Antonio Giordano, MD, PhD; Sarah Sammons, MD; and Morgan Rutter, MS, BSN, RN, discuss advances in research and treatment for patients with triple negative metastatic breast cancer.
Hello everyone. My name is morgan rudder. I'm a research nurse with the breast with the breast oncology group. Um I'd like to welcome you all to the embrace metastatic breast cancer virtual forum series. Um Dr Giordano and dr Sammons will be reviewing what's new in research and treatment for triple negative metastatic breast cancer. So our first presenter, Dr Sarah Sammons, is currently a medical oncologist at the Duke University Cancer Center. As of November 2022. She will be joining Dana Farber as a new faculty member and will take on the role of associate director of the embrace program. Her clinical and research focus is on developing new treatments for patients with metastatic breast cancer including patients with brain metastases. Our second presenter, dr Antonio Giordano is a medical oncologist and our breast oncology program and assistant professor of medicine at Harvard Medical School. He leads numerous phase one clinical trials covering all major breast cancer subtypes. His focus is on bringing new targeted treatments into the clinic. So we'll have Dr. Sammons and Dr. Giordano present on the current treatment options clinical trials and research for triple negative metastatic breast cancer for the 1st 30 minutes. And then we'll try to devote 30 minutes for Q. And a. So we'd like you to submit your questions in the Q. And a button at the bottom of your screen. And we'd like to encourage you all to submit your questions as we go. Thank you so much more organ and thank you for having me here today to talk about all of the new treatment advances in metastatic triple negative breast cancer in 2020 I've entitled the talk from negative to positive because there has just been a lot of advances in the last five years that I think are important for everyone to know about next line. So in terms of I wanted to start out by talking about the different breast cancer subtypes because the breast cancer subtypes are how we identify the type of breast cancer that you have. And in doing that, we can then understand what treatments that you might benefit from. The vast majority of breast cancers are hormone or estrogen receptor positive. About 65-70% are estrogen receptor positive. And those patients initially benefit from endocrine or hormonally based therapies, 15-20% of patients are her two positive, meaning that their breast cancer expresses a protein called here too. If you're breast cancer does not express estrogen or her too, then you're put into this category called triple negative breast cancer. Um which is what we're going to be talking about today. So, all triple negative breast cancer really means. It tells us what you won't benefit from. Um but it doesn't give us a good understanding, at least in its title about what you might benefit from. It just means that you have negative expression of estrogen And her too. And that's about 15-20% of all breast cancers. Next slide, what do we know about triple negative breast cancer? We know that it's the minority of breast cancers. It's 10 to 20%. Um And by guidelines we think of triple negative breast cancer as lacking estrogen. So your tumor cells express less than 1% of estrogen, less than 1% of progesterone. And your breast cancer is negative by asco cap guidelines for her too. Um Now that's changed a little bit and we're gonna talk a little bit more about her too low later in this talk. Um But still triple negative breast cancer is estrogen progesterone and her two negative um We know that triple negative breast cancer is considered more aggressive. The tumor cells have a more rapid proliferation, meaning that they grow faster um When triple negative breast cancer comes back and and relapses distantly usually happens early in the first five years after your diagnosis of early stage breast cancer. We also know that triple negative breast cancer disproportionately affects younger women brat germline braca one carriers, so women that have um a gene mutation in BRCA one which is a hereditary breast cancer syndrome. Um And it also disproportionately affects african american and hispanic patients. Um But with that being said there are still plenty of caucasian and white patients and older patients that are diagnosed with triple negative breast cancer. And we also know that triple negative breast cancer. Um Though we are making major strides and we have a lot of hope has um historically lower survival rates than other types and it's a high need area. Um It's been identified as an area that we really focus on finding new and improved therapies. Next slide not all one of the difficult parts about studying triple negative breast cancer and drug development and clinical trials and triple negative breast cancer is even though we lump it we lump all of the patients that have triple negative breast cancer generally in one category we know from historical studies that look at the D. N. A. And the RNA within breast tumors that not all triple negative breast cancer is actually the same and there are differences amongst patients. Um One of the most recent um studies by bursting that was published in 2015 essentially showed from RNA and DNA that there's mostly four different types of triple negative breast cancer. Um The first being Luminal androgen receptor um Those um tumors are more likely to express something called androgen receptor which we haven't fully figured out how to target yet. Um Then there's mesenchymal um which has activation of several growth factor pathways. And then there's basil like immuno suppressed so tumors that um are not as likely to probably benefit from immune therapies. Um And then there's basil like immune activated and these are tumors that are probably more likely to benefit from immunotherapy tick approaches. And even though we know that there's different subsets amongst triple negative breast cancer and practice. We don't test for these specific RNA signatures um because we don't have treatments um for them individually yet. Um But we do definitely recommend um next generation sequencing testing the mutations within the tumor. And we also recommend PD L. One testing which I'll talk more about, which helps us at least understand those patients that are