Testing in MBC

Transcript

Debu Tripathy, MD [00:00]

I'm going to be talking about testing for metastatic breast cancer, which is such an important topic. And I really have my patients and the patient community to thank for my interest and ability to communicate about this topic.

I learned so much from my patients, their questions, their concerns, their history, the way they tell their history, the way they describe their symptoms. All of those things really help us as physicians be better communicators. And that is really a two-way street.

So in that vein and in that spirit, I want to share with you some of the latest technologies and also some of the things that we’ve been doing for many years to evaluate patients with metastatic breast cancer.

The field is changing so quickly that this lecture probably could be given several times a year. And I will focus not only on the new but the established technologies as well, and how to interpret these results, which of course is critically important.

You have, in my title slide—I try to be economic and put as much information on the title slides—depictions of different types of assays that I’m going to go into in more detail that give us multidimensional looks at the tumor, the proteins, and the genetics that not only dictate their behavior, but more importantly help us find the best treatment strategy.

We’ve known that breast cancer is really a collection of many different genetic diseases for many years. This slide up here is one of the main representations of the Cancer Genome Atlas, a very ambitious project that went on for several decades to sequence many different tumors. These were all tumors for patients that were newly diagnosed, so they didn’t really give us a look at metastatic cancer, which is a little bit different. But what they showed us, what’s diagrammed in this picture, and I won’t go into the details of it, is that no cancer is the same. When you look at the genes that are mutated and the genes that are amplified, which are depicted across the horizontal side of this slide and the different colors on the left bar indicate the different receptor subtypes, hormone receptor-positive, HER2-negative, HER2-positive, triple-negative, and so on. And you can see that the small gray bars representing different genetic mutations are very different among the different subtypes.

No two cancers are the same. All of these mutations contribute in one way or another to the development of cancer and also to the biologic behavior of the cancer, such as the propensity to metastasize and in some cases even what drugs might be successful. So the key thing is to decode that information to understand what these genes do and how to measure them and analyze them in individuals. This was the first step in us understanding the personalized behavior of every person’s cancer and maybe the secrets behind treatment.

Now this is a depiction of another big challenge that we have in in cancer development and cancer progression and the development of drug resistance. And this is evolution of cancer. What you see here is a depiction of a cancer cell mass, and each different color that shades the circles are different genetic makeups of a particular cancer. So when someone is told they have a HER2-positive cancer, every cell actually is not HER2-positive. As you heard from Jamil, there’s a billion cells in about one centimeter of tumor. And you can imagine that there is diversity in tumor cells, just like there is diversity in the bacteria in your body and there is diversity of human beings on our planet. A tumor is not a carbon copy of one cell after another. There’s already some variation. So when you apply a therapy, you may be selecting for a subset, and over time you actually get tumoral evolution, which is depicted on the right side of the diagram. And when you expose a patient to therapy or when the tumor is just selecting not against a drug, but against a property, for example, the ability to metastasize the ability to leave its original spot in the breast and actually travel, that’s an inefficient process. Most cancer cells cannot metastasize, but one of them may have the ability to do that. And then that cell divides, and now that colony that has metastasized is actually different from the original site. So a part of testing that we do takes into account that things are changing over time. And you’ll hear me say that sometimes repeat testing is important.

Debu Tripathy, MD [05:04]

Then we have the technology that allows us to do much of this work. And I’m going to get into the specifics of testing, but I wanted to make some of these general comments first.

We now have the ability to take a very small piece of tissue and amplify its DNA and look at its RNA and also to look at proteins through immunohistochemical staining, to give us different dimensions of the tumor that affect its behavior. The technology that allows us to do that is important, but what’s really, really important is for us to know what to do with that information. And this is what requires large trials. It requires patients who have volunteered over the years to have some of their tumor subjected to research, to gene sequencing back before we knew what to do with the information, these were patients that were giving of themselves for no direct benefit, but to contribute to research. And after years of doing that and being able to follow how these patients did over time. What areas did their tumors travel to? To what drugs did they respond? To what drugs did they not respond? We’ve been able to put together an encyclopedia, so to speak, of what these genetic aberrations mean. Because without that information, we couldn’t really apply this information to make personalized decisions.

You’ve got a depiction here of some of the technology that has allowed us to do this. One of the biggest ones is our ability to amplify the genome and to sequence it rapidly.

The human genome project that started in the nineties took forever to get completed, but the last part of it was done really quickly because of the development of next generation sequencing, which is really cool technology. And basically what it does is it takes the DNA, which of course is billions of base pairs for any individual, and chops it up into little pieces. And it adds base pairs that are colored with different dyes. Then the DNA is analyzed very quickly with a colorimetric analyzer. And the computer information that we have now with rapid computing technology allows software to then tile these colored pieces of DNA to actually assemble them in their real sequence. And very quickly, you get the whole sequence of a piece of DNA, you can sequence an entire genome now within a day, which would’ve been unheard of years ago.

How and why do we test breast cancer?

