Breast cancer is one of the most diagnosed cancers among women, with an estimated 2.1 million new cases of breast cancer globally each year. Immunotherapy for breast cancer is developing rapidly following the first FDA-approved checkpoint inhibitor for triple-negative breast cancer in March 2019. New treatment regimens combining immunotherapy with chemotherapy, radiation, or surgery are showing promise in clinical trials. Dr. Leisha Emens of UPMC Hillman Cancer Center will answer your questions and discuss current immunotherapy research for breast cancer.
Tamron Hall: Now, it’s my pleasure to welcome and introduce our expert in breast cancer and immunotherapy, Dr. Leisha Emens. Dr. Emens is joining us from the UPMC Hillman Cancer Center, where she is a professor of medicine, director of translational immunotherapy for the Women’s Cancer Research Center and co-leader of the Cancer Immunology and Immunotherapy Program. Dr. Emens is also joined by Barbara Bigelow, a breast cancer veteran who will moderate today’s session. Breast cancer is newly diagnosed in 2.3 million women each year, making it the most diagnosed cancer in the world, so thank you, Dr. Emens and Barbara for being here with us and answering our questions about immunotherapy for breast cancer.
Dr. Leisha Emens: My name is Leisha Emens and I’m a professor of medicine and the director of Translational Immunotherapy for the Women’s Cancer Research Center and co-leader of the Cancer Immunology and Immunotherapy Program at the University of Pittsburgh Medical Center, the Hillman Cancer Center. I’ve been involved in developing immunotherapies for breast cancer since about 1999, first on a breast cancer vaccine and more recently on immune checkpoint blockade, and it’s really a pleasure to be here today and to talk to you guys about the progress that we’ve made in using immunotherapy to treat breast cancer, as well as the future promise of expanding its use to even more patients. So just by way of introduction, I’d like to use a few slides to give you a broad overview of where we are. As you all probably know, breast cancer is a very complex disease, very heterogeneous group of diseases. You can broadly define breast cancers into several different types that are clinically relevant by far. The largest group of breast cancers expresses hormone receptors, meaning that they are potentially responsive to endocrine therapy that blocks estrogen signaling. These cancers that are hormone receptor positive but negative for another growth factor signaling pathway, called her to account for almost three quarters of breast cancers. The HER2 breast cancers express a protein on the surface of the cells that actually gives the cells gas and encourages the tumor cells to grow. Some of those are hormone receptor negative and are really driven only by this overexpression of this HER2 protein when you think about it from a simple point of view. So you would only treat those tumors with HER2 directed therapy. Some of these expressed both hormone receptors, as well as the HER2 protein, and you can utilize both HER2 directed therapies, as well as endocrine therapies for that group of tumors. Her2 overexpressing breast cancers account for approximately 15 percent of breast cancers overall. Finally, there’s this a group of breast cancers that we call triple negative breast cancer, and that group is really defined by what they lack. So they do not express the estrogen receptor or the progesterone receptors, the two hormone receptors, and they also lack expression of HER2, hence the nomenclature we use triple negative. You have to keep in mind, though, that this accounts for 13% of breast cancers overall and within this group, there’s actually a lot of biologic heterogeneity. So triple negative breast cancers are pretty diverse and they have different types of biology’s, and that’s really a major challenge for us to work on in terms of developing therapies that can specifically target the biology of each of these distinct types of triple negative breast cancer.
So getting to immunotherapy, we typically use immunotherapy at this point in combinations and the most straightforward combination to think about our standard cancer therapies, such as chemotherapy, radiation therapy and targeted therapy. The advantage of using these in combination with immunotherapy is that they induce something called immunogenic tumor cell death in the cancer cells so the cancer cells die. Respond to these therapies in a way that enables the immune system to see them. Dendritic cells are actually the minesweepers, let’s say, of the immune system. So these dendritic cells come into where the cancer cells are dying and kind of like Pac-Man, take up and break apart the little bits of the cancer cells that they engulf and then break them down into small pieces and present them on their surface, where you can see that triangle presented on the MHC molecule, which denotes itself. So the T-cells are actually the workhorses of the immune system, and they are the cells that kill the cancer cells. The job of this dendritic cell, the minesweeper cell, is to educate the T-cell and to teach it what to go out to search out and destroy. You can see this education process happening on the right-hand side of this slide. The T cells express other proteins that help control how activated they become, and PDL one is one checkpoint that’s expressed on T-cells that help to down regulate the extent of T-cell activation, and that helps prevent the T cells from becoming over activated.
