Ask the expert: Metastatic breast cancer

Webinar transcript

Janine E. Guglielmino, MA: 

Thank you so much, Dr. Isaacs, for joining us this evening.

Claudine Isaacs, MD: 

Thank you so much for having me.

Janine E. Guglielmino, MA: 

Why don't we start by having you just share a little bit about what was most interesting to you in San Antonio? There was quite a bit of data reported for people with metastatic, hormone receptor-positive, HER2-negative breast cancer. Why don't we start there. What was most interesting to you?

Claudine Isaacs, MD: 

There were a lot of new drugs, and new findings presented at San Antonio. A lot of them, as you mentioned, focused on hormone receptor-positive, HER2-negative breast cancer. It's not that there aren't other things going on in other subtypes of metastatic breast cancer, just that the majority of new presentations were on that. There are a lot of new drugs out there, so people are trying to really develop some alternatives, or some additional types of agents.

There's this whole class of drugs known as oral SERDs. They're similar to a drug that has been around for quite a while, a drug called Faslodex, or fulvestrant, which is an injection. That's a very effective therapy that we've had around for a long time, and companies have been developing oral versions of it. So, there were a number of trials presented about some of these oral SERDs. And, there is one in particular that has made it out in front of the rest of the pack – although there are a lot of them following behind – that compared it to Faslodex, which is that injection, which is painful, it's inconvenient. So, we all want to find better ways of giving effective therapies. And that trial presented their data in women who'd received prior therapy, second line or beyond, who'd received a class of drugs known as CDK 4/6 inhibitors, and showed that it was really effective in that setting as well, particularly for women who'd been on the CDK 4/6 inhibitor for a while. Those were very encouraging findings, as well as [the findings on] some of the other drugs in that class that were presented, that also looked like they have some exciting data.

And then a whole new class of endocrine or hormonal therapies known as PROTACs, they are a new way of degrading or breaking down proteins. What this drug does is, in a different way, it breaks down the estrogen receptor. And the estrogen receptor is sort of an antenna, you know, it's like the old-style television antennas, for those of you who are old enough to remember old-style television antennas. They're sitting there waiting to receive a signal. The estrogen receptor is like the antenna, and when estrogen comes around and it hits that signal, it turns it on. And, basically, what we want to do is not let that happen. We want it to be turned off. So, this new class of drugs gets rid of the antenna, degrades the antenna, in a different way than other drugs have. That's a drug that we'll see moving forward as well.

Those were some of them, but there were a lot of other interesting presentations. There were some updates on another new class of drugs that has really come on the scene, what's known as antibody-drug conjugates. It's a chemotherapy, but attached very firmly to an antibody. It uses the antibody to hone in on the cancer cell, to be taken into the cancer cell and released, locally, into the cancer cell. The thought on that is that you'll minimize side effects from the chemotherapy just floating around in the bloodstream. It gets into the cancer cell and has its activity there. There's a drug, Trodelvy, where they presented some updated data in the hormone receptor-positive space, as well. That's actually a new drug for us, also, in metastatic, triple-negative breast cancer. So it's encouraging to see its activity in different types of metastatic disease.

Janine E. Guglielmino, MA: 

Thanks so much for that overview. So much information there. We're already getting follow-up questions to some of what you talked about. A question that I was hearing from some folks onsite at San Antonio was about the side effect profile of the oral SERDs. Does it look any different than the side effect profile for fulvestrant?

Claudine Isaacs, MD: 

Yeah, they do. They have some different side effects. Elacestrant – they don't yet have a cute name, so it's hard for us to pronounce, let alone for everyone else to pronounce. You have to say it about 15 times before you can say it properly. But that drug has a little bit more in terms of GI toxicity, unfortunately. Fulvestrant itself is typically quite a well-tolerated medication. I tell people, literally, it's a pain in the butt, because that's really what it is. It's two shots monthly, and those are uncomfortable things to go through, and they tie people to infusion units. So, obviously what we want to be able to do is to let people live their lives, and now that we're actually getting back out in the world post-COVID, be able to travel and get places, not be tied down to infusion units like that. So, it [Elacestrant] does have a little bit more in terms of toxicity. Some of them have a little bit of visual stuff going on, although it looks like in the studies that were presented, it was less than we saw in the very early studies. So that was encouraging. But they do seem to have a different side effect profile than fulvestrant. They have the convenience of oral administration, but some people have a little nausea with it, some people have some diarrhea. So, there are some different side effects that we're seeing.

Editor’s note: On January 30, 2023, elacestrant (Orserdu) was FDA-approved to treat hormone receptor-positive, HER2-negative advanced or metastatic breast cancer that has tested positive for an ESR1 mutation with disease progression following treatment with at least one hormonal therapy. Read more about elacestrant.

Janine E. Guglielmino, MA: 

Thanks for answering that because it does seem like there are a number of these medications that are coming through and we may start seeing them in the clinic in the next year or so. You also talked a little bit about trastuzumab deruxtican, or Enhertu, and there are a few questions already about whether there were any new reports about HER2-low breast cancers, which I don't recall seeing any, but there was a whole session in the afternoon that was talking about how to test for HER2-low. It seemed like there was a lot of conversation about how to identify who might be able to take this medication. Can you tell us a little bit more about what you're seeing and what you're experiencing?

Claudine Isaacs, MD: 

Absolutely. I think that's a really important question that we're all trying to sort out as well. So, up until a few years ago HER2 was HER2-positive, and HER2-negative was anything that wasn't HER2-positive. I think for anyone who's seen a pathology report and seen the HER2 results, it actually comes out in a sort of confusing fashion. What we had called HER2-positive was by looking at the intensity of staining for HER2 on the cancer cells. Positive was either HER2 3+, or what's called FISH-amplified, which is a separate test, which they typically do only if it's HER2 2+, because some of those can have HER2 in excess amounts.

