Filipa Lynce, MD; Nikhil Wagle, MD; and Lindsay Shaw, AOCNP, ACHPN, discuss advances in research and treatment for patients with ER-positive metastatic breast cancer.
Good morning and welcome everyone to our breakout session. We will be discussing what's new in research and treatment for her two positive metastatic breast cancer. I am Christine age is one of the nurse practitioners in our breast oncology center at Dana Farber. I've been working there at 16 years care of patients and I'll be moderating today's session. I would now like to introduce our presenters. Um Dr Philpott who is a medical oncologist in our breast oncology program, an instructor in medicine at Harvard Medical School, he cares for individuals of all ages but has a particular focus on young adults living with breast cancer. Doctor who is also the director of breast network integration. And I'd like to say hello to DR ADa wax, who is also a medical oncologist. Um Associate director of clinical trials and R breast center at Dana Farber. She's also an instructor in medicine at Harvard Medical School. Her research focuses on two positive breast cancer including leading clinical trials testing new approaches to treatment and translational translational research. Sorry aimed at understanding mechanisms of resistance to her two positive targeted treatments. So the forum will go as follows. We will have dr Pollux and dr wax present on our current treatment options clinical trials and going research for her two positive metastatic breast cancer for about 30 minutes. And then we'll leave about 30 minutes for questions and answers and we would like to encourage everyone of questions to submit them in the Q. And a button at the bottom of the screen. Um And just as a side note we are not able to answer clinical personal clinical questions regarding care. But we'll do our best to sort of go through everything that comes through our way and without further ado I'd like to introduce dr wonderful thank you, Christine and thanks to all for for being here today and we're really excited to get to take part in this embrace forum series and there's a lot of great sessions coming up as well. Um So we'll be talking about the treatment of metastatic her two positive breast cancer today and I'll focus up a little bit on how we think about care where things are currently a little bit of what's happening in research and dr wax will focus a bit more on where things are heading through trials and other research. Um So so first let's talk just broadly about metastatic breast cancer. And so breast cancer of course arises in the breast. And metastatic breast cancer occurs when cells spread from the breast through the bloodstream to somewhere else in the body. And so that's this is a situation which we can detect cancer outside of the breast or the under arm in a different part of the body And gently on the skin or through a biopsy. And metastatic breast cancer develops in about 20% of patients who are treated for early breast cancer. So most patients who have made aesthetic breast cancer were diagnosed With early breast cancer initially. But actually about 5% of patients who have met with breast cancer are diagnosed with metastatic breast cancer at the time of their initial diagnosis. when cancer spreads from the breast elsewhere in the body. Again, it spreads through the bloodstream. And although there are areas that we can see on a scan will know that there's cancer which is residing in the blood and can circulate in the blood. And in this setting, when cancer has spread through the blood, treatment is generally not considered curative. So patients are on treatment to control the growth and spread of cancer into prolong life. But generally, although with maybe some exceptions, which dr wax will talk a little bit more about. With some exceptions were not able to get rid of it indefinitely. That said, new medications have dramatically improved outcomes for actually all types for patients with all types of breast cancer. And we've seen significant headway made over the past few years. One question that comes up especially at the initial diagnosis, is whether a biopsy is really needed and you can see here in this figure, um kind of a picture of a patient who would be undergoing a biopsy of the liver, of the liver, for instance. So in this setting, a needle is introduced into a tumor in the liver guided by usually an ultrasound or in real time with a ct scan in a small core of tissue is removed. Often, you know, 1 to 4 cores will be removed at that time, And the answer is yes. A biopsy is really important in establishing the diagnosis of metastatic breast cancer. It is so important that we know we're treating the patient in the right setting with the right treatments. And so really we consider this to be absolutely standard at the time of the initial diagnosis of metastatic breast cancer, we generally try to target an area outside of the breast because you have to biopsy an area outside to confirm that it has spread outside of the breast. And the question is, are biopsies safe and they're quite safe and complications can happen, infections are actually quite uncommon, leading overall is uncommon as well. Occasionally we'll get a biopsy of an area within the lung. There is a risk of something called a pneumothorax or air spreading around the lung tissue and collapsing the lung. But thankfully that's uncommon as well. Sometimes you might be approached to do a biopsy as part of a research study or to do additional to take additional chords when you're having a biopsy performed otherwise, we think that these are safe as well. And these research biopsies can be really important in furthering our understanding of breast cancer and her two positive breast cancer hopefully yield better outcomes in the future. Um it's not without some risk, but generally these are are safe things to do. One question that's come up more recently is um more frequently recently is when should a biopsy be repeated? And generally you repeat a biopsy if we think that it is going to change our care if we should direct our treatment in a different manner. So in some types of cancer or breast cancer we might look for a specific mutation in the tumor and that can guide treatment with a specific drug. Sometimes if the cancer isn't really behaving as we would expect, that might be another chance to get another biopsy as well to confirm. For instance, is the cancer really her two positive or is it estrogen receptor positive as well? And medication treatments are really the mainstay of treatment for patients who have metastatic breast cancer. And again, this is because medication treatments address cancer cells throughout the body. They're given usually by ivy sometimes by injection and or subcutaneous injection and sometimes by mouth, but they're all absorbed into the bloodstream and treat cells wherever they might be in the body. And the good news is that we have a long list of available treatment options, particularly for patients who have metastatic purchase positive breast cancer. That list. It's not infinite though. And because of that, we want to get the most