to that estrogen-targeting pathway. But then look on the other side, the curve flattens out and about 30%, 25% to 30% have excellent control just on the elacestrant going out years, at least 2 years or more. And then in the middle, you see about 50% to 60% of patients, they get some benefit on the order of a change of a few months of additional control, but not enough to kind of stay totally flat for a long period of time on the curve.

(00:37:15):

And this is the group of patients who had the ESR1. If you look at the overall population or the group that doesn’t have ESR1, the curves don’t separate quite as much. So we realized that the mutation in ESR1 is a predictive factor for continued dependence on estrogen and benefit of these newer drugs. And because of this data, the FDA approved elacestrant, as we’ve just heard 3 years ago, I think in January, as the first oral drug ever approved for patients who have ESR1 mutation, which is almost half of the patients with metastatic hormone receptor-positive breast cancer.

(00:37:51):

Our colleagues went on to look at other factors that help predict who’s going to do particularly well here. So having ESR1 is a predictive factor, but so is the duration on the front-line therapy. So if a patient is more than a year or a year and a half on their front-line therapy suggesting more sensitivity to estrogen, if you look on the right hand side, the curves split apart even further. Now on average, you’re getting more than a 6 month benefit in this population with a drug that has very little toxicity, that isn’t an IV, that doesn’t require a lot of laboratory monitoring. So we’re using clinical features and genetic features to help predict who’s going to get the best outcome on these medications.

(00:38:30):

Here’s a toxicity table without belaboring this. Most of the toxicity is sort of in the low grade 1 to 2. In my experience, and we were talking about this with some folks last night who I think were agreeing, patients tend to feel better on these drugs than they do on aromatase inhibitors. There’s less hot flashes, less joint and muscle pain. The trade-off may be slightly higher GI, usually kind of grade 1 nausea, but these drugs, in my experience, having given many, many, many hundreds or thousands of doses now are generally very, very well tolerated.

(00:39:03):

Here’s the next oral SERD that was approved, imlunestrant. This is based on a study called EMBER3. Different population, only one prior line of endocrine therapy, no chemotherapy, 40% of the patients had never had a CDK inhibitor. So a lot less prior therapy here than on EMERALD, when you think about comparing between the two studies.

(00:39:24):

Very similar, they had endocrine therapy alone or this new oral SERD imlunestrant and then later on they added a third arm imlunestrant plus the CDK inhibitor abemaciclib, so a double combination.

(00:39:38):

Here’s the curve for the ESR1 mutant group with imlunestrant alone versus endocrine therapy alone. And you see a similar pattern. You have that steep drop about 20% to 30% really don’t seem to get benefit from either approach. Then the curves begin to separate and there was an improvement from under 4 months to almost 6 months. But again, there are some patients sort of on the bottom of the curve, about 20%, 15% to 25%, doing well for more than a year, getting out to 2 years, similar pattern.

(00:40:09):

And then when you add the abemaciclib, so now the yellow line is with abemaciclib, the number starts to shift up even higher. So if you combine these drugs with a targeted therapy like a CDK inhibitor, now we’re looking at benefits on the order of 9 to 10 months on average with many patients exceeding that by a lot. So we have an FDA approval for imlunestrant, very similar to elacestrant as a single agent. The FDA is considering this data right now. We don’t yet have an approval for the doublet with abemaciclib, but it’s starting to make its way into the guidelines because we all want to be able to use these doublets in clinic to start to push these curves up higher and higher. And remember here, no IV, no chemotherapy. There is some more lab monitoring because you have a CDK inhibitor, so we’ve got to keep an eye on the blood counts. And of course there’s more toxicity here with diarrhea and other things.

(00:41:02):

This is a very interesting study. I think this is the last endocrine study I’m going to mention here. This is the SERENA-6 study, which has really been the focus of a lot of attention over the last 6 to 12 months. Very innovative study, very different from everything I just showed you.