So this educated T-cell then goes and finds an intact cancer cell. It’s been educated what to recognize. The cancer cell actually is a pretty wily thing, and it hijacks part of the immune system that helps control overreaction. So the cancer cell itself actually expresses PD-L1. On the surface, T cells, in addition to expressing PD-L1, express the receptor for PD-L1 and the interaction of PD-L1 and PD one actually shuts down the T cells the way that immunotherapy works. It’s an antibody that blocks that interaction between PD one and PD-L1 prevents that break from being put on the immune system and allows the T cell to become activated and kill the cancer cell and that’s shown here, so you get elimination and this breaking apart of the cancer cell can then kind of reignite the process again and hopefully keep it going until everything is eliminated.
So we now have some FDA approved immunotherapies for triple negative breast cancer. There are three different regimens in two different settings that have shown promise. The first is the combination of atezolizumab and nab paclitaxel for advanced or incurable PDL one positive triple negative breast cancer, and this was given accelerated approval pending further information, and it actually was just voluntarily withdrawn so that accelerated approval is no longer applicable. The combination of pembrolizumab and chemotherapy for advanced or incurable PDL one positive triple negative breast cancer currently has full approval from the FDA, and this is generally for metastatic disease or locally advanced disease. It’s not resectable, and it’s specifically it’s important to keep in mind that the disease has to be PD-L1 positive and then the combination of pembrolizumab and neoadjuvant chemotherapy was given full approval, also for high risk stage two and three triple negative breast cancer, and it’s important to keep in mind that in this setting, PD-L1 expression by the tumor is not required. Whether your tumor is PD-L1 positive or negative, you can still benefit from the addition of immunotherapy to chemotherapy. So this is just the beginning of the progress that we need to make, and clinical trial enrollment remains a priority so that we can further understand the benefit of checkpoint inhibition in breast cancer. As you can see, from what I just told you these, this progress has been made specifically in triple negative breast cancer, which only accounts for about 13% of breast cancers overall. So we have a lot of work to do for the hormone receptor positive breast cancers, as well as the HER2 positive breast cancers to make immunotherapy a reality for them. Thank you very much for listening, and I look forward to the discussion.
Barbara Bigelow: Hi, this is Barbara Bigelow. Thank you. Dr. Emens for such a great presentation and the slides, I’ll be moderating this panel. I am a breast cancer patient and advocate very long term. I’ve had cancer for over 19 years. I became metastatic 13 years after remission. I was initially ER-positive and I mutated to triple negative. I also went into a clinical trial of immunotherapy with chemotherapy. I had one of the most adverse reactions. You could have had long term hospitalization, but I have been without any evidence of cancer and without any treatment in over five and a half years, which is kind of unheard of for triple negative metastatic breast cancer. So we’re going to be talking about that a lot in the coming questions, and I just want you to know that on the right-hand side of your screen, that’s a place for the chat where you can see questions, and if you don’t get a chance to get your question in, they will be answered later on in the blog at the Cancer Research Institute. So having said all that, thank you for being here, Dr. Emens, and I guess the first question I would have would be, can you tell us something about the global field? What’s the most promising things coming up in clinical trials with immunotherapy?
