Massimo Cristofanilli, M.D.
Professor of Medicine
Welcome to this educational event sponsored by [The University of Texas] MD Anderson Cancer Center, entitled "Inflammatory Breast Cancer: Biological Features." I am Massimo Cristofanilli. I'm a Professor of Medicine and an expert in inflammatory breast cancer as a physician-scientist involved with research and clinical management of this disease.
Today's objectives of this presentation are: understanding the clinical and pathological features of inflammatory breast cancer; understanding the role of targeted therapies in the standard management of the disease; and also understanding the new molecular targets with potential therapeutic application.
Let's start first reviewing the clinical and pathological features of IBC.
We know this is an advanced disease so it has to be treated by a multidisciplinary team of physicians. And this requires induction on neoadjuvant chemotherapy typically involving anthracyclines and taxanes, followed by mastectomy, and chest wall radiation. This is the standard of care for inflammatory breast cancer. Patients completing induction chemotherapy are then evaluated at the time of mastectomy for pathological response. The complete pathological response is the most important prognostic factor.
Past Studies: I reviewed the importance of surgery in the multimodality management of IBC. This experience from Dr. Panades and the Canadian group published in JCO, 2005, suggests that omitting mastectomy is responsible for an increased locoregional relapse. And the sequence of mastectomy after chemotherapy and radiation therapy is the best possible sequence.
At MD Anderson we reviewed the retrospective experience of these patients that completed neoadjuvant therapy, particularly to evaluate the risk factors associated with recurrence. And we saw that the pathological CR in the axillary node is probably the most important factor. This graph reproduced the probability of progression-free survival; survival for patients without evidence of axillary lymph node disease or with axillary lymph node disease.
So looking at the retrospective evaluations of patients treated with multimodality therapy, particularly with anthracycline-based regimens, where you can see that in the last 30 years most of the experience suggests that the major change in prognosis is related to the inclusion of chemotherapy in the neoadjuvant setting and adjuvant setting of these patients from only locoregional treatment. Back in 1970s, the treatment of this disease consisted only of surgery and/or radiation. But over the last decades the management of this disease has really not improved significantly, continues to offer a significant low survival probability at 5 years compared to other forms of breast cancer.
When you look at the pathological features at the time of diagnosis and time of surgery, we can see in these two figures. One on the left suggested a patient that at the time of surgery has extensive edema in the skin still, even though there is no evidence of mass in the center of the breast. The disease will remain eventually. And patients do not respond in the skin where originally the patients had the clinical evidence of disease. At the time of diagnosis, the typical presentation [was] represented by tumor emboli, the classes of cancer cells that occupy and block the lymphatics. So for the first time the pathology at diagnosis being us the importance of the lymphatics.
Lymphangiogenesis is, in fact, an important factor in inflammatory breast cancer. Several investigators have demonstrated that the particular way of this disease to spread, is from invading the lymphatics, as we show in this particular slide. And it has been hypothesized that this is actually a possible passive phenomenon. But most recent research has demonstrated that this is an active phenomenon and the first step in the process of metastasis in inflammatory breast cancer.
This lymphatic spread is actually extremely important because even in patients that achieve optimal response, but not a pathological response, their recurrence happens very early on in the first two or three years compared to non-inflammatory breast cancer. These translate in a difference of recurrence-free survival that is quite significant. It is believed that this is related to the persistence of micrometastatic disease distantly and also in the lymphatics.
When we go to analyze "where does this recurrence occur", we found out that actually the incidence of soft tissue recurrence is extremely high; suggesting once again that the lymphatic spread within the skin is an important contributor to the recurrence. Most of these patients had, in fact, chest wall recurrence or lymph node recurrence locally.
The results of distant soft tissue recurrence that is quite significant compared to non-inflammatory breast cancer. Once again highlighting the specific and important role of lymphangiogenesis and the difference in the biology underlying this particular type of spreading.
So we can now move on reviewing the targeted therapy that are currently utilized in the standard management of inflammatory breast cancer.
We previously mentioned that the combination of neoadjuvant chemotherapy, surgery, radiation, constitute the standard experience for a patient with inflammatory breast cancer. This comes from retrospective studies and prospective clinical trials that are being ran at the MD Anderson since 1974. Actually the first study that was in 1974 to 76 and did not include surgery but radiation therapy was the only local modality. Subsequently all the protocols include mastectomy. They were testing different strategy in terms of chemotherapy including adjuvant chemotherapy, non-cross-resistant regimens, and additional evaluation of patients in non-cross-resistant regimens based on the quality of pathological response.