The test of estrogen receptor, and I have a few of these listed here as an example, just as a primer as we go forward. The estrogen receptor, for example, is a protein. And that tells us whether a cancer cell will respond to hormonal therapy. And I think most of you know that.

The HER2 receptor is a growth factor that happens to be amplified in about 20% of the cases. We can test that either by looking at the protein directly on a microscope slide that is stained, and when we say stained we’re usually talking about an antibody that recognizes HER2, that is colored with a specific color so the pathologist can read what percentage of the cells are HER2 positive. And not only that, they can say how intensely it is staining on a scale of zero to three. And they can also say what percentage of the cells are staining. And based on several criteria, we will determine that the tumor is HER2 positive or not.

PD-L1 is a protein that measures the ability of the cancer cell to respond to the immune environment. As you may know, and actually it’s very surprising, that our body can mount an immune response against cancer and usually does. Our immune system can recognize things like bacteria and viruses as foreign bodies and fight them by turning on special immune cells that produce antibodies—these are known as B cells—and also by activating T cells, which directly kill cells by contact.

Once the invader is gone and the infection is treated, the immune system withdraws so that it doesn’t cause collateral damage, which is damage to normal tissue due to inflammation. You all probably know when you get the virus, you get the fevers and chills, that’s when the virus is multiplying. And then once the infection is treated by your immune system, that’s when you actually feel crummy, because of the inflammation, the cough, and the phlegm. So our body is able to do this.

Debu Tripathy, MD [09:55]

Cancer cells are also foreign. They are not normal, but they’re very similar to your normal tissue because they came from your own cells. So the immune system has a harder time recognizing that. But it does. In fact, people are developing cancer every day and then the immune system wipes out those very early signs, and the individual never even knows it but their immune system has worked. And people that have defective immune systems actually do have a higher risk of certain cancers.

By the time a cancer develops, it has already been able to overcome the immune system in certain ways that we have discovered over the last few years that has allowed us to develop drugs to turn that around. And one of those is a protein called PD-L1, which basically turns the immune system off as though the immune system was withdrawing. And cancer cells are very clever. They adapt to things—they’re not really clever, what it is that one cancer cell out of a billion just happens to have a low PD-L1 and guess what? That cancer cell is going to be the one that continues to grow.

When we find that PD-L1 is actually expressed, that tells us this is an opportunity to use immunotherapy.

The other important thing we test, and I’m going to go into these in more detail, is the germline DNA. Now the germline DNA is the DNA that we all carry, that we propagate to our offspring.

In the gonads of the male and in the ovary and the eggs of the female, there is a line of DNA that is propagated to individuals that tell us and give us the instructions of life. One copy from the father and one from the mother.

Defects that are seen in DNA are quite common. All of us are born with changes in our DNA. Some of them are normal variations that give us like different colors of our eyes, but some of them are actually mutations that are not supposed to be there and can pass on diseases like sickle cell disease. Some of them can involve genes that are important in protecting us from developing cancer, like repairing our DNA when a mutation develops.

When our cells are dividing, they can sometimes make mistakes in the DNA and those mistakes are propagated in all the cells that develop afterwards. So you would think we get mutations all the time, and we do. But usually a mutation leads to the death of the cell because it’s in a critical area that affects cell metabolism or something else. But every now and then, very rarely, it happens to be in a growth factor or something that actually triggers the cell to grow.

Just think about a car being in an accident or being jumbled around. Most of the things are going to make the car stop. But every now and then something may involve the accelerator and make the car go more quickly. These are rare mutations, but they’re critical. They get the cell going in the wrong direction, not able to respond to the stop signals, and grow in an uncontrolled fashion. And so when that happens you can get the development of cancer.

One of the things that can also go wrong is that the cell cannot repair these mutations. We have a very elaborate system of repairing mutations when they happen. There’s an enzyme that senses where the DNA is broken. There’s another one that comes in and changes the base pair and there’s another one that actually proofreads it. It’s amazing the DNA repair machinery that are in all of us but also in yeast and in lower forms of life—I shouldn’t say lower forms, but more primitive forms. So this is something that’s been around for a long time and when you have a mutation in that gene that does not allow you to repair your DNA sufficiently or quickly enough and that can lead to cancer as well. So that’s something that we test for.

You’re familiar with genes like BRCA1 and BRCA2 and other not so common ones like PALB2. These are all involved in DNA repair. These were first discovered in the early nineties when we knew that breast cancer and ovarian and many other cancers ran in families but had no idea what genes drove them. And when, sequencing technology got advanced enough for us to search the entire genome, we were able to find these genes and understand how they work biologically.

Initially it was just a diagnosis. You could tell someone they had an elevated risk of breast cancer because they have a BRCA2 mutation when you look at their family history and they would have enhanced surveillance. So that was helpful of course.

But now we actually know how these cancer cells are biologically different and what they’re vulnerable to. And now we have drugs like PARP inhibitors. So that’s a very important part of the biomarker analysis of patients with metastatic breast cancer. There are other mutations that give cells a growth advantage as well that also can lead to us pointing to a drug.