more likely to benefit from immunotherapy. Next line We have made um substantial progress in recent years and our ability to offer new treatments that do improve outcomes in patients with metastatic triple negative breast cancer. I want to note that before 2017 that was which was only five years ago. All we had was chemotherapy for the treatment of metastatic triple negative breast cancer. And and we've come a long way. In 2018 we had FDA approval for two different part inhibitors which are specifically for patients that have germline Bracha mutations. Either braca one bracket to um we also have approval of immunotherapy that is biomarker specific, meaning that you would only benefit from immunotherapy if your tumor was tumor molecular burden high or Pd L. One positive. And then we have approval for all patients of a new antibody drug conjugate called sassy to some of the Vatican. And then very recently in the last month we have a new approval of a drug called Tres directs the can or in Her two in patients that have low level expression of her two which we'll talk more about as well. Um And all of this is through research and patient participation in clinical trials next time. So when I meet a new patient with triple negative breast cancer, um one of the most important things that we need to know are what are the biomarkers are characteristics in their tumor in 2022 that are important so that I can identify what standard of care therapies that they might benefit from. And when I say standard of care, I mean already studied in clinical trials already FADA approved. And the most important thing to know on the tumor is what is the PD L. One expression When I'm trying to determine um what is the best first line therapy? What's the first treatment for metastatic triple negative breast cancer that the patient would benefit from. And so PD L one expression um should be ordered on the tumor. Um It's a specific PD L. One test. It's using the deco 22 C three Pd L one essay. And we know that tumors that are CP have CPS scores of 10 or higher. Those patients benefit from adding pemberley is a mob to their chemotherapy. In the first line setting, it's very important to introduce immunotherapy in the first line as early as possible in metastatic triple negative breast cancer in the second line and beyond. So after first line treatment it's important to know what's the her two on your tumor and now it's not as important to know positive or negative. It's actually important for us to know what exactly is your immuno history chemistry score. Are you one plus or two plus and you know if you're hurt too negative then your fish is amplified. But it's important for us to understand now what is the immuno history chemistry testing one plus or two plus because you could benefit from a drug called can or in her too. It's also important for you to know do you have a germline BRCA mutation and um that is done by um usually genetic counseling um and germline genetic testing. So have you had that done that's important to know and then there's very rare um tumor agnostic which means that we have approvals for all types of cancer um based on these biomarkers. So M. S. I. High is extremely rare and breast cancer it's about 0.5 to 1%. But it would be important to know if you had that um what's your tumor molecular burden and transfusions are also exceedingly rare. But any um next generation sequencing platform that you would have done a standard either your institutional platform or foundation caress Tempus. Um they would all test for these types of things. Next slide in the last decade. Um we've been studying and we've made definite headway in terms of immunotherapy and when I talk about immunotherapy. I'm talking about drugs and antibodies that put the brakes on the immune system and then help your immune system in turn fight the cancer. And so that is the umbrella term for what we call immunotherapy and immunotherapy. In terms of breast cancer. To date, we have only had success in triple negative breast cancer. We have not had success using immunotherapy and hormone receptor positive or her two positive breast cancer. And the reason for that is that triple negative breast cancer, unlike other subtypes, does have a higher mutation. Right? So when you look at the number of mutations within the tumor, there's a higher number of mutations generally on average and triple negative than other subtypes. Also when we look in the tumor cell there's more um infiltrate of immune cells, different types of immune cells that can help the immune system in turn um fight the breast cancer. So there's higher levels of that in general in triple negative breast cancer and triple negative breast cancer also has higher rates of something called PD L. One expression. And that's important because PD L. One is a biomarker in breast cancer for patients who in the metastatic setting might benefit from immunotherapy. Next sign. Now we've also we've been studying immunotherapy and breast cancer now for almost a decade. Um and we have realized that immunotherapy in breast cancer works better when you give it with chemotherapy and it does not work as well at all when we give it alone. Um and the reason for that is that chemotherapy induces um immunological changes within the tumor and the cells around the tumor which we call the micro environment that influence the effectiveness of immunotherapy. And we know from studies that when you give chemotherapy and immunotherapy together it works better if you're going to benefit from immunotherapy. Um And the reason for that is you know with chemotherapy we kill the tumor cells. Um And in doing that we expose the tumor we expose the tumor and the tumor cells um and your body to more antigens. Um which then helped the immunotherapy um and your immune cell then attack the cancer cells essentially. So I get that question a lot in the clinic, why don't we just give immunotherapy by itself? Hopefully one day we'll have more powerful um successful immunotherapy is that we can but for now with the immuno therapeutics that we use they work best with chemotherapy next time. So the first line standard of care FDA approved treatments for triple negative breast cancer depends on whether or not your breast cancer expresses Pd L. One which is programmed death ligand one. And we know this from clinical trials which I'll