Philip Poorvu, MD; Adrienne Waks, MD; and Christine Agius, NP, discuss advances in research and treatment for patients with HER2-positive metastatic breast cancer.
Good morning everybody. Um My name is lindsey Shaw. I'm a nurse practitioner here in the breast oncology center at Dana Farber. And I am joined this morning by doctors Philip talents and nick Wagner to discuss um current research and treatments for estrogen receptor positive metastatic breast cancer. DR Linz is a medical oncologist here at Dana Farber and she's also the director of the inflammatory breast cancer program. Her research focuses on developing targeted therapies for more aggressive forms of breast cancer. And she works with the lab scientists to bring those insights to the clinic in the form of clinical trials. Dr Wobbly is also a medical oncologist here in the breast oncology center and a associate professor of medicine at Harvard Medical School and his research focuses on cancer genomics, precision medicine and therapeutic resistance for breast cancer. Um So this morning, as I mentioned, we're going to be talking about research and treatments for er positive metastatic breast cancer. They're each going to speak for a total of about 30 to 40 minutes and then we're going to devote the rest of the hour to Q and A. So please submit any questions you have in the Q. And A button below and we'll get to as many of them as we can. So welcome Dr Linz. Thank you very much Lindsay. Thank you for the invitation and I'm delighted to be here with you with all of you. Um I wish it was in person but we we will get there at some point and it's so great to be able to connect and to talk about some of these important topics and before I talk about some of the novel therapies that are now available for patients with er positive her two negative breast cancer. We thought that it be important just to look at how we have been treating er e er positive her two negative breast cancer. As some of these characteristics of the treatments are not changing. So um most often the initial treatment of patients that have er positive her two negative advanced breast cancer starts with hormones. And there are different terms that we can use to talk about. These cardinal therapy, endocrine therapy or anti high estrogen therapy. I often like to call it endocrine therapy because hormonal therapy can be confused with hormonal replacement therapy which is actually the opposite of what we are trying to do here that in the treatment of hormone receptor positive breast cancer, what we really want is to block estrogens and the therapies that are available to block estrogens are different. Although the goal the ultimate goal of these drugs are all the same. But the different categories we have our our mateys innovators and these include lectures all and astro dollar XMS thing for restaurant or tamoxifen. And most recently these endocrine therapies are often most of the times combined with targeted therapies that what they want to do. These targeted therapies is to block other pathways that are important in cancer cells. And therefore try to potentially eight the response to endocrine therapies. So uh this is a list of the endocrine therapies that we have available and how they work. I'll go through them very briefly. So our mateys innovators decrease the conversion of androgens to estrogens. What is really important is that these drugs do not work if given alone in premenopausal women because premenopausal women still have their ovaries that are producing estrogen. So if a normative inhibitory is offered to a premenopausal women we have to make sure that that woman is getting injections as well to shut down their ovarian function. Full restaurant is what we call the cirm. It degrades the estrogen. Sir, I'm sorry, degrades the estrogen receptor on the surface of the cells. It's given as an injection every four weeks because it's an injection and patients often say that it's painful. The intravascular administration. We have been working hard in developing oral versions of this type of treatment and I'll show tell you one of these studies later during my talk and then tamoxifen. It's a SERM. So selective estrogen receptor modulator that attach is to estrogen receptors and blocks the estrogen from binding to the cancer cells. So on this next slide this is the cartoon that just shows you how this works. So on the left the aromatase inhibitor because it blocks an important step in the conversion of testosterone to um estrogen. What happens is that you don't have estrogen to connect or you have less estrogen to bind to the estrogen receptor in the middle. You see tamoxifen an example of what I mentioned a cern. So what it does is that it competes with estrogen to activate the receptor. So if tamoxifen is there you have less space for estrogen to activate this receptor on the top of the cancer cell and then on your rights and and that it's here in red you have professions and elastic strand. That is one of these novel oral surgery. That what they do is that not only the attached to the estrogen receptor instead of the estrogen but they also at the same time lead to the degradation of these estrogen receptors. So uh potentially a little bit stronger than the tamoxifen. So I mentioned to you as well these targeted therapies and the first one, the first one that we have to talk about is C. D. K. For six innovators. So cd case are important proteins that that are involved in cell division. Um And they work together with with our endocrine therapies to try to prevent or delay development of resistance to endocrine therapies. We currently have three C. D. K. For six innovators approved for the treatment of advanced endocrine uh er positive breast cancer. And I listed here the names for you both the the and included the commercial name as well. All have very similar results. Uh These are usually they have changed the way that we treat breast cancer and they are usually given as first line together with endocrine therapies we still don't know at time of progression if continuing syndicate for six innovators beyond progression can be something that can help patients. And there was a small trial that was presented earlier this year that suggested that yes that that might be a good strategy but we continue to further investigate these and we will probably hear more about it later this year at san Antonio. So in this busy table, I just wanted to highlight what are the different side effects that one might expect with these agents. Um And you can see here that although the side effects are are similar across the three agents, neutropenia trump aside opinion. So this means low blood counts, both in terms of your neutral fuel counts and your plate fatigue, diarrhea, nausea. However, Balbo cyclamen right basically are are known to have more neutropenia and not only