(00:41:16):

Up until this point, we had really designed studies based on clinical or radiographic progression. If the tumor’s growing on the scan or causing more symptoms, that’s when the patient would be eligible to change therapy. SERENA-6 was quite different. They took thousands of patients who were on first-line therapy with ER-positive HER2-negative disease. They were on an aromatase inhibitor, letrozole or anastrozole with any CDK inhibitor, palbo-, ribo-, abemaciclib. They were checking them every 2 to 3 months. And if the patient had a new ESR1 but no progression, you couldn’t see anything on the scan, no symptoms. So you could tell genetically there was a change happening in the tumor. Then they were randomized. Half the patients stayed on the current therapy, and we were watching for any signs of change on the scan. Half the patients made an early switch. They kept the CDK inhibitor, but they switched to camizestrant, which is an oral SERD, same class of drugs, in an effort to go after that ESR1 mutation proactively.

(00:42:17):

And here are those curves. Notice from the moment that you make a switch there’s a pretty dramatic change here. On average, the patients who stay on an aromatase inhibitor, they still do OK, but it’s only for about 9 to 10 months on average. If you make the switch, you get more than 7 months additional benefit. The updated data actually looks a little bit better. It’s about 7 1/2 months.

(00:42:39):

Perhaps the most impressive data is this next curve right here. This is time to deterioration in quality of life. These are not the scans, these are not the doctors or the nurses measuring toxicity. These are the patient-reported surveys. This is the patient-reported outcome. And what you notice here is a really rapid shift where the patients on camizestrant have less deterioration in quality of life almost right away, and that persists way out in time. So if you don’t make the change, the patients begin to report deterioration and quality of life within about 6 months. If you make the change, they report deterioration almost 2 years later. So this is a huge, huge difference in quality of life.

(00:43:20):

I should mention, which I didn’t mention earlier, this is a double blind placebo controlled trial. Neither the doctor nor the patient knew whether they were given the oral SERD or not, but you could tell immediately they felt better. To me, this suggests better tolerance of the drug — less joint pain, less muscle pain, less hot flashes — and slower growth of the cancer — less bone pain, less symptoms. And this was done in a double blind fashion, so very impressive.

(00:43:48):

Now Elena and I are biomarker people, so we want to see what’s going on with the genetics. This to me is very, very exciting data. So here, what you’re looking at are the patients on SERENA-6, double blind, 2 to 3 months after they make the switch. What happens in the blood to the level of ESR1?

(00:44:06):

So in the group that doesn’t make a change, meaning they just stay on the aromatase inhibitor, you have a resistance mechanism and it continues to expand. The population, the frequency of ESR1 on average goes up 70% over the next 2 to 3 months.

(00:44:21):

But look at the left hand side. The women who get the camizestrant, almost all the patients had complete loss of ESR1 in the blood. It went down to undetectable. The median reduction was 100%. Out of 130 patients here, you can see 1, 2, 3, 4, 5, 6, 7, 8, 9 out of 130 who you could still detect it in. That to me is very powerful genetic evidence that we’ve identified the target, we switched the drug, and we obliterated the target. You cannot detect it on these very sensitive sequencing assays. And this is why the patients have less progression, better disease control over longer period of time.

(00:45:01):

I’m just going to briefly mention the PI3K and HER2-low disease strategies because I want to make sure we have time for our discussion.

(00:45:10):

PI3K is a critical pathway. It’s abnormal in about 40% of ER-positive breast cancer. It also occurs in appreciable amounts of HER2-positive and triple-negative breast cancer. It drives a lot of different things. It’s a signaling protein on the surface of the cell. When it gets turned on by different cancer signals, it turns on AKT and mTOR, which is like a ladder. And it goes down this ladder and it drives survival of the cancer cell, division of the cancer cell, motility, and metastasis to other areas. And so this is a critical area of tumor growth.

(00:45:49):

I’m just showing you on the left hand side here that we’ve identified this and other areas as key drivers of resistance to endocrine therapy like letrozole, like fulvestrant, and to CDK inhibitors like palbociclib and like ribociclib.

(00:46:02):

And on the right hand side in red, I’m showing you the different drugs we have. We’ve had everolimus for a long time now, dating back more than 10 to 15 years, that blocks mTOR. We have alpelisib and inavolisib. These are recent FDA approvals in the last few years that targets PI3K. We have capivasertib, which is now the most widely used drug in this class that targets AKT. And then we have this newcomer, a drug called gedatolisib.