But before that, we used to ignore the HER2 1+ and 2+ because those all fell into the HER2-negatives, the HER2 2+ that were FISH not-amplified. And more recently, there's been a great deal of interest in looking at HER2-low because there are some drugs that target HER2, some of those antibody drug-conjugates. The one that I was talking about beforehand, the Trodelvy, which is an antibody drug-conjugate. There are some antibody drug-conjugates where the antibody is actually looking for HER2 and so what it's doing, it's actually – it's trastuzumab, in some ways, that's looking for HER2. And what we've recognized is that it appears to be able to locate it and do damage, even if it's not traditionally HER2-positive.

So, if the staining on the tumor was HER2 1+ or 2+, then we now have data from a trial that was not presented at San Antonio, it was presented at ASCO a few months ago, where they showed significant activity of that drug in tumors that were HER2-low. And this was looking both in the hormone receptor-positive, HER2-low, and in the hormone receptor-negative, HER2-low, which previously we just called triple-negative. Because everything that was HER2 1+, 2+, or 0 classified as HER2-low. So, it's a really, really active drug. What we know when we have a drug that has a specific target, it's really important for us to be able to accurately measure the target. So there's been a lot of discussion, you know, what's the difference between HER2 0, HER2 1+, HER2 2+, where do you draw the line, and how consistent is it across different pathologists?

There's a lot of focus on being able to make sure that we are, as a medical community, properly assessing the tumors and properly determining whether somebody would be a candidate for this drug. As an aside on that, there's also a great deal of interest. We've shown that this drug Enhertu works in HER2-positive disease, but we've shown that it works in HER2-low. But there's interest in saying, well might it work even if it's super-duper low, like the ultra-lows? There are some studies ongoing to look whether it might be active in things that previously have been called HER2 0, maybe there's actually some activity even in people who have tumors that have HER2 ultra-low. I think we don't know how far down we're getting that boundary for that class of drugs. There are other drugs that are coming down that are also looking at that space, in terms of the HER2-low space.

Janine E. Guglielmino, MA: 

Thanks, Dr. Isaacs. While you were talking, I saw a question pop up in the chat. Could you clarify, is triple-negative breast cancer now considered HER2-low? Could you talk a little bit about how doctors are thinking about this and how they're approaching the idea of triple-negative breast cancer and HER2?

Claudine Isaacs, MD: 

So maybe I can step back from that and go back to what we talked about a couple of decades up until about a year and a half ago, or a year ago. Okay, so, traditionally we divided breast cancer into different subtypes based on the presence or absence of certain receptors in the cancer cells. We had estrogen receptor, progesterone receptor, and HER2. And these are all like these antenna that are sticking up there. They're these proteins that are sitting either on the cell surface or within the cell that are waiting for a signal to turn them on. We don't want them to be turned on, we want them to be turned off, because when they're on, they drive the cancer cell growth. So, we used to divide tumors into hormone receptor-positive, which was either estrogen receptor-positive or progesterone receptor-positive, and then HER2-positive or HER2-negative – and HER2-positive was either that HER2 was present in a very high amount, either it was called IHC, which is immunohistochemistry, meaning that the cell stained very uniformly and very significantly 3+, or that when they looked for the gene that codes for that protein that it was present in excess amounts, and that's what amplified means. We were left with tumors that were negative for estrogen receptor, progesterone receptor, and HER2 by the standard way, and those were called triple-negative. We have hormone receptor-positive and HER2-negative and then we had hormone receptor-positive and HER2-positive. And that's what we had. That was how we approached the treatment of breast cancer prior to the advent of these drugs that looked at HER2-low. There's one more class that I didn't tell you: there's hormone receptor-negative and HER2-positive that can also exist.

So, the HER2-positives are still HER2-positive, and we really look at treatment there that is geared towards the HER2 positivity. But now what's happened for what used to be hormone receptor-positive, HER2-negative and triple-negative, which is really hormone receptor-negative and HER2-negative, we've now exploded out that HER2-negative group, and we're now dividing it. We're saying, okay, negative is not clear enough for us anymore. We need to see is there any HER2 at all present on this, because now we have a drug that targets that, and that's effective for that.

That's why we need to know that. We've divided those classes out now into HER2-low and then ones that are really HER2-negative, which is HER2 0. We've gotten two more classes and we've broken those groups into those different categories. For the time being, at least, we consider that somebody has a tumor that is HER2-low if on any biopsy there was some HER2 staining. It doesn't have to be the last biopsy, it could have been the first biopsy, or any biopsy in between. Any time that the tumor stained positive – 1+ or 2+ -- and didn't have the excess amount of protein, so was FISH-negative…I know we're getting really technical, but I don't know how to do this without getting technical. I'm sorry if I'm confusing all of you. I'm not trying to.

But that is how we break things up, and now we have to break that up because we have this effective therapy that we need to think about whether we give. The other class that we break out as an entirely separate class are women who have genetic mutations or genetic predisposition to breast cancer who have either a BRCA1 or BRCA2 mutation or maybe a PALB2 mutation, because we also have specific therapy. So, now it's important to know a lot of different things so I can be sure a clinician and you can be sure as a patient that we are thinking of the right treatment for the tumor that you have been diagnosed with, and now that we have these new therapies, we need to know all these things.

Janine E. Guglielmino, MA: 

Thank you so much for explaining that Dr. Isaacs. We do know this is extremely confusing. It's a lot of information, and at LBBC we're working on updating our content to explain more about what HER2-low is and how we test for it. So please look for that in the coming weeks on LBBC.org and it will help reinforce some of the things that Dr. Isaacs just explained.