out of each treatment that we have. And and so we continue a given treatment as long as it's working and we try to be pretty methodical about how we assess that because we don't want to take a patient off of a drug too early when they could still continue to get benefit from it. So we really rely upon how the patient is feeling, how you're feeling. And then also on scans as well. So you'll see that there's this cycle in which you'll have a scan. You'll then do you know three or four cycles of treatment lasting 3-4 months generally. And then we'll repeat the scan to confirm hopefully that the cancer is well controlled that there's no new areas or no areas which are clearly getting larger. This cycle can be difficult though and I think this is the you know the process of getting scans can be really challenging and really anxiety provoking. I think we all recognize this. And so um one question is how can we make this easier for my patients? I suggest that they try to avoid scans on Fridays. I have a clinic on Mondays. So sometimes the schedules will arrange for them to have a scans on friday. And I personally don't love that for my patients. It's really hard to sit through the weekend wondering what your scans show and what we're gonna do about it. And so although I know this isn't maybe something that we try to encourage for everybody and in the clinic but for my patients I am okay with them having a scan on monday morning and seeing me in the afternoon, sometimes it's not always feasible. But that can be a nice trick to make this process a little bit easier Nowadays all of your information is available online, all of your reports and I think that's good. It's empowering the information is yours and but that can make things a little bit tricky as well. The reports aren't really written in a patient friendly manner and it can be difficult to interpret and and and you won't necessarily have immediate access to your provider to really help interpret it. And so you might consider whether it's really the right thing for you to read about your scans online. Sometimes it might be sometimes it might not be certainly leaning on coping tools can be important. Things like yoga mindfulness exercise can be helpful. You know sometimes distraction, occasional glass of wine can be helpful as well. Um And then I think getting reassurance from your treatment team that if the skin does show some growth or spread that there are other effective options lying ahead as well. So hopefully the treatment is working in patients can be on given treatments for a long period of time. But when scans show growth are spread, we then switched to a new treatment and kind of start this cycle again. So then initiate a new treatment, do that for you know 3-4 months and get another scan every step of the way. We're considering options which are both standard options as well as clinical trials and that's something which is a real pleasure to one reason why it's a pleasure to work at Dana Farber because we have access to a lot of trials which we think can help improve upon care and led by people like dr wax which is great. Before we talk about how we think about sequencing treatment. I thought I'd just bring up the question of whether areas um whether metastases should be removed or irradiated and this is a common question that comes up as well. Sometimes the patient will have just one or a couple of areas of cancer that has spread to a different site of the body. And it would be really tempting to say can we just remove it or radiate it and hope to not hear from this again again. We've only considered metastatic breast cancer to be be a disease of the body. And so that really hasn't been our approach of Dana Farber. But there was a recent trial that tried to address this question and really gave us a lot of information. So there was this trial called N. R. G. B. R. 02 in which patients who had so called Oliver metastatic breast cancer meaning breast cancer with only a limited number of metastases in this case defined as four or fewer patients were randomized have got medication treatment half got medication treatment plus ablation to each of the sites of metastasis. And what we saw was that ablation actually didn't improve disease control and patients didn't live longer for having those sites of cancer removed or irradiated. And I thought something was really interesting was that the rate of progression outside of the areas that had been a bladed was actually no difference. So rating those areas didn't yield better disease control outside of the areas that were a bladed. And the conclusions that we all took away from this or that really medication treatment remains the standard of care that we're not generally doing ablation to try to get rid of the cancer and definitely or improve long term outcomes. That said, we often use radiation if there's an area which is causing pain because radiation can be very effective and quickly managing pain or preventing a fracture for instance. And I think in the end this really confirmed our longstanding practice at Dana Farber. We really have been leaning towards relying upon medication treatments and only very rarely using ablation and I think especially for patients who have her two positive breast cancer, the ideas that we really should be relying upon are highly effective. Anti her two medications. We have a number of very successful and very effective medications that target her too. We should use those instead rather than ablation or surgery. So how is treatment sequenced. And as I mentioned, we have a long list of treatments are first treatment is with the regimen called THP tea stands for taxed. I'll generally given at a low dose once a week, which is a standard chemotherapy along with two anti her two antibodies antibodies which target the her two protein on the tumor cell. These are called Herceptin again which targets Her two and Pirjeta which also targets her two. Those are given once every three weeks usually by ivy although sometimes by subcutaneous injection. And generally patients will continue this and um that said about after about 6-8 cycles will often drop the Taxol and continue the hp alone. And this is how it was studied in in the trial called Cleopatra. And generally after you know about 6-8 cycles, patients will often develop neuropathy numbness or tingling in the fingers or toes which is often tempered but can be permanent. And we want to avoid this from being long standing. And so will often drop the Taxol and then continue HP afterwards when patients are on H. P. That can be associated with fewer side effects and really better quality of life. And the good news is that patients can be on this treatment for months and years at times. So one question that comes up is how can we make treatment easier with this regimen? Actually scalp cooling can be very effective and the vast majority of patients who do scalp cooling and can actually keep most of their hair. Um patients will have some hair thinning but usually not hair loss or like larger areas um of uh you know bald patches for instance. And so this can be very successful and that's very nice. That