all grades, but also grade three and four. While Obama's eclipse is more known to cause more diarrhea, requiring at least at the beginning. The use of the modem or other medications to try to control the diarrhea. So in the next slides, I'll go over other targeted therapies that sometimes we use for the treatment of our patients. The first is every lima's. This is an enter innovator that has been FDA approved to be given with the awesomest thing um for the treatment of patients with advanced breast cancer. Um Usually or sometimes it's it's given after progression on city K. For six innovators for these medication we need to have in mind because itis is inflammation of the mouth. Um You we have to watch out for non minorities as well. So inflammation of your lungs, hyperglycemia. These so high blood sugar. These are all among some of the expected side defense. Our policy was more recently approved in 2019 to be given in combination with four veterans now. Um uh something that is unique about our policy compared to syndicate for six innovators or even uh every LIMAs is that in order for a patient to be eligible for these medication there has to be an alteration in the tumor of a patient that can be detected either in the humor itself or in the bloodstream. That shows that uh this tumor has a particular alteration at PIK three C. A mutation. That is that predicts a benefit from this drug similar to ever alignment. It can also cause high blood sugars. And whenever if a humor has this alteration. We commonly use our policy with full restaurant as the second line of treatments. So eventually all tumors that are uh er positive become resistant to endocrine based treatments. Although we try to delay that as much as possible. And that's why you see all these options in terms of combining different targeted therapies with different endocrine therapies. But once the tumor stops responding to endocrine therapy, then chemotherapy becomes our next lines of treatments. And the chemotherapies are similar to what is used in triple negative breast cancer. And I listed here the agents that are most commonly used now this year has been an important year for breast cancer in general but but very importantly for er positive breast cancer as well. Given that we saw two antibody drug conjugate trance to some of the rocks taken and sexy to Zuma being tested. And in this setting and we saw the results that already led to the approval of trans to some of the rocks taken in er positive her two low breast cancer. And we saw results of substitution model as well. And uh we might be seeing another FDA approval later this year. So for that reason, I'll take now a few slides to talk about antibody congregates many of you might be familiarized with these novel class of drugs, although not that novel as you see here, one of the examples that or T DM one that has been available for the treatment of our patients with her two positive breast cancer for many years now. But just taking a step back and looking at what is this class of drugs this antibody drug congregates. They are targeted cancer therapies that deliver site a toxic drugs. And you can look at here in the cartoon the site a toxic drug that it's called. The payload is here represented in blue and these delivers. This is the way of delivering chemotherapy strong chemo therapist to cancer cells via a linker that is attached to an antibody that is here this big piece of the cartoon represented in green that binds to a specific target expressed on cancer cells. So this is the structure of an antibody drug conjugate. And as you can see for each of our agents we will have a different antibody and a different site of toxic truck. Next slide. Okay, so here is the first that I wanted to talk to you about it now that we we review the concept of an antibody drug conjugate. So trans to some of the Rocks stick and the antibodies trans twosome app and the chemotherapy is the rocks taken. And in addition to work to the cells that strongly expressed her to it has what we call a bystander effects, meaning that some of the drug is released in the adjacent cells being able to also kill some cells that are either her two negative or have very low her two on the top of the cells. And and when we talk about trans to some of the rock stick and we need to bring an important concept that it's her two testing and many of you might think why is she talking about trans to some of the rock stick and that it's we know about that in her two positive when the topic of this talk is er positive, her two negative and that's why this is important her two testing in the past we only cared about if a tumor was her two positive or her two negative. But more more recently we learned that there is this what seems to be a new cat Category. That it's hard to low that it's the cells the cancer cells have some expression of her two. So it's not for 20 but not enough to be called her two positive. And why does this matter? It matters because we've learned this year that trans to some of the rocks to con is also effective on this patient. So more tumors now have evidence that benefit from trans to some of the rock stick on. That's why this matters. So this was the trial that leads to the approval of trans to some of the rocks taken for patients with common receptor positive, her two low breast cancer. And I you know I will not bring a lot of these curves during this talk. But the reason why I wanted to show you is this was a plenary session at Pascoe this year. As you can see I'll guide you hear what it shows was that the addition the use of trance to some of the rock stick and compared to the the chemotherapy that the physicians thought it was the best option for the particular patient led to an improve a well of seven months in terms of progression free survival meaning that I'm sorry not seven months five months in median progression free survival. So the number of months that the patient is on the same treatment without evidence of progression. But I think that the most important is what you can see here at the bottom that patients on trans to some of the rocks taken on average lived six months more than when a physician chose the best chemotherapy for them. And these these results were so impressive. We commonly don't see benefits in survival in the metastatic setting. Just because a patient can go from a line to another line of therapy that when these results were were presented at Pasco they were received with a standing ovation by physicians, researchers, patient advocates, everybody that was present in the audience. Next slides okay so next ends just to finish toxic on is now FDA approved for patients with Corman sector positive for too low metastatic breast cancer. So sexy, sexy. Is an ad antibody drug conjugate. You recognize that here the scheme of an antibody drug conjugate. So