We have a participant who is on Enhertu right now and is finding the side effects to be difficult and is asking whether it may be possible, over time, that the side effects could become less or if there were a different dosage it might be easier to take?

Claudine Isaacs, MD: 

There are certainly side effects from these new drugs. Enhertu is a drug that has a potential to have some nausea with it, and some GI toxicities. It can have some fatigue with it and a number of other things, including very rarely causing some damage to the lungs, which is something that we are really very careful for and very vigilant about. There are two things that I want to answer with respect to that question. One is, over time, hopefully you and your doctor and healthcare team are able to work together to try and figure out how to manage the symptoms. We tend to try and start with something that we think is appropriate, in general, to try and minimize symptoms, but everyone is different and you never know how one person is going to experience a drug versus another.

Usually, once you see how somebody's gone through the first cycle, you can work with them to adjust the anti-nausea medication. Or, if somebody's not having nausea at all, but the Zofran is giving them constipation, so you want to bring it down. You really need to adjust like that. So, over time there is certainly that potential to address and to try and mitigate side effects. We also often dose-reduce, and we often have to dose-reduce because, again, what we're trying to do is to try and help people live the best lives that they can live. And giving medications gives a ton of side effects. That's a problem and that's something that we don't want to do as clinicians either. We want to make sure that people tell us how they're doing, tell us how they're managing, so we can help to try and deal with those side effects and try and figure out how we can manage them and diminish the side effects as much as possible.

But we often dose-reduce drugs, and there's this whole movement at the FDA, very appropriately, to try and figure out what's the right dosing of drugs. The way that we have traditionally dosed drugs and the way that we've done drug development as a medical community, is that we've gone to what we call the maximum tolerated dose. The dose at which the side effects are acceptable, but they might be significant, still. We'd love to figure out what is the biological dose, what dose is the lowest dose that we can go to for it to be effective. And I think the FDA's really starting to turn in that, when they're actually requiring it for all new drugs to really focus on the lowest dose that can be effective as opposed to the highest dose that people can manage.

And sometimes there's a big window between that, sometimes there's not. But for different drugs we really wanted to look at that. I know there was a terrific presentation…the years are blending particularly with COVID, but there was a fantastic presentation that was done by a patient advocate group that, in very short times, got feedback about what patients wanted and how they'd want to talk about dose reductions. And I think we heard that and we know that, but there was also then, in follow up, a survey of doctors, and doctors say they're happy to dose-reduce. So, it was good to see that most doctors were also happy and interested in reducing doses because we really do want to be giving effective treatments, but giving them with the minimal amount of side effects as possible.

Janine E. Guglielmino, MA: 

Dr. Isaacs, when a person gets a reduced dose, can they feel confident that the medication will work as well?

Claudine Isaacs, MD: 

I can't answer that in a blanket way. We know for some drugs, yes. For many of the CDK 4/6 inhibitors, we know that for lots and lots of people at dose reductions, there was no difference in the efficacy in women who were dose-reduced versus not. We know that in the real world we do a lot of dose reductions and we see efficacy, we see that the drug is beneficial. But it's hard to say. There are some drugs where probably we're not. There some of the drugs where we know you could decrease a little bit, but if you decrease a little bit more, you're below the dose where it's effective. But I think for many drugs, we think that we can reduce the dose at least some and still have efficacy.

Janine E. Guglielmino, MA: 

Great. Thank you for answering that question. I'm going to jump into some of our participant questions since we have quite a few of them. I'm also going to ask a few that we got in advance, so hopefully we'll get to as many questions as we can.

One of our participants is asking about targeted therapies in triple-negative breast cancer, and what is on the horizon for those? Which ones exist, particularly after cancer growth from other types of treatments?

Claudine Isaacs, MD: 

Hmm. As I mentioned, we're already starting to break triple-negative breast cancer into different categories. We recognize traditionally it had been defined by what it didn't have, but not what could be targeted. We know that we treat triple-negative breast cancer that is PD-L1 positive with immunotherapy. There's a subset of triple-negative breast cancer where there's positivity for the androgen receptor. There are studies that are ongoing, we're about to launch, looking at targeting the androgen receptor in these triple-negative breast cancers. They're the antibody drug-conjugates that are look being looked at. Those are really, I think, the wave of the future when we think about chemotherapy because what they are, are more targeted ways of delivering chemotherapy.

So, sacituzumab, Trodelvy, is a drug that targets a protein that's expressed on many triple-negative breast cancers. It hones in, finds a cancer cell and gets internalized in the cancer cell, and releases the chemotherapy there. There is a lot of interest in these antibody drug-conjugates and looking at different proteins that are expressed within different cancers. There's a lot that's going on, and then there's a lot to try and augment the benefit of immunotherapy, to try and use other immunotherapy drugs, or try and use other types of chemotherapy to potentiate the immunotherapy. So, there's a lot going on there.

Janine E. Guglielmino, MA: 

Great, thank you for answering that. I am going to ask a couple of really excellent questions that we got ahead of time. The first question is, can you explain why I have to wait to take a drug that's been shown to be successful but only after I've experienced a progression on one or more treatments?

Claudine Isaacs, MD: 

That's a great question to start with. Drugs are approved and studied in sequential ways in medicine. A lot of us are trying to figure out whether we could upend a little bit of that as well. But when drugs are studied, let's take Trodelvy. Trodelvy was studied in women who'd received at least two prior chemotherapies, and no more than five. So, that's where it's approved, because that's where it's shown its benefit. There are studies ongoing to look at it earlier on [in the treatment process], but the study, the place where it was shown to be effective was in that particular setting. And that's how the FDA approves the drug. They approve the drug, typically, based on the setting in which it was studied. And there are often, you know, some subtleties to that.