can make treatment a lot easier. We all recognize that hair loss is one of the most difficult parts of treatment, scalp cooling can still be expensive. It's really not covered by insurance. Although that's a financial support is available. And that's going to talk with your provider about our second line treatment called chicken is new. And this has been one of the biggest advances that's happened over the past year or so. So trust who directs the can is an antibody drug conjugate which means that links chemotherapy to an antibody in this case Herceptin. It's given in a three week cycle and here's a little bit more information on antibody drug conjugate. So translucent, direct sicken or T. DM. One replaced trash em tensing. Sorry trust addressing TXT replaced T. DM one is our standard second line treatment. So both are antibody drug conjugate. It's and linking chemotherapy to Herceptin. But there are some key differences between these two different drugs. T. D. X. D. Has more copies of the chemotherapy. Her antibody molecule in this case. Eight whereas T. DM. One has you know 3.5 or four copies of the chemotherapy for every perception antibody T. X. D. Has what we call it. A tumor selective cleave a ble linker which means that the antibody releases the chemotherapy only once it binds to the her two positive cell whereas TDM one can release the chemotherapy often in the bloodstream. And with this tumor selective believable linker that can lead to a more potent response in the in the cancer cell. There's also evidence of the so called bystander effect whereby the the molecule combined to a given cancer cell can release the chemotherapy and then that chemotherapy can actually diffuse to surrounding cells and kill surrounding cells as well. And we think that is responsible for at least in part of why C. X. D. Has been so effective. So there was this trial called Destiny breast 03 which was presented about a year ago. And in this study patients who had metastatic her two positive grass cancer and had previously received first line THP were then randomized. Half received TTXT have received T. DM. One. The prior standard of care and outcomes were dramatically improved with T. D. X. D. The likelihood of progression was reduced by 74%. With TXT over T. DM. One higher proportion of patients had substantial substantial shrinkage of the tumor here defined by more than 30% shrinkage And actually it appears that survival is gonna be improved with txt over T. DM1. It wasn't quite statistically significant but it's really trending in that direction and we'll get more information on this with further follow up from the trial. So um TXT can have some important side effects nausea can be a little bit um longer lasting with TXT than with some other chemotherapy. So patients might have nausea lasting seven or 10 days after their infusion. So we've learned to up our nausea medications given proactively during the infusion. And we give patients more nausea medications to take it home. Sometimes doing drugs like OLANZapine Zyprexa which can be really effective particularly at nighttime. We did see that long information can be a really important side effect of T. D. X. D. And this can be serious and especially in the earlier trials with this drug patients can get really sick and some patients actually died of inflammation of the lungs. I think that's less common now. We've gotten better at recognizing the importance of this and stopping treatment sooner if we see inflammation of the lungs on scans or symptoms develop and generally this is reversible by stopping the drug or treating with steroids. But it really is important if you're experiencing cough or shortness of breath on TXT that you alert your team to this. Some patients can have hair loss with T. D. X. D. And we've seen that it's not clear whether scalp cooling works. And that's an open question. And actually this song that we're looking at here at Dana Farber and there's a trial led by Dr Ellen who's one of our nurse practitioners looking at scalp cooling for patients who have metastatic breast cancer receiving TD XD. Or other drugs like society or a ribbon. And patients are receiving TD XD in this setting um in a role in the trial actually provided with scalp cooling through the trial. Which is which is really nice. And we're hoping to learn more about how effective scalp cooling is in this setting. We also have new data on the use of T. D. X. D. For patients with active brain metastases. So there was this trial called tuxedo one in which patients who had her two positive metastatic breast cancer with new or growing brain metastases received T. D. X. D. Wasn't a large trial but there were about 15 patients. And in this study actually 11 out of 15 experienced substantial shrinkage of the tumor of the brain metastases which was really encouraging. And there's gonna be a larger trial um called Destiny breast 12 which is now enrolling dr nancy Lynn, the leader of the embraced program and the associate director of breast oncology here at Dana Farber is actually the co leader of this worldwide trial which is a really important study for patients with or without active brain metastases. And they all receive T. D. X. D. So this is a really nice trial open now at Dana Farber. And actually at many sites across the world given how effective TXT has been one question that has come up as well as should we move TtXT earlier. Should we use it in the in the first line setting. And there's another trial called Destiny breast 09 which is looking at these patients with newly diagnosed her two positive metastatic breast cancer are randomized to either what has been the standard THP shown in the bottom T. D. X. D. Alone or with the placebo rather versus TXT with Pertuzumab. And so this is a trial which is enrolling as well. And we're looking eerily to get information from this to to learn better how we should see treatment. And the third line setting were also frequently using a regimen and with a combination of three medications, Capeside been, which is an oral chemotherapy to Catnip which is an oral targeted anti her two medication and Herceptin. And that that anti her two antibody which we usually throughout treatment. Um One thing that's notable about this is that we've seen nice responses for patients with active brain metastases with this regimen as well and we'll see how that can impact sequencing in a moment. Um This is the the schema for how it's given a little bit confusing. Capeside is given twice a day by mouth for two weeks followed by a week off to Catnip is given twice a day throughout treatment and Herceptin given once every three weeks. So still a three week cycle of treatment. There can be some important side effects especially with Cape 17 patients can develop a rash on the hands and feet. That can actually often develop a few cycles in that can be really bothersome. And so it's really important as well. We'll see to use a lot of moisturizer on the hands and feet. Diarrhea can be important as well. So again how can we minimize this using moisturizer multiple times a day on the hands and feet can really help to prevent or manage