Dr. Leisha Emens: Well, you know, I think everyone’s really excited about the clinical activity and the relatively favorable safety profile of PD-1 and PD- L1 blockade for breast cancer. So for triple negative breast cancer, the most promising trials I think we have now are trying to build on that and make it better. There’s an overall survival benefit with the current immunotherapies of about seven months, which is pretty significant for that particular disease, but obviously we need to do better for more patients, and some of the things that we can think about doing are adding additional immunotherapies to pembrolizumab and chemotherapy. It’s almost like there are other pathways that put additional brakes on the immune system, and there may be a redundant break that’s in place even when you get immunotherapy. So you may need another agent to take that second break off, almost like having the regular foot pedal break in the emergency brake in your car, so you might need two ways to take that negative effect on the immune system off. There are some very interesting, for example, antibody drug conjugates where the antibody targets specific proteins on breast cancer cells. So it’s precision medicine and it’s got either chemotherapy or other drugs directly linked to it. Those are showing great promise for both triple negative breast cancer, as well as HER2 positive breast cancer. Some of the ones that are harnessing the potential power of the immune system is that there are trials that are testing those antibodies, like antibodies that target HER2, and instead of attaching a chemotherapy drug to it, they attach a type of drug that can activate a different part of the immune system than the T-cell, and that can potentially be synergistic. So I think there’s a number of different potentials, highly-promising approaches. The other interesting combinations to think about are these antibody drug conjugates, which look very promising in and of themselves, and combining those with immunotherapy may be a very powerful way of improving our results.
Barbara Bigelow: Wow. One of the questions we have is, “If an immunotherapy treatment for triple negative breast cancer is voluntarily withdrawn, can a person still access it at a later point in time?”
Dr. Leisha Emens: So the expert thinking on this is that with that voluntary withdrawal, the drug is not available to be newly prescribed to patients because we now have an effective combination with pembrolizumab and chemotherapy for advanced disease. However, for those patients who’ve been on atezolizumab and are benefiting from it clinically, I think I think the expert opinion is that those patients should and will be allowed to remain on that drug.
Barbara Bigelow: Ok. Is there a recommended duration of immunotherapy treatment advised a certain length of time, you should be using that drug?
Dr. Leisha Emens: So that’s a pressing question in the field. In the metastatic setting, we’ve tended to continue immunotherapy as long as it was working. That’s typically how we’ve managed advanced stage disease. That’s how the drug Herceptin was developed, and that leaves open the question of how much is actually enough and do we really need to keep giving these expensive drugs to patients? So I think there are a number of trials that are looking at the duration of therapy, and it remains an active area of importance and investigation because of the cost of the drugs and the potential toxicities with prolonged exposure to the drugs, and it may be that you only need a more limited exposure because the whole job of your immune system is to discern what is you and what’s not you. If it’s not you, it’s a threat, and the immune system is designed to remember that threat so appropriately given and active, the immunotherapy should induce a durable ability of your immune system to recognize the cancer.
Barbara Bigelow: Ok. Do patients need to discontinue other treatments they might be on in order to access the immunotherapy?
Dr. Leisha Emens: I mean, in general, immunotherapy is given as a very defined treatment, so if you are on other cancer treatments, generally, you would stop those treatments and be given if you’re eligible for it, the immunotherapy that’s approved for your clinical situation. So you don’t typically add a bunch of stuff together to see how things go. So you usually you follow the data pretty strictly.
Barbara Bigelow: Okay. Here’s a question, “I have autoimmune diseases and metastatic breast cancer. The treatments for these two diseases often clash. Would you recommend immunotherapy for someone like me?”
Dr. Leisha Emens: So that’s a really good question. It’s also an area of active interest for our community. Just to kind of reiterate, this PD-1 PD-L1 pathway is the pathway your body uses to not get autoimmune disease. So by virtue of the fact that you have an autoimmune disease, you may be more at risk for the autoimmune side effects of immunotherapy. The very first trials did not include patients with autoimmune type diseases because of that perceived risk. Now that immunotherapy has been available to patients with various types of cancers for a while, there are certain situations for it with certain autoimmune diseases, depending on their severity and depending on what cancer the patient has. Where a physician may try immunotherapy, but the risk is certainly higher, particularly if you if you have required significant systemic immune suppression for your autoimmunity in the past and depending on how well controlled it is.
Barbara Bigelow: Does immunotherapy treatment affect fertility? I think that’s a great question.