So it depends. It doesn't mean that everyone has to wait until that point. It depends how quickly the disease has progressed or what's going on. And sometimes we can get it approved for an earlier setting, and sometimes there are ways to get around it. But that's really how drug development has been done. There is a rationale behind it. One wouldn't want to upend a drug that really does well and the first line setting just because we think we have something that might work better, because we're wrong sometimes, right? Studies are negative. And we've seen that over and over again. So, there is a rationale behind it. It is frustrating when there's this really exciting drug, and one has to wait for it. But the good news is that for other drugs, things didn't push out things that were available to us earlier on.

That is a problem that we encounter, when we're thinking about why couldn't we use some of these drugs in the earlier-stage setting where we might be able to cure more people. The natural progression is to look at it this way and then move it into earlier studies. There are studies, for instance, with Enhertu,  the drug that we've talked about, that are now underway looking at the first line setting. At San Antonio the first study that we saw about Enhertu in HER2-positive disease was in the second line setting. But there was another study coming that actually had been designed first that was looking at the third line setting and showed a benefit, and that was presented at San Antonio, showing us this drug is active at all sorts of different phases. I think some of the relief that I take and I think is present is, I was happy to see the results of the trial in in third line setting for Enhertu, for HER2-positive. There was a survival benefit scene. So that meant for everyone who'd already gotten their first or second or third line therapy, even getting it later on still provided significant benefit. So that was a reassuring finding when we look at things and figure and try and think about how we recommend drugs in different settings.

Janine E. Guglielmino, MA: 

Thank you. Thanks for addressing that. And another related question from someone is would an initial treatment after a recurrence be any different if the recurrence was a very late recurrence versus if it was very soon after an early-stage breast cancer diagnosis?

Claudine Isaacs, MD: 

Again, that's a great question. The answer is yes. If somebody has a recurrence long after completing other therapy, then those therapies that we used way back when, we could think about reusing them. Or, it could say something about the behavior of the tumor. So yes, we do, we very much factor that in, in terms of determining what we think is the best treatment. I did this with LBBC, I think, a number of years ago: it's hard, because what I say today will be wrong in about two months. Which is fantastic because that means we have all these new agents that are coming and are available to us and that we can use and that are effective. It's a lot harder to answer these questions because it's so nuanced, so individual.

It's harder to wrap your head around it and to say exactly what you're going to do, and what we would do, in what situation. But the underlying reason for that is fantastic because we have all these new treatments and we're getting better and better at treating this specific type of tumor that somebody has, and not just this huge group of people that we're just putting all together. But it makes it harder to transmit messages because the messages are so unique and so changing.

Janine E. Guglielmino, MA: 

Definitely. How important is it to get a new biopsy before changing treatments, and how can that be done if you have bone-only mets?

Claudine Isaacs, MD: 

I don't think it's important to get a biopsy every time that there's a need for change of treatment. But it is really important these days to get a biopsy and to make sure that it's sent off and it has what we call next generation sequencing, or molecular profiling, done on it. It's a process that takes a little while. It takes a few weeks, typically, to get the result back, but we get sort of a comprehensive portrait of the proteins or genes that are turned on or have changes in them. It really helps to guide the treatment recommendations because there are therapies out there. Then the other thing to think of is to think about a clinical trial and to look for a clinical trial if there is a change in the tumor.

It is important to get those biopsies, certainly at the time of diagnosis. For most – the vast majority of people – we’re doing it. It didn't used to be universally done. I'll tell you, at most academic centers we've been doing it for 25 years or more. I think it's become very mainstream now to do that, to make sure of what are the characteristics of the tumor. We recognized a number of years ago that hormone receptor and HER2 status could change, but now we have so many other things that we need to be looking at.

It is really important in terms of the bone. There are different ways to look at the molecular profile of the tumor. The traditional way is to get a biopsy and to get tissue, but we now have abilities to detect circulating tumor DNA. Sometimes you can get what what's called a liquid biopsy, which is from a blood test. They can do molecular profiling and see if there's any circulating tumor DNA, or circulating tumor cells, or other things that they can look at. And they can see whether the tumor has mutations or changes within it that they can detect in the circulation. There are different ways to do that. So, sometimes for women, particularly women with bone-only disease, that's something we think of. But honestly, we obviously want to think about it for everyone because it's much nicer to have a blood test than to have a biopsy. The issue with doing a biopsy of the bone is that for the pathologist to be able to really get at that specimen, they have to get rid of the bone. They slice the tumor, they take it, they put it basically in wax, and then they slice it into very slip-thin slices, and that's when they look at different things on the tumor.

But if it's in bone and there's bone around it, they can't do that. They have to use a system to get rid of the bony tissue and that can change the tumor tissues that are there. So, you could get false negatives because in getting rid of the bone, they can get rid of some of the proteins that might have been there on the tumor. One just has to be careful if it comes back negative, particularly for hormone receptors or or HER2 done by certain methods, it could be a false negative. If something comes back and it's present, well we know it's present, but the fact that it's absent, it could have just been the method that they had to use that made it appear to be falsely negative. There is a lot that we could still get for bone and we do sometimes do that and we sometimes get some very helpful information from it.

Janine E. Guglielmino, MA: 

Thank you. That's very helpful. There is a question about circulating tumor DNA or ctDNA testing. Is this currently recommended, in general, for metastatic disease surveillance?

Claudine Isaacs, MD: 

The answer, in December 2022, for breast cancer: No. That is something that we are all looking at and there are a lot of studies looking at ctDNA. There are lots of different ways to look at it to see how quickly ctDNA decreases. Would that mean something? Does that mean that the treatment is working or, if it's not going down quickly enough, should we do something about it? There're all sorts of things that are being looked at in terms of ctDNA. We're thinking about it for surveillance, or for suggestions for early recurrence, or something like that. But there are not solid data on breast cancer right now to be using it as standard of care. I personally would not recommend it for standard of care. I think that it's something that needs to be done within the setting of a study, so that we can better understand things and understand how to interpret the results.