what it changes is what is the antibody The antibody now is against trump two and the chemotherapy or the payloads The payload is F. N. 38 that it's a potent chemotherapy similar to your emoticon that some of you might know. Next slide So substitution map has been approved for the treatment of triple negative breast cancer since 2020 we saw presented earlier this year. The results of the tropics. Oh to trial that compared the use of sacks. It is a map with standard chemotherapy. So similar design to the other study that I showed you. But here uh what they what they were able to to show as well was that it leads to an improvement in progression free survival but most importantly lead to an improvement in about three months in terms of overall survival. This was recently presented. So it's currently being reviewed by the FDA. So not FDA approved yet but already included in our guidelines. And we are already offering these to our appropriate patients. So just one slides or two slides to talk about spark innovators. They are as well, a type of targeted therapy but with the only documented benefit to patients that have a bracket one or bracket imitations. And the reason why is because the park innovators take advantage of a defect that exists in the bracken and bracket to associated tumors to kill cancer cells in a more effective way. So currently there are two part innovators that are approved for the treatment of metastatic er positive breast cancer in patients only that have a Bracha one or bracket to mutation. You can see here the results of the two trials that led to the approval of these agents for patients with Braca one or two associated breast cancers and the purpose of this slide is to show you on the right. A trial debt was led by investigators at Dana Farber and Israel show that perhaps patients with Germline, how the two imitations benefit in a similar way from these agents. And that trial is continuing to enroll. So stay tuned more to come in the next months. So this is just a slide to show you that there are no novel hormonal therapies that are being developed to even potentially eight more. The benefits of what we see when these tumors are exposed to endocrine therapies. And the names are quite complicated using different letters. But I'll show you here an example a little bit later of oral surgeons and an agent that has some activity as a as a serum. But this is just to show you that there's reason to be hopeful and there are many of these agents that are currently under development. Okay, so I promise. This is a slide showing the results of Emerald Phase three trial design. So well, last restaurants is an oral, it's like an oral for restaurants. And on this trial patients that participated on this study either received L assessed Ron's or investigator's choice. And you can see here a list of many different endocrine therapies. Next slides, just showing what were the patients that were eligible that they had to have received acidic it for six innovator. And uh in this study we looked at progression free survival, both in terms of for all patients that went on this trial and also for patients that had any S. R. One mutation and you see that there was a benefit. So patients that the molasses trends were had a slightly superior progression free survival when compared to full restaurants. I think that uh most importantly this is more convenient for patients with an oral agents and associated with better outcomes. Okay so now just for the next few minutes I'll just guide you through some of the trials that we currently have opened here at Dana Farber that that are being offered for patients with estrogen receptor positive advanced breast cancer. So this is the first one. This this trial illustrates a very important concept. So many of you have already heard about circulating tumor DNA. So detecting uh fractions of cancer in the bloodstream. How can that help us? Should we be if we identify that? Should we be changing our treatments? And this trial tries to answer that question. So the study schema, this is a busy trial, but a busy slide what it tries to show you is that patients that go on this trial that they are being treated as standard of care with first line and aromatase inhibitor and syndicate for six inhibitors. So for example, someone that is on lectures solved and Pablo cycling for rival cycling for Obama cycling. And they go on this trial where we don't change the way that patients are being treated. But we just do serial blood tests to see if with the text these E. S. R. One mutation that can sometimes be associated with a decreased response to our mateys innovators. So patients are still doing well. There's scans show that the cancer is responding to the treatments uh next slide and patients are asking the question. So if we switch therapy once you have this alteration in your bloodstream to a drug that is thought to work better for these patients, are we going to improve outcomes? And you might think, well this is a non brain or of course this is going to help. We don't know that yet. We don't know if switching earlier rather than waiting for the tumor to show in the scans that is stopping to to respond to this treatment if down the stream if that makes a difference. So I think that this is a very important study. This is another study. The other one was led by DR Mayer. This one is being led by DR Freedman where we are looking at patients that have 70 years old or more and they are being treated with M. A. C. Clip after progression on Pablo sick leave or right go cycling. There's no reorganization here. Everybody receives Obama secret. This is a trial that is looking at one of our novel endocrine therapies. So this is O. P. 12 50. A trial led by dr nancy lean and O. P 12 50 is an interesting compounds that has both uh works both as a third. So I showed you a prior search before and the serum as well that it's a complete estrogen receptor antagonism. So tries to take the best of two different class of drugs. And this is currently an expansion expansion those two. So in this type as well in this trial patients are not there's no random ization. So everybody receives the same drug. So this is a trial led by Dr Garrido Castro that is looking at an antibody tree congregates that we discussed before succeed. But here is asking the question if we add the checkpoint inhibitory, if we add immunotherapy federalism have in this case will patients do better. And this is another trial. Looking at another antibody to congregate that. I did not mention to you before the data. D. X. D. Being compared with the physician's choice of chemotherapy. And it's open for enrollment as well. Led by dr Delaney and finally last but not the least. An important trial. Led by one of our nurse practitioners. Ella. Hey Salahi looking at the impact of scalp cooling in patients with