(00:46:28):

Notice that I put arrows, it goes for PI3K, AKT and mTOR. It actually blocks across the entire pathway. We have phase III data for that right now.

(00:46:37):

We have some newer trials going on right now. So this is the INAVO123 trial. This is with a newer PI3K inhibitor called inavolisib. This is actually a front line study. So traditionally we’ve used these drugs in the second or third line setting. So somebody gets a CDK inhibitor, they hopefully do well for a long period of time. If the cancer’s growing and you have PIK3CA, then we make a switch. But here, because these drugs have been better tolerated, they’re taking patients at the time of metastatic diagnosis and they’re offering the PI3K inhibitor right away at the start in combination with the endocrine and the CDK inhibitor.

(00:47:14):

So we’re developing better drugs with less toxicity, and we’re moving them earlier in therapy because if you have the target, we should be optimizing treatment for the target right away.

(00:47:23):

To that end, we have some newer drugs coming on. This is a drug from a company called Relay. There are a number of different new PI3K inhibitors. These are really cool because they’re specific to certain mutations. So they don’t just target all the different kinds of PI3K. They target this type of PI3K mutation. So this is a phase I trial, and this is a waterfall plot showing how deep the responses are on a scan. And you can see here that about a third or almost half of the patients had a response. Most of the other patients had stability, meaning the curves are staying right near zero. Only one or two patients actually had progression when they started this drug because they all have the specific target.

(00:48:06):

You can see that these patients all had prior CDK, half had prior fulvestrant, 25% had prior chemo, but they were still getting 9 to 10 months of control with this next generation PI3K inhibitor.

(00:48:20):

For those of us who are more biomarker centric, this is what happens to the level of PI3K in the blood for these patients. You can see probably about two-thirds of the patients have 100% reduction. So the farther down it goes is the lower the level of PI3K mutation in the blood. So when you hit the right mutation with the right drug, just like I showed you on SERENA-6 you have almost a hundred percent reduction in two-thirds of the patients. Almost everybody else had some reduction. You can see there were only four or five patients out of this entire group here where it didn’t reduce. And we’re looking at why, what’s happening with those one or two patients. There must be some other genomic factor that’s trumping the PI3K. And look on the bottom, ESR1. The PI3K, when you hit that, is also dragging the ESR1 mutation down along with it. So these two things can go together. They’re probably existing to some extent in the same cells.

(00:49:14):

And just to end, I want to mention HER2 low. Elena taught us about this, that you have HER2 positive, you have HER2-zero, but actually in ER-positive disease, about 60% to 70% of patients are actually HER2-low. And in triple-negative disease on the right, you can see about 30% to 40% of patients are HER2-low. So this is a new class that we’ve defined.

(00:49:34):

We use these antibody-drug conjugates. We heard about this as well. I sort of think of this as like a guided missile. The antibody goes all around the body. If it finds the cancer cell, it then drops the chemotherapy in and around the cancer cell. So in theory, you’re not getting as much toxicity all over. It’s just enriching the chemo inside of the tumor environment.

(00:49:56):

This is the DESTINY-Breast06 study, which many of you have heard about over the last couple years. This really set the field on fire when we heard about this data, I think at ASCO a couple years ago. So these are patients with ER-positive or triple-negative, HER2-low disease. They had to have had endocrine therapy, but they had no prior chemotherapy. So this was a chemotherapy-naive setting, and if they were triple negative, I think they were allowed to have one prior line of chemotherapy.

(00:50:23):

Here they went to other chemo of clinician choice or Enhertu, trastuzumab deruxtecan. And you can see the curves shifting up and to the right, blue versus yellow. And there was an improvement from about 8 months average control to over 13 months average control. And this was, again, quite durable. You can see many of these patients, upwards of 20% or 30%, doing really well on the Enhertu 2 more years out, and I’ve had a lot of these patients in my own clinic.