go into that. The only patients that benefit from immunotherapy added to standard chemotherapy are those patients that are PD L. One positive. And so if your tumor um when you're first diagnosed metastatic triple negative breast cancer in 2022 will test your tumor with the um deco essay for PD. L. One. And if you're PD L. one positive outside of a clinical trial which we always encourage your Pd L. One positive than our recommendation would be chemotherapy with Pemberley is a map which is immunotherapy. And there are several different chemotherapy backbones that we could choose. Um But it's usually either a taxi and a platinum based and 40% of patients will be positive for Pd L. One. If your PD L one negative then the standard treatment to start would be would be chemotherapy. Next slide. Um and this comes from the keynote 355 clinical trial that studied embolism ob with chemotherapy versus placebo with chemotherapy. Next slide. And it basically showed that in all patients there was really not a huge benefit from adding Pemberley is a map of the immunotherapy to chemotherapy. But in patients that were PD L. One positive with the cps for greater than 10 these patients had um about a four month benefit. Um in terms of progression. So how long their tumor grew when immunotherapy was added. So right now um it's incremental progress. Um but only about 40% of patients will benefit from immunotherapy in the first line setting added to their chemotherapy. Next slide now we have more second line options. Um And the second line and beyond options than we've ever had before. Um we have standard chemotherapies up in the left corner. If you have a germline bracket mutation. Then this is generally when will recommend apart inhibitor with black river telescopic rib. If you're not germline BRCA mutated then we would think about um Sassy choose Amigo Vatican which is an antibody drug conjugate. Um And if you're hurt too low in the second line and beyond um we now have the option for a drug called drugs to cannes next line. It's very important to understand if you've had germline bracket testing because 15% of patients with triple negative breast cancer will have germline Bracha mutations. And if you have a germline mutation um you would benefit um from getting an oral pretty well tolerated therapy called Apart inhibitor. And we wouldn't know if you would benefit from that drug if you haven't had testing next line. Now antibody drug conjugate are a new very new and triple negative breast cancer and are very exciting. And I know dr giordano is going to talk more about them. But um essentially they're a fancy chemotherapy delivery system in which there's an antibody that targets a certain antigens to either trope to or her two and triple negative breast cancer. There's a linker that's stable in the circulation and then there's a payload of chemotherapy. And that chemotherapy is generally only released once the antibody and the drug delivery system attaches to the cell on the tumor. Um Next line we have FDA approval for an antibody drug conjugate called Sassy Vatican which improves um the time to tumor growth and overall survival in the second line and beyond in triple negative breast cancer. And it's an antibody that targets trope to um and then the payload is a topo one um inhibitor payload. And this was studied against um single agent chemotherapy and was found to be more effective. Um So this is definitely something that we would recommend in the second line and beyond for all comers next slide. And now we have learned in the last year that one third of triple negative breast cancer patients are considered her too low. And what is her too low? That means that you're her two immuno history chemistry is one plus or two plus with a negative fish and that will be about one third of patients with triple negative breast cancer. And it's also important to note. Um This is a study by Paula Tolentino out of the dana Farber and they looked at the differences in her too low expression between primary and metastatic tumors. And it did show that it can change from the primary and metastatic setting. So very important to make sure that you have a fresh her two testing and the metastatic setting. And we don't just take our word from it from your um prior tumor. Next slide. And this is the destiny of for clinical trial that looked at in her to or trust is a direct stickin in her too low patients and showed that there was a substantial improvement in progression free survival and overall survival within her two versus standard of care chemotherapy next line. So in terms of standard therapies for metastatic triple negative breast cancer in 2022 we have more options than ever. More hope than ever. It's still large on that need and we still need to do better. And the only way to do better is through clinical trials. Um and there are many ongoing strategies and immuno oncology, antibody drug conjugate and targeted therapies that I'll now have. Dr. Giordano. Talk to you about. Thank you so much. Sarah and thank you melissa and dr lin to put together this very helpful and interesting forum. Thank you morgen morgen for moderating. Um after reviewing some of the current option available for stage four triple negative breast cancer. We are going to dive a little more about the research behind the triple negative breast cancer. The current active clinical trial um here at in A four by four triple negative breast cancer. And I also show how um what's behind the scene of a clinical trial. Next slide please. So as you know the road for two FD approval is really long and a molecule. Um We start usually in a lab with preclinical work um to try to figure out if a molecule as the ability to block in any bit like specific subtype in this case. In this case triple negative breast cancer advancing from Phase 1 to 2 to three we treat more and more people to uh in phase one determine like the safety and those like side effects of of a new molecule in the phase two clinical trial we specifically look at the activity While we are keep looked keeping an eye on toxicity and the safety profile till to the Phase three clinical trial where we actually compare usually a new regiment versus like standard or care to seek for the F. D. A. approval. Next slide. Um In line with one of this is one of the other algorithm for triple negative breast cancer that I