metastatic breast cancer that are going to be treated with substitution reactions to some of the rocks taken or terrible in. So thank you for your attention. And I look forward to hear from Dr bagley on what is new in research for er positive metastatic presidents. Thanks very much for that uh great overview of both current and future treatments for for er positive metastatic breast cancer. What I wanted to do for the remaining time is not give a comprehensive overview of all the research in er positive metastatic breast cancer which would be would be far too much but really focus on one particular area of interest. Um And I see from the questions this is an area of interest for um you go back one side please. Area of interest. Um From a lot of a lot of folks who are listening which is the study of resistance. Thinking about how uh er positive metastatic breast cancer develops resistance to the standard therapies that we use like endocrine therapies and cd 46 inhibitors. And what kind of research has been doing to understand that and help think about how we might prevent or overcome resistance. Next slide these are my disclosures. Okay next slide. Um No back one please. So the problem of resistance in er positive metastatic breast cancer um is that most er positive breast cancers initially start out sensitive to the therapies that dr Lindsay just talked about. So we now use combinations of hormonal therapies like tamoxifen and other selective estrogen receptor modulators, aroma taste inhibitors and full restaurant or other surges that we also just heard about often now in combination with drugs like C. D. K. 46 inhibitors such as I brands or others Presidio ever LIMAs or alP Ellison and um although many breast cancers start out sensitive to these therapies do these combinations in the metastatic setting? Most if not nearly all tumors eventually develop resistance to these combinations. And this is I would say the major challenge that we currently face in the treatment of er positive metastatic breast cancer. And so what many researchers in the field including my own lab think about um are these two questions how does resistance to these therapies occur? And can we develop therapeutic strategies that can overcome or prevent this resistance? Next slide. And so one way um that has been really effective in studying resistance in general in cancer and particularly in this setting is to think about studying tumor biopsies from patients who have developed resistance to these therapies. And so in these studies um that we conducted back one side please in these studies that we conducted dana Farber. Um and that are conducted at many other institutions around the world. We compare a biopsy that we obtained from someone who has developed resistance to these therapies. And compare that to the biopsy that was obtained before they develop resistance. Um And those biopsies might be tumor biopsies or they might be blood biopsies or liquid biopsies where we take a blood sample and we actually look at the tumor DNA that's circulating in the blood and by comparing the tumor that is that is from the resistant time to the same tumor that was from before the treatments. We might be able to understand what changes developed in the tumor. What evolution happened in the tumor and understand then why that tumor became resistance. And that may help us understand how we might develop new strategies. And so this is the kind of next like this is the kind of work that um that we've been doing here at Dana Farber. So over 2015 to 2020. And this is in collaboration with um dr lin dr Weiner, our whole breast oncology group. Um we collected um biopsies from patients with metastatic disease who were cared for Dana Farber Cancer Institute and at the time they had developed resistance to endocrine therapy or C. D. K 46 inhibitors. And over about five years we collected a huge number of biopsies. Almost 600 biopsies from 530 patients. This is one of the largest collections of metastatic research biopsies that exist in the world right now. And we used those biopsies that were generously donated by patients who are willing to participate in this research to do comprehensive genomic and molecular studies. And you can see lists of what those kinds of studies are here. And we linked that information to all of the clinical data, including what drugs people got, how well they did on them, how, how much they responded when they developed resistance. And this is allowing us to put together what we are calling an atlas of resistance next life. And so this atlas of resistance has a number of pillars. We are able to look at the primary biopsy the original diagnostic biopsy when the patient was first diagnosed with breast cancer, then we're able to look at this metastatic biopsy um that represents resistance. Were able look at the circulating tumor DNA that allows us to look at for changes over time. We look at the journal in DNA and we look at all the clinical and data imaging and we have now used state of the art technology to analyze all of these different layers to try and understand resistance better. Next slide. So what are we learning? So this is a high level summary of all the things that we've been learning over the last several years by doing these types of studies. Well. One is that when we look at the tumors from patients with resistant metastatic breast cancer, they look different, They look different from the same tumors at the time of diagnosis or they look different uh than tumors from people with early stage er positive breast cancer. And second, the reason these tumors look different is because they clearly evolve. So as they develop resistance over months and years, they develop additional mutations and additional other changes. They essentially evolve to develop resistance to the therapies were using Because they evolve and because they look different at the time of resistance as compared to initially it highlights for us. # three the importance of metastatic tumor biopsies and blood biopsies. If we want to know why a tumor is resistant. We want to know what it looks like today. Looking at a tumor that was biopsy two years ago or three years ago or four years ago. Doesn't necessarily tell us why the tumor is behaving the way it is right now. And so it highlights the importance of trying to get a look at the tumor as close to um now as possible if you're trying to make treatment decisions or you're trying to understand why the tumor has become resistant. Fourth, we've learned that there is a set number of things that seem to be a set number of things that tumors due to evade treatment to develop resistance. And we call these nodes, we call these nodes of endocrine resistance. And we've identified now over the last several years, several of these nodes of resistance. Um 5th we also have learned that