Janine E. Guglielmino, MA: 

Thank you. What are your thoughts about new diagnostic tools such as FES PET scans and using them to look at the hormone receptor uptake?

Claudine Isaacs, MD: 

So, that is a technique that I think is going to be incredibly useful. Because one of the things that we're trying to think about and try and increasingly do, is be personalized and individualized in our therapy. The FES PET, and then there are variations of it as well, is a way of seeing whether the tumor lights up because there's estrogen receptors present there. It's a way of telling us that the tumor might continue to be responsive to endocrine therapy or to hormonal therapy. There’s actually a variation on that where they give a dose of estrogen and see if there's a change, and that suggests that the tumor is still responsive to endocrine therapy. There are all sorts of things coming down the line for that, and I see that as a place where we're really going to have a lot of new developments that will help us figure out whether somebody's tumor is likely to respond to a particular therapy, and help what we're trying to do.

What we want to be is increasingly individualized because not only do we want to treat somebody who's going to get a benefit from a therapy, but we also don't want to treat somebody who's not [going to get a benefit] and just going to have the side effects. So, there are two sides of that that are really, really important for us.

Janine E. Guglielmino, MA: 

Great, thank you. When you were talking before, one of our participants asked why metastatic breast cancers sometimes change subtype. Could you talk a little bit about what we know about why that happens?

Claudine Isaacs, MD: 

Again, these are all amazing questions, so thank you. We don't fully understand that. There are a couple of different things that we think about. One is that the tumors are not just one thing. They're not homogeneous. So, they probably have different clones within them and those different clones exist. What we think could happen is that under treatment that's effective for some of them, the other ones can grow out. Sometimes what can happen as a tumor is disseminating or is spreading, one goes here and one goes there. So, some of it could be under the pressure of treatment, causing that other subtype to occur. And then it could just be some of the heterogeneity of the tumor itself. But it's just that tumors are composed of many cells, and there are different subtypes within it. Even if we say something is hormone receptor-positive, not every cancer cell is hormone receptor-positive within a hormone receptor-positive tumor.

Janine E. Guglielmino, MA: 

Right. Thank you for that explanation. Someone is asking, do patients have to come off a current treatment before starting a clinical trial?

Claudine Isaacs, MD: 

Typically the answer is yes. There are some trials where that might not be required, but most clinical trials would require somebody to come off the treatment they're on. But typically people are going on a clinical trial because the treatment that they are on is no longer working. So it's really a time when there would be a treatment change anyway. Now, sometimes people stay on some form of endocrine therapy or something like that. So, there are exceptions. The one answer in medicine that's always wrong is “always” or “never.” Take that with a grain of salt from whatever I'm saying, but I'm saying, in general, people go on clinical trials typically because the treatment that they're on is no longer working and they should be then be considering another treatment.

Janine E. Guglielmino, MA: 

Sure. Although certainly it's great to consider a clinical trial at any point in your treatment. Are there any benefits to doing a clinical trial at specific points in metastatic breast cancer treatment?

Claudine Isaacs, MD: 

Today's standard of care is based on yesterday's clinical trial. And what we're always striving to do is to do something better. Clinical trials are also a way to get access to some of these newer drugs that are promising drugs. And, I would say certainly, whenever one is considering or needing to consider a treatment change, it's worth it to think about is there a clinical trial. I think these days we often have fantastic first line standard of care, for many women. And it's definitely worth it to ask. But I would urge you to have a conversation with your doctor to say, well, you know, how does this compare to standard of care?

Because the standard of cares for today are about a year old or two years old, in many of the instances. You really want to weigh the pluses and minuses of a clinical trial. But absolutely, particularly second line, third line, fourth line, I would definitely be looking at clinical trials. First line as well, but what you'd want to know is what are the pluses and minuses for me, and what are the thoughts about this? If one had an unusual mutation or change in the tumor, then absolutely one would want to look for a clinical trial that potentially targets that.

Janine E. Guglielmino, MA: 

Right. Thank you, Dr. Isaacs. A couple of people have this question. Could there be benefits to having chemotherapy earlier in metastatic breast cancer treatment, when you're still feeling strong or when you're still feeling better? Is chemotherapy reserved for later lines because it works more broadly, or because of the side effects?

Claudine Isaacs, MD: 

That question is one that we typically think of most in hormone receptor-positive, HER2-negative breast cancer. For the time being for triple-negative or HER2-low, hormone receptor-negative, we're thinking about chemotherapy and potentially antibody drug-conjugates, which are a version of chemotherapy, just a targeted chemotherapy. In hormone receptor-positive, HER2-negative breast cancer, that is something that has really evolved over time. I think that if you go back a while, our first thought was if we give somebody side effects and the drug is harsher, maybe it works better. That was sort of the instinctive thing. When I first start to practice medicine, which was longer ago than I'd like to admit to any of you, but when I first started to practice as an oncologist, for women with hormone receptor-positive, HER2-negative breast cancer, if they had any evidence the disease had spread to anything aside from bone or skin, the standard of care was to recommend chemotherapy.

That has gradually changed over time, where we've recognized that what we call hormonal therapy, and I know it's confusing because we also have lots of names here, hormonal therapy, endocrine therapy. It's really estrogen-blocking therapy. But it's a hard thing to say. So, estrogen-blocking therapy tends to be better tolerated than chemotherapy. But if you think of it, estrogen-blocking therapy is targeted therapy. So drugs like tamoxifen and aromatase inhibitors, things like Arimidex or Femara or all of those drugs, are targeted therapies. They're targeted to not let the estrogen receptor be turned on. And so there's actually a really interesting trial that was presented at San Antonio this year that looked at comparing, in a modern world, chemotherapy first or estrogen-blocking therapy plus this class of drugs and CDK 4/6 inhibitors. So, drugs like Ibrance, Kisqali, all of those drugs.