Dr. Leisha Emens: That is a great question. Cancer treatment in general affects fertility, and I think we are early in the use of immunotherapy for breast cancer patients, so the young breast cancer patients that are treated and have a great response. We don’t have enough data to really know what the long-term risks of infertility are. I think you would have to assume based on the fact that we know the side effects of immunotherapy could be an autoimmune type reaction and almost any organ site with different frequencies, depending on the organ site that a long term. A problem with infertility could certainly develop, so what I would recommend for young patients about ready to embark on immunotherapy if future childbearing is an interest of yours and is appropriate for you, then I would explore fertility preservation up front.
Barbara Bigelow: Good. That’s good to know. We talked about this a little bit if the side effects of the immunotherapy are too severe. Can you discontinue it for a period of time and then resume it later? Or would it just kick back to having those same severe side effects?
Dr. Leisha Emens: Yeah. So the unique side effects of immunotherapy are these autoimmune type side effects because of the normal job of the pathway that we’re breaking down, right? So usually if a patient develops a very severe autoimmune side effect that requires high levels of systemic immune suppression to get it back under control, it’s considered too risky to reintroduce immunotherapy to that particular patient because the likelihood is that it could happen again if it’s a more low-grade autoimmune type side effect. Typically, what we do is get the patient down to a reasonable dose of steroid, and for these lower grade autoimmune type side effects, sometimes we will reintroduce the immunotherapy, so it really is a case by case basis.
Barbara Bigelow: Yes, I would think that would be extremely individualized. Myself, I have permanent renal damage and have to take steroids for the rest of my life, I can’t function without them, so I mean, that’s also when you’re weighing whether to do a clinical trial and the possibility of side effects that might be permanent, versus the outcome of the trial is, I have permanent side effects, but I’ve been cancer free and all treatment for over five and a half years, and I wouldn’t have gotten those five and a half years if I hadn’t done the clinical trial. So I think that’s something patients always have to bear in mind that. You really have to talk to your oncologist and really consider all of those questions. Here’s a question, “I have an inherited BRCA mutation and a family history of breast cancer. Does this mean I could benefit from immunotherapy if I were diagnosed with cancer?” You’ve kind of answered that already, but…
Dr. Leisha Emens: Yeah, I mean, there’s in the early stage setting, you know a feature of a BRCA mutation is that it sets your tumor up to express mutated proteins. They’re more likely to be seen as foreign by your immune system because they’re not normal proteins, and we think that there’s a possibility that those tumors may be more readily recognized by the immune system. We also have PARP inhibitors for patients with BRCA mutations, and those drugs may be able to work well with immunotherapy. So I think we’re still learning a lot about that, and stay tuned for the next wave of data.
Barbara Bigelow: This is a question, a live question from Barbara, “I was diagnosed with breast cancer at an early stage and opted for a mastectomy. I read that there is a risk of this cancer recurring in five to 10 years as metastatic. If my breast cancer recurs as metastatic, am I a candidate for immunotherapy?” Well, I think isn’t there a 30% chance of recurrence in early stage breast cancer?
Dr. Leisha Emens: There is a chance of recurrence if you are diagnosed with metastatic breast cancer, typically what we always do is re-biopsy at the time of relapse to make sure that the tumor is still the same has those same air and HER2 proteins that it had when you were diagnosed. Because sometimes they switch. So it’s really important to make sure of what the biology of the tumor is at the time of relapse if it is triple negative. Currently, that’s the only subtype of breast cancer that has an immunotherapy option. We would test that tumor for PD-L1, and if it’s triple negative and PDL one positive, you would be a candidate for immunotherapy, most likely.
Barbara Bigelow: I have been hearing a lot of people questioning getting into clinical trials who are not triple negative and don’t have PD-L1 positivity and are trying to circumvent to get into clinical trials for immunotherapy. Is that just a rumor or are people actually doing that?