put here. There was adapted from dr lisa Carey. Um And recently presented at at is mo there are several different options for triple negative breast cancer um that has metastatic. So it's a stage four. But what I want to put here next to each standard clip medical um care and approved the regiment is that the importance of always keeping an eye with your with your primary oncologist or like the team you're working with about clinical trial options. And um usually we see like clinical trial like a late phase like phase three or phase two in the early setting. But way when we go down the lines we start to see like more phase two of phase one clinical trial. And um one message that would hear like um that we uh I wanna give is like never start like an arrival in regiment without a phase one consult problem. I'm a phase one physician as well. Of course I do other clinical trial. But I'm really um wanna point the importance of having to see a fees one specialist in a comprehensive cancer center like dana Farber. We have like a phase one group early on in your face. And I would still also um y next slide in these like um retrospective analysis of patient that went on a phase one and this was only breast cancer but other like also a type of cancer that was done at University of Alabama. They look at a patient on phase one between 2015 and 2017. So in this almost two years span and they they presented that you know the overall survival media and the clinical benefit for more than six months with phase one clinical trial was actually pretty good um With immunotherapy being an overall survival around 20 months and in targeted therapies for specific molecule that targeted specific mutation or characteristics of the tumor was actually above the the two years next slide. And when they when they actually looked at what factors were Connected to the good outcome. So like better not 90 day mortality time to treatment failure or like response to their body. They found them mainly the most important thing where the performance status. So and you know the look at how fun functional, how well a patient feels during the uh during treatment and during like the coming back and forth from from clinic and also the number of prior line of therapy in this guy in this case they compare like two or less number of chemotherapy versus more than two and phase one clinical trial should always be considered for advanced patients. And in this case for advanced advanced triple negative breast cancer early in the treatment phase preferably upon progression of a frontline definitely systemic treatment. Next slide the therapeutic approach as Sarah is shown as really evolved for triple negative breast cancer. We now way more options as we try to understand more about the biology behind breast cancer. We have seen the new antibody drug conjugate that we are going to show you what are like the new ones that are in pipeline here at Dana Farber row in other institution we have seen DNA repair and so all the par inhibitors and other type of molecules that are trying to overcome resistance to barb inhibitor and of course um and I is important also on the A. K. T. And P. I. Three kind of spot way um that there's a little struggle so far for triple negative breast cancer even because those struggles usually really toxic um they have a very narrow safety window um and alone they are not um enough to into a block the proliferation of triple negative breast cancer and of course immunotherapy has broken the wall finally in breast cancer with the first FDA approval for breast cancer was in the first line setting for triple negative breast cancer. And there is a lot now of work um in the lab and preclinical work about the immunotherapy. Um Next slide please So much that is actually in this very nice review of my Italian friend Gianpaolo. Um it showed that there are more in right now um there are more than like almost 200 clinical trial for um with immunotherapy before triple negative breast cancer. And our our colleague lions put side that he works uh now a Yale cancer center say that if all the immune oncology trial for they will complete our cool there are no not even enough triple negative breast cancer patient to complete their crew in those clinical trials. So immunotherapy is really there is a lot of attention with different combinations and different forms of immunotherapy till to arrive like um uh cell therapy like the car T. Therapy And uh as a reminder please um Place question in the Q. And a while I talk so. And and so no one forgets about question that that come up during my presentation. Next slide one very important and novel strategy to attack triple negative breast cancer and breast cancer. And in general as being the antibody drug conjugate as sarah pointed. There is different way to modify those A. D. C. And make a like attractive and um target the the cancer cells. We can change the top of the antibody in order to recognize different tumor antigens. We can also change the payload so change to different chemotherapy agents. But actually um recently um we could attach to these antibody also like immunotherapy or like immuno immuno signals which are like bi specific antibody. Those are cool. So there is a we can make like different cocktails like changing one molecule to deliver to the tumor antigens so to the target but also to what we want to bring to those tumor cells. Um And the payload also is very important because there are also company working on how we actually detach like when do we detach the payload from the antibody delivered to the cancer cells. Next slide those are actually some of the novel antibody drug conjugate. Have you seen uh trod LV henner too that are coming up in the clinic after the recent FDA approval but we have seen um uh some success with some of these clinical trial that have actually completed. Not reported yet. The target leave one and acting four and coming up soon. Um um as well as Dana Farber there are gonna be novel antibody drug conjugate that targets for example B. Seven H. Four that is an immune protein that is overly expressed in triple negative breast cancer and also Mac one that also very frequently over expressed in triple negative breast cancer. Next slide the um another way to um improve the outcome in triple negative breast cancer is combining different molecule for example a DC