Debu Tripathy, MD [14:56]

Then there’s RNA expression profiles. These are looking at the RNA where you can look at how multiple genes are expressed. Right now these are used mostly in early-stage breast cancer to give us information about the behavior of the cancer cell that we can’t get through other tests—you’ve probably heard of Oncotype DX, which is used in early-stage breast cancer—but we’re increasingly developing these signatures to be used in advanced breast cancer to tell us which drugs might be best. So that’s an overview of the different tests that we do.

Let me now step back a little bit and, and just go over what the general recommendations are for testing patients with metastatic breast cancer. Not all of these are tissue testing. Of course you’re familiar with the fact that we know where the cancer is and what organs it’s involving. We do that with imaging tests, that are by the way, also becoming increasingly more sophisticated. CT scan of the chest, abdomen, and pelvis and a whole body bone scan are the most common ones that we use. But we also use PET-CT scan, which allows us to look not only at the tumor size but the metabolic activity, which of course is higher in cancer cells.

The other important part of testing someone who is newly diagnosed with metastatic breast cancer is to have them undergo genetic testing and germline DNA testing. We used to only reserve this for people with strong family histories, but now we recommend that everybody with metastatic breast cancer be tested because of some of the newer drugs like PARP inhibitors, olaparib and talazoparib that are used and can be helpful in patients that have BRCA 1 and 2 mutations. And over time we’re going to develop more drugs for people that have some of the other mutations. Just recently PARP1 inhibition seems to be better than olaparib and talazoparib, also known as Lynparza and Talzenna. So, this field is going to continue to evolve mostly because of our greater understanding of these lesions and people participating in trials.

The other thing that we always do when someone is diagnosed is we biopsy the tumor. And sometimes even when they already have metastatic cancer and the tumor is progressing, we may biopsy it because over time the biomarkers may change. Remember that evolution slide I showed you? If you’re treating a HER2-positive cancer with a drug like Herceptin, there may be a few HER2-negative cells that aren’t sensitive to that and they may grow up. The next metastasis might actually be a clonal selection of those HER2-negative tests. And that can actually influence therapy. I’ve actually been talking to several people who have experienced that and that’s why it’s important to retest.

Then we also get next generation sequencing, which you all are also becoming familiar with, which is looking at mutations in the tumor itself. This is different than germline testing because the tumor itself has acquired many new mutations that your original DNA did not have. And those can actually spell certain aspects of the behavior of the cancer and help us identify who should be treated with what drug. I’ll go over the details of some of the more common mutations that we find in the tumor DNA that can point us in the right direction.

The first set of tests we do are the biomarkers for the receptors. That drives a lot of the primary treatment. When someone has a new metastasis or maybe progression, we check for estrogen receptor itself to see if they may be a candidate for endocrine therapies. About two-thirds of all breast cancer cases are hormone receptor positive, and as initial treatment we usually use some form of endocrine therapy that interrupts the ability of estrogen to bind to the estrogen receptor and stimulate growth—the estrogen receptor is a growth factor of sorts. Different levels of the estrogen receptor can be seen and might point to whether or not patients can be a candidate for these therapies. We grade it by how intense it is staining and the more intense staining we see, the more likely it is to respond to endocrine therapies.

And we still are developing many new endocrine therapies. It remains a very important part of our treatment armamentarium. We’re finding stronger drugs like PROTACs and SERMs. I won’t go into that as much in detail but only to tell you that it is still an important target. And not only that, we’re hoping that we can use these types of treatments longer and longer, because we know at some point people become resistant to endocrine therapies, but some people respond to them for years and decades even. And we want to understand why they respond, but we also want to make more options where we can still target the estrogen receptor even though they may develop resistance to the first-line treatment like aromatase inhibitors or tamoxifen. I won’t go into those details since we don’t really have time to talk about them, but it underscores the importance of testing for estrogen receptor.

Debu Tripathy, MD [20:10]

This is just a diagram as to how the different therapies work. One of them is simply to remove the source of estrogen, and you’ve heard of people having ovarian suppression to do that or androgens that get converted to estrogens, which is the source of estrogen in postmenopausal patients where there’s still estrogen around. And we use aromatase inhibitors for that. I won’t go into as much detail into the biology of how we treat patients other than to say it is critical to know that status.

Estrogen receptor can be overcome by growth factor signaling. That’s one of the main mechanisms of resistance to endocrine therapy. But signaling through growth factors is also a driver of cancer as well. Growth factors are proteins that tell cells when to grow and when to stop growing, and of course they’re necessary for us to develop properly. Many mutations that lead to cancer are mutations where these growth factors are dysregulated. So that’s an important part of us knowing what is driving someone’s cancer. For example, PI3 kinase is a very important signaling pathway that’s actually depicted on this slide, and mutations in one of the parts of that protein, it’s a multi proteins that come together for one enzyme, can lead to overgrowth. Targeting that mutation, one that’s known as PI3 kinase, can actually help and is used as a treatment.