the story is pretty complex and by doing our standard, what has become standard to approach these studies which is to do DNA sequencing um that gives us a lot of information but not the whole story. And so over the more recent years, we've started to expand the way we've looked at these tumors. We started to look at RNA and protein and methylation and ePA genetics to try and really get the whole story of how these tumors become resistant. And then sixth, all of what we're learning in the first five bullets have significant in clinical implications. Because it's already telling us how we might treat patients with er positive metastatic breast cancer better by using clever combinations or novel drugs to try and overcome or prevent these resistance mechanisms. So next slide. So here is what we've learned so far. So as I said patient tumors start out sensitive to these drug combinations. Then they develop existence and we've identified three categories by which these tumors tend to become resistant. The first category is probably the thing we see most commonly which is secondary alterations in the target the target in this case being the estrogen receptor. And so one of the earliest understood mechanisms of resistance and one that we still see frequently are mutations in the estrogen receptor itself or the S. R. One mutations. These are mutations in the estrogen receptor that essentially make aromatase inhibitors ineffective and also decrease the effectiveness of tamoxifen or full vestment and very often in metastatic er positive breast cancer. These tumors will develop mutations in E. S. R. One or the estrogen interceptor that will make them resistant to the therapies we commonly use and so that is one thing we've understood and now that we're developing strategies to try and overcome them more or less infrequently er doesn't develop mutations but it might develop fusions and we're also starting to see mutations or alterations and to other genes that we target C. D. K. Four and C. D. K. Six. The most novel and interesting work to think about new treatment strategies is the second um bucket over here which we call bypass or compensatory mechanisms. And so the tumors when you target the estrogen receptor or C. D. K. 46 with these drugs the tumors have evolved ways of activating other pathways to essentially evade the treatments were using. And interestingly the pathways that these tumors evolve are ones that we actually recognize because they are common in lung cancer or melanoma or colon cancer. And it turns out breast cancers can adapt some of these mechanisms. Some of these pathways that are usually not seen in breast cancer but when the tumors are looking for a way to escape are commonly used therapies they do start activating these therapies genetic pathways that are usually only seen in other cancers and some of those are listed here Now. The good news is we actually know how to treat a lot of these mutations in other cancers. And so what I'll talk about in a minute is how we are thinking about borrowing drugs from lung cancer or melanoma or other types of cancers for use in resistant er positive breast cancer. And then the third bucket is what we call pathway indifference which is an er positive metastatic breast cancer may decide decide may become um E. R. Negative and so some tumors about 20% of tumors lose er and become what looks like triple negative breast cancer. And that's yet another mechanism of resistance that we're actively studying in the lab to understand what what how do you treat those tumors? Do they look really like triple negative breast cancer or are they something altogether different? And what we're learning in that case is that some of them actually are still very much er positive tumors even though they've lost er expression. And we might continue to treat them with er targeting drugs while others really do look like triple negative breast cancer. And we might think of treating them with things like immunotherapy. Next slide. So based on what we've learned here we've been thinking about a number of potential approaches after resistance. This answers some of the questions that have been in the Q. And A. And and Dr Linz also reviewed some of these. And so here are five strategies that are being researched right now for potential um use after resistance to endocrine therapy plus C. D. K. For six inhibitors. The first is to use other therapies for approved er positive metastatic breast cancer things um like Al pellucida plus for investment or ever dilemmas. And when those were developed C. D. K. +46 inhibitors had not been approved. And so we're now learning whether they are effective after resistance to C. D. K. +46 inhibitors are developed. But those studies are ongoing next slide. A second strategy of previous likeliest second strategy is to think about um continuing the C. D K 46 inhibitor and switching the endocrine therapy. So going from a c D K 46 inhibitor plus aromatase inhibitor like letrozole and switching to uh C D K +46 like Calvin cycle plus full investment. And this is something that's being studied um in a couple of different studies, one that was presented at Asco earlier this year, another that's led by dr Erica mayor at the dana Farber that we will present, she will present at the san Antonio breast cancer symposium in december. But this is another strategy. Can we switch the endocrine therapy and keep C D K +46 inverters going next line. A third approach is switching the C D K 46 inhibitor. So if you develop resistance to my grants pell bonsai club, could you switch to a different C. D. K 46 inhibitor, like Obama, cyclops or Virginia? And that's a study. A lot of the work is being led by a colleague of our Seth wander and mass General Hospital. Um And there's an interest in figuring out can you in some people might you get effectiveness by switching the C. D K 46 and next slide now. Fourth we I mentioned we think about these combination therapies. So can we pull in new drugs, particularly drugs that we may already understand from other cancers like lung cancer or melanoma and combine them with C. D. K. 46 interviews and these are particularly for those cancers that develop those bypass pathways where they develop new mutations that might benefit from adding a new drug. And this is an active area of investigation at Dana Farber and elsewhere. And the next slide. Fifth alternative approaches. So particularly for those tumors that look like they no longer depend on er or look like triple negative might we choose alternative approaches? And here immunotherapy becomes particularly interesting and there's growing evidence that in some patients who develop resistance immunotherapy or other chemotherapies might be particularly effective and the goal of our precision medicine approaches to try and figure out who will benefit from each of