Dr. Lim Hi, I'm Dr. Bora Lim an associate professor of Breast Medical Oncology at MD Anderson Cancer Center. I'm here today with my good friend, professor of Breast Medical Oncology at MD Anderson, Dr. Rachel Layman. Thank you for joining us today. This is the Cancerwise Podcast. Dr. Layman, thank you for being here today with me. 

Dr. Layman Yes, great to be here. 

Dr. Lim You and I have worked together for a number of years, you know, to curate and then treat patients with one of the most difficult cancers, inflammatory breast cancer. Can we start by you sharing some overview about the inflammatory breast cancer today? 

Dr. Layman Yes, of course. So unfortunately, inflammatory breast cancer is probably the most aggressive type of breast cancer that we see. It's fortunately rare. So only about 2% to 4% of breast cancers are inflammatory, but it's responsible for up to 10% of breast cancer deaths. So, we have to treat this very aggressively. Inflammatory breast cancer presents a little bit differently than we might expect for other breast cancers. Mammography screening usually does not pick up this cancer early like it does with other cancers. Typically, patients are diagnosed in between screenings because it tends to come on so fast and it may or may not have a breast mass associated with it. What we typically see is that one of the breasts becomes very inflamed-looking. So, it may become red. It may be swollen. And sometimes we see these skin changes, which are called "peau d'orange" meaning "skin of the orange." And so, what that can look like is the skin can look, have dimples similar to what you might see on an orange. And that can be associated with some of the swelling that we see. If patients develop these signs, they might have inflammatory breast cancer. In order to have a diagnosis of inflammatory breast cancer, the patient also needs to have a biopsy showing that they have invasive breast cancer. 

Dr. Lim Yeah, I mean, it's very hard to diagnose. And I know that you and I have treated a lot of patients. And one of the things that I kind of noted by talking with the other, even breast oncologists, is that there are some differences in their pathology when we look at their tissue, and even the sequence and maybe the team members of the treatment might slightly different than the other breast cancers. 

Dr. Layman Yes, that's true because of the aggressive nature of this cancer and because it involves the skin, we typically need to treat it with chemo first before doing any surgery. And typically, these cancers are not considered operable at first diagnosis. Unlike other cancers of the breast, there is not a stage I or a stage II inflammatory breast cancer. So, inflammatory breast cancers are either stage III or if the cancer has spread to other parts of the body, it could be stage IV at diagnosis. And the cancer is best treated with a specialized team of doctors. And that would include a medical oncologist to give chemotherapy and other medications, a surgical oncologist to do surgery after chemotherapy, a radiation oncologist to give radiation after the chemo and surgery, and we also work closely with our pathologists regarding diagnosis and our radiologist, regarding determining the extent of disease and how the disease is responding to treatment. 

Dr. Lim Yeah, that is very accurate. And I also know that compared to some of the other breast cancers that we see common in the clinic, these patients tend to be a little bit younger in general, you know, so if you caught the median age, there's a certain shift. And I think you and I also carry a lot of patients that for more darker-skinned patients, you know, Hispanic background or Black background, and those patients, even with the same stage, tend to have a slightly worse prognosis. So, I think there's still a lot of things that unpack in those health disparity issues. Would you add any comments to that? 

Dr. Layman Yeah, I agree. We often see patients that are very young and many times when associated with a pregnancy. So, the problem with really young patients is that the doctors that they are seeing aren't expecting a young woman to have breast cancer. They think of breast cancer as being a disease in older patients. And so, sometimes there's a delay in getting diagnosed. They will be told that they might have an infection or it might be related to pregnancy and that it's probably not cancer. And sometimes the young patients, especially, end up going a longer time before being diagnosed, even though they are seeking medical attention. Also, as with many other types of cancer and diseases, we do see that sometimes the minority populations tend to have more aggressive disease. And in addition, they may not always have the best access to care. I think another thing that can be confusing regarding the inflammatory breast cancer in patients that have darker pigmentation is that their skin may not look red. So, I would say although we sometimes explain that you look for a red breast, red may not show up as red on someone with darker skin. So, I would say a change in skin color, not necessarily having to be red. 

Dr. Lim Absolutely. And then sometimes we may not even actually see the changes, the color itself, but just the texture or the heaviness. And we think that that might be coming from this existing tumor emboli, which goes and block this all the lymphatic ducts. So, while we are learning slightly more about the IBC, I think one of the major like, forefront of how we can improve the care of these patients is through the research. And I know that you've been leading the clinical research of IBC group at MD Anderson. Can you share some of your insights on why it's important and then what are some new excitements in that? And what are the some of the roles that patients play in there? 