Hormonal therapy is increasingly being made more effective by drugs that partner with hormonal therapy to augment their effect like cyclin-dependent kinase inhibitors and PI3K inhibitors. And that’s why it’s important for us to understand that part of the pathway. This shows you how complex that pathway is and how it can be targeted by certain drugs like PI3K inhibitors.

Don’t worry really about the details of these diagrams because they’re more there to show you conceptual path. That these growth pathways each can have aberrations that we want to know about because some of the drugs we use can then be used to treat them.

This is one example of a drug called alpelisib (Piqray) that makes a small difference in how patients do if they have a PI3 kinase mutation, and this led to the approval of this drug. Now there are some newer drugs that also work and may actually work better against PI3K. And we’re going to need to do these trials where we know the mutational status of PI3K and we test patients with drugs that inhibit that pathway that I showed you earlier.

This is an example of one of those newer drugs called capivasertib (Truqap), which was just recently approved back in December and shows an improvement in patients who have genetic abnormalities in that pathway. Again, underscoring the need to test that pathway.

HER2 testing is quite complicated and this diagram shows you how we look at not only the intensity of the staining, but whether or not the gene is present in many copies. One of the ways that HER2 exhibits a high level is either through a mutation but more commonly simply because the gene has multiple copies and results in more production of HER2 growth factor, which then stimulates growth. We actually test both the protein and amplification of the gene and the pathologist has to take both of those into account to make the ultimate call. Is this cell HER2 positive or not? So it’s rather complicated as you can see in that diagram.

You may have heard about immunohistochemical testing that stands for the protein and then FISH, fluorescence in situ hybridization, that tells you if the gene is present in multiple copies, which is another way that that protein could be over expressed. And the HER2 pathway is a complicated pathway. HER2 and related receptors bind to a ligand and signal to the nucleus of the cell to grow. And that’s generally how growth factors work. HER2 is one that overdrives cancer cells and that’s why blocking HER2 is important in people who have tumors that make an excessive amount of HER2. That is targeted with the antibody Herceptin, also known as trastuzumab, and there’s many newer drugs now that are available to target HER2, not just trastuzumab but another antibody known as pertuzumab or Perjeta and other small molecule inhibitors known as kinase inhibitors, lapatinib, neratinib (Nerlynx) and tucatinib (Tukysa). And again, I won’t go into those details because I really want to underscore the importance of HER2 testing.

Debu Tripathy, MD [25:03]

We also know that growth factors can be important in how the cell responds; mTOR is a part of the growth factor pathway that I showed you earlier in blocking that with a drug called everolimus (Afinitor) can improve outcomes.

These curves that I’m showing you are progression-free survival curves that show you how long people go without progressing. And when the curve is higher, that means the drug is more effective, more people are going without progression. And in this case, it doubled the time to progression. And we need to push these PFS curves out further and further with newer drugs. We want to see the upper curve almost be horizontal line. That’s what we’re aiming for and we’re getting there slowly.

I’m going to move to HER2 therapy for metastatic breast cancer, just to briefly cover it, to underscore the importance of HER2 testing. And I’m going to go straight to this trial here, which is the CLEOPATRA trial, which shows you that patients on this trial that was done 10 years ago—and we still use as first-line therapy—the red curve shows how patients on the addition of pertuzumab do better than just with trastuzumab alone.

This is given with the first few months being given with chemotherapy. And then after that just with maintenance therapy. And you can see that 10 years out, about 30% of patients on this trial are still alive. Now of course we want to see that number even go higher, but it is good to know that some of these newer drugs can give us these very long disease-free survival and really ultimately what we hope to find is that through proper selection and the identification of the right treatment, that we will match a drug to the biology of that patient’s cancer. And not only is our ability to understand the biology going to improve, but the drugs we use are going to improve as well.

In fact, one of the drugs, an antibody-drug conjugate known as Enhertu or trastuzumab deruxtecan, is giving us a much wider separation of this curve. This was a study that compared an older drug called T-DM1, also known as Kadcyla, to the new drug Enhertu. And this has now become our second line go-to drug because of its performance. And again, we expect these types of curves to separate more and more.

DNA repair, as I mentioned, can be affected by people that have BRCA 1 and 2 mutations. So it’s very important to test for that as well. We actually have drugs that can augment impaired DNA repair so that when you already have a BRCA mutation that inhibits DNA repair and now you add another drug, you get an effect that’s known as synthetic lethal, where both of these conditions make the cell unable to survive. And that’s why PARP inhibitors can be effective and have shown improvements in outcome when added or when compared to chemotherapy as illustrated in this trial looking at the PARP inhibitor olaparib compared to standard chemotherapy.

The KEYNOTE study was one that looked at immunotherapy and this was the first study that actually led to approval of immunotherapy in breast cancer with a drug known as pembrolizumab. Also the trade name is Keytruda. And when it was added to chemotherapy, it gave us improvements in disease-free survival. And again, these curves are a good sign, but we want to do better. And as we understand the immune system more we will get there. But this speaks to the importance of PD-L1 testing specifically for patients with triple-negative breast cancers.

