Optimizing Treatment Strategies in Inflammatory Breast Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host Dr. Dale Shepard, a Medical Oncologist and Co-Director of the Sarcoma Program at Cleveland Clinic. Today I'm happy to be joined by Dr. Julie Lang, Professor of Surgery, a Breast Surgical Oncologist and a Translational Researcher. She previously a guest on this podcast to discuss the use of liquid biopsies in breast cancer and that episode is still available for you to listen to. She's here today to discuss advancing care for patients with inflammatory breast cancer. So, welcome back.

Julie Lang, MD: Dr. Shepard. It's a pleasure to be here.

Dale Shepard, MD, PhD: Well, tell us again a little bit about what you do here.

Julie Lang, MD: Yeah, I have a breast surgical oncologist. My specialty is taking care of patients with breast cancer and benign breast disease, and I also lead a translational research program in the Lerner Cancer Research Institute, and I am a clinical trialist.

Dale Shepard, MD, PhD: Very good. We're going to talk about inflammatory breast cancer today. So, a lot of people might be listening in, different backgrounds. Give us a little bit of an idea when we say inflammatory breast cancer. What is that?

Julie Lang, MD: Inflammatory breast cancer is one of the most aggressive forms of breast cancer that we see. It's at least stage three if not stage four upon diagnosis. And it's a misunderstood diagnosis by many clinicians. So, I'm glad that we're here today to review this. Inflammatory breast cancer is characterized by skin changes often occurring rapidly within six months from the time of onset of symptoms, we should be seeing the patient in the clinic and making the diagnosis or else we worry that it's not actually a diagnosis of inflammatory breast cancer. In clinical practice, there's often ambiguity between breast infections and inflammatory breast cancer, and this is a point of confusion for the practicing surgeons. So, we see a lot of inflammatory breast cancer in a breast surgical oncology practice, but for primary care physicians or general surgeons, they may not see this diagnosis as often. So, it's an important topic to review.

Dale Shepard, MD, PhD: Because of the skin changes. Is this one where patients are more likely to come in because they see an abnormality instead of feeling a lump?

Julie Lang, MD: That's correct. So, patients may have breast cancer but have no breast lump actually present. So, this could present as skin changes, redness of the skin known clinically as erythema, and this is due to the fact that there's dermal lymphatic invasion causing the erythema and edema of the breast. This can lead to swelling and engorgement of the breast and other abnormalities such as nipple abnormalities.

Dale Shepard, MD, PhD: As a surgeon, from your perspective, what are some of the most important things to set this apart from other types of breast cancer?

Julie Lang, MD: The patient might present with this story of rapid onset that occurs, but mammography may or may not find a mass, and so the patient may be told to go see a surgeon and consider a punch biopsy, particularly if there's thickening of the skin. So, being aware of what this looks like is very important. Looking for characteristics such as peau d'orange, an orange peel-like characteristic of the skin, a skin thickening or edema, particularly we're looking for erythema or edema over a third of the breasts in these patients and we're looking if the patient has evidence of infection.

So, is there a fever, is there a white count, is there purulent drainage and things like that. Often inflammatory breast cancer can also be confused with a locally advanced non-inflammatory breast cancer, which is basically a breast cancer left to grow over time and eventually it becomes large and problematic and can create tumor wounds and things like that. In the case of concern for inflammatory breast cancer where there's an area of thickening of the breast, breast surgeons will often be asked to do a punch biopsy of the skin, and this is where a full thickness piece of skin and underlying subcutaneous tissue is taken and sent to pathology to rule out cancer.

Dale Shepard, MD, PhD: And then when you look at that pathology and that the pathologist gives you a report, how does that report differ? What do you see on the report that would say inflammatory breast cancer compared to another type of breast cancer?

Julie Lang, MD: Typically in these reports they would see adenocarcinoma. They may or may not see the ductal elements within the skin, but they would see lymphovascular invasion present. Dermal lymphatic invasion is pathognomonic, so these are the things that our pathologists are looking for. And so it's important to document with a photo in the chart of what the breast looks like so different clinicians can see the progression and that later on once the diagnosis is made, these patients often are presented in tumor board forums so that patients can be considered if they have inflammatory breast cancer and then treated as per NCCN guidelines.

Dale Shepard, MD, PhD: When you think about hormonal status, HER2, things like that, what's characteristic of inflammatory breast cancer?