So these protocols actually were compared and did not show significant difference in terms of complete clinical response. Obviously the pathological response could not be assessed in the first group of patients that had only radiation therapy. So maintaining overall around 12%, obviously quite low compared to what we see in other forms of breast cancer.
So we started to look at the various biomarkers that could explain or identify patients with a high recurrence rate and worse prognosis. And the first one we looked at was HER-2. And as you recall, HER-2 has been associated with poor prognosis in early breast cancer. But in this particular disease, very aggressive, you see that HER-2 status at presentation, in patients who did not receive HER-2 targeted therapy, but only chemotherapy, is not associated with recurrence-free survival probability. And overall survival is better in this group once they start HER-2 targeted therapy for their recurrent disease.
So this brought to the introduction, of course, of Herceptin® in the neoadjuvant management of these patients or the induction phase, and the --- the NOAH study is very much one of the most important protocols in this sense because it included HER2-positive patients locally advanced and inflammatory breast cancer that were compared receiving the same chemotherapy or chemotherapy with Herceptin®. And the group that received chemoth --- Herceptin® continued also with Herceptin®. There was also a control arm that were HER2-negative locally advanced patients.
You can see from this slide that there were a number of patients with HER2-positive disease. Most of the HER2-positive disease were also ER- or PR-negative. So makes it obviously quite an attractive patient population to study with neoadjuvant treatment.
And the results was as expected, as seen in other non-inflammatory disease, particularly the --- in HER2-positive, the addition of chemotherapy brought up the pathological CR within the breast to 55% and total eradication of the disease, invasive disease within the breast and the lymph node to 48%. So quite a significant improvement when compared to the overall 12% that we achieved only with chemotherapy.
When you look at a patient that achieved pathological CR, they do much better obviously when they receive Herceptin®; their survival is better, and overall, the survival is better irrespective of the pathological CR. Again we are comparing a group of patients treated with Herceptin® and treated without Herceptin® with just chemotherapy. So this makes Herceptin® the standard therapy for HER2-positive inflammatory breast cancer, particularly in the neoadjuvant setting, followed by the adjuvant disease treatment.
So at MD Anderson, we also reviewed the retrospective experience of patients that received neoadjuvant therapy with trastuzumab-based regimens. These were a group of 16 newly diagnosed, treatment-naïve patients who received preoperative trastuzumab and chemotherapy. The chemotherapy were two different regimens – FEC-Paclitaxel, and TCH – according to the investigator choice, that were administered for 20 weeks. Ten patients had a pathological complete response, approximately 62%. It is interesting to know that even Stage IV disease was included in this analysis, and they proceeded with surgery and were able to obtain pathological complete response.
When we looked at the follow-up at 24 months, we noticed that these patients had --- had evidence of recurrence and for the first time, we started to notice that this disease is associated with a significant high incidence of brain metastasis even in patients who have high pathological complete responses.
So we started to look at the role of chemokines and growth factor receptors, excluding HER2, particular for the homing of --- of metastasis in particular sites. As I mentioned, the chest wall disease, but also the bone, and the brain. And we looked at the CXCL4, EGFR, also HER2, and CCR7.
And what we noticed is that what the chemokine independently did not have, in terms of expression, [was] any correlation with prognosis. EGFR had a significant association. Even with this small study, only 43 patients, EFGR-positive definitely performed worse. And these were all patients that completed neoadjuvant chemotherapy had residual disease after surgery.
So we started to investigate how a treatment targeting EGFR could eventually contribute to reduce the metastatic process. And we looked, in specific, at the ERK signal and the EMT phenomenon associated with the metastatic process, in particular for IBC. So this was SUM 149 cell lines that were treated with different doses of erlotinib. And we see with different doses of erlotinib there is more apoptosis for the cells. And there is a decrease in the expression of vimentin, suggesting that the reverse of the EMT phenomenon; suggesting somewhat that this drugs, or this class of drug, could be used to reverse or to prevent the metastatic process and maybe should be considered for the adjuvant treatment of inflammatory breast cancer.
But certainly one drug that has made a significant contribution to the management of IBC is the use of lapatinib. As we know lapatinib is a receptor tyrosine kinase inhibitor that prevents the phosphorylation and activation of EGFR and HER2, so it is an optimal drug for a disease in which EGFR has also a significant role. So the dual blockage of the signal is very appealing for this disease.