There is some early evidence that hormone receptor-positive cancers, especially the more high grade ones, may also respond to immunotherapy. And it’s not clear what role PD-L1 will play. So the story is still unfolding. It’s not yet approved for hormone receptor-positive, but there are some newer data that will say that a subset of these may respond. More importantly, the whole field of immunotherapy is rapidly evolving, not as fast in breast cancer as it is in other cancers. But I think that as we unlock more about the immune system in breast cancer, we will get more specific drugs, maybe even specifically for breast cancer.

This is a summary of the genomic testing that we do and how it points to different drugs. And I won’t get into all the details. This is a very detailed slide. And by the way, I hope these slides are all available to you and I’m sure they are. If not, I can make sure that you get these and can have them for your own use. Because I can’t really go over all of these, but we can get to some of these in the question and answer.

Debu Tripathy, MD [30:03]

There’s a lot of mutations now that actually lead to a specific drug and every year now we see a couple new ones approved for different tumors. Some of them are approved for across the board. For example, if you have a high tumor mutational burden, that means a lot of mutations per segment of DNA—essentially a hyper-mutated tumor genome—you will more likely respond to immunotherapy and pembrolizumab is actually approved on a tumor agnostic basis. That means for any type of tumor that has a high mutational tumor burden. And that is a way to get access to that drug even though you may be one in maybe 20 people that might have a high TMB that you would be eligible for Keytruda even if your PD-L1 is negative.

There’s many other examples of drugs that we actually now can use for these. It’s a small number of cases. Now there’s some mutations that are common like PIK3CA. About 40% of people have that and that might make them eligible for some of the drugs that I mentioned that target that pathway.

ESR1 mutation is another common mutation that we see. ESR1 is the gene that encodes the estrogen receptor, and it turns out that the estrogen receptor itself can be mutated so that it is active without even binding to estrogen. Now you have an activated autonomous estrogen receptor and there are now a new generation of drugs that can affect that. This is the first one to be approved specifically for ESR1 mutations, a drug called elacestrant (Orserdu), that showed an improvement as you can see specifically in patients whose tumors carried the ESR1 mutation. They tested both the non-mutated and mutated version.

That gives you a snapshot as to why and how we do genetic testing. The key things to remember is that everybody with metastatic cancer at some point should have an initial biopsy to establish the diagnosis, make sure it’s not a different cancer; know what the receptors are so we choose the right treatment; and to get sequencing.

We can get sequencing not only from the tumor but nowadays we can also get it from the blood with what’s known as a liquid biopsy where the same DNA that you measure from a tumor biopsy that’s making its way into the blood, it’s shed into the blood, can now be picked up and detected and amplified. And this is probably going to be the technology of the future because we can get such high amounts of information from the blood that we probably won’t even need to do tumor biopsies for genomics, but we’ll still need to do it for receptor. And then germline testing. And that rounds things out for personalizing your treatment decisions.

Thank you for your attention. I know it’s a complicated topic to cover, but we’ll have a chance to take some questions. And thanks to LBBC for putting this on.

By the way, that last picture was my mother’s art. She’s an artist that lives in New Orleans, and I want to give her credit.

Jean Sachs, MSS, MLSP [33:23]

That was an incredible presentation. Everybody, the slides will be available. I know a lot of you are asking that question.

We are going to do our best to go through as many questions as we can. We probably won’t get to all of them, but we will do our best.

I just want to start by combining a few questions, because obviously we have people here in the room as well as watching who are coming from all over the country, not necessarily at an academic center. So there are a couple questions. Can any doctor get these tests? Are they available regardless as to where you are? So let’s start with that one.

Debu Tripathy, MD [33:59]

Yes. These tests are broadly available. Typically what it requires is that the pathologist identify a biopsy that is optimal. They actually have to look at the slides to make sure it contains enough tumor. Then they send that slide to the company where it’s subjected to multiplication of the DNA and sequencing.

There are numerous companies that do this now. There’s probably a dozen companies and it’s rapidly growing. Usually the turnaround time for the test is about 1 to 2 weeks. It’s going to get quicker. And so, it is very widely available. And again, they’re send out tests, the pathology departments know how to do this and process it.

I would say that maybe at very small hospitals it might be more challenging to do that or in practices that are in rural areas and don’t have access to it. But increasingly the companies that do the testing are making sure that the people that help coordinate this can be available to all oncologists. It’s very important to ask though. It’s unfortunate that our patients have to be guardrails, but they are. It’s very important that, just as a general issue, that our patients ask questions and ask why isn’t this being done? You would be amazed at how many times that triggers something. We’re all humans, and even I will get some cues from my patients, “Oh, here’s something I need to explain better.” Or “Maybe they’re right, I didn’t think this test might help. But now that I think about it, it’s possible that it may, let’s cover that base.”

So it is very important to have a dialogue and an honest dialogue. You’re not putting your oncologist down by questioning them. You’re just clarifying it for yourself. And even though they may not admit it, sometimes you are influencing their behavior. It really is teamwork. And I think patients that are communicative are really to be congratulated.