(00:50:51):

These drugs do have some toxicity. I say when I talk to patients about these drugs, they’re in between. They’re a little more toxic than targeted therapy, hormone therapy, but they’re less toxic than combination chemotherapy like Adriamycin, Cytoxan, Taxol, carboplatin. There’s fatigue, there can be hair loss, there can be changes in the blood counts, abnormalities in the liver labs.

(00:51:11):

So we haven’t gotten to the point where we’ve gotten rid of the toxicity with the antibody-drug conjugate. We’re doing better with it. We’re getting less toxicity and some of the newer agents that are more selective actually even have less toxicity because there’s less disruption in other areas of the body.

(00:51:27):

To end and give us time for some questions, this is where I think the landscape is right now. Remember I showed you at the beginning AI, fulvestrant, chemo. So for ER-positive, HER2-negative, look how complicated it’s gotten. In the first line, it’s an aromatase inhibitor with ribociclib. Some people can get inavolisib if they have endocrine refractory, PIK3CA-mutant disease. This is why we need to be sequencing. Look at the second line now. In red, I’m showing you the genetic changes, and in black, I’m showing you the different drugs. And you can use multiple drugs. So if somebody has both the PIK3CA and ESR1, we can target both potentially.

(00:52:00):

And then after we exhaust all those options, we still have trastuzumab deruxtecan, we have sacituzumab, we have dato, we have many chemo, which I’m not even listing here because we push them all the way back in time. And then now all the italics there, that’s phase III data that we don’t yet have FDA approvals. I joke every time I have to give a talk, I have to remake this slide every 3 to 4 weeks because we have new phase III data coming out. We have new FDA approvals. It’s a good problem to have. It makes it hard, particularly for community oncologists who don’t specialize in breast cancer. Things are changing every week, every month, every 6 months. So it’s a very, very complex field, but we’re starting to see more choices, more tools in the toolbox. And in red, you’re seeing the different areas where genetic testing and sequencing are coming into play.

(00:52:48):

And here’s the shape of the curve. Remember, you have some people who kind of don’t get any benefit in red from endocrine therapy. Then you have in yellow some people who get a little bit of benefit, and then in green, the people doing really well for 2, 3, 4, 5 years. So we’re developing new tools, composite DNA signatures, RNA signatures so that we can test patients and say, “OK, this person’s more likely to benefit from an antibody-drug conjugate like Enhertu right away.” Or “This person’s more likely to go on elacestrant and do great for 5 years.” And if we can refine that, we can avoid unnecessary cost, unnecessary toxicity, and develop the right trials for these three groups: highly sensitive, intermediate sensitive, or not sensitive to the endocrine therapy.

(00:53:29):

Let me conclude, we talked about BRCA, DNA damage, and how to target that with a PARP inhibitor. We talked about the PI3K pathway and how these mutations are about 40%. We talked about ESR1 as being acquired after progression on an aromatase inhibitor. We talked about how we’re deploying these drugs with targeted sequencing. And really the question is, should we be using ctDNA right at the beginning like SERENA-6. Should we be testing all the time from the beginning? Will this help with other targets? For triple negative? For HER2-positive? I think that this is not limited to ESR1. We’re going to start to deploy all these drugs based on this strategy.

(00:54:07):

What causes resistance to elacestrant and other SERDs? We don’t know. We’re working on that right now.

(00:54:12):

What are the resistance mechanisms to capivasertib, PI3K? We don’t know. We’re working on that as well right now.

(00:54:19):

How do we personalize therapy and use dynamic blood-based sequencing in this rapidly evolving landscape? That’s something all patients, all clinicians, community, academic, everybody is thinking about this question right now.

(00:54:32):

So with that, let me thank you. We’re happy to take your questions.

Caroline Koffke, RN, BSN, OCN (00:54:45):

Thank you so much, first and foremost, for those amazing presentations. I learned a ton. You’re busy. You’re very busy. That is what I have learned first and foremost. There’s so much to keep up with.

(00:54:58):

We have lots of questions as you can imagine. I also have two helpers, Dr. Kelly Shanahan was diagnosed with metastatic breast cancer in 2013 and my colleague, Theresa Petee. So I will be bouncing to them with questions as well.