these five strategies. Clearly not everyone will benefit from all five strategies. We do believe that some people will benefit from some of these strategies. And now our goal is to try and figure out who will benefit from which and being able to assign people to the right strategy for their resistant tumor. Next slide and so if we come back to this idea of all the different kinds of mechanisms of resistance that we're seeing and how they might impact therapies. Um Next slide you start to think about trials where you profile the patient and their resistant tumor and you figure out what's the cause of resistance in there too. And here listed here are various things that we've identified that might be causing resistance and for each of them there might be an ideal therapy and listed below are the ideal therapies and to try and decrease the complexity. Next slide we might use additional molecular tests to group people into particular pathways that have particular drugs that target them. Maybe aurora kinase inhibitors for one group of patients, map kinase pathway drugs for another group of patients, M Touray Katie drugs for a third group of patients and cycling C D K two or cycling any drugs for 1/4 group of patients. And we have now trials that are being developed in each of these categories for patients with resistance to er positive endocrine therapy and c D K 46 inhibitors. Next slide and um one more um and so and in the future we might think about a combination strategy that targets all of these. And we're thinking about how we might in a safe and tolerable way combine these drugs in a clever way to target all of the risk different resistance mechanisms. Next slide and also thinking about, well can we move this up front, not just to overcome resistance when it occurs but to prevent resistance altogether. And that is our hope when we think about how we might ultimately cure er positive metastatic breast cancer for good. Next slide And so I'll just close with thinking about how we might accelerate this work. And so we've made a huge amount of progress over the last several decades and an accelerated progress over the last several years, as you've already heard from DR Linz And as you might hear from other talks in this embrace symposium. So what do we need to accelerate and improve research advances in precision medicine and metastatic breast cancer? Well, I think we need to do more characterization of these resistant tumors from patients. We need comprehensive genomic and molecular characterization of many thousands or tens of thousands or even hundreds of thousands of tumor and germline specimens from patients along with their detailed medical information. We can't rely on data that we've generated in the past. We need to do this going forward prospectively because we need to think about modern treatment regimens. CTK 46 inhibitors didn't exist 10 years ago or more. Um these new adcs that you just heard about didn't exist 10 years ago. And so we need to study tumors from patients who are getting modern treatment regimens. Third, we need to make sure these studies include underrepresented and historically excluded patients. Cause we need to make sure our research advances are applicable to everyone and reflect everyone who get cancer. And fourth, we need collaboration and open data sharing so that we don't silo our data and we can learn from the shared learnings of everyone and you can see some organizations and institutions here that are leading the way in thinking about open data sharing and collaboration. Next slide. And I'll close with a project that we've been leading here called Count Me in which allows patients to be part of that collaboration, to be part of that open data sharing. In fact I launched we launched this project when I presented at this symposium back in 2015. And at the time I think 50 patients had signed up when I gave this talk in 2015. Now over 6400 women and men with metastatic breast cancer from all over the U. S. And Canada have joined the project. They represented by over 1700 institutions and we've now been sharing the day openly and it's been contributing to lots of research. And so one way that patients with metastatic breast cancer can help contribute to advancing this precision medicine approach is by doing things like signing up for this project or other projects that your local cancer center to try and help push forward research by sharing your information and your data and I'm happy to talk about that. More folks have questions next slide. So that's the end of the talk. We're happy to dr Lindsay are happy to um answer more questions after this. Thanks so much. Thank you both so much for that. Um I was thinking of some questions as the talk was going on but you answered many of them as you were going along. We did have um a handful of questions from our listeners. Um one that I wanted to ask about that that was brought up a few times was the idea of sort of recycling therapies or going back to a therapy, say, an endocrine therapy combination after being on chemotherapy, multiple lines of chemo. Um how does that look or how do you think about doing that now that we know so much more about targeting people's individual cancers? I am happy to start and then dr wobbly can can follow. Uh I think that that is a very interesting question and uh um it all depends. So many things can happen. It all depends. What was the reason why a patient was switched from endocrine therapies to chemotherapy. It might be that the disease is rapidly progressing and the physician has the sense that we need something stronger or faster. Although there is data showing that syndicate for six in innovators and endocrine therapy work as fast as chemotherapy. But sometimes we need we feel that we need something different or even combination chemotherapy so that once the disease is well controlled the humor, you know, it's not progressing, it's stable. You might consider to go back to endocrine therapy. Sometimes it happened as well that we have we we do a biopsy That shows that the tumor is being less responsive to to endocrine therapies because the yard that used to be 90% is now, you know 10 or 20% sense or 5%. And although those are still technically former receptor positives. Uh you worry that they might not responsible to endocrine therapy and then later you have another biopsy that it shows that the tumor is er more positive. So there's all these hydrogenated in the tumor. So you might consider endocrine therapy at that time as well. So I'm giving different examples examples to say that it does not mean if you move for chemotherapy that you can never go back to endocrine therapy. It really depends on a patient by patient situation Along those lines Linssen before I pass the microphone to dr ugly. A question that I saw in the chat as well is where do we stand right