That’s one thing our pro our profession has to do is make sure physicians are listening, make sure that they are considering that a positive thing to be asked a question or to be asked why this is not being done. But it is absolutely essential that anyone with metastatic breast cancer has their tumor sequenced, maybe not right at initial diagnosis because many of our first line therapies don’t require that information. But more and more in the future, they will. And it’s good to have at the beginning because when people are having progression of their cancer, sometimes it’s progression that needs to be treated more quickly. And you want to have that information ahead of time and sort of have a roadmap already laid out.

Jean Sachs, MSS, MLSP [36:55]

Right. So it’s important to ask and ask at each progression: Does it make sense to test again?

Toni and Shehzin are going to help sort through the questions. I just wanted to remind everyone, the second speaker will be talking about medical advances. We’re really going to not go into those questions, not that Dr. Tripathy couldn’t answer them. So Toni, do you want to get the next question?

Toni Willis [37:18]

This question from the audience is a two-part question. Is a blood biopsy sufficient to detect mutations? And how frequently should we retest or biopsy, especially when progression occurs?

Debu Tripathy, MD [37:30]

A blood test is generally sufficient to get the mutational profile, especially with some of the more sensitive assays, but still not fully.

For certain mutations it is recommended that if, especially for PIK3CA, which is a common mutation, but one that may not be seen in the blood because you happen to be testing the patient at a time when their tumor burden is low, and all tumors don’t secrete DNA into the blood the same as others. So there are situations where if the liquid biopsy is negative and there is a biopsy available or you get a new biopsy that it should be sent for confirmation for certain genes.

Jean Sachs, MSS, MLSP [38:17]

There’s several questions about the timing of testing, which you did address. Sorry, I’m seeing so many come on.

Debu Tripathy, MD [38:33]

While you are, the other part of that question was should it be tested at every time? Which sort of goes to that question of timing. Maybe not necessarily, it really depends on the situation.

For example, if I have someone on anti-HER2 therapy, and they’re recurring in one area, like a new area in the liver or an area that was existing but is growing, but all the other areas aren’t, I’m actually going to biopsy that area because it may be different. I’ve mentioned clonal selection and one of the things I’m going to see is, is it still positive for HER2. So in that situation, I’m going to test, make sure I have HER2, ER, PR, but I’m also going to get gene sequencing because of the situation. So generally speaking, you may not need all of this with every progression, but in certain cases it is helpful. So again, that’s why the nuances are so important.

Jean Sachs, MSS, MLSP [39:27]

Okay, I found my question. Thank you. This question is interesting: I any progression due to resistance? And the second part, are all resistances due to a mutation?

Debu Tripathy, MD [39:38]

So the answer is usually progression is due to resistance if you’re on treatment. Otherwise you would still have some control of the cancer, but not always. There may be mutations that cause the cell to simply grow more rapidly independent of the drug. In other words, the drug might sort of be keeping it in check and it’s growing very slowly and now a new mutation just increases its growth rate. But usually it is due to resistance.

Not all mechanisms of drug resistance are due to a mutation. There are changes in tumor behavior where the DNA sequence doesn’t change, you silence one of the genes. That’s called epigenetic modulation of a tumor where it’s not due to an actual base pair change, but it’s due to a gene being silenced. There are other adaptive processes that do not involve DNA and that is sort of a dark area for us. It’s an area that we need to learn more about, epigenetics, other adaptive. And as we get more sophisticated protein analysis with things like mass spectroscopy, we’re going to be able to look not only at the genome but what we call the proteome and the transcriptome, which is RNA. So those are the three different levels of control of the cell, some of which we aren’t yet looking at.

Jean Sachs, MSS, MLSP [40:57]

Right. So along the same lines, can you develop a PIK3CA mutation and/or an ESR1 mutation?

Debu Tripathy, MD [41:06]

Yeah, that’s a great question.

Some genetic lesions are what we call acquired, whereas others are known as truncal. They’re there from the beginning. PIC3CA tends to be a truncal mutation. You see it at the beginning. If you biopsy the early-stage tumor, it’s probably going to be the same as a metastasis.

ESR1 is an acquired mutation, and it’s not truly acquired. There’s probably such a small percentage of the original tumors that are ESR1 mutant that you can’t detect it. But because those are the ones that survive, they get enriched for and then they look as though they’re acquired. So ESR1 mutations at diagnosis of initial cancer is very rare, less than 1%. But in patients, particularly on estrogen deprivation therapy, things that lower estrogen level like aromatase inhibitors, patients that are on that for a long time, either in the adjuvant setting for early stage or a long time for metastatic disease, they’re the ones that have a higher chance of having an ESR1 mutation.

Shehzin Tietjen [42:08]

Along those lines, Can you elaborate on a situation where there are no biomarkers, no circulating tumor cells, but there is a progression?