Dr. Leisha Emens: Well, there are trials for other subtypes of breast cancer. Kate two is a trial that tested Atezolizumab, the anti-PD-L1 antibody with Kadcyla, the TDM-1 one antibody that was specifically for HER2 positive breast cancer patients. Patients had to be advanced and incurable, but they did not have PD-L1 expression to be enrolled, and what we learned from that phase two trial is that it appeared that the PD-L1 positive patients like triple negative breast cancer were the ones that benefited. So we took those findings, and there’s now a phase three trial. Looking at this question of whether the addition of atezolizumab to TDM one or Kadcyla can improve outcomes relative to TDM one alone in this patient group, and for that trial, it requires PD-L1 expression because of what we learned in the phase two. There’s also great interest and much less progress in developing immunotherapy for, ER, positive breast cancer. The immunobiology of ER positive breast cancer is very different from the immunobiology of HER2 positive and triple negative breast cancer. I think what we know is that triple negative breast cancer is the most immune activated. Not all of them are, but it’s the most likely to be immune activated. Of the three main subtypes, HER2 is slightly behind that and ER-positive breast cancer is really pretty cold, so it’s not very immune activated. It doesn’t have very many T cells in it. It’s got a lot of macrophages and things that suppress the immune system. So we have a lot to learn about how to kind of transform those ER-positive breast cancers into a more activated tumor with the capacity for responding to immunotherapy. So there are trials looking at that, but they’re much earlier on in the road to progress.
Barbara Bigelow: Ok, I’m glad you answered that. “What is the industry’s standard for surveillance after immunotherapy is concluded? What is the timescale for follow up scans?”
Dr. Leisha Emens: So that really so in the advanced disease setting, we tend to follow patients who’ve been treated immunotherapy much the same way we follow patients treated with traditional chemotherapy. Some physicians don’t scan as long as you’re feeling well. Others scan intermittently and let the frequency be guided by symptoms for early stage disease. We typically don’t do scans because earlier trials have demonstrated that the best way to follow people who’ve been treated for cure with either adjuvant or neoadjuvant therapy. The best way to follow them is simply with routine mammography and physician exams, and that scanning patients in the early stage setting doesn’t really change overall survival, and it just spends a lot of money and creates a lot of anxiety.
Barbara Bigelow: Ok. This is a question I think we’re going to touch on a little bit later, but, “Thinking about can breast cancer treatment ten years from now, do you think that surgeries like lumpectomy and mastectomies and chemotherapy will be a thing of the past?”
Dr. Leisha Emens: That’s a really good question. So, you know, there’s great interest in and breast cancer has really led the different types of cancer in this regard. You know, we’ve always developed approach to treating cancer as adding more on so we can do better right? Now we’re very interested in can we peel some of the stuff back for certain patients so they don’t have to get so much therapy that they may not need all of it? So there are trials that are looking at giving neoadjuvant therapies and in patients who have an exceptional response so that they have no evidence of disease after the neoadjuvant therapy, they’re randomized to either surgery or no surgery to see if those patients really still need to have surgery or can they get away without that? I think we’ve seen over the years a de-escalation of surgery on the axilla or the armpit where we used to do a full axillary dissection. Now we do a sentinel node biopsy that’s much less aggressive, and now for some low risk tumors in elderly patients, we don’t even look at the nodes sometimes, and then, of course, with mastectomy or, you know, removal of the breast, that surgical approach has changed dramatically from the initial very radical mastectomy, and now we tend to use lumpectomy and are actually looking at what I mentioned, you know, not even using surgery, potentially in the future in these exceptional responders to. Neoadjuvant therapy.
Barbara Bigelow: That’s exciting. I know you’ve talked about car T cell therapy before, but “Can adoptive cellular therapies like CAR-T cell therapy be used to treat breast cancer?”
Dr. Leisha Emens: So there are two main challenges, CAR-T has been a huge success for certain hematologic malignancies, and when you think about it, that kind of makes sense because those tumors are widespread and circulate in the blood and they don’t form a big mass. So the two challenges for solid tumors is that they do have a solid tumor mass and it’s hard for the adaptively transferred cells, whether they’re ’till or CAR-T to get into that tumor just because of the physical barrier. The other challenge for solid tumors is that the antigens in those tumors are typically expressed on some normal tissues, too. So there’s the potential for the transfer T-cells to recognize not just the tumor, but, for example, maybe lung that expresses her, too, if it’s a HER2 car and destroy your normal lung tissue, too. So finding the right antigens to target is going to be critical to utilize them in solid tumors compared to the liquid tumors.