It was looking at one of those drugs and they actually found that women did better and stayed on their first line treatment for longer. They had disease under control for longer with the estrogen-blocking therapy and the CDK 4/6 inhibitor as opposed to with the chemotherapy. And I think that, in this country, I think that the vast majority of women with hormone receptor-positive, HER2-negative breast cancer in first line therapy are getting estrogen-blocking therapies plus a CDK 4/6 inhibitor. But there are lots of countries where they always did chemotherapy first because they thought it was more aggressive and it would work better. This trial was a really interesting, a modern-day trial that showed that absolutely that wasn't true. So, the answer is it's probably best to get good targeted therapy, if possible, because that's what makes most sense.

Janine E. Guglielmino, MA: 

Thank you. I'm going to ask a couple of questions about specific situations or medications. One of our participants is asking if it is OK to stop taking Herceptin if you are HER2-positive, if the drug resulted in heart damage?

Claudine Isaacs, MD: 

So again, it one has to be very individualized about that. We did a study a number of years ago with one of my cardiology colleagues who's fantastic, and working closely with her, we were able to show that we could safely give drugs like Herceptin to women who had some moderate decrease in their heart function if we follow them closely and work closely with a cardiologist. There is a specialty of cardiology that has sort of evolved with these, cardio-oncologists. I have the luxury of working with a couple of cardiologists who really have an interest in this and who specialize in this. What it's proven to me is that clearly, we can do it, and women can stay on HER2 targeted therapies.

Now again, that's a graded phenomenon. It depends how low the heart function goes and what's going on. But I think it speaks to the fact that it's important to work as a team. I specialize only in breast cancer. I can't treat any other types of cancer, let alone think about being a cardiologist. I need to partner with a specialist who really knows how to manage this. I think it's something that has really disseminated into the cardiology world, as well. I think many cardiologists are aware of this, whereas before they said “you have to stop.” But I think there are ways to manage things, for many women, some mild to moderate diminished heart function and still remain on drugs like Herceptin.

Janine E. Guglielmino, MA: 

Thank you. Can you talk about the differences among the CDK inhibitors? Are there differences between Ibrance, Kisqali, and Verzenio?

Claudine Isaacs, MD: 

The million-dollar question. A year ago, or a year and a half ago, or two years ago, we would've said no. I mean there are differences. They clearly have some differences because they have differences in side effects. So, they have to be somewhat different drugs.

There are some studies coming out that are suggesting that some of them might have differential activity that we really have to be careful, as a medical profession, to compare across trials. Even if trials were done in what looked like a similar setting, there are differences between the patients and that's why we have to randomize in trials. Some of the randomized trials with Kisqali have shown a survival benefit, whereas they haven't shown the clearest survival benefit in some of the trials with Ibrance. There's actually also been a great deal of interest in looking at real world data in addition to standard randomized trials. I guess the answer that I would say is, yes, it's possible there are some differences between the CDK 4/6 inhibitors, but I don't know that we know for sure yet that they are.

Janine E. Guglielmino, MA: 

Dr. Isaacs, can you explain what real world data is?

Claudine Isaacs, MD: 

Real world data is trying to look at data from regular practices to try and see how people do, and try and help that inform how some drugs work and how they work in the clinical setting. Clinical trials – for any of you participating in clinical trials, you know – many of them are quite rigid things, and they have to be rigid because in order to have a clear conclusion, they have to be done in a uniform way. But what typically happens is the people who go to clinical trials are people who have access to those clinical trials, who can get to the facility, who can do whatever, and have to meet the characteristics that they have to have, and relatively little in terms of other health issues. It's a very pristine world, so you always wonder how it's going to work in the real world.

Electronic medical records and electronic data have made it much easier to get access to some of that. One of the issues to just look at, you know, what's my clinical experience? Well, you know, they're skewed. There might be reasons why an individual doctor decides to give somebody one drug versus another drug, and because one of the drugs work better might have nothing to do with a drug, but because they were selecting a certain group of people to give it to. So, you have to get around some of those issues in terms of the biases that you would have in just at looking at clinical data. But these real world data are done within these data sets often with these companies that really have a way of culling through the electronic medical record and being able to match people relatively well in terms of different characteristics. So, you're able to get a sense of how one drug is performing versus another in the setting of the standard clinic. But there still are issues with it. It's not as statistically sound in terms of data, but it can give you some good ideas about whether there are benefits to a particular drug or how it's tolerated. And so there are methods for us to be able to control for some of those things.

Janine E. Guglielmino, MA: 

Thank you. One of our participants is asking what it means if you're on a medication and have multiple tumors and some of them get smaller, but some of them don't.

Claudine Isaacs, MD: 

That could be due to a number of factors. One of the things could be that tumors are not all identical at different sites. It's possible that at some sites the tumor is more sensitive to that particular therapy than at some of the other sites. There is what we call heterogeneity in the tumor. The other thing is, the way that we're visualizing this on scans, scans are not perfect things. Sometimes what it sees is a mass, or an area within a bone that has uptake, or things like that. But it doesn't necessarily say that what is there is alive and viable. So, sometimes you could just have dead tissue there, but it would still look the same size on the scan. One has to be careful interpreting these scans.

One of the areas that's hardest for us to see are bone. When bone heals because there's response and the tumor is being killed, and new bone is being put down, it looks exactly the same on some scans. On a bone scan that will look exactly the same as the tumor growing. So one always has to be careful interpreting the scans. Then there's just a little variability. A couple of millimeters is just…they're technical differences. So again, one needs to be cautious looking at these things and not interpreting them too strictly.