now in terms of receiving another syndicate for six inhibitor after progressing on a different syndicate for six inhibitor. And I think that there were some questions in particular about Obama C clip. As you saw from the last slide There is definitely a strategy that it's under investigation. There are clinical trials that are answering that question. They're trying to answer that question and we'll learn more about it. At San Antonio. There was a clinical trial that was recently presented and that's why I think that this has got so much attraction. That was the maintained trial that was led by Dr. Kalinsky that looked at about 120 patients that progressed on a C. D. K. For six innovator. And the line of endocrine therapy and those patients the endocrine therapy was switched and they continue on the CTK for six innovator in this case was rival cycling and patients had a longer progression free survival if they were continuing the city K for six innovator rather than just switching the endocrine therapy. So I think, I think that this was received with excitement. It's still a small trial. So I think that most of us are waiting to see more trials supporting the same data before we adopt this in the clinic to our patients. Sometimes, you know, Obama secret, there was a trial, one of the first trials that looked at the pharmacy, click for patients that have progressed after prior chemotherapies and in this case Obama cyclic given. So the Virginia was given without endocrine therapy. But in this setting and it's something that sometimes we forget patients have not received the CTK for six innovator with endocrine therapy. So it's hard to know how much you can gain from endocrine from acidic it for six innovator alone after progression on a syndicate for six innovator with endocrine therapy. So, all great questions. I think that uh we are going to learn more about it in the next month. So stay tuned. Yeah, nothing, nothing to add. I think we can go to another question that was have nothing, nothing more sure. I there was also a question about a lot of questions about oral surgeons and what some of those trials do we have any um feedback on how those trials are going. Yeah, maybe, maybe I'll start briefly and dr Linz may have may have things to add. Think there had been and there has been a lot of excitement about oral surgeons because of the improvement of drugs like full restaurant over aromatase inhibitors or tamoxifen, particularly for E. S. R. One mutants. And oral surgeons being particularly exciting because they overcome that one challenge part of the investment, which is that you have to get it as an injection um and it can be painful and inconvenience. Um So oral surgeons have been really exciting drug category that's been under development for many years and more recently as we started to get the readouts of oral serves in clinical trials presented at meetings. Unfortunately, the results have been a little bit more disappointing than we had hoped. And in fact some of the oral served programs have have have been stopped being developed because because they see that they're probably not going to be the or not all of them are going to be the game changers that we once hoped they would be. There are still a couple of oral surgeons in development and we are expecting to hear about those trials. I don't know what the ultimate out is going to be. I think there's a very good chance that there may be oral surgeons that are as good as full restaurant or maybe even a little better than Full restaurant in which case they might be successful because they will take away that need for the monthly injection. Um but but we're still waiting for that the kind of endocrine therapy targeted drug that is really going to take us forward a huge leap. Um oral surgeons might be them. But there are now these other classes that you heard Dr Lynn's talk about like the pro tax and the circus and the Sarandon's which are different than surges they're still endocrine estrogen receptor targeting drugs but using a different mechanism and I think that's where the real promise lies in the future. Yeah, I think that's a great answer and that that addresses as well some of the questions that we got in the Q and A. That is if I progress on the full restaurants, should I go on an oral surgeon And I think that right now we don't have data to support that. I think that most of these trials um they are not answering that question. It's more if neural service as as good as full restaurant or better. We know that it's more convenient and looking at the these specific role in the S. R. One mutations. But as Dr Wagner was mentioning some of those trials have not been as promising as we were hoping for so more to come. But um I don't think that if I would have progressed on full restaurant I would go to an all sorts right now unless there is a clinical trial asking that specific question, can I just I think that there was a great question here that we see coming all the time. That is someone is doing well for a long period of time and can we stop the therapy and you know, and this is in general and we hear this for uh in terms of for example the trans to zoom upon on her two positive and syndicate for six innovators. And I would encourage um I think that there are different case scenarios. There is the situation where you know, people are developing some toxicities and it's really time to take a break with closely monitoring and this toxicity can be financial toxicity as well. And we we don't know what is going to happen, but we monitor the patients closely. Uh, not that it's our first option, but sometimes we do it and uh someone you know cannot tolerate the toxicity anymore and it's really impacting their quality of life. If it's really the question of, am I cured right now, Can I just stop these therapies? And even if stage four by definition is not curable, perhaps that's the perhaps that's not the case for for someone in particular. I would say that we don't know the answer yet. There are a lot of clinical trials that are coming. So look for those either trials that will be monitoring patients with circulating tumor DNA or stopping and just doing scans more closely. So I would encourage everybody to search for look for those trials and participate whenever possible. one thing I just wanted to highlight again, um outside of of the research regarding endocrine therapy is this new approval for Trust us a mob direct stick and which I think is so exciting. Um often when I'm seeing patients in clinic and people have progressed on multiple lines of hormonal therapy and they perhaps have had a few chemotherapies being able to offer this, especially with um that survival benefit that you talked about is just such an exciting thing that's happened. Yes. And thank you so much for bringing that up because this is so