So, we already talked about that recognition is the key to optimal treatment and outcome.

Hi, I m Dr. Anthony Lucci from the University of Texas MD Anderson Cancer Center in Houston. And today, I d like to talk to you about the role of surgery in inflammatory breast cancer patients. So, there s a few learning objectives we will try to complete. And, the first one will be to determine the optimal timing and indications for surgery in the multimodal treatment of patients with inflammatory breast cancer which, throughout the talk, you ll see abbreviated as IBC, capital IBC. We ll also discuss optimal surgical treatments for the breast and regional lymph nodes in patients with IBC. And, we ll identify the reconstructive and rehabilitative issues that occur after surgery in patients with IBC. So, how s IBC different from regular breast cancer? I mean, we all know about regular breast cancer, but how is IBC different? Well, inflammatory breast cancer has early dissemination, a higher recurrence rate, and still has a 50 percent mortality rate. So, even now, with improved treatments, patients still have about a 50 percent mortality rate with this disease. Now, treatment planning in IBC is really a key to success. And, so, in general, the protocol is pretty simple. Almost all patients with inflammatory breast cancer need as their primary therapy, neoadjuvant chemotherapy. And, then, if the patient has a response, meaning if the tumor responds and shrinks either partially or completely, then it s been shown that that patient would benefit from local therapy, such as surgery. Now, breast-conserving therapy as a surgery option for breast cancer is well accepted. But, in inflammatory breast cancer, it s not optimal, simply due to the involvement of the skin and surrounding structures, and the dermal lymphatic invasion with the tumor. So, breast conservation is not an optimal treatment option for inflammatory breast cancer and should not be offered to patients with IBC. As far as lymph nodes management, we know about sentinel node biopsies as another real great option for patients with operable stage I to III breast cancer. But, not for inflammatory breast cancer because there are several studies that have shown a high false-negative rate in patients with inflammatory breast cancer. So, generally, these patients will need an axillary dissection. And, then, following the surgical therapy, post-mastectomy radiation in the standard four fields is given, and that s the optimal treatment modality currently for inflammatory breast cancer, the one that offers the best outcomes. Now, why even do surgery? Is surgery really going to help? Well, surgery is important because you can achieve local control in the majority of patients if you perform a mastectomy. However, we said before that surgery would not be perhaps indicated in all patients suspending --- depending on the response to therapy, and we ll talk a little bit more about that in a minute. Also, surgery allows for pathologic staging after neoadjuvant chemotherapy because there will be some patients that have a --- what appears to be a complete clinical response. But, we will find residual disease at pathologic evaluation of the mastectomy specimen and perhaps give better prognostic information and maybe even indications for additional therapy. And, finally, surgery has been a component of multimodal therapy that has been shown by several studies. And,

you can see the references in the bottom right corner of the slide that offer improved disease-free and overall survival after a response to neoadjuvant chemotherapy. So, surgery is an important modality to --- for the overall protocol of --- of what we talked about of the trimodal therapy neoadjuvant chemotherapy, surgery, and then radiation post-mastectomy to give the best outcome. So, we already talked about --- a little bit about selection, but the best selection criteria are patients who response to chemotherapy are offered modified radical mastectomy. And, what we mean by response is a partial or a complete response to the chemotherapy, a clinical partial or complete response. Now, one thing I d like to point out is that historically mastectomy alone for inflammatory breast cancer is a terrible option. And, if you look at the reason why, surgery alone, this is outcome --- this slide shows outcome after mastectomy alone for inflammatory breast cancer. And, we can see that in general, the outcomes are dismal. So, when you see here, mean survival in months, after mastectomy only, the numbers are quite low. In fact, the total or the medians are right --- somewhere around 22 months. So, surgery as a as a --- as a single modality therapy is not successful and is not recommended. Now, one thing surgery is good for in part --- as part of a combined therapy, is for providing local control of the disease. And, here we see that when you look at local regional recurrence after combined modality therapy, again, systemic chemotherapy followed by mastectomy, followed by post-mastectomy radiation, we have local regional recurrences somewhere around 20 percent. So, gr--- I think that s great that in 80 percent of the patients, we can control the local disease with --- with the use of surgery. So, again, this is why surgery is an important component of the treatment of patients with IBC. So, how is the surgeon important in diagnosis? Well, we have to remember that in general, patients with inflammatory breast cancer will be often younger aged than those with locally advanced breast cancer. Now, that s not all, but that s a trend. Also, we have to remember that the surgeon has a role in rec --- recognizing the signs of IBC erythema, edema, which again can cause the peau d orange, the characteristic peau d orange from the enlargement of the hair follicle pits. And, we ll see some pictures of that in just a second, for a better demonstration. Also, wheals or ridges in the skin of the breast, and then usually, that rapid progression of redness covering at least a third or more of the breast would be criteria --- diagnostic criteria for inflammatory breast cancer. We talked about the peau d orange. I think this is a pretty nice demonstration. And, you can see here the enlarged hair follicle pits create the orange peel appearance of the skin, that gives you that characteristic peau d orange which is oftentimes present, but not always, in patients with IBC. Now, one thing that is a little bit different about IBC is that often times, there s no palpable mass in the breast. So, in about a third of the patients, they may have an