Janine E. Guglielmino, MA: 

There's another question about scans actually. Can you please touch on the topic of using CT instead of PET scans to follow progression or regression? Can you tell us more about Serena PET scans? I think that's SIRA Sariana PET scans. I'm thinking

Claudine Isaacs, MD: 

I can tell you about PET scans and CT scans in general. CT scans give a clearer picture of the size of the tumor and see things in much crisper detail. CT scans only do a portion of the body, but it does it quite quickly, and that's different than an MRI, which is really focused. The technique for an MRI is very much focused on exactly the organ that it's looking at. Whereas a CT scan can quickly scan from here to one’s pelvis and the radiologist can see all of the organs, the bone, the skin, everything that's within that, they get a pretty clear picture with a PET scan. Typically, the standard PET scan, not the FES PET, but the standard PET scan, picks up activity increase, it picks up glucose activity, which occurs when cells are inflamed or when there's tumor there, when there's infection there.

So, a PET scan gives an idea if there's an area that has more glucose update, it will be hot on PET scan, but it's not a crisp clear picture. It's sort of an area that's hot, but it doesn't tell you exactly where it is. It's not easy to measure in size. So CTs are much more precise in terms of size, but they don't show activity, and so they can be complementary studies. Typically, you can do a PET scan with a diagnostic CT, sometimes. That's sort of the best of all worlds. Often what people get are CT scans and bone scans because the bone scan looks at all of the bones, everywhere, and looks at activity there. And then the CT is looking at the chest, abdomen, and pelvis area.

Janine E. Guglielmino, MA: 

Thanks for explaining that. Another participant was asking, once you're diagnosed with metastatic breast cancer, whether there's a value to finding a progression sooner rather than later. And in addition to scans, what other ways might a doctor be looking for a progression?

Claudine Isaacs, MD: 

And again, that's something being investigated really within clinical trials. Obviously a very important question. The important question is, if you found that things were progressing earlier and you changed therapy, would people do better? Would they live longer? And there are some studies that are looking at that. There's certainly a lot of ongoing studies that are looking at that. There was one large study that looked at circulating tumor cells and changed therapy if the results didn't go down quickly enough or went up, and that's how you didn't show a difference and people stopped using circulating tumor cells because of that. But that doesn't mean there won't be other techniques that come and that are helpful. But we want to make sure that making that change early actually has an impact.

There are two big categories that you could think of, one, probably the most important, is if you got off of a therapy that was no longer working early, and go on something that worked, could that prolong survival? And then the other thing is, could you be spared the unnecessary toxicity of continuing on a drug that has side effects? So, that is something that is being really heavily investigated in clinical trials. I think you're hearing a bit of a theme from Sharon, and from Janine, and from me that clinical trials are really trying to address a lot of the questions that you are all asking, and that are so important.

There are new drugs within clinical trials, and then embedded in many of these clinical trials is trying to also figure out who does a drug work for and who does it not work for? Are there better ways for us to figure out whether we should move more quickly or, or not move more quickly? Or are there things that are telling us that it's not working in this person? For those who participated in clinical trials recently, there are a lot of additional specimens that are being collected. Blood tests, biopsies, tissue, all of those things. The point of it is to be able to figure out who's responding to this and who isn't, but also by looking at the biology, understanding who's responding and why they're responding.

And maybe we could do something even better. For the people who aren't responding well, what's the target and maybe we should go after that. That idea of, how do we follow people? Maybe what that question just asked is, yeah, we should come off sooner because the ctDNA is going up, or something is happening, and we should go off sooner because it's no longer effective. There is a tremendous amount of work in all of these clinical trials are trying to get at. I think a lot of what these questions are asking is, what's a better drug, and what's a better way for me to be monitored, and what should I be doing? And helping figure out what the drugs of tomorrow should be, that really can hit those targets that that crop up when the tumor stops responding, so you can get more and more effective treatment.

Janine E. Guglielmino, MA: 

Thank you. We have a couple questions about some specific targets, and one person's asking whether there are drugs being developed for people whose cancers have an ESR1 mutation. Can you explain what that is and how that's being discussed?

Claudine Isaacs, MD: 

Yeah, absolutely. So, there's a lot of interest. An ESR1 mutation is a mutation in that estrogen receptor. Okay? Remember that antenna that's sitting up there on the cell waiting for estrogen to bind to it, and there's a mutation in that receptor that makes it active even when estrogen isn't binding to it. It no longer needs estrogen to turn it on. It turns itself on.

There's a lot going on research-wise to target tumors that have these ESR1 mutations. In fact, fulvestrant, which we talked about, and these oral SERDs, look like they have activity. The oral SERDs might be even better than fulvestrant for tumors that have ESR1 mutations. So, there is a lot of work that's being done. That drug that I told you about that sort of broke down the estrogen receptor by other means – it doesn't care whether there's a change in the estrogen receptor that makes it act independently of estrogen, it’s going to destroy the estrogen receptor anyway.

There is a lot that's going on looking specifically at these ESR1 mutations that seem to develop under pressure of drugs. If we talk about evolution of tumors and finding out about that, those ESR1 mutations happen in some women who are on the aromatase inhibitors, the AIs, anastrozole, letrozole – those drugs – and that's when we often see these ESR1 mutations emerging. So yes, there is a lot going on, that, and there are drugs that are active. Fulvestrant is a drug that retains some activity for ESR1 mutations and these oral SERDs also look like they have activity, and there are lots of other drugs that are following on the heels that are trying to develop activity, or are trying to be developed that are being looked at in patients who have ESR1 mutations in their tumor.