two part inhibitor or to immunotherapy in this phase two clinical trial for frontline that is open a currently a dana Farber and uh and dr ana Garrido Castro is the principal in investigator, patient will be randomly randomized in in the first line when there is a negative PD L one expression. So PD L one that is not um enough to um undergo chemotherapy plus Pemba realism and patients will be randomized to Traudl the first line minus or plus keytruda. Uh This is currently active and enrolling at dana Farber next slide. And in this other trial that completed phase one um we are actually combining traditional Visa and I. D. C. With a Park inhibitor. Uh And in during this phase two expansion patient with triple negative breast cancer that are more than second line that did not receive Viet are allowed to go on this clinical trial in we which we try to empower the the activity of of um of MLB. Um there is a lot of rational on doing that because the payload of um of trade lb that is a top of one I summaries like type of chemotherapy is synergize with apart inhibitors. So we expect to improve the outcome with this combination next slide But as you know going back to see this jump out. Oh nice work that was recently published on triple negative breast cancer. There are so many genes that are involved in the biology and making triple negative breast cancer. So aggressive and investigator and researcher are struggling on how to identify the gene that is the key to stop proliferation and growth of triple negative breast cancer cells. And I want to show you an example of how we work from the lab. So from the bench to bring like a molecule to um to the clinic. Next slide and give me, I'm giving out to you here my homemade fresh pasta recipe. So you can all um will take a pen a piece of paper. It's super easy. Um and tonight you can all make fresh pasta and have a very nice glass of red wine, preferably italian. Um So two cups of flour, three eggs, a little of oil, of oil, a teaspoon of salt and a lot of passion of course. Now how do we recognize the order of importance of those ingredients things that those ingredients are our gene for triple negative breast cancer. And how we are gonna recognize like the rank of importance what we did a tomb with my um treasons. We made the pasta five times and each time we removed an ingredient so and at the end we taste the five different type of pasta and based on like the flavor and how we liked it. We rank it the importance of the ingredients. Next slide what we have done in the lab was exactly the same but using removing one gene at a time from a triple negative cancer cell and then we observe the cells for a period of time and so how they actually proliferate in vitro and based on how much sales survived we were able to classify the importance of the genes and it came up that in these basal like triple negative breast cancer cell line genes in the cell proliferation in the cell cycle were very important. Next slide specifically in the lab with when I um during my K 12 en Ci grant with Dr Stevie here that was my mentor of underground we identified this this gene called Polo like kindness one P. L. K. One that was essential for the survival was the most important ingredient was the passion of the fresh pasta to um let's survive those cells in vitro. Next slide we observed that Polo like kinase one P. L. K one inhibition was actually very active across subtypes of triple negative breast cancer cells. And also we noticed that the expression of polo like kinase one went up in the subtype of triple negative and also was associated to high proliferation. So high key I 67 a methodic stage that are all characteristics of triple negative breast cancer that make this subtype really aggressive. Next line we went to perform some experiments we did experiments in vivo. So in mice with a combination of an oral available Polo like kinase inhibitor Columbia conservative in combination with paclitaxel. And we found that there was synergy when we um at the drug um together next slide so all these signs was behind the design of this phase 12. So there are gonna be to step of on vance assertive in combination with paclitaxel in triple negative metastatic breast cancer patients. Um um Mansour tip is an oral pill. So it's a pill that is taken um for 21 days with a week off while paclitaxel is an ivy chemotherapy that is given weekly in the first step of the trial. We are gonna identify the toxicity of the combination and the recommended those for a phase two trial in this phase two study phase study phase we're gonna keep looking for safety and toxicity of course. But also we are gonna now look for like activity and tumor shrinkage of this novel combination. Um Here I put some key eligibility criteria. This is for any line of chemotherapy during the phase one B. And from 1 to 3 line during the phase two of the clinical trial. Next line and you know the road from the bench to clinic just to give you an idea it's actually pretty long as this actually as the same age of my first son. Um And I will never I will always have actually a good comparison for like where is my trial what how many years? He's my trial from bench to the clinic because as the exact same age of my first son. Um And you know there is a lot of work behind in the clinic in the preclinical space um dealing with you know compounds company trying to find the grand and the support for the clinical trials and of course um it's for me And an immense pleasure when I see something that was born in the lab and I was able to brought to the clinic and actually perfect timing yesterday September 30 of 2022. Um I treated the first patient with this combination and I'm gonna say hi to her because I'm sure she's here listening and um the first patient in the world remember. Um and so it's like an immense pleasure for a translational researcher to see like something coming to the clinic for like hope and like um for such a difficult um some type of breast cancer next slide. So in conclusion, okay, the optimum treatment strategy for patients with triple negative breast cancer remain a major and and not meet this stop type of breast cancer still carry a poor prognosis that we have to do a lot to try to improve a lot of research. Research takes time as you can see patients and determination and clinical trial are the key to make progress