important. I would encourage everyone who is listening to us and you know people, you know, and you know you have friends, relatives diagnosed with uh norman sector positive, her two negative breast cancer. To go back to your records or or to your doctor and clarify, what is this for? Two negative because we used to talk about it this way, right? But now it really matters to know if the herd to negative means her to zero or if it means her too low because now you might be uh eligible to another therapy that was not available six months ago. So it really matters now that patients are fully aware of their herd to status beyond her two positive or negative. Great. I'm just taking a look in the chat again to see if we've covered everybody's questions, There was a question about a r positivity that came in early on and if there's any research being done looking at treatments for a are positive cancers androgen receptor positive cancers. Yeah that's it. That's a great one. I think dr Lynn answered that question. Um There have been trials largely the trials that have been conducted have been not particularly successful targeting the androgen receptor but I think many of us are still quite interested in the androgen receptor as a target in metastatic breast cancer and even as a mechanism of resistance in metastatic breast cancer. Um there are androgen receptors also present in triple negative breast cancer and that's where most of the drug development is happening right now. But in er positive breast cancer there there was a new a new approach that was presented back in san Antonio in the last year or two. That's very interesting and is now in Phase three trials um which is essentially an agonist of the androgen receptor. Um and that is uh I think that's really promising. We'll see. We'll see more results from that trial in the coming year or so. Well we're getting close to our time. I don't know. Let's see, I wanted to say doctor Wobbly, it sounds like um Things have you alluded to. Things having changed a lot in the past two decades and I think this whole talk highlights just how much has been accomplished and how much is going on, which is exciting. Can you speak just a little bit more and again to how things have changed in the past, say 20 years in terms of treating this type of cancer. Yeah. Um that's a great great question. Thanks for that. I think that The the way we have thought about breast cancer has changed a lot over the last 20 years. You know breast cancer used to be used to be just one thing breast cancer. Then we realized breast cancer could be split up into the different subtypes hormone receptor positive, her two positive triple negative. But we didn't know what to do about it. We just knew that those were the different categories. And at that time if you had her two positive breast cancer that was that was one of the worst things that you could have because we had no drugs for her two positive breast cancer. Then we started learning how to target these drugs and we developed new and more endocrine therapies beyond tamoxifen aromatase inhibitors, full vestments C. D. K 46 inhibitors. And in that subtype and that changed things a lot. And now we are at this stage of even more precise targeting more precision medicine where we're trying to use additional information like is her to expressed at all. Um as her too low concept, are there pik three C A mutations are there B. R C. A one or two mutations or pal B two mutations. And so we essentially have now developed technology and we figured out how to use that technology in the clinical setting to further refine our decision making. That's the whole concept of precision medicine, which is really I would say coming into its own in metastatic breast cancer. Maybe even a little late breast cancer had precision medicine before there was precision medicine because we had endocrine therapy, we had her to therapy and then we had this long gap where we didn't have anything new. And now we have this explosion in new ideas for how we might use targeted therapies like pick three C. A or B. R. C. A one or possibly two or her too low. Um and and that is really changing the way we're starting to think about about targeting patients. And so um so getting that sort of fingerprints, getting that profile as someone in the questions mentioned is going to be increasingly important. And I would say that's one of the biggest changes in metastatic disease. That's great. Thank you. Thank you both for joining us today. This is wonderful. And lindsey, can I have 30 seconds of course please. I just saw two very good questions coming to chat. And so one is for in most cases you don't need to do extra testing to know if you're humorous for too low or not. It is in the report. So you just need to ask your doctor and if for some reason those results were not available in most of the situations we can go back and ask it. So don't feel shy to try to understand if your tumor is her too low or her two negative. And secondly immunotherapy in er positive breast cancer. And you know this is obviously a hot topic. Although I feel in the last year antibody drug congregates took over immunotherapy right now we don't care immunotherapy uh approved in er positive breast cancer unless for tumors that have high reputational burden. But there are a lot of clinical trials that are trying to learn more about what are the patients with er positive her two negative breast cancer that can benefit from chemotherapy. I showed you uh that can benefit, I'm sorry, from immunotherapy. I showed you one of those we are going to have trials in iBC as well. So stay tuned and look for it. I think that it's worth exploring. It's just I think that we are still trying to learn who are those patients that can benefit from this type of approach. I think a big take home from both of what we both said is that much of what we're excited about and all of the, most of the answers to all of the questions that have been asked today are all in the realm of research right there. They're all they're all require clinical trials. And so that just highlights the importance of clinical trials. We we knew, you know we know what we know and that's basically the standard therapy. But all of these nuances, all of these questions for investment, after served served after full restaurant or which C. D. K. 46 or immunotherapy or different kinds of P. Three kind of all of that. They're all great questions but we're basically learning the answers to them along with patients through clinical trials. Great well thank you again. Um thank you both for joining us. This has been a great discussion and I want to remind all of the participants that this has been recorded and it will be posted to the D. F. C. I embraced web page so you can watch it again if you'd like. Thank you so much. Thank you all take care.