Janine E. Guglielmino, MA: 

Thank you. Another person is asking about BRCA mutations, especially after a progression on a PARP inhibitor medication. Are there next generation PARP inhibitors? Can you tell us more about that?

Claudine Isaacs, MD: 

Absolutely there are next generation PARP inhibitors being developed. There's a lot of interest, again, in that field and looking at other drugs that could act along that pathway. Maybe I can step back from that question. A broader thing is just how important it is to know whether one carries a BRCA1 or BRCA2 mutation because we have specific targeted therapies. Obviously, it's important for a lot of reasons. But I've been doing this for long enough that I remember that when we started to be able to do it, we couldn't tell anyone anything about it. It just felt like a nasty crystal ball that you were looking in and telling somebody they had a BRCA1 or BRCA2 mutation.

But now we can do things for people who are healthy and are found to carry BRCA1 or BRCA2 mutations. There are things that we can do that prevent them from getting cancer and show improved outcome and improved survival for people who are unaffected with cancer, who have those mutations. And then for somebody who has a cancer diagnosis and has a BRCA1 and BRCA2 mutation, we have evidence for these PARP inhibitors being very active drugs in that setting and being better tolerated than our standard chemotherapies, which is what we used to do. So, it's really, really important, and our current guidelines say that if anyone has HER2-negative breast cancer – and that we mean by old school HER2-negative, so that includes HER2-low – [if anyone has] HER2-low or HER2-negative breast cancer, we should be recommending genetic testing on all of those women with metastatic breast cancer, so we can make sure whether they should be considered for treatment with a PARP inhibitor. We also have some evidence from some trials suggesting that women who carry PALB2 mutations might also benefit from PARP inhibitors. So, if you know somebody or you're in that position, please talk to your healthcare provider and say, have I had genetic testing? Do we know? Because we have drugs that are specific for people who carry mutations.

Janine E. Guglielmino, MA: 

Thanks, Dr. Isaacs. Our next question is from someone with metastatic TNBC, triple-negative breast cancer, whose cancer has responded well to treatment and is seeking a mastectomy, but is having difficulty getting it. Can you comment about what the standard of care is with using surgery in metastatic breast cancer, and how you can get more information if you're seeking a mastectomy?

Claudine Isaacs, MD: 

I would go to an academic medical center and get a second opinion about this. The question is for somebody who has metastatic breast cancer. If somebody had metastatic disease at the time that they were diagnosed with breast cancer, the question is: should they have surgery on the breast? This is typically what we do for localized breast cancer. Does that impact outcome? Should somebody have that if they have metastatic disease? That again is a very individual discussion. Let me just stress that, and stress that it's hard to say on an individual basis. There are certain subtypes and certain situations where we think of it, but right now, our literature suggests that for the majority of women who are diagnosed with metastatic breast cancer, we don't have evidence that doing a mastectomy or doing local therapy prolongs survival. It could improve quality of life.

In some cases, it could be used for symptom control. That is not universal. I really want to make that very clear. If we have women who are doing well for a long time on therapy or have a very limited amount of metastatic disease and have a tumor that's HER2-positive, where we know we can often get a very long response, we do think of it. We do individualize things.

I want to share with you what the literature has now told us based on some randomized trials. The studies are limited because it was hard to accrue to the studies. But that is something that one would consider on an individual basis. The reason for that is not just because somebody doesn't want to take somebody to the OR, but that there are risks with surgery. And what we're always trying to do is to make sure that if we're recommending an intervention, that there's a good reason for it and that we're not exposing somebody to unnecessary risks. But I would say if somebody is thinking of that, understand why their healthcare provider is not recommending it. Ask them to please explain it to me. And if you're not satisfied with that explanation, go get a second opinion about it.

Janine E. Guglielmino, MA: 

Well, it's hard to believe, but the hour is really flown by. I'm going to ask our last question and just give you a moment for any closing thoughts. One of our participants is asking, what questions should we be asking of our oncologist to understand some of these really recent developments? How can you get more information directly from your doctor so that people can understand the latest therapies and be able to discuss them better with their doctors?

Claudine Isaacs, MD: 

I think a question like, “Do any of the latest findings apply to me? Should I be thinking about some of these new drugs?”

I think often one word of caution is, people, institutions, organizations, will pose very early research and we have to be careful about applying very early research to the clinic. But there's so much coming out all the time from well done trials that are really changing things. You've heard how hard it is for me to explain, to try to explain all of this to you. And what it's like in a busy clinic setting, it's not like your doctor can stop and give you a treatise about everything new that's going on. But I think questions like, “I'm seeing all these exciting new things coming out. Does any of that apply to me? Does it apply to me now? Would you think about it down the line? What should I be thinking about? Should I be thinking about a clinical trial? Are there new developments that are impacting how you view how you're treating me?”

Janine E. Guglielmino, MA: 

Thanks for answering that question. Before I make closing remarks, is there anything more that you'd like to share with our community this evening?

Claudine Isaacs, MD: 

I think just the hope of all the advances that we're making. It's dizzying in some ways, which is fantastic. It's fantastic because we have new treatments, we have new effective treatments, they are changing the landscape and there are a ton more coming behind them. I think one of the things that I've seen over the last number of years is how industry has gotten much more interested in just small niches and small targets. Before that they only used to focus on big things, the things that were the most common. But I think what we've recognized is we have to think of cancer in a more individual way and that a treatment that works for one person, won't necessarily work for the other. I look at the trainees. I work at an academic institution. I look at the fellows who are just about to come out of their training. And I think, you are going to be in such a different world than I was. Your world is going to change over and over again. And it’s really felt like it. Things have been changing quickly over the past 5 to 10 years and are going to evolve. There are new treatments coming down the pike every moment.

Janine E. Guglielmino, MA: 

Thank you so much, Dr. Isaacs, and thanks for covering so much tonight.