to advance secure for triple negative breast cancer because without clinical trial we cannot have FDA approved drugs and we cannot make advancement in these um in the quality and the the care of triple negative breast cancer. The advancement of molecular biology is definitely helping us to understand more about triple negative breast cancer. That is a subtype aggressive not only because of the um intrinsic aggressiveness of the cancer center but also the environment and the micro environment and the immunology around triple negative breast cancer has been a challenge. Um And I wanna finish with my next slide with the acknowledgement and thank you of course all the patients around the clinical trials or the agency that supported that for research and all the patient advocate in this case Christine. That was the patient advocate when I was at M. U. S. C. During my pre clinical work. And the one that actually helped me putting all together for the meta viable grant. And surprised when I moved to dana Farber Christine is actually now one of the patient advocate here at Dana Farber. Um because she's shared time between like boston and charleston. Thank you so much. Well thank you both so much for those presentations and um now we can start the question and answer portion. Um So the first question that came through was for stage four triple negative breast cancer. That is both greater than 10% Pd L. One positive and germline BRCA positive. What do you think about the option of using elaborate as first line and pem bro as second line or even adding PEM bro two apart inhibitor. I'm happy to take that one. Dr. Giordano. That's a really good question. Um So uh we actually have some data from the first line triple negative phase three clinical trials that included bracket carriers. Um And the one that I always reference um for patients in this unique situation is that in the impassioned 1 30 clinical trial there are actually 90 germline bracket carriers. Um and the german line bracket carriers and impassioned 1 30 that derived benefit from immunotherapy. Um We're the ones that were PD L. One positive. So amongst bracket carriers we still identify who will benefit from immunotherapy based on Pd L. One. Um for um I would still um personally recommend in a Pd L. One positive patient doing chemotherapy with immunotherapy in the first line setting. And the reason for that is that there is a substantial overall survival benefit. Um And it's it's important for me to talk to my patients about what their goals are. Um But for the majority of patients you know their their goals are to live you know as long as they can. Um That is not some people's goals but but that is a lot of people's goals. We would talk about goals and if that was a goal I would want to offer anything up front that was going to prolong survival the most which even in a bracket patient would be immunotherapy added to chemotherapy. Unfortunately um part inhibitors have they're more successful in the second line and beyond than chemotherapy. But they have not shown an overall survival benefit. And for that reason I would not unless the patient was really adverse to chemotherapy. And despite my counseling you know wasn't concerned I would I would still do chemo and immunotherapy in the first line outside of a clinical trial of course. Um there are some clinical trials that are looking at part inhibitor and immunotherapy combinations together and if we had a trial like that I would absolutely recommend it. Um But outside of a trial um it's it's not standard um or approved. So we can't do harp inhibitor immunotherapy combinations outside of a trial. But it would be a very exciting trial to look for. Yeah, definitely. Um For the next question it's for pd L one cps greater than 20 and 60% T. I. L. S. Or tumor infiltrating lymphocytes. Any consideration of using keytruda alone. So I'll take this one um they that it does actually have um FDA approval for um tumor um additional barden that is elevated as a single agent however um with the cps there is there is such of a correlation but no strong enough to justify the use of alone. I would say. We know that in triple negative breast cancer specifically for stage four the improvement of the outcome in terms of progression free survival and overall survival were seen with the combination of Chemo terry. Um I we we actually have also seen um we have done some study here at Dana Farber where we looked at the tumor mutation. All barden. The tumor mutation all body for which keytruda was approved was actually around 10 mutation for mega base of D. N. A. While the activity in breast cancer it's we've seen for single agent a little higher than that. So I would still prefer to treat such a patient with high PD L. One score and deals with the combination of um chemotherapy plus keytruda immunotherapy. Um Of course there are there are clinical trial ongoing with single agent immunotherapy. However for for breast cancer we are learning more and more. The combination with chemotherapy helps. And also early on we see better responses as well. Great thank you. Um So the next question is I'm onto centric as a single agent. I have stage four triple negative breast cancer. It's working to keep my tumors stable. I was previously on carbon Platten is my case an outlier to two years stable. I'm happy to answer this one. Two centric or tess Eliza mob was our first FDA approved immunotherapy in PDO and positive triple negative breast cancer and there was subsequently a negative trial. So then the company decided to withdraw um It's F. D. A. Application. So eccentric no longer approved. However any patient that is deriving benefit from two centric, we we've kept them on because if a drug is working, why why would we want to stop it. So, so first of all that's wonderful that you've been to your stable onto centric. Um just statistically I would say that yes yes you are an outlier. Which is great news. Um You know we know the average amount of time that chemotherapy and immunotherapy works and and it's usually around you know 5-7 months. So so two years. But those are medians. So you always talk to a patient that you know, I can tell you statistics but I can't. You are an individual. And and we'll just have to see how you do personally. So I would say that yes you are an outlier. You have um one of those breast cancers that is