that rash. The modem can be very effective for diarrhea with this regimen And then if a patient doesn't have a port actually Herceptin is now available as a subcutaneous injection. And that one benefit there is that it can substantially shorten time in the infusion area. And actually we think back to the first line th p there's a combination hp injection as well which can really shorten treatment time in the infusion area as I mentioned. Um This is a really effective regimen for patients who have active brain metastases. And so if a patient who's finished first line THP has brain metastases will often move this up to the second line setting. Even before T. V. X. T. In the fourth line were also were often using TDM one another highly effective anti her two antibody. Even if it's been pushed back to the fourth line. Very effective. And overall a well tolerated drug can have some important side effects including neuropathy and then in the fifth line and beyond we have a number of highly effective treatment options available. And we're always thinking about clinical trials every step of the way for patients with er positive. Her two positive breast cancer were often using different lines of hormone therapy with Herceptin. Herceptin plus Pirjeta different chemotherapy options including a rebellion Doxil novel being several others as well with Herceptin. Or a different drug called margin toxin or March which is a re engineered form of Herceptin which more tightly targets her binds to her too. Um And again you know I think as I sit here on the lower right we are concerned trials each step of the way. We have a number of trials open here at Dana Farber for patients with metastatic her two positive breast cancer. And now I'm gonna turn it over to dr wax who's going to talk a little bit more about this. Thank you dr Porvoo. Um Thank you everyone for being here today. It's been exciting over the last couple of minutes just to see your awesome already. So many awesome questions coming in on the chat. Um So I will try to keep this to like 7 to 10 minutes or so so that we have plenty of time um to get to your which are wonderful. So I'm gonna talk a little bit more. You know you just heard a wonderful summary from dr overview about the current status of management for her two positive metastatic breast cancer and I'm going to try to talk a little bit more um for just a couple of minutes about you know looking forward to the next 1 to 5 years. What are we excited about? And wanted to B. C. Coming down the pike. Um So first are the antibody drug conjugate. And you heard already from doctor about some really exciting important progress that's been made here when we saw just over within the last year that TXT or Trust director Can is significantly better than T. DM. One. The older antibody drug conjugate for patients with her two positive metastatic breast cancer. And of course now that we've seen you know how much much difference it can make when we engineer a better antibody drug conjugate. Now there's all sorts of ongoing efforts to try to do even better and expand further in this antibody drug conjugate space. So I'll go through this real quick because I know Phil um already sort of addressed it. But in terms of what is an antibody drug conjugate just to like depict this very concretely. So an antibody drug conjugate is an antibody treatment that's shown here as sort of the blue y. Picture. Um And that's an antibody that can attach to a target on the surface of the breast cancer cell. In this case we're only talking about her to being the target but there's certainly other targets that we develop in other types of breast cancer. So that's the first component, the second component. Um Doctor can you just like press the you can go forward so there you go. So the second component is this linker And that's that's where the conjugation comes in. Um So the linker is what attaches or conjugated this antibody um to the third component which is uh the drug um the chemo drug and that's the toxin here with the skull and crossbones. Um and that's sort of the active or the payload component of this treatment but it's targeted specifically to the um the cancer cell in this case with the her two on the cancer cell by the antibody. And so the nice thing about antibody drug conjugate is because you have all three of those components you have an antibody. You have the linker the conjugation mechanism and you have the drug. There are three ways three opportunities to change and engineer these drugs to try to make them um better. So if you want to go to the next slide please. Um So you know there are many her two targeted antibody drug conjugate in current clinical trials. The point here is not to read every entry on this page. Um it's too small to do that. But just to sort of make the point that because there are all those different ways to customize these antibodies there are now lots of different companies and efforts to find ways to improve even upon the current antibody drug conjugate one um molecule that we at Dana Farber have thought looks especially exciting as this drug A. R. X. 788. So we have a trial for that one open at Dana Farber. Um and you can see from this list that there's lots of similar trials being run all over the country and all over the world. Next slide please. Um One trial that we're particularly interested in and eager in seeing the results from Is that her to climb. Oh to trial. So this is just a call out to be on the lookout for these results. We as breast medical oncologists are certainly on the lookout for these results. We don't know when they will come in but I would say probably somewhere in the next 6 to 12 months. Um we hope this is a trial that already completed its accrual. All the patients have already enrolled on the trial and we're just waiting to see um what the results of the trial will be. So this trial enrolled patients with metastatic her two positive breast cancer. Um And then randomized them. Um Every patient got T. DM. One the sort of standard older um antibody drug conjugate drug. And then patients were randomized because half of them got the do catnip drug. The one that dr Porter who spoke about that's an oral drug and then half got plus and so basically the question that we're asking in this trial is can we improve the effectiveness of that older um T. DM. One drug by combining it with the two cabinet which is a really new um and promising drug. So we'll see what the results of this trial show again. Hopefully we'll get them certainly within the next year. If not sooner. Next slide. Another question that I get all the time from patients, which is very appropriate is what about immunotherapy? You know we hear so much about immunotherapy and other types of cancers and other types of breast cancer. You know immunotherapy um drugs or one drug is FDA approved for triple negative breast cancer. So what about her two positive breast cancer patients? Ask me that all. Um the time. And so and just to be just make sure we're on the same page when I say immunotherapy, what I mean um are drugs that work by activating your immune system to fight your cancer