(00:55:12):

My first question though. You both mentioned this as well as one of our talks this morning. We’re doing combination therapy. We’re doing triplets. How many drugs is too many drugs? Is it going to limit treatment options further down the road if we utilize a CDK 4/6 with something? How are you kind of grappling with that situation?

Elena Michaels, MD (00:55:38):

I think first and foremost, just like we mentioned, we want to match the right treatment to the right patient at the right time. And so there is sometimes a bit of tension between balancing using up some of the drugs that we have all in one go and potentially, like you said, burning out our options. However, if we have identified the right genetic mutation in the right patient and combine it in the right way in some of these doublet or triplet combinations that Dr. Wander mentioned, might we alternatively give somebody more time on this regimen of drugs and leave them with better quality of life, less worry about their cancer, and have more stable control for a longer period. I think that’s actually what we’re seeing oftentimes when we end up combining these drugs. There was an initial concern that maybe we were burning our options out, but in fact, we’re seeing more stability, more control as we’re able to very precisely line up treatments for our patients.

Seth Wander, MD, PhD (00:56:47):

I think as I’ve gotten older, I’ve become more diplomatic and I tend to answer questions both ways so that you can’t be wrong. Right?

Caroline Koffke, RN, BSN, OCN (00:56:56):

Great strategy. [laughter]

Seth Wander, MD, PhD (00:56:56):

It’s very lawyerly, I think. Let me say a couple things, and I agree with everything that Elena said. First is this concept of therapeutic index, which is a term that we use about the window between effectiveness and toxicity. For example, there are lots of drugs that are extraordinarily effective if you look at them in lab models and in animal models, but when you try to use them in patients in phase I and II clinical trials, they’re extremely toxic. And you think about the lessons, for example, from HIV therapy. We don’t hear so much anymore about curing HIV because you have these triplet, quadruplet antiviral regimens that the virus can’t find its way around. You hit all the different sides of it. It cannot create a resistance mechanism to the four drugs combined. There’s a very wide therapeutic index. The drugs are effective. The toxicity is low so you can combine them all together.

(00:57:50):

It’s true in cancer, if we could do that, if I could give a four or five drug combination knowing the potential resistance mechanisms, it’s very unlikely that the tumor would find a way around it for an extremely long period of time. Unlike antiretroviral therapy, though the toxicities become too high. So what you’re certainly seeing in the last few years, and I was showing you that from some of the PI3K inhibitors, we are getting to the point where we’re going to think about using triplets in the front-line therapy because the drugs are less toxic. There’s less hyperglycemia, they’re oral for the most part, diarrhea is less than before. That doesn’t mean there’s no toxicity. It just means we’re getting closer to combinability, and I think we’re going to continue to improve on that.

(00:58:30):

The drug companies know about this. They’re working on this.

(00:58:34):

I think your question about resistance is the other issue. I was always taught, which means that she’s now being taught, that you use the best drug you have as early as feasible. And I still think that that’s philosophically true, but it does create challenges. I’ve been giving talks about resistance to CDK inhibitors for 10 years now almost. If we had been sitting here 12 years ago, and you had asked me what is the average amount of time that a second line ER-positive, HER2-negative metastatic patient gets fulvestrant, I would have told you 8 to 12 months. But today in the modern era, it’s about 2 to 4 months, and the reason is because of CDK 4/6 inhibitors. They’re better drugs. They provoke more control in the front-line setting, but with that pressure when the tumor progresses, it’s not as readily controlled, for example, by fulvestrant alone.

(00:59:25):

To me, that’s not a reason to avoid using it, but it means we have to work harder and faster and better to create the new drugs. The next generation CDK inhibitors, the next generation PI3K inhibitors, the next generation antibody-drug conjugates. So we have to innovate as we develop better drugs to understand resistance and to develop better second, third, fourth line drugs, which I think we’re seeing. We’re seeing those drugs moving through.

Caroline Koffke, RN, BSN, OCN (00:59:50):

Thank you both. Kelly and Teresa.