enlarged, swollen breast with some of these characteristic findings like erythema, edema, or peau d orange but they may have no palpable mass. Also, they may have a higher likelihood of presenting with palpable axillary adenopathy due to early local regional spread. And, also, the signs of nipple retraction or skin ulceration are often times present in IBC. So, here s again some pictures which I think will give us a much better idea of what we re talking about. Here, we see ulceration of the skin with breast tissue. We see widespread edema and swelling. And, I think, again, this would be hard to --- to misdiagnose because it s a fairly pronounced case. But, I think it does give a clear picture of what we re talking about with IBC, with its rapid progression and pronounced findings. Here s a little bit more subtle with the redness covering around the nipple areolar complex, the swelling and, again, in this patient, there was no palpable mass. It was simply an enlargement of the entire breast. And, oftentimes what happens is these cases are misdiagnosed as infection. And, the patients are treated long-term with antibiotics. So, it s important for the surgeon and any clinician to really be aware of the fact that you can never let that diagnosis be out of your differential. IBC has always got to be considered when you see redness over a significant portion of the breast and any of those other characteristic findings. Again, here s the wheals and ridges we talked about, very obvious, almost looking like the spokes of a wheel coming out in the breast. Very clear demonstration of how IBC can cause this ridging. And, then you see the characteristic redness that s covering a significant portion of the breast. Again, very pathognomonic, or I should say very characteristic of IBC. Again, more subtle, but in this patient, the patient presented initially with swelling and edema, had core biopsy, I should say core biopsies of the breast tissue which showed invasive carcinoma. And, then had punch biopsies of the skin which showed dermal lymphatic invasion tumor emboli characteristic of IBC. And, then, this patient has been treated and now has significant reduction of the redness that was present. So, we just talked a little bit about diagnostic techniques, such as punch biopsies. So, let s talk about when those may be helpful. First of all, though, I ll talk about imaging. Because obviously that s the first step with any patient with breast cancer is they re going have imaging of the breast. One thing to remember in inflammatory breast cancer is that many times, the imaging may be negative or difficult to interpret due to the level of edema and swelling of the breast. And, you can have patients where there s no clear mass within the breast but they could still have inflammatory breast cancer that s invading into the skin. It just may not show a clear mass in the breast. And, then, the thickening is often times noted as a finding on either the mammogram, the ultrasound, or even on CTs or MRIs. Core biopsy is still the best diagnostic modality. There s really no role for incisional biopsy. There s no role for incisional biopsy in --- in early breast cancer in any case. I think nowadays, it --- it really has to be a core biopsy