for you essentially. So cancer chemotherapies um act by killing cancer cells that are growing too quickly. They kill those cancer cells select immunotherapy has a completely different mechanism where it's drugs that can work in a variety of different ways to kill the cancer cells. Um for the for the patient. So that's how immunotherapy is is entirely different from chemotherapy. Um So on the next slide um So what is immuno therapies role in her two positive metastatic breast cancer? Well, I would make sort of three comments here. The bottom line being I think this is a very exciting, very important area but it is also a work in progress. Um So first uh so if you want to advance just to the first bullet point there, we know that immune system cells that are active around her two positive breast tumor can impact patient outcomes. So we know this to be true in her two positive breast cancer. In fact, we know it to be true in all subtypes of breast cancer. Um And so because patients outcomes do seem to be affected by how their immune system is interacting with their cancer, you know, that certainly implies that we should be able to figure out how to impact the immune system to treat the cancer better. So it's it's definitely a promising idea in cancer overall and in her two positive breast cancer. Um if you go on to the next bullet, that being said, you know, disappointingly in metastatic her two positive breast cancer so far, checkpoint inhibitor immunotherapy um hasn't shown as much activity as we had hoped it would and for example, hasn't shown as much activity as it has in triple negative breast cancer and triple negative breast cancer checkpoint inhibitors are now FDA approved and that is not the case in her two positive metastatic breast cancer. Because the result that we've seen so far haven't shown a widespread benefit for this type of immunotherapy. And when I say checkpoint inhibitor immunotherapy, what I mean are drugs that are targeted against the proteins either PD one or PD L one. Um So drugs like Pemberley is a map or keytruda. Um but that those have been sort of a disappointment so far um in her two positive metastatic breast cancer for most patients. Um So yeah, the next the next bullet point now however, I definitely want to underscore that. I absolutely think immunotherapy has an important role to play here and her two positive metastatic breast cancer and actually all breast cancer subtypes. But we're still figuring out which drugs we should use at what times and we may need to be exploring, you know, different mechanisms of immunotherapy drugs may need to be combining them with different medicines than we've done so far. So I think it's a promising area but it's it is a work in progress. Next slide. Um One trial that I think sort of illustrates this well is the panacea trial and this was a trial that was done for patients with her two positive metastatic breast cancer. Who got this regiment of Pemberley is a map which is an immunotherapy drug that you probably see it advertised on Tv that's a widely used immunotherapy drug. It's FDA approved for triple negative breast cancers. Um So the that drug was combined with Trustees mob or Herceptin. And these were all in this was all done in patients whose cancer has already been treated with Herceptin or trust in the past. So you know, we really needed the Pemberley is um ab immunotherapy drug to be like the workhorse of this. Um regimen and what you can see on the left here. This is called a waterfall plot. And it just shows how patients tumors grew or shrink in response to this regimen. Um is that you know, there was a spectrum of responses. Many of the patients had their cancer tumors grow. Some of them did see good shrinkage. Um So this wasn't, you know, certainly wasn't a home run but there was some activity seen. Um And another important point is that this plot here that I'm showing was only for patients with her two positive metastatic breast cancer that was PD L. One positive. Um And that even that is just about a third of her two positive metastatic breast cancer patients. So even in that subset of patients there were um some responses seen but not many. So you know, on the one hand, it's promising and exciting that we saw some patients benefit. But at the same time it it was disappointing that many did not and I think we need to figure out how can we find a few patients who will benefit because they're definitely out there and then for the rest, you know, how can we be using different drugs and be smarter about how we harness the power of immunotherapy. So like I said, it's a work in progress, I think an exciting one. Um and want to keep an eye on next slide. Um another trial to watch that's gonna help us sort of understand the role of immunotherapy and her two positive metastatic breast cancer is the K. Three trial. This trial is far behind the other one I just showed you. So that trial has already completed. Its a cruel and we're just waiting for the results. The Cape Three trial um is still enrolling. So this is probably a couple years away from us seeing the results of this trial. But this is patients with her two positive metastatic breast cancer who are PD L. One positive. So again that's maybe a third or 40% of her two positive metastatic breast cancer patients. Um and then randomizing them to get TDM one with or without a test Eliza map, which is another immunotherapy drugs that start targeting the Pd L. One protein. Um and so this will be I think an interesting trial again will help us move the needle in terms of understanding how um and when we can incorporate immunotherapy drugs for our patients. Um so Kate three is one to keep an eye on as well. But a few years from knowing the results from this. Unfortunately. Next slide. So I think that might be, oh the last so this is my final slide. The last thing that I wanted to mention um is you know this is a different type, totally different type of inquiry and in many ways a good problem to have. Um So you know, we know that for some of our patients with her two positive metastatic breast cancer. They will actually have such good results from their treatments. Um that that we will see all of the cancer go away or have you know, really durable prolonged control of the cancer for many years. Again that's of course a wonderful problem to have. Uh And then you know what ends up happening is that the patient and their doctor um look at each other every appointment and and wonder you know, is it safe to stop these treatments that I've been on for three years or five years or eight years or whatever or do I need to continue them in order to maintain control of my cancer. Um And frustrating that we don't have an answer to that question for those patients. And so I just wanted to also let you know about a trial that will be led by our colleague heather Parsons at Dana Farber called the stop her to trial. Which is gonna hopefully help us answer this question about when patients have had really prolonged control of their cancer. Could they possibly stop their anti her two therapy? Um And so this trial will enroll patients with her two positive metastatic