Julie Lang, MD: The majority of inflammatory breast cancers are either triple negative or HER2-positive, which is different than the proportion of the subtypes of breast cancers that we see for the non-inflammatory breast cancer patients.

Dale Shepard, MD, PhD: You mentioned tumor boards, so certainly multidisciplinary care is important. Give us a little bit of an idea of that process. Again, people might not be necessarily familiar with how that works.

Julie Lang, MD: Absolutely. So, when a patient is diagnosed with inflammatory breast cancer, it's really urgent that they're seen by a team of specialists including a breast surgical oncologist, a breast medical oncologist, and a radiation oncologist. And these patients should all be presented at tumor boards. They should all be treated at large institutions that have clinical trials and are capable of timely care with evidence-based treatments. Typical treatments includes staging the patient because many of these patients will unfortunately have metastatic disease, so PET-CT or other staging scans would be ordered as appropriate and then the patient would be considered for neoadjuvant systemic therapy. All inflammatory breast cancer patients who are potential candidates for surgery are treated primarily with systemic therapy first upfront, and we evaluate for response and agents include anthracyclines and taxines patients. Also, if they're triple negative, genetic testing is important to see if they're eligible for PARP inhibitors.

And then when they're evaluated for consideration for surgery, first we have to see did the erythema recede so that it's within the confines of a traditional mastectomy. If the erythema is so extensive, in some cases, we have to ask our medical oncology colleagues to give additional systemic therapy to render the patient operable. At the time that a decision's made that the disease is now operable and it's within the confines of a mastectomy. The operative management is modified radical mastectomy, which means a total mastectomy with a complete axillary lymph node dissection. This is one of the few areas in breast surgery where we're not talking about deescalating management of the axilla. Here, the guidelines tell us we should do a modified radical mastectomy and subsequently the patient is then treated by our radiation oncology colleagues with comprehensive radiotherapy.

Dale Shepard, MD, PhD: And so I guess this underlines the importance of getting the accurate diagnosis to make sure you're staggering each of those therapies appropriately and making sure you don't undertreat from a surgical standpoint, right?

Julie Lang, MD: Absolutely. So, if you have a patient and you're not sure if it's inflammatory breast cancer, it's great to discuss them at tumor board and let colleagues take a look because the treatment for inflammatory breast cancer is maximal, often based on the subtypes though. So, if a patient has a HER2-positive cancer or a triple-negative breast cancer that is a locally advanced cancer, they might receive similar systemic therapy upfront. But this particular pathway of neoadjuvant therapy, modified radical mastectomy and comprehensive radiotherapy is definitely indicated for all inflammatory breast cancer, if operable.

Dale Shepard, MD, PhD: There is an inflammatory breast cancer calculator. Tell me a little bit about that.

Julie Lang, MD: Oh, thank you for bringing that up. I was lucky to be involved with a Susan G. Komen task force for inflammatory breast cancer, and so I participated in a team that described the state of the science and inflammatory breast cancer. And as part of that team's efforts, a group led by Filipa Lynce from Dana-Farber and Wendy Woodward from MD Anderson work together to validate an inflammatory breast cancer calculator. And the components of the calculator include skin changes, swelling and engorgement of the breasts, erythema or other skin discoloration, the nipple abnormalities, timing of the signs and symptoms, lymphatic tumor cell emboli and breast imaging. And there's a factor that is multiplied to give prioritization and it gives an IBC score that is it likely to be inflammatory breast cancer? Is it possible or not very possible or improbable? And so clinicians can go on this calculator at komen.org/IBC/calculator to locate this. And so if we're in clinics seeing a patient and we're not sure we can enter the factors of the patient's case there and get an opinion. And this has been validated with two independent large institutions, cohorts.

Dale Shepard, MD, PhD: Does this also get incorporated into your tumor board discussions?

Julie Lang, MD: It does. So, when cases are presented at our tumor board, and if we're unsure if it's inflammatory breast cancer, I will pull up this calculator. So, I'm trying to get the word out that this new calculator is out there and it's been validated and published and available for all clinicians to use.

Dale Shepard, MD, PhD: You mentioned that oftentimes these patients have stage three or four disease, the importance of neoadjuvant treatment. How has neoadjuvant treatment changed over time in terms of the therapies we use and the responses we get?