or it may --- perhaps even an FNA if you re talking about of the lymph nodes. But, open biopsy just really doesn t have a role. It s very limited. There ll be rare cases where you would need that. Punch biopsy, we talked about punch biopsy of the skin. Punch biopsy of the skin can be used in cases where there s not a clear diagnosis and you may see dermal lymphatic tumor emboli in up to 72 percent of patients. But, remember, it s not required for diagnosis. So, there may be cases where you don t see that in the skin, but there s redness covering a significant portion of the skin. You have edema, you have a core biopsy showing invasive carcinoma, that can still be a diagnosis of inflammatory breast cancer. You do not have to have dermal lymphatic tumor emboli, and I think that s an important point. We already talked about this. Excisional or incisional biopsy is just a terrible idea, and it s rarely necessary. And we ll see why in a little bit, it can actually be detrimental to the patient. So, here s a --- a patient who was seen at an outside institution, underwent an excisional biopsy, and here s one of the problems with IBC. It s a disease that s often involving the skin extensively. And, many times, these excisional biopsies don t heal and they can become open wounds that will delay the further treatment of the patient. Again, this patient was found to have bilateral inflammatory breast cancer, underwent an excisional biopsy unnecessarily on both sides. The one on the left side here actually didn t heal and opened up, and delayed, again, the treatment of the patient. Now, what about staging? So, at --- with inflammatory breast cancer, it s important to note that up to 30 percent of the patients can already have metastatic disease at the time of diagnosis, which is higher than your run of the mill breast can --- invasive breast cancer. So, traditionally, chest x-ray or bone scans, and in some cases, even PET scans or CT scans or PET/CTs combined can be used for imaging up front. I ll say there s no obvious, you know, right treatment protocol. Here, we tend to use PET/CT not only as a diagnostic, but, also, as a research tool to see if we can identify patients with disease up front. But, it is an option to use for patients with inflammatory. I would say, however, that PET/CT is generally not a good idea for staging patients with noninflammatory early stage breast cancer. It would be not necessary in the majority of cases. The other reason why staging is important is IBC is more likely to recur in the soft tissue. We also have looked at research studies here, looking at circulating tumor cells in the blood and disseminated tumor cells in the bone marrow, and that research is ongoing now, to try to see if we can identify patients at additional risk who are already spreading disease hematogenously, through the bloodstream, and may give us some insight in the future as to why this disease spreads rapidly to other areas. So, again, we talked about the role of the surgeon. The first thing is to recognize that it s inflammatory cancer. Keep that in mind. Don t always consider that it s an abscess. If you think it s an abscess or breast mastitis, you could treat with one course of

antibiotics and watch closely. But, if it doesn t get better, I think right away, you have to start thinking about is this something else. And, hopefully there s already been imaging obtained, and if the imaging shows a mass, then directed biopsy with core needle and perhaps, even like we said, punch biopsy of the skin may be necessary. Once the diagnosis is made, the patient needs to be referred for neoadjuvant therapy, then a modified radical mastectomy if a partial or a complete response, and then postmastectomy radiation. I keep harping back on that point simply because that s the treatment protocol that s going to give the best outcome. Now, what about the axillary lymph nodes? We already talked about sentinel node not being optimal. But, one other thing is that we can do imaging. We can do ultrasound of the axilla as we do here at MD Anderson, and we ll actually do a fine needle aspiration of any suspicious lymph nodes that will give us information up front about whether or not the lymph nodes were involved with tumor. And, then, axillary lymph node dissection is still considered the gold standard for IBC patients. So, we already talked about that recognition is the key to optimal treatment and outcome. Let s go over a few cases that might bring this all to a more poignant kind of situation that we can all relate to. The first case would be a 48-year-old patient who presented with IBC. She was considered inoperable because of the extent of the disease. But, there was no distant metastasis and we ll see why that was in just a second. The patient had an Er positive, Pgr negative, Her-2 negative primary tumor. This is why the patient was seen at an outside institution and was told you re not operable, we really can t treat you. Obviously, the first thing we thought is, this is a very advanced case of IBC. We see the ulceration of the skin as we talked about, widespread redness and edema, and so, the first thought here is, again, going back to the protocol, neoadjuvant chemotherapy. So, this patient was treated on neoadjuvant chemotherapy with FEC and Taxol. The patient actually had a partial response. We re seeing already after the first few treatments a decrease in the size of the swelling, decrease in the size of the ulcerative areas, and we re seeing a general overall softening of the breast tissue. The patient eventually had an excellent response and was able to go --- undergo a modified radical mastectomy with negative margins. And, this patient went from, remember, advanced disease to disease that was softening and shrinking, significantly reduced, was able to have a mastectomy with negative margins, and then here, you can see the treatment planning has been done for postmastectomy radiation. So, again, even advanced cases, if they follow the protocol, can receive successful treatment.