So the first study was actually evaluating as a single agent, the role of lapatinib in patients that were HER2-positive or EGFR-positive/HER2-negative. And these patients received a biopsy before starting the treatment, were treated with lapatinib as a single agent. There was extensive evaluation of chest wall disease as well as evaluation of the measurable disease by RECIST criteria.
And this study confirmed actually that in spite of the dual inhibition, the lapatinib treatment only show eff --- efficacy in patients that were HER2-positive and not EGFR-positive/HER2-negative. So this is a demonstration of patient, a typical patient with chest wall disease during treatment had almost a complete disappearance of her chest wall disease. And this was proved also by the PET-CT associated with some lymphadenopathy. This is a typical inflammatory breast patient with local disease and chest wall disease.
And in fact, the evaluation demonstrated this disease is effective also in patients who have been exposed to long treatment with HER2 targeted therapy with Herceptin®. In fact, the median number of cycles of different regimens was six in these studies and you see the efficacy is still being present. This is cumulative progression-free survival over weeks. So it clearly establish that lapatinib is an effective agent in the management of HER2-positive inflammatory breast cancer.
So the next step was trying to evaluate how we could improve in the efficacy of lapatinib. We know that from preclinical models, that inflammatory breast cancer has a specific process of vasculogenic mimicry that is associated with the recapitulation of the lymphatic vessels in the endothelial lining of the vessels, and this favors the tumor emboli spreading.
This has been shown with various models of inflammatory breast cancer, SUM149, IBC-1, and this suggests that lymphangiogenesis and angiogenesis are important factors in the spreading of inflammatory breast cancer cells. So targeting angiogenesis and lymphangiogenesis could be an optimal strategy to treat the disease, possibly together with lapatinib.
That was the rationale behind the study conducted at MD Anderson, a multicenter --- a multicenter study of lapatinib/pazopanib versus lapatinib, single agent, in patients with HER2-positive inflammatory breast cancer.
The primary objective of this study was, of course, to evaluate objective response of this combination versus the monotherapy in these patients who are refractory to HER2 targeted therapy or relapsed. And they are not been exposed to HER2 targeted therapy yet. And we want to evaluate the overall surviv --- progression-free survival, response --- response duration,…
…and safety. Safety was actually an important concern for this study. The study started with an ambitious goal of demonstrating in a randomized fashion the superiority of the combination versus the single agent. But the dose chosen of 1500 lapatinib and pazopanib 800 were not tolerable. So that the new design actually included a reduced dose of lapatinib and pazopanib, and the third arm of pazopanib as a control. So we have two cohorts of patients treated, with a number of patients that you see outlined in this slide.
The inclusion criteria were very clear. These should have metastatic HER2-positive inflammatory breast cancer to define by either immunohistochemistry of FISH or combination of both, normal organ function,…
…and they should not have been exposed to lapatinib but could have been exposed to Herceptin® and should not have been exposed to any other anti-VEGF angiogenetic therapy.
The assessment of response was actually very carefully done, in particular, with regard to the skin disease. In fact, the first cohort was assessed using evaluation of the Skin Assessment Tool that has been developed for T-cell lymphoma. And this was evaluating the skin, the breast, and recorded very carefully for the known measurable disease. In the second cohort, all patients were required to have skin disease, and it was --- an evaluation tool was developed to improve on the previous one. It was called the Inflammatory Breast Cancer Skin Assessment Tool. This will allow comparison of assessment from different investigators; in particular in cases that was a discordance.
So once again, evaluation of response for RECIST criteria for measurable disease and overall survival from the date of randomization.
This slide summarizes the characteristics of the patients in the two cohorts. You see overall, there is a consistence in terms of median age and population in terms of re --- race and stage. The majority of patients were in fact Stage IV and half of them had received previous Herceptin®. All of them had received previous chemotherapy.
When we look at the treatment adverse events, lapatinib has the acceptable GI toxicity that's been described previously and minimal increase in liver function tests. But notice the combination with the higher dose actually resulted in increase in the GI toxicity as well as increase of liver toxicity that required the modification of this dose. And this was the basis for the Cohort 2. Actually the second cohort did not have significant problem, was much better tolerated.
When we look at the response rate between the two, remember this is a combination of best response, measurable response, and non-measurable response. There is a trend in having the group of patients that has a combination to a better response, compared to the one that have single arm management. And this is for both cohorts.