breast cancer who have had at least three years of stability on their first treatment regimen. Um And then patients the option, this is not a randomized trial. This is patients choosing what they want to do. Patients have the option to choose to either continue their anti her two treatment at that three plus year time time point or stop their anti her two treatment. And then we'll try to understand what happens to them from there. So um I think this will be another important answer that will start to get for the question of how do we approach patients who actually have had really good responses to their um anti her two drugs for metastatic breast cancer? So that without that truly is my last slide. I think I have a final, thank you slide on there. Um But we can absolutely turn it over to your excellent questions and I'll turn it over to Christine. Thank you both for giving such a great overview on research and treatment that's been going on for this subgroup of breast cancer. Um Yes we have a lot of great questions. Uh So we'll start with this is a two part question for triple positive patients. Can drugs for estrogen suppression be used with the A. D. C. S. Uh Antibody drug conjugate is focusing on her two positivity. And are there any clinical trials that focused on this specific group? So I can I can take that first question. The and it's it's an excellent question. It's a question that we get all the time actually from oncologists as well. Um So it's a really good question. Um Right now so the two FDA approved antibody drug conjugate that we have right now are trust use map directs to can which is called on her to and T. DM. One which is called Godzilla. And so in the big sort of um landmark trial that dr pou showed um the destiny breast oh three trial that compared those two. So that's sort of the best most modern data we have about those two agents um using anti estrogen medications was not allowed in any patients on that trial. Um either who was getting the and her two or the cat silent drug. So because those are the most again sort of best most modern data we have about those agents. Um I and and it wasn't allowed to use the anti estrogen medicines on the trial at the same time. Um I would say the current standard is not to combine the antibody drug conjugate um with an anti estrogen medication. Now there's certainly exceptions to every rule. Um but but by and large I would say you know, that's the current standard. And then are their trials going on um to look specifically at these triple positive or estrogen driven as well as for two driven um tumors. The answer is absolutely. Um Yes, there have been trials done and there are other trials are going to look specifically at that subset um You know, it is potentially a unique um upset that might warrant different treatment approaches. I would say the regimen that comes to mind is the one that's been sort of best studied so far that we use um sometimes in those patients is a regimen that combines the anti her two treatment, full restaurant. Um Sorry the anti estrogen treatment. Full restaurant with the anti her two drug Herceptin or trust the map and then the C. D K 46 inhibitor Obama cycling or verse Ennio. And so that's sort of a triplet regimen that borrows from how we treat her two positive breast cancer with the trust us a map and how we treat estrogen driven breast cancer with the full restaurant and the Obama cycling medicine and sort of combines them and has been shown in a trial to be a good active regimen for triple positive patients. So yes, some of that research has been done and is on and is ongoing. But no at this point I would say we would typically um we don't have ways that we know work well to combine it with the antibody drug conjugate. It's okay, thank you so much. Uh We'll move on to the next one. Is there a different approach when considering ablation and removal when the first and only metastasis is in the brain, maybe I'll take this. That's an excellent question. And this is a bit of a different scenario. And and you know, one concern is that when there's a metastases in the brain, if it could be causing symptoms. And so oftentimes we will do surgery to remove a brain metastases or do radiation to those areas. And and whether we do um surgery or radiation depends on the size of the areas of metastases and the number of them. Um Sometimes a patient will present with, you know, one area or maybe two areas and they might be causing symptoms for instance. And that's a situation which will, you know, often ask the neurosurgeon whether it might be feasible to do surgery to remove that after after that is removed. Generally, patients will receive radiation to the area around where the tumor was. And if there's multiple areas, sometimes we'll do what we call stereotyped radiosurgery or highly directed beams of radiation to the individual sites. And so if it's the first time of disease recurrence in the brain, probably most often patients will get surgery or radiation that really wasn't a question that was addressed to that energy trial. So that's that's a really good point. And and um it gets a little bit more complicated from there. If those areas are the only sites of recurrence, oftentimes will just continue, you know, how receptive the patient was on Herceptin or if they weren't on Herceptin who might continue to observe. So that gets a little bit more complicated. And one thing which I will point out, which is a great resource, you know, here is that Dr Lynn is really a worldwide expert in the treatment of brain metastases and we have a multidisciplinary team with surgeons, radiation oncologists, Medical oncologists who meet together to really talk about these cases on a very routine basis because it really does require everyone's input together. Thank you Phil thanks so much. And on the same line of brain mets there's a question how common is brain mets in her two positivity and um why isn't the brain scan typically in the absence of symptoms? Yeah, I mean those are questions one really you know, begs the question too. So I think those are great questions and the answer is you know, her two positive metastatic breast cancer is a subtype of metastatic breast cancer that we know is more likely to develop brain metastases. And over the course of their whole experience with her two positive metastatic breast cancer actually up to half of patients with her two metal her two positive metastatic breast cancer will will experience brain metastases. So it is a you know a reasonably high proportion. Um so then you know, the follow up question is, well why don't we do standard um M. R. I. Scans of the brain is a really good one. And and you're absolutely what the question asked her um implied it is absolutely the current standard is not to do like a screening just a surveillance brain M. R. I. In a patient with her two positive breast cancer or any type of metastatic breast cancer unless there are any symptoms. So we don't just screen for this. Um although we have a very low threshold to do some sort of brain imaging if there is a symptom like headaches or any sort of weird funny you know