Dr. Layman So, I can't express enough how important clinical research is to make progress with this disease. One of the issues with inflammatory breast cancer may be similar to issues that other, more rare cancers have: they make up a small proportion of breast cancers. And so, even if they're included in clinical trials, there may be only a very small number of these patients represented. So, it's hard to really get enough data to understand how these patients truly respond to the different treatments because the cancers often do behave differently from what we see from a non-inflammatory breast cancer. The other issue that we have is that many clinical trials exclude patients with inflammatory breast cancer. And this may be for several reasons. It is thought and I think there is some truth to this, that patients with inflammatory breast cancer may not respond as well as those without inflammatory breast cancer to the same treatment. So, sometimes the investigators don't want to have this poor prognostic population that would alter their clinical trial results. But I would argue that as they would make up a small percentage of a clinical trial for all breast cancer patients, it would be very unlikely that it would change the results. But it would be very important to allow us to learn more about inflammatory breast cancer. Many times we use treatments that have never really been evaluated in clinical trials for inflammatory breast cancer. We're using the results from trials that didn't have inflammatory breast cancer patients and trying to apply it to patients with inflammatory breast cancer. 

Dr. Lim So, the other thing I wanted to ask you, Dr. Layman, is that because we are dealing with such a rare type of breast cancer, the one of the key members in the society for not medical, but part of our day-to-day life called patient advocates. And I'm sure some of the audience are familiar with this patient advocates, but these are living patients who are either dealing with the disease itself or have dealt with the disease, or even have a family member who has succumbed to such a disease, and who are very passionate and deliver their efforts in very concerted or individualized way to help with the research and clinical activity in  the day-to-day. So, we work with the patient advocates all the time. But for the audience who are not too familiar with, can you just say a few words and how they're involved in our day-to-day clinical research? 

Dr. Layman Yeah, I'd be happy to. So, the patient advocates have been a really indispensable part of our program. They serve several purposes. One is they can be a resource for patients who are just received the diagnosis recently and who want to talk with someone who has been through this before, and can provide more information. They also can do a really good job of advocating for getting the word out about this rare disease and also trying to raise money that's needed to do additional research for this disease. But you also made a very good point that we can learn a lot from doing studies of inflammatory breast cancer. If a treatment works well in the most aggressive type of breast cancer, then it's probably going to work very well in non-inflammatory breast cancer as well. 

Dr. Lim Absolutely. So, I can share some examples of that. And so, of course, we treat a lot of IBC patients, but we also share a lot of non-IBC, who are also behaving very aggressively. For example, if you do have triple negative breast cancer, within that, there are very like, chronic inflammations where the cancer is behaving as if there are different cells like a muscle cells or other immune cells. Those have a very mimicking kind of criteria that, you know, sometimes patients or the physicians gets confused, especially in their advanced setting, that, you know, could it be IBC? And then by comparing and crossing and analyzing their tissue, we have actually learned maybe what these cancers share is something we call tumor microenvironment. You know how this IBC, we have done a lot of genomic testing? So, we dissected the small tumors. We collected like 120 patients, which is a victory for this rare tumor, analyzed them and dissected them, the oldest genes that we knew. Unfortunately, what we found was all the genes that were mutated or altered were not that different from the non-inflammatory breast cancers. It makes us wonder, then what is the secret of IBC behaving so differently? What we have discovered for the last few years is that if you actually take not just the tumors, but surrounding tissues and look into them in a really closer microscope, their immune cell who are supposed to be there to kill the cancer cells are not there or there are a lot of immune cells, but they're the bad players and blocking the good immune cells and interfering and then causing more chronic inflammations, make the patient sick, but not doing their job. So, studying this tumor microenvironment has opened up a lot of opportunities for even bringing the clinical trials that you are helping and co-developing with us. Such as, you know, there is this NewSTART study they were hoping to open next year that trying to get rid of these bad immune cells from the tumor microenvironment. And by doing so, we kind of opened the path for these new treatments to come in and work better. So, even if you deliver the same immunotherapy, it actually can work better. And the other aspect of such a, you know, improvement in the care is that while it is not really directly immunotherapy, the drugs using the antibody-based medications like antibody-drug conjugate, such as trastuzumab deruxtecan or sacituzumab govitecan, and there are many more that are coming in the pipeline. So, all of this something we called antibody-drug conjugate that delivers chemotherapy in a very specific, targeted manner in combination with the some of those new immunotherapy inhibitors and targeted therapies actually could eradicate some of the most aggressive breast cancers, like an IBC. So, we do have a trial in collaboration with the Boston team that we are developing it, the new treatments. And some of these agents may even cross the blood-brain barrier, which is another big problem for our patients. So, there's a lot of excitement that is coming up around. 

Dr. Layman I agree. And I think it is important to really think about also preventing brain metastases. We sometimes see that these patients will develop metastasis to the brain, but not develop it anywhere else, and it might be because of the blood-brain barrier, the treatments just don't penetrate into the central nervous system as well as to the rest of the body. And some of these drugs that are able to cross the blood-brain barrier are very promising, and especially for inflammatory breast cancer, where we see more brain metastases than we would expect in a patient with non-inflammatory breast cancer. 