Julie Lang, MD: Yeah, so we've seen quite a bit of changes since I've been in practice. So, now we have highly effective therapies for certain types of breast cancer, namely the HER2-positive and triple negative breast cancers. So, patients often receive dual HER2 targeting agents for HER2-positive breast cancer, and patients also often receive specialized treatment for triple negative breast cancer, namely chemoimmunotherapy. We have the KEYNOTE-522, which has been highly effective in our triple negative breast cancer patients, but still inflammatory breast cancer patients do lag behind in terms of survival compared to their non-inflammatory breast cancer patients stage for stage. So, more research is needed to improve outcomes for inflammatory breast cancer patients.

Dale Shepard, MD, PhD: So, if you get a good response, you talked about not de-escalating, if you get a good response, you get sort of retraction of the disease that really doesn't impact what you're doing surgically, is that correct?

Julie Lang, MD: This is the one example where we would not de-escalate to lumpectomy even if we had a response by MRI. It looks like an exceptional response. The guidelines still tell us to do a modified radical mastectomy. This is a great topic for a clinical trial, and I know there are folks that are thinking of doing this, but we don't have that kind of trial data ready to change practice at this time.

Dale Shepard, MD, PhD: Given the sort of extent that you've talked about, what are the challenges from a surgical standpoint when you go to do these surgeries?

Julie Lang, MD: Yeah, one challenge is you don't always know where does the tumor start and stop in the skin. There's not a mass that you can palpate. So, we're all very familiar as breast surgeons for what does cancer feel like, but when it's in the skin, sometimes you need to do punch biopsies and so punch biopsies can be done with frozen section, but that puts the pathologist on the spot. So, a better idea would be do your punch biopsies in the clinic under local before the time of operation. If there's a patient where you're concerned that there's some erythema or some skin changes that look kind of funny and it's going across the area where you'd be making an incision, do your punch biopsies ahead of time to allow sufficient time for the pathology to come back, and then your pathologist will thank you for not putting them on the spot and cutting into that precious tissue. They can take their time and do the antibody stains that they need to do to make the appropriate diagnosis.

Dale Shepard, MD, PhD: And then when you think about surgery itself, you mentioned that difficulty knowing where things start and stop, and particularly if you've had treatment and you may have sort of regression of tumor, certainly always looking for negative margins, is it less likely to get negative margins with this subtype of breast cancer because of that challenge?

Julie Lang, MD: I think prior to the availability of the KEYNOTE-522 regimen and prior to the availability of dual HER2 targeting agents, this was more of a problem. This is less of a problem now, but indeed we worry about it and we do sometimes need to do punch biopsies, which we don't do for other types of breast cancer.

Dale Shepard, MD, PhD: What are the implications for reconstruction?

Julie Lang, MD: So, per NCCN guidelines, we do not offer immediate breast reconstructions to patients with inflammatory breast cancer because we know they'll need comprehensive breast radiotherapy. And at some institutions they use specialized regimens for inflammatory breast cancer patients that are more intense twice a day regimens. So, with that in mind, typically patients wait about a year from the conclusion of radiotherapy until the time of breast reconstruction, but there's certainly a candidate for it at the appropriate time down the road.

Dale Shepard, MD, PhD: You mentioned maybe somebody might take on a trial looking at current surgical practices, de-escalation of that surgical practice. Are there any other things going on from changes in surgery, surgical approach? Is there anything that's being looked at?

Julie Lang, MD: I think de-escalation of the axilla will also be important to study, and I think people are talking about this concept that I'm not aware of a trial. One limitation is that the number of cases is rather rare for inflammatory breast cancer. It's between two and 5% of all the breast cancers that we treat. So, even a large institution like Cleveland Clinic doesn't have very many cases per year, so it's very hard to organize such a trial.

Dale Shepard, MD, PhD: And would the thought be if you de-escalate looking at sentinel lymph node concept or instead of just going ahead with the dissection?

Julie Lang, MD: Yeah, so if they were node negative at the time of diagnosis, and they might potentially in the future be a candidate for sentinel node biopsy, but we have an intermediate procedure called the targeted axillary dissection where a patient was node positive at the time of diagnosis and the radiologist placed a tissue marker clip in the lymph node. And so at the time of surgery, a device for localization such as a Savi SCOUT device could be placed in that lymph node. And that's a radar detector reflector that we use. We have a handheld Savi SCOUT wand that we use to detect signal from that reflector so that we can target that lymph node at the time of sentinel node biopsy using radio tracer and blue dye to identify sentinel lymph nodes in addition to using the Savi SCOUT to resect the previously biopsy proven sentinel node. And we do a frozen section. And so that's what a targeted axillary dissection is. But targeted dissection is not normally offered to inflammatory breast cancer patients, but in the future, this is something worthy of consideration if it's studied in an inappropriate trial.