feelings or weakness or anything like that. Um And you know the reason for that is that we don't have research telling us that doing those screening MRI's um is helpful. Um We know that if we if we do that we know that patients live with her two positive metastatic breast cancer for a very long time in general. Which is good news. We know that if we were to do those brain M. R. S. You know sort of forever from the time of metastatic diagnosis for all her two positive breast cancer patients, we would be exposing a lot of patients to a lot of MRI's that wouldn't actually benefit them. Um And so you know we're actually trying to do research right now um to understand um if and how we help patients by doing um some surveillance or screening MRI's in patients who are asymptomatic with her two positive metastatic breast cancer. Um But that's sort of in a research phase because again we know for sure that we would be doing way extra unnecessary scans if we sort of rolled that out in a really broad way to everybody. Um So you know I think it's a super valid question and it's an area where we need to and are doing more research right now as we speak. But at present the standard is to have a very low threshold to do an M. R. I. In anybody with any any sort of you know even mildly concerning head symptoms but not to do it. Um As a matter of routine in the absence of any symptoms at all. Yeah. Yeah. I might just say there is a trial open run by Dr Azar here at Dana Farber Brigham looking at this. So it is enrolling patients who are asymptomatic and doing at least one or multiple screening MRI's. I think one concern as well is that if you have a you know if you're asymptomatic and you and you find brain metastases, the question is do you benefit from doing treatment at that time or would you be better served by just monitoring and sometimes you know I have seen patients who had a large number of areas and then the question is do you do radiation to the whole brain and that can cause more side effects. And so the question is, you know what you do to act upon it in the setting of no symptoms. And that's a challenging situation as well. Thanks God, we'll move on to a question about, have there been any advances for her two positive patients in regards to pick three C. A mutations that do you want me to? Yeah, I think that that's a great question. Um we know that the presence of pIK three C A mutations um can be can be a marker of resistance to some treatments and her two positive breast cancer. Um That is also true in estrogen receptor positive breast cancer. So an estrogen receptor positive breast cancer um we actually have an FDA approved treatment um for patients who have picked three C. A mutations because we know that it's sort of a resistance pathway that if we overcome it it can make a positive difference for those patients outcomes in her two positive metastatic breast cancer and her two positive breast cancer in general. Um We're a little bit behind that I would say you know, we know um that pIC three C A mutations can be a resistance mechanism to these treatments in some cases but it hasn't been clear um that uh targeting the PIK three C A mutation with a treatment is something that can that can change outcomes or improve outcomes for patients specifically with her two positive metastatic breast cancer. So it is an important sort of resistance pathway and breast cancer in general. Um and you know, want to do continued research on for sure. The other thing I'll say is that you know, unfortunately so far drugs that target pick three C. A. The pathway that it's part of um can be effective like as an not in her two positive necessarily but like an estrogen driven breast cancer but can come with an enormous number of side effects. So we're really trying to do a better job developing even more targeted treatments that that address that pathway and that resistance mechanism. Because the ones that we have at present have shown themselves to be sometimes effective but very very heavy side effect burden. So we obviously need to do better than that. Thank you. Um This is a question that and her two for patients on in her to do you have any comments thoughts on patients losing her two positivity and the effect on this for their future treatment options as they go through. Yeah that's a really good question. And it's not so clear that that patients lose her to um as a result of treatment with T. D. X. D. Um It can happen um Especially in earlier breast cancer when we see when we treat early breast cancer and then patients have surgery. That what is left is her two negative but a little bit less common for patients who have advanced her two positive breast cancer. So um and I think that the results were really so encouraging from that trial Destiny breast 03. Even the suggestion that patients were living longer um That I think you know clearly has become the standard and you know inexperienced patients continue to receive benefit from anti her two therapies afterwards. I think it is. Um Yeah I totally agree. It's a it's a very astute question. Um And it's it's basically you know uncharted territory um in in her two positive metastatic breast cancer. Now that's in some ways great you know it's uncharted territory because we've got this new really effective drug that we you know, we just have learned about how well it works really again within the past year. So that's great news on the flip side that we are kind of in uncharted territory about. Well now that we're going to really roll that drug out in a big way for everybody pretty early on in the treatment courses there are two positive metastatic breast cancer. What what's gonna happen after that and what are the mechanisms of resistance to that drug? Um And the answer really for the most part is at this point we really don't know, there's a lot of research going on to try to understand mechanisms of resistance. It absolutely does seem um just like Dr Porter said and just like the question asked her is asking, it does seem that for some patients that their mechanism of resistance might be that they lose the cancer's dependency on that herd to protein. And they turn into you know like I heard to zero um type of cancer after the fact but we don't know how commonly that happens. Um We don't know what happens after that point if we treat you with other anti her two treatments. Um And you know, we don't know there's no question that's not the only mechanism of resistance that's going to exist to the drug and we don't know um you know what are gonna be all the other mechanisms of resistance. So um it's a really good really interesting question. And one that we're really I mean racing to try to work on thanks along the lines of T. D. X. D. A. Question about we know that T. DM. One well known side effect is purple neuropathy. How does T. D. X. D. Compare in this regard? And are there any advances in how to treat advancing neuropathy? Yeah. We've seen much less neuropathy with with TXT um The chemotherapy component is different and the entrancing component um we know to really be a risk factor for developing neuropathy damaging long nerves in the