Barbara Bigelow: Here’s a live question. “What exactly is it PDL one for and what is the cutoff of PDL1 for treatment?”
Dr. Leisha Emens: So for pembrolizumab, which is the current FDA approval, the score is something called a combined positive score, and it looks at PD-L1 expression in the tumor microenvironment and calculates it based on expression in immune cells and tumor cells and other cells in the tumor microenvironment, and you get a score in order to be eligible to receive pembrolizumab. Your score has to be at least 10 or more for atezolizumab. When that was available, the assay was very different and PD-L1 expression was scored on immune cells only, and they calculated that as a percentage of PD-L1 positive immune cells within the tumor microenvironment, and for that particular score, you had to have a percentage of at least one percent. So currently, the one that’s relevant for breast cancer is the CPS score, and for metastatic disease, it has to be at least 10.
Barbara Bigelow: Ok. Must be hard if you’re a nine. This is a good question if you don’t know anything about immunotherapy, “How often is the treatment given?”
Dr. Leisha Emens: Yeah, so pembrolizumab is given every three weeks at 200 mg IV, atezolizumab has several different dosing schedules just because of the way it’s cleared from the body, so you can get atezolizumab at different doses. So there’s an every two-week dose and every three-week dose and in every four-week dose. Pembrolizumab, we just have the one dose so far that I’m aware of.
Barbara Bigelow: “Is there a particular chemotherapy that you like to combine with pembrolizumab?”
Dr. Leisha Emens: The trial with pembrolizumab that tested it in advanced, incurable disease, tested it with either NAB, paclitaxel Taxol or the combination of Jim and Carbo. If you look at the clinical activity, it looks like there may be more activity with Taxol than the other two. But you have to choose it based on. What you’ve been exposed to in the past and how long it’s been since your last treatment, so.
Barbara Bigelow: Yeah, I mean, I was seeing a patient might be thinking I would only go once every three weeks and get the pembrolizumab when in reality you’d go every three weeks for that, but maybe biweekly for the weekly.
Dr. Leisha Emens: Yeah.
Barbara Bigelow: So I mean, it doesn’t. That’s quite a few appointments at the infusion center, which I don’t know if that’s clear to patients at the outset that their treatment will be quite complicated and there will be a lot of surveillance going on.
Dr. Leisha Emens: Agreed.
Barbara Bigelow: We have ten minutes left, so I just want to make sure we’re keeping on track. How has immunotherapy changed your outlook on cancer care as an expert?
Dr. Leisha Emens: I mean, I think this is the future of cancer care. It’s very gratifying to see immunotherapy finally work in the clinic. People have been working on it for 100 years. I started out my career developing a vaccine and trying to harness the immune system, and, you know, the great success in vaccines has been with infectious diseases. We’ve eradicated some from the face of the Earth, and the reason vaccines work is because they educate your immune system to recognize these foreign invaders as a threat and as dangerous, and to eliminate them, then the immune system establishes memory so that if you get re-exposed, it immediately becomes activated to get rid of that threat. So the hope is that we can optimize that process for immunotherapy, for cancer and really create the situation where it’s your immune system and not actually giving you the drug. That’s going to give you the protection from recurrence because that’s the job of your immune system is to recognize what is you from what not is you and then to protect you from that threat and what not is you as a threat? So I’m very optimistic that we’re going to make a lot more progress.
Barbara Bigelow: This is another live question, ” Can immunotherapy be combined with oncolytic viruses to treat more types of breast cancer?”
Dr. Leisha Emens: So that’s a great question. Oncolytic viruses are often given intro-tumorolly or provide it in a way that they home to the tumor, and that would be one way, for example, of transforming a cold tumor to a hot tumor that’s immune activated and then coming in with immunotherapy. So that’s certainly one combination that’s under active investigation.
All right, thank you. We’re just about time to wrap up, I want to thank you, Dr. Emens, for the great responses I know we kind of jumped all over the board there. For those of you watching, we’d love for you to respond to the poll. What was your biggest takeaway from this conversation today? There will be more questions answered on CRI blog. So stay tuned for that and thank you ever so much.