most responsive to immunotherapy. Um and and and that would be my answer. Okay so the next question is regarding her too low. And trust is a mob directs to can from a patient caregiver perspective since triple negative breast cancer is considered to be a heterogeneous disease. Should one ask their oncologists and pathologists to be extra careful in declaring our tumor her two negative. Yeah, this is a very actual question. A very great question that we actually debated a lot here dana Farber with our pathologist as well. Um The first of all when they actually there are some of the destiny trials that are the clinical trial with Henner to that have shown responses even we then have two on zero. So this tells a lot about two more heterogeneous city and also the quality of the actuality have to immunize sto chemistry score. The type of score was developed about 20 years ago for trust that is an anti her two therapy. And was just mean to look for like extremely positive versus like negative I think pathologies they are aware of these and they are very careful about calling zero versus one plus or two plus now. Um The um it is also sometimes important to re biopsy the tumor site uh in order to look for you no more either raja Nadiya for um for for a higher score on a have to. Um So it's um they are aware of that and um I think to T. D. X. D. Is is an excellent drug for um for patients that have had too low right now. So and and we are glad that FDA um approved the drug for I have two negatives. So either you are positive than have to you know your negative have two negatives or triple negative breast cancer. And the next question is what non medical interventions work best to help prevent or slow tumor progression. Oh I leave it to. Thank you. Um This is a very good question. Um Outside in metastatic triple negative breast cancer. Um systemic treatments are you know that we've been discussing are are what works best to control tumor growth and prolonged survival um interventions outside of that such as surgery um has never been shown to help. Um You know, there's a lot, there is a lot of research going on um looking at diet and exercise and non pharmacological interventions and how that might improve patient outcomes. Um We don't have any data to date to say that a certain diet such as you know, the ketogenic diet or intermittent fasting or anything like that can improve outcomes. Um But with that being said, I do think that it's very important um for my patients to stay active and and have a healthy and well balanced diet. Um But unfortunately there have not been any non pharmacological interventions to date um that have been shown to improve outcomes in metastatic triple negative breast cancer. But I do think that leading a healthy and active lifestyle is really important. I agree. And I was my vision to you know keep doing activity, physical activity if they can as as as much as they can tolerate to to keep you know their performance status and what they do in life and to preserve the quality of life also. It's very important. So the mental status will help with you know, going from from a treatment to the next and um improve the overall outcomes because we know that keeping a good performance status will improve the outcome when you go as the data show when you're gonna face one clinical trial that performance study is actually the most important value in order to see the um the in order to determine the efficacy the activity on a study. And I would just add, you know, it's really important if you're considering any medications outside those prescribed by your medical team to just talk to your medical team about them. Um because we would just want to make sure that anything that you were trying was safe and was not going to negatively impact the treatment that we know would help. Um So these next two are not questions. They're nice comments. Um The first person said, I just want to thank you for all the work you're doing on stage for triple negative and a mom. Your efforts are giving my family and myself and my child a new life. So much gratitude. Thank you. And the next one says thank you for your kindness and education and for letting me be the first and now back to the questions we have. I'm a stage four metastatic triple negative breast cancer. I'm fully clear after chemo and Pem bro currently on immuno an elaborate any other suggestions? So this is very interesting actually. The next two questions. Um it seems like our patients that are video and positive have received chemo therapy with immunotherapy and are also Bracha positive. So they've been placed on kind of maintenance, what I would call maintenance therapy with elaborate and immunotherapy. Um I actually did a clinical trial of of maintenance elaborate and volume of after platinum sensitivity um that I'll be presenting this year at SAn Antonio. And there's a phase three trial called Key link. Um That's specifically looking at this question if you have a very good response to platinum based chemotherapy and immunotherapy um can you then go on to maintenance either immunotherapy alone immunotherapy with apart inhibitor or chemo therapy and which which will work better. Um So I would say that that your treatments are are novel right now and and are still under investigation as to whether or not you know they're better than chemo but you know your medical team has has put you on a treatment and um generally in metastatic breast cancer um we treat with a treatment until your breast cancer is no longer controlled anymore on scan. So until there's progression. Um and we generally don't stop a treatment until there's progression or until you're having a side effect that um you know is is impacting your quality of life and and makes us not want to give you that treatment anymore. And it's always a discussion. So I would say you know that in general we continue a treatment um until it's not working anymore. You're having an intolerable toxicity or side effects from it. Um And the short answer is there's gonna be a lot of options for you when those two therapies are not working any longer. Um And um I don't know how aggressive you are Antonio about re biopsy in but um especially in my patients that have had these long term disease control on immunotherapy or immunotherapy and then part inhibitors I do find it helpful especially now that we