body. Um I really haven't seen that with with TXT nearly to the same extent. So um You know for patients who do develop neuropathy if it's on T. DM1 or Taxol or other drugs and there's different approaches to manage that. Sometimes it's through dose reduction and that's a common approach that we take and in the setting of first line th people often regionally drop Taxol after a certain period of time. Um Depending upon the type of neuropathy is and if it's numbness or more painful tingling or medications which can treat the discomfort associated with neuropathy. Common ones being Gabba Penton or Lyrica for instance. Um or Cymbalta but I think oftentimes you know trying to you know, manage and prevent it rather than just treating it is important as well. Absolutely. Thank you. This is an interesting question. Um if someone's on a clinical trial do they track the estrogen positivity meaning if somebody is 95% versus 8%. And how does that maybe matter in the overall picture? You know somebody can somebody be affected by this may be something you probably don't know now. But it's interesting idea if estrogen positivity is trapped within a clinical trial. Um Yeah I think that you know it's an interesting question and I would say it's interesting if you're in a clinical trial and even if you're not in a clinical trial you know how we um track and think about the level of estrogen receptor positivity or for that matter the level of her two positivity which the previous question asked her was was um wondering about and so um you know the only good way we have at this point to track those levels. The er and the her two on the pr um is by doing repeat biopsies. You know it's not something unfortunately at this point that we can track in a in a blood test or anything like that. Um And so you know we generally don't um put patients through biopsies with enormous regularity because obviously that comes with some discomfort on some risks. Um And so um you know I I absolutely think that what we do see is that over time yes tumors can change in terms of their estrogen receptor positivity that's true of her two positive and non her two pas cancers. But we do see that change. There's probably also potentially some heterogeneity between, you know, if I were to biopsy the liver on one day and then biopsy the breast on that same day or a bone on that same day. You know, I might see heterogeneity even between sites at the same time point. Um, and yes, I think that we I think that that sort of heterogeneity exists between tumor sites and I think it also is dynamic over time. But because the best way to assess that is biopsies and we don't, you know, routinely we're not going to do a biopsy once a month for six months or a year or anything like that. Um I think our data is a little bit limited. But yes, we see changes both between tumor sites. Um, and uh, and over time. Thank you. This is a scan question. Are there times when someone's restaging scans might show mixed results and what would sort of make you decide to keep someone on the current treatment even though there might have been some small growth in a liver or a long nodule? Yeah, I think it's an excellent question. And this is one that that can come up and I think my approach is going to work with the radiologist to really try to better understand what's going on. There are times in which you can take a little bit of time from an initial scan showing growth to starting treatment. And so if that if that's been the case you know I might wonder whether there was some growth initially even before starting treatment that could account for that mixed response in that setting might give more of the benefit of the doubt. But if if it seems like there are areas that are clearly growing or spreading even if other areas are shrinking then I think we have to assume that it's not well enough controlled and we move on to a new treatment. So it's very subtle. We really try to give the benefit of the doubt and carry on and maybe do another scan a little bit sooner. It really looks like it's clearly growing then you probably need to move on to something different. Thank you. Is there a trial Latina al Costello and her two positive therapy. Um And in that respect. What about carp inhibitors combined with her two positive treatment plan? Yeah. Both good questions. So I'll pull a sip which is the drug that targets um pick three C. A. So the one that we were talking about in the most recent question. Not actually no I don't know. Do you know dr corbeau if there's a trial going on with that currently in her two positive breast cancer. But um in the past I believe there was a trial combining there was a small trial at least to show safety of combining um with Herceptin. Um You were traveling with tassel listed I think this is maybe about five years or so ago and I'm not sure I know where that went. They haven't I I know that there are some data for safety from like a small phase one trial but that those are really only safety data. They are not any any sort of useful efficacy data. And I don't believe there's been any you know, promising efficacy day that's come out for all policy of or like you're saying dr other sort of similar drugs in that class. Um And I don't believe there's any certainly not any like big phase three trials in the United States going on with those agents. Um Right now in terms of part inhibitors. So yeah it's a good that's a great question. You know, part inhibitors are medications that are FDA approved in metastatic breast cancer but specifically metastatic breast cancer, that's her two negative. Um for patients who carry a mutation in BRCA one or BRCA two. So in a patient who carries a BRCA one or BRCA two mutation um we don't uh we um and it doesn't have a her two pas breast cancer we know that we can use and those patients can benefit from part inhibitor sort of targeted treatment to the broccoli one of the two mutation. Um And we really just don't have those data in her two positive breast cancer. Um Part of that is because patients with her two positive breast cancer are significantly less likely. Although it's certainly possible with their are significantly less likely to have a mutation in the BRCA one or two um gene. And so um I would assume that there have been are some small trials, you know, plans to look at the part inhibitors in her two positive um patients. But to date they have been actually excluded from all of the trials looking at part inhibitors. Yeah, I think there might have been once the affiliate trial which might have looked at this and and demonstrated some responses. So I think you know, if if there is an inherited BRCA one or BRCA two mutation, even if the tumor is her two positive, it might be considered at some point. All the data again are quite limited, but generally we might use these other treatment options which which we talked about earlier, that would be a less common circumstance. Thank you both. There's been some really great discussions. Um It's 12 30. So I think we have to wrap up. Um And I think we've actually gone through most of our questions so that was great. Thank you both again,