Debu Tripathy, MD [42:22]

Yes, there are situations where certain cancers grow in sort of a stealth mode and they don’t shed their DNA. So if you look at patients that may have even similar looking scans, you may find different levels of tumor DNA, because the act of the DNA being released by the cell is also governed by a lot of biological processes that may vary from one person to another. So there are some of those variables.

Certain histologies are also associated with lower tumor mutational rates like lobular cancers start with low tumor mutation rates. But then over the course of treatment they actually can evolve to become more hyper mutated. So they behave a little bit differently. It really varies from tumor to tumor. We’re not perfect at detecting, we’re not there yet, but we’re going to get better and better as the technology improves.

Jean Sachs, MSS, MLSP [43:15]

There’s some questions about imaging. So I thought maybe we’ll move away from biomarkers. What advantage does a PET scan offer versus a full body scan combined with a CT torso scan?

Debu Tripathy, MD [43:27]

This is a really good question because we as clinicians often struggle with what is the best testing to obtain. Sometimes insurance companies won’t approve a PET-CT if you haven’t done a CT scan first, which I think is wrong, but in a way reflects a little bit of our ignorance in knowing who should get what.

In general, the more rapidly proliferating tumors like triple-negative cancers or even some of the hormone receptor-positive cancers, but the ones that are high grade, those show up better on a PET-CT scan because the metabolic activity is higher. So it helps us a little bit more.

Most other cancers, I would say that a combination of a CT scan with iodine contrast and a bone scan can together give you a pretty accurate picture.

Jean Sachs, MSS, MLSP [44:09]

I’m glad you mentioned insurance companies. I’m sure a number of you have had scans denied. And so what’s your advice? I know doctors play a big role in advocating. What do you do if it’s denied?

Debu Tripathy, MD [44:24]

Many times there’s what’s called a peer-to-peer review where you have an opportunity to talk to a medical director that is responsible for sort of being the gatekeeper and explaining to them why you want to get it. Sometimes they will make you do the regular scan and show that the results in the liver are equivocal and need further definition. And then you can either get an MRI or maybe a PET-CT scan. It’s really designed to help insurance companies manage, maybe the doctors not being as selective, but it’s also a barrier. And so we have to bridge the gap and it basically takes additional communication with the medical director.

I have spent, in some cases, hours on the phone trying to discuss a case and getting them to overturn it. It’s really a matter of making sure that you justify it. And it’s best if you do it ahead of time, when you send the request and say exactly why you’re ordering it, do it ahead of time so that they will approve it. And you have to code it right. All the diagnostic codes have to be in there so they know that the patient has metastatic disease and so on and so forth.

Jean Sachs, MSS, MLSP [45:31]

Yeah. So just another call, if you’re not happy with your medical oncologist, you need to find someone who will really advocate for you because clearly they are out there. Go ahead, Toni.

Toni Willis [45:42]

Along those same lines: Are insurance companies starting to cover the genetic testing more? Because I know that was a problem before. And then also: Are these tests going to be more mainstream? Because often doctors don’t know what to do with the results of the test.

Debu Tripathy, MD [46:03]

Yeah, so generally insurance companies are now covering genomic testing for someone who has metastatic cancer of any type. So it’s really a matter of being proactive. It also helps if the doctors are more willing to engage with the representative of the different companies. A lot of doctors just don’t like drug reps and pharmaceutical reps, and I think that’s probably gone too far because they can actually tell you how to get access to their technology and to their drugs and to work collaboratively with the practices. They know how to navigate the system.

So yes, it is covered, increasingly so. And Medicare covers it and really the diagnostic codes have to be right.

Jean Sachs, MSS, MLSP [46:46]

There’s a couple of questions about defining somatic mutations and germline. I know you did that, but it’s a complicated one.

Debu Tripathy, MD [46:55]

Right. Germline mutations are the genes that you pass on to your children. It’s the same copy of the DNA that you have from a direct blood relative, or you have a 50/50 chance of having it. Inherited mutations like BRCA 1 and 2 are passed on and they not only affect your risk of cancer, but if you have cancer, they affect your biology.

Acquired mutations are mutations that you did not have when you were born and that other cells in your body that are normal cells like blood cells do not have, but only the tumor has it. We call those somatic mutations because somatic means a cell of the body that is not the germline cell, like the egg and the sperm. So those are acquired and that’s where most of the tumor mutations are.

Of all patients with breast cancer, probably 5% of them have an inherited mutation, but everyone has some mutation in their tumor. There is a mutation somewhere. It may not be an informative mutation, but definitely there’s a lot of mutations in any cancer. And even in cells that are precancerous, we can see them too.

Jean Sachs, MSS, MLSP [48:03]

Interesting. Go ahead.

Toni Willis [48:05]

What is the estimated precision of a liquid biopsy test?

Debu Tripathy, MD [48:09]

That’s a hard question to answer because it really depends on how much tumor there is. And someone that has a very low burden of tumor, let’s say they have a solitary lung metastasis, it’s going to be a lower chance of picking it up. So that may not be the ideal person to count on a liquid biopsy. And if I have someone with a small solitary tumor, I’m actually going to biopsy and send that rather than count on a liquid biopsy.