have this for too low indication. Um To probably re biopsy the tumor at the time of progression. Recheck what you're hurt too. I. H. C. Scores are um you know and and then make a decision based on that. But you know you'll have clinical trial options at the time of progression. Um We have to choose a mob if you're hurt too low. You know tried L. B. Will be an option. We have standard chemo is an option and um the field is only moving forward. Um So lots of options. Lots of hope. Great. And yeah that answered both of those two questions. Um So the last question is how about the treatment for the patient who still has 10% from 90 during initial diagnosis at the recurrence is chemo plus keytruda. Still the first line treatment for this patient at early stage pd L. 1 10%. Yeah that's a great question. Um Historically how we The term in triple negative breast cancer has actually changed with time. One time a long time ago the positivity for er was 10% and that was lower to 1% technically. Um for the F. D. A. Approval of keytruda plus chemotherapy the tumor must be less than +11%. However um We pretty much believe that below 10% the estrogen receptor is not gonna really um play an important oncogene IQ role like is probably not the important gene um for that type of tumor. Um Dana Farber is not an issue because we have actually a clinical trial for a patient with less than 10% with immunotherapy and chemotherapy. But I would say um that based on the of the time interval of the recurrence would be also important. So if it slaps a very long time between the first diagnosis and the recurrence and The patient would be was on an aromatase inhibitor on tamoxifen in somebody with a low burden of disease a good quality of life. I would still with a tumor that is around 10% and not in what's like an imminent visceral crisis like numeral mitosis in the language deliver. I would probably try a selective estrogen receptor the greater Um like full restaurant that is approved for 10% er positive her two negative breast cancer. Um because there is um there are some tumors that even if they lower the estrogen receptor expression in the surface they still depend on the estrogen receptor activation and served in that in that specific population could still work. Uh So I would not necessarily jump on pembroke, oh plus you know abraxane for such a patient um Still trying like a certain like full restaurant unless there is an imminent um need for chemotherapy. The other thing is doing that way. You know with hormone therapy first is not gonna preclude the um you know the approval of the the activity of the chemotherapy plus in unitary. Okay great. So a couple more questions came through. Um We have reached 12 30 but are you two okay with answering two more? You can do two more and then cut it off. Yeah. Okay so the next one is for metastatic triple negative breast cancer. How many years of no evidence of disease could be enough to consider stopping current treatment. That's a really good question. Um And I would say a pretty unique um scenario in metastatic triple negative breast cancer. Um In general. Um Certainly wonderful to be thinking about that. Um In a position if you are any d after a couple of years for for my patients specifically um that have these long disease free intervals that are any d for several years. Um Usually on immunotherapy um You know we continually just talk about how are they doing um If they're not having any toxicity um from the treatment if they're tolerating the treatment quite well. Um Then I generally um recommend continuing. Um We don't have any data um Today in 2022 in metastatic triple negative breast cancer to tell us. Um If we stop treatment after a long disease you know being any d for a long time after immunotherapy, how many patients they're disease will come back. We simply don't have that data. We have data from years prior telling us that there is a benefit in doing sequential chemotherapy. So just continuing treating and not doing treatment breaks. So we know that there is a benefit to to continual therapy. Um But we are in this new realm of these people of of patients. The minority of patients that have long term you know disease control with immunotherapy. And the short answer is we don't know if it's safe to stop ever and and if it would be better to continue. Um So as long as the patient is tolerating therapy um I genuinely I generally continue it. I don't know if you think about it any differently uh Antonio. No. So the that's a great question because in other in other disease they actually stop like melanoma and cancer. Historical impressed. We are always we always fear about stopping with Dana Farber. We are actually gonna start studying that. We are gonna start from her two positive disease with a clinical trial. That is um where we are going to observe patient any d on have to ante have to therapy. Um So you know like stopping the anti her two therapy for triple negative. I would say it also could make sense based on the how fast and proliferating ourselves And the idea that cut off would be about two years. So after two years. Um Biologically we could stop. However in my practice I probably would not do it without a clinical trial. I would not be comfortable dropping if if of course the patient is tolerating the treatment without any side effects in melanoma and lung cancer. And patients that have these immunotherapy complete responses they generally stop after two years. Um And we just don't have that data today and triple negative breast cancer. So it's a case by case basis a discussion um with your clinical team. Great. And the last question is any advances on personal vaccines. There is a lot of work on that um Like building vaccine based on tumor specific individually. Um Is is still in a very early phase right now. Um We are actually trying to work some you know um cell therapy based on um specific antigens on triple negative breast cancer. However we are not ready yet for an individually based vaccine. Um Is all very in very early phase right now. Okay. Um and that was it for the question and answer portion. So I'd like to thank Dr Sammons and dr Giordano as well as all of the participants here. Um And the recording of the session and the calendar of upcoming sessions will be posted on the D. F. C. I embrace web page. Thank you for having us. Thanks. Organ