Kelly Shanahan, MD (00:59:54):

I had some amazing questions here. I could spend all day. I could make Seth sit here and answer these questions all day long, but I want to try to get some that many people asked about. We have PARP inhibitors for germline BRCA mutations. What about ATM, PALB, CHEK2? Any data on that?

Seth Wander, MD, PhD (01:00:13):

Yeah, great question. There is data being developed, and we do have some data there. So PALB2 probably has the strongest track record with PARP inhibitors, and I have used them “off label,” although there’s some guidelines that would suggest that this is fine. And I’ve had patients who’ve responded with PALB2.

(01:00:30):

The philosophy is the same. These other mutations also impact DNA damage repair inside the cells, and by the same mechanism, by putting that extra pressure on the DNA damage. We’re also getting closer to using what we would call somatic BRCA, and Elena told us about germline versus acquired. So there can be tumors where there’s no inherited BRCA or PALB2 or ATM, but the tumor develops it randomly over time. It’s not passed from parent to child. Those tumors are also potentially sensitive to these PARP inhibitors.

(01:01:01):

We want to think about trying to get these drugs, which are generally well tolerated out as broadly as possible. There are trials going on looking at those other mutations and actually thinking about a signature of DNA damage. So not unique just to BRCA or PALB2, but to sort of lump all of this into one entity so that we can get the drug out to everybody who would potentially benefit not just BRCA.

Kelly Shanahan, MD (01:01:25):

Given that there’s no data from ELEVATE or other similar trials, how do you choose which mutation to go after when someone has more than one currently actionable mutation? And related to that, right now we really have PIK3CA and ESR1. Are there other potential actionable biomarkers that are coming down the pike?

Elena Michaels, MD (01:01:51):

Yeah, I can talk first about dual mutants, and then Seth can chime in, of course. But I think one thing that he mentioned throughout his talk, of course, is toxicity and balancing toxicity with benefit for patients. Especially when we have dual mutations in the same patient, I think of course we want the most effective treatment, but we also want the treatment that people can tolerate the best. And so we know, and he mentioned this as well, that in our PI3K inhibitors, our AKT inhibitors that are currently approved, hyperglycemia, or elevated blood glucose levels, can be a big, big issue. Patients need a lot of glucose monitoring. Oftentimes they have to have a continuous glucose monitor on. We oftentimes have to start patients on treatment with things like metformin if we are seeing the blood glucose rise, and then we can balance that maybe with some of that GI toxicity that we see with elacestrant and imlunestrant.

(01:02:50):

And so if we have somebody who came in already with a history of Type 2 diabetes who already has problems with blood sugar control, maybe we’re going to be more likely to reach for elacestrant or imlunestrant if we’re thinking of our standard therapies. Whereas somebody who might have IBS or IBD and already has GI toxicity, we might reach more for one of those AKT, PI3K inhibitors.

(01:03:12):

But especially in our clinics as well, if we have clinical trials available for one of these very selective mutations that Seth mentioned, like a very specific PI3K mutation, where we’re seeing much less toxicity and tons of benefit, we might then reach for that instead of some of these more standard options.

Seth Wander, MD, PhD (01:03:32):

Yeah, I agree. This is probably the most common question I get at tumor boards or when other doctors email me. You look at that second line setting on the last slide I had and it’s very complex, lots of different choices. It’s a good problem because we have more options, but it’s very overwhelming for patients and for particularly community practice oncologists who maybe are trying to deal with 20 different diseases, all of which have as many FDA approvals as we have in breast cancer.

(01:03:58):

To Elena’s point, I think you’re looking at how well did the patient do on their front-line therapy, how much disease is there, what are the symptoms, which mutations are present and you’re trying to kind of put the whole picture together. If the patient has been stable for a long time, I love the idea of trying to use the next-generation antiestrogens, a lot less lab monitoring, potentially a lot less toxicity. If the response to the initial estrogen therapy wasn’t as great, or if there’s more disease we need to move quicker, I’d be thinking about using like a doublet regimen.