Jean Sachs, MSS, MLSP [48:33]

OK, I think this is an important question to address. This is a person who was tested for the BRCA mutation and I assume a full panel and has an unknown variant. It doesn’t have anything actionable, but she does have a daughter. What age are you recommending for daughters or sons to be tested, whether there’s a known mutation or not, for genetics?

Debu Tripathy, MD [48:57]

Well, we always want to start with knowing who has a genetic mutation rather than screening the general population. So if you have breast cancer and you have had germline sequencing and it’s negative, your children really are not going to have that risk.

Variants of unknown significance have always been challenging, because what that is, is the gene sequence is not normal, so there is a mutation, but we don’t know if it’s a normal variant. Because there are some changes in our DNA that some of us have where we only have a minority of that sequence, but it is seen in other people and it doesn’t affect the function of the protein. So we call those normal variants, that don’t cause a disease state. So that’s always hard to know.

When we first started doing genetic testing, we were really selective because we didn’t want to find a variant that we didn’t know that it was a real mutation. But over the years we’ve assembled these very large familial cohorts. Some of you may have participated in some of these studies where we now were able to link, did that mutation track with someone that actually got cancer. And by studying large families, the variants of unknown significance now we have more confidence that they’re normal and we actually treat them as normal, but we always track them because they could be reclassified later as we get more information. And I think that was the main question.

Toni Willis [50:21]

We do have an imaging question. Can you talk a little bit about the new PET FES scan that’s available?

Debu Tripathy, MD [50:35]

Yes, so the way PET scans work is that you use a slightly radioactive material that binds to some aspect, some protein in the body and can be seen on a scan. The standard FDG PET, which stands for fluorodeoxyglucose, is looking at metabolic activity, which is higher in a cancer cell. So that’s what the normal PET scan is looking at, metabolic activity.

FES is looking at the estrogen receptor, it’s fluoroestradiol, so it’s actually estrogen that binds the estrogen receptor and it’s labeled with a radionuclide of fluorine that that allows the detector to pick it up. For patients who have estrogen receptor-positive tumors, it may be a more accurate way to detect it.

Estrogen receptor-positive tumors sometimes have a slower growth rate. They tend to have a slower growth rate, so they’re not as metabolically active and might be missed on a conventional PET scan. So that’s why the FES test is helpful, is in patients who we know they have an estrogen receptor positive tumor, we may be able to use those with more clarity.

We still need a little more data to know who to get it in, but I am starting to now get it in certain patients where imaging is difficult, like lobular cancers that are ER-positive, that’s one area where we’re using it.

And you can’t be on a drug that degrades the estrogen receptor like Faslodex, otherwise it won’t work. But aromatase inhibitors, that’s fine. We’re going to be seeing more of these PET reagents, not just fluoroestradiol, but there’s one that’s called PSMA PET which is used in prostate cancer, and we’re seeing that it might be helpful in breast cancer. So there’s going to be some new advances in nuclear medicine imaging as time goes on.

Toni Willis [52:23]

If a patient is still on their first line of treatment and has not had progression and had proper testing at the time of diagnosis, what additional testing, if any, would be recommended?

Debu Tripathy, MD [52:34]

In someone who’s getting first line therapy and their scans are stable, we sometimes will also check serum markers, which are protein markers. They’re not as specific. In other words, they can sometimes drift up for no reason at all and the scans are stable. So we’re still learning how to use that a little bit better.

But what’s emerging as a new technology now, it’s not that new, but as I had mentioned earlier, circulating tumor DNA where we can actually quantify it. So that may become another technology that even may at some point totally replace imaging. But if we’re having a hard time looking at it by scan—some tumors just don’t show well on scans—this is a technology that is still being developed for that purpose, but might be a supplemental way to track the amount of tumor.

Jean Sachs, MSS, MLSP [53:20]

Great. I’m being told we only have time for one more question, so I’m going to ask something and generalize it, but there is someone who’s saying that she’s HER2-positive and she’s been doing well for six years, so she wants to know how can she contribute. And then I thought that might be just a good way for you maybe to talk about the importance of clinical trials.

Debu Tripathy, MD [53:40]

Yeah, so people with HER2-positive cancers can have stable disease for a very long time. I’ve been fortunate enough to just talk to several people here. As long as the scans are stable and you’re clinically doing well and tolerating your treatment well, we recommend continuing ongoing monitoring and ongoing treatment. Although we don’t have a lot of data, if someone maybe can stop and do well, we simply don’t know. It may be that some of the circulating tumor DNA tests may help us do this in the future. As you mentioned, we need clinical trials to do this, but as long as you’re stable and tolerating your therapy, I recommend continue scanning unless your doctor gives you a reason why they don’t think it’s necessary. And we also recommend staying on treatment, but admittedly we don’t know for how long that should be.

Jean Sachs, MSS, MLSP [54:29]

Right. And I know Dana-Farber does have a STOP-HER2, stop Herceptin trial and we do know some people on that trial who have been doing well for eight months. So it’s amazing to see that happening.