Dr. Lim Yeah. Even for patients who are supposed to be having a really good prognosis,  by achieving like pathogical complete response. So, there's so much more to learn. In terms of the, going back a little bit on the immunotherapy, you are actually leading two main immunotherapy-based, IBC-dedicated clinical trials at MD Anderson. Can you share a little bit more about the insight on those trials? 

Dr. Layman Yes. And I think one thing that's interesting is that the trials are incorporating inflammatory breast cancer, but in two different ways, which provides an example of the different ways we can do clinical trials for patients with inflammatory breast cancer. So, one trial that we have is being run by the Southwest Oncology Group, which is a large cooperative group sponsored by the United States government. It does large clinical trials across the United States. Essentially, there is a study which is looking at ER-positive breast cancer, estrogen receptor-positive breast cancer, but not all estrogen receptor-positive breast cancer, the ones that are more aggressive. So, there are some estrogen receptor-driven breast cancers which really don't benefit that much from chemotherapy. They do very well with anti-estrogen therapy. But there is a subset where, of patients that really need chemotherapy as well. Of course, inflammatory breast cancer tends to be in that more aggressive category. So, in this study, it's looking at patients that have the more aggressive type of ER-positive breast cancer at diagnosis, and it's for patients in which the cancer has not metastasized. The aggressiveness is measured by a test called MammaPrint. And so, the patients on this trial have to have a ultra-high MammaPrint test. And we actually don't know the MammaPrint results for most patients with inflammatory breast cancer because we don't need it much. It's typically a test that is used to decide whether to give chemo or not. But with inflammatory breast cancer, all the patients are going to get chemo anyways. So, we suspect that given the aggressive nature of this type of breast cancer, that many of the inflammatory breast cancers will have this ultra-high MammaPrint. So, for patients that have that ultra-high MammaPrint, they are given the standard chemotherapy that anyone would get. And then they are randomized to either get that chemotherapy by itself or to add the immunotherapy. And the immunotherapy drug in this case is called durvalumab. This study is for all breast cancers, whether they're inflammatory or non-inflammatory. And I really applaud the investigators for including inflammatory breast cancer. This is a perfect example of a study which would apply to inflammatory breast cancer and can include this population, and allow us to learn more about it. We're very excited about this study. The other study that we have is called TRUDI. Now, this one is different because it's only for inflammatory breast cancer. And these studies can be hard to do because inflammatory breast cancer is so rare. Even at large, academic medical centers and oncologists might only see a couple of these inflammatory breast cancers in a year. There are some centers across the United States that see more of these. And at MD Anderson, we have an Inflammatory Breast Cancer Clinic, and we see patients with newly diagnosed inflammatory breast cancer every single week in our clinic. So, we are able to do such a study. So, this study is for patients with HER2 positive or HER2 low breast cancer. So, HER2 positive is a known type of breast cancer. We've been treating patients with HER2 positive breast cancer for many years. HER2 low is a newer designation in which the HER2 status, the protein staining on the cancer, it's not high enough to be considered HER2 positive, but there's some staining there. So, the only patients that wouldn't be able to go on this is if the HER2 was completely zero, there was absolutely no staining. So, this study is evaluating two groups of patients: those with HER2 positive and those with HER2 low breast cancer. So, the patients will get a drug that you mentioned, trastuzumab deruxtecan. This is an antibody-drug conjugate in which an antibody to HER2 is used to localize the chemotherapy to the tumor and have more sparing for the rest of the body. And then we're also giving that with durvalumab, the immunotherapy that is being studied in the other clinical trial. And because we feel that this tumor microenvironment and the inflammation is so important for inflammatory breast cancer, so patients are being treated with a combination of these two drugs, instead of getting standard chemotherapy. They're getting the treatment eight times and then going to surgery and radiation as they normally would. And we're going to see how well they respond and compare it to what we would expect with standard chemotherapy. 

Dr. Lim I'm sure with these new treatments coming in the pipeline, you may experience some like, new types of side effects as well. So, I think you and I have to be prepared for the new waves of different side effects. And, you know, piggybacking on that excitement around the antibody-drug conjugate and immunotherapy, there's a new, you know, the natural killer cell-based therapy that we may trying to bring it into our IBC patients. And there's some new agent that binds to both PD-1 as well as the VEGF anti-angiogenesis signal and which we think that we can potentiate the activity of this, what's known and have some efficacy, but in a better sense. So, hopefully we will have more tools in our toolbox to offer to our patients. 

Dr. Layman I hope so. And those new treatments are really promising. And I think it would just be such a great opportunity for our patients to have access to these. 

Dr. Lim Thank you so much for all these insights and wonderful sharing of your knowledge today, Dr. Layman. 

Dr. Layman Thank you. 

Dr. Lim Thank you very much for being with us today. For more information or to request an appointment at MD Anderson, please call 1-877-632-6789 or visit MDAnderson.org.