Let s look at a second case. This was a 52-year-old patient who presented with a right breast mass, developed redness very quickly, that encompassed a half --- about half of the breast. A punch biopsy was performed that showed poorly differentiated adenocarcinoma in the dermis and the lymphatics. She, again, was referred for neoadjuvant chemotherapy, as was appropriate. So, this patient had a complete response with all the resolution of the disease. You see the punch biopsy scar, complete resolution of the redness and the swelling and the edema. The patient, again, this is the only sequela you see left is just the punch biopsy scar. That patient, --- excuse me, was able to undergo mastectomy, had a complete pathologic response, underwent postmastectomy radiation therapy. So, again, following the protocol, we can get patients through this and get good outcomes. The third case was a 56-year-old patient who had erythema of the left breast and a 13 cm mass. Now, this patient was seen elsewhere. And, so, again, we talked about this. Suboptimally, surgery is not the best first choice. But this patient was treated with a left modified radical mastectomy for what was clearly very locally advanced disease. The patient was then referred to a medical oncologist. By then, she had redness that had moved to the opposite breast just in the short interval from the --- the time of the first operation. The patient was, again, still at an outside institution and was then treated with a right modified radical mastectomy, rather than being sent for neoadjuvant therapy. This patient had margins widely positive for disease, both sides, and had, as you can see here, a wound breakdown that resulted in a significant delay in her therapy. So, again, I want to harp back to the protocol and show that surgery as a first treatment option is a bad idea. And, so, this was a case where the patient was treated with surgery up front, had an open wound, delayed therapy, suboptimal outcome. Now, the good news is, is that when we see these patients early and we can get them started on neoadjuvant therapy, we can have a significant number of patients that will be treatable by --- they will be surgically operable. They will be able to come and have an operation. So, another patient who was seen had chemotherapy, had a complete clinical response with complete resolution of the redness, had a mastectomy with widely free margins, underwent postmastectomy radiation. And again, these patients do have a high risker of recurrence somewhere else, as we talked about, but if we can achieve this, we already said we re going to get local control in 80 percent. And, we re going to provide the optimal outcomes possible by that mo --- triple modality of chemotherapy, mastectomy, radiation. And, again, another patient status post modified radical mastectomy, complete clinical response, gets radiation, good outcome.

More examples of the complete clinical response: A patient who had widespread redness and you can see the punch biopsy sites to, again, secure the diagnosis, has chemotherapy, no redi --- no residual mass, and by the time she finished her chemotherapy, all this redness had resolved, was able to undergo mastectomy subsequently and then radiation. Now, the one other point we wanted to touch about, is what about doing immediate breast reconstruction for patients with IBC? So, here at MD Anderson, we generally do not recommend immediate breast reconstruction for either our patients with locally advanced breast cancer or inflammatory breast cancer who will need postmastectomy radiation therapy. And, there s a couple of reasons for that. I think our plastic surgeons would feel that that best outcomes will be a delayed reconstruction. We can often times put in tissue expanders or end --- implants for thin patients who don t have enough autologous tissue for reconstruction later. But, they have to understand there s a higher failure rate after radiation therapy than using the delayed approach. Also, if you do an autologous reconstruction, which you can do, there will oftentimes be shrinkage or fat necrosis after the radiation therapy. And, a significant number of these patients will require repeat or revision of their reconstruction. Lastly, and I think one other important point that our radiation oncologists always point out is that when you provide a reconstructed breast mound, they often times will need higher energies to achieve the same dose to, let s say, the internal mammary lymph nodes. And, then you potentially increase the dose that you are giving to the heart or lungs. So, in general, here, we would ask that our patients, if they can, be patient, undergo the mastectomy, complete the postmastectomy radiation, and then undergo the reconstruction in a delayed fashion. Now, that s not for every patient. There are some patients who, you know, really want to have tissue expanders or things placed up front. But, again, these are kind of the reasons why we would favor the delayed approach. So, in conclusion, the really important point that I think I ve harped on several times throughout the talk is that diagnosis is really the key. Recognizing the signs and symptoms of IBC, not treating for a prolonged time as an infection, recognizing what it is and getting it treated with systemic therapy up front is --- and then followed by surgery for the patients who respond, followed by radiation, is going to give you the best outcomes. So, really, recognition is really important. And, I think part of this whole educational program is making sure that clinicians are aware that these are patients that really do require recognition of the disease early on to provide really a chance at getting a cure. So, we already talked about the protocol multiple times. Neoadjuvant chemotherapy, modified radical mastectomy for partial or complete responders, followed by postmastectomy radiation. And, really, I think the way we re going to get improved outcomes is --- is early identification, diagnosis, early institution of systemic therapy. And, then really, I think, in the future, if we can find out which patients are likely to have already disseminated disease or cell --- circulating cells that may be responsible for later recurrences, we can try to target those and improve outcomes. And, I think as we move along, patients with IBC will be a great group to study as far as targeted

therapies, personalized therapies that may have a higher chance of working against these cells which generally behave a little different than your normal run of the mill and basic breast cancers. So, with that, I would just like to say thank you for your attention, and we d really appreciate any questions or feedback you have about this educational presentation. Thank you.