Dale Shepard, MD, PhD: I guess just the fact that these inflammatory breast cancers don't really exist as a mass in the breast, they're more diffuse. Is that some of the concern with lymph nodes that you may not have necessarily as much targeting to individual lymph nodes?

Julie Lang, MD: That's right. It spreads really diffusely through the lymphatics. It really has a proclivity to the lymphatics that is different than any other cancer.

Dale Shepard, MD, PhD: People, after they've gotten neoadjuvant therapy, are there clinical responses, pathologic responses that you can use to sort of assess prognosis?

Julie Lang, MD: Yeah, I think the response categorization that's most used is a residual cancer burden, which was developed by Fraser Simmons at MD Anderson Cancer Center, and we're looking for the RCB score for patients. So, RCB-0 pathologic complete response is what we're going for. But patients that even have a major response RCB-I, they still do better than patients that don't have such a major response. So, the outcomes are getting better for all breast cancer patients, including inflammatory breast cancer patients. Although it is lagging behind and more research is needed.

Dale Shepard, MD, PhD: It seems like it's becoming fairly pervasive in some diseases. What's the role of circulating tumor DNA at this point in inflammatory breasts? Is there really much data in this subtype?

Julie Lang, MD: So, when they have looked at patients with an inflammatory breast cancer and locally advanced breast cancers in clinical trials who were treated and had pathologic complete response, the patients that did best had their ctDNA levels undetectable at the time of surgery and then never appeared afterwards. But more data is needed because there are so few patients with IBC. This is definitely an area of prioritization for future research.

Dale Shepard, MD, PhD: Are there any other things either from the surgical side, the medical side, radiation, imaging, is there anything else that looks particularly promising that might make that next big step?

Julie Lang, MD: I'm not aware of very many IBC-specific studies. Treatment is really based on non-IBC, so more clinical trials are needed, but I am aware that Komen is trying to organize a biobank and so patients can give consent to Komen for collection of their tissues after the time of their surgery. And so with this specimens can be collected and be available for researchers to study in the future. This is really the most exciting thing that I've heard of recently. That can help because if they can look at those specimens, if they can do sequencing studies, we may be able to advance cancer research.

Dale Shepard, MD, PhD: And as we think about cancer research, you being a translational researcher, is there anything that looks promising in your lab that might be leading to the therapies we'll talk about in an upcoming podcast?

Julie Lang, MD: Thank you for that question. My lab has helped to derive an inflammatory breast cancer patient-derived xenograft, so this is a mouse model of inflammatory breast cancer from a HER2-positive patient. And this patient was treated with neoadjuvant chemotherapy with two HER2-targeting agents and chemotherapy. Following the time of surgery, we immediately took pieces of tumor and we had immunocompromised mice available to implant the tumor cells into the mice, and this actually occurred during the time of the COVID-19 pandemic, so we had special approval to keep the mouse model going. So, it's very fortunate the mouse model even survived. But the mouse model is now submitted for publication and we're awaiting word if it will be published, but essentially the mouse model faithfully reproduces what the patient's model showed. It's a HER2 positive model. We were able to do single-cell RNA sequencing to figure out that there's a lot of heterogeneity in the inflammatory breast cancer and we're able to compare it to other models of inflammatory breast cancer.

It turns out there's very few of these models. So, we had the only data set for a HER2 positive model with single cell RNA sequencing, but a colleague, Kornelia Polyak at Dana-Farber, had single cell RNA sequencing data from triple negative inflammatory breast cancer. So, we're able to make these comparisons and we hope that in the future the model could be used to test experimental therapeutics. Our model has a PIK3CA mutation, so there's a specific PIK3CA mutation that we are interested in following up on. But when we tested the PIK3CA Alpelisib in our model, it actually worked very well.

Dale Shepard, MD, PhD: Very good. So, lots of reasons to be enthusiastic for progress.

Julie Lang, MD: Definitely. Yeah. There's a lot of people that are interested in advancing inflammatory breast cancer research, so it's important to get the word out.

Dale Shepard, MD, PhD: Very good. Well, I appreciate you being with us for your insights today.

Julie Lang, MD: Thanks so much.

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