(01:04:30):

But to Elena’s point, luckily if we get together in another year or 2, this is a moot point because we’re going to have great combinations of next-gen antiestrogen and next-gen PI3K, AKT inhibitor together, like from studies like ELEVATE. And so we’re not going to have to choose. We’re going to say we can actually hit both of these things optimally at the same time.

(01:04:51):

To your last question, there are I think a number of other biomarkers coming. We know, for example, tumor mutational burden is already something we can use to help maybe predict response to immune therapy in all tumor types. Alterations in genes like RB or retinoblastoma, aurora kinase, these are genes that regulate the cell cycle that we and others have shown are important for resistance to CDK inhibitors.

(01:05:16):

We’re developing new RAS pathway inhibitors, new aurora kinase inhibitors, new CDK2 inhibitors, all of which are targets after progression on, for example, palbo-, ribo-, or abemaciclib.

(01:05:29):

So over the next few years, you’re going to see, I think, more biomarkers come into the fold. You’re going to see more combinations that target multiple concurrent biomarkers. And again, we’re going to get farther and farther toward personalizing, not just based on one mutation, but based on multiple mutations at the same time.

Caroline Koffke, RN, BSN, OCN (01:05:43):

That was incredibly helpful.

(01:05:46):

Another question, obviously all of these mutations have to be tested for. We talked about ctDNA or liquid biopsies versus solid tumor biopsies. All of that takes time. We know that ctDNA testing we can do at diagnosis and at progression. How do you talk patients through the waiting period? They’ve just received a progression and now you’re asking them to get a test and they have to wait for the results perhaps. How do you weigh the risks and benefits of waiting and kind of explain to your patient why that waiting period might be important?

Elena Michaels, MD (01:06:20):

I think ultimately, of course, when someone comes in with a new diagnosis of metastatic breast cancer, there is nothing scarier. And our role and our goal, of course, is to improve symptoms and make you feel better. But I think very importantly, what we want to do is to identify the right treatment for you. And that does take time but not significant amounts of time. When we draw a liquid biopsy, it can take about 1 to 2 weeks to come back. And I know that can feel like an eternity for a patient, but I think it’s really coming to an understanding with them that in the scheme of their cancer’s lifetime, that really is not that much time for us to wait so that we can identify the appropriate treatment for them. There are certainly circumstances, especially in hormone-sensitive metastatic breast cancer where if we know if someone progressed on an aromatase inhibitor or after they already completed their antiestrogen therapy, we have an idea that they’re like Seth mentioned, very likely not going to have an ESR1 mutation and so we can actually get them started on treatment while we wait for that initial liquid biopsy to come back. So we might be able to start you on fulvestrant, we might be able to start you on an aromatase inhibitor. And I think it’s also having a conversation of the fact that that really is effective treatment. While we eventually want to turn that into a doublet and add additional medication depending on what your genetic profile is from your tumor, just that one antiestrogen therapy can be effective in controlling the breast cancer during that time we’re waiting.

Seth Wander, MD, PhD (01:07:54):

I agree. And I would just add the work that you all are doing here is so critically important to help patients and caregivers understand how valuable that information can be. So I want to thank you for that on behalf of all of us on the clinical side.

(01:08:08):

I also would say to Elena’s point that when I was in your shoes, we didn’t have liquid biopsies, so we would have to wait and work with the radiology team or the surgeon to get a tissue biopsy, which took you twice as long, three times as long. And even just in the last 5 years, the technology has moved at such a rate that now instead of waiting 2 to 3 weeks for a liquid biopsy to come back, it’s really on the order of 7 to 10 days. And I think in the next few years, it’s going to actually get faster and faster and faster. So we’re not going to be waiting weeks and weeks. I think this, again, is a temporary problem. There’s a lot of pressure, a lot of competition. You saw the boxes she had up on the slide. All of them are innovating to move quicker, to be more patient focused, to have good software where you can go online and get all the information right away. So that’s a good thing. That’s a positive thing for the field.

Caroline Koffke, RN, BSN, OCN (01:08:57):

Great. Well, thank you so, so much, Dr. Wander and Dr. Michaels. This was incredibly informative. Thank you to our audience for their questions.

Elena Michaels, MD (01:09:04):

Thank you all.