But this actually did not translate in an improved progression-free survival. So there was no difference in progression-free survival between the three arms, and there was no difference between the two arms in the Cohort 1. To notice, the median progression-free survival is 16 weeks, is compatible and is slightly superior actually, in this particular study, compared to others that are investigating lapatinib as a single agent. Suggesting once again, that lapatinib is a --- is an extremely important agent for the management of HER2-positive inflammatory breast cancer.
So obviously after having -revised --- reviewed the details of the retrospective study done in metastatic disease,…
…lapatinib is also being tested in primary inflammatory breast cancer, with some limitations, I would say, particularly because the first studies we were investigating once again the role of lapatinib in two populations of ErbB2-positive, ErbB1-positive/HER2-negative, and did not include, particularly the first study, any treatment with anthracycline. This combination only includes lapatinib/paclitaxel, which was associated once again with some GI toxicity. And these patients will receive this combination before undergoing clinical assessment, subsequent to surgery, and then received the additional chemotherapy with anthracycline and Herceptin® completion as an adjuvant treatment.
This study showed that it is possible to achieve a pathological response in these patients treated only with taxane and lapatinib, and this translates in a pathological response of 17%; obviously, a shorter period of time treatment, lack of anthracyclines. And this paper was published in the JCO in 2010 suggests the feasibility of this combination for patients that had HER2-positive Stage III inflammatory breast cancer.
So this prompted [us] to design of another study which we wanted to introduce anthracyclines after taxane together with lapatinib in order to evaluate the full benefit of HER2 blockage, together with the longer chemotherapy and more standard chemotherapy in patients with inflammatory breast cancer. This study was designed as a two-step design, Simon design, and unfortunately, after the first 14 patients, there was no evidence of pathological response as we defined, also with evid --- with minimal residual disease in a couple of patients, not enough to actually move to the second step. So this was abandoned, suggesting that lapatinib together with this longer chemotherapy combination does not appear to provide any additional benefit in direct comparison to combinations that use Herceptin®.
But the combination of anti-androgenic therapy and HER2 therapy has been tested in the neoadjuvant setting from the French group in the BEVERLY-2 study that has been presented as a first analysis, where bevacizumab and trastuzumab have been combined with chemotherapy.
This is a very complex study in which epirubicin and cyclophosphamide have been given for four cycles, followed by docetaxel for four cycles. Neoadjuvant bevacizumab is given concomitantly with chemotherapy but interrupted four to six weeks in order to decrease the possibility of a complication from surgery. Neoadjuvant trastuzumab is used with the docetaxel in order to reduce the possibility of heart failure and problems. And then in the adjuvant setting after surgery, the patient would receive adjuvant trastuzumab and would restart adjuvant bevacizumab for 30 weeks.
So quite heavy treatment. The first part has been presented and published, and consists in pathologic and complete response defined according to the Sataloff Classification, looking at the amount of residual disease, or residual disease burden. You see that it is quite high incidence of pathologic complete response in a --- in a total of 52 patients, suggesting that maybe [the] addition of bevacizumab on top of Herceptin® with chemotherapy may contribute to increased pathological response. But this is only an assumption because there was no control arm.
So what about new molecular therapy for IBC? As we mentioned, the patients that do not achieve a pathological CR have a worse prognosis, have a chance of recurrence very early on, and there are limited treatments for these patients, except for the HER2-positive group. So the majority of triple negative actually do not have molecular therapies for that.
So there were several studies in the last three or four years that have looked at the possibility to identify specific biomarkers that would suggest that we direct new molecular therapy. The study by Sil --- Silvera actually showed that the translation into transcriptional machinery is activated in IBC, where elF4G1 is present and associated to SUM149 IBC cell line and SUM 149 tumors, and then…
…in an --- in vivo model, you can see that that is shutting down or using shRNA in order to reduce the expression of elF4G1 is associated with reduction for marking information of tumors, slowing down the tumor growth. The tumor volume is much less and also the synthetic activity is significantly --- statistically significantly reduced. And this is the difference between the expression in normal epithelia and in IBC.
So with regarding to the molecular subtypes that we use for classification of regular breast cancer, this has been also evaluated for inflammatory breast cancer. In the majority of inflammatory breast cancer class actually basal-like in the HER2-positive group, much less with luminal A or luminal B group, suggesting that these patients derive less benefit from endocrine therapy and are more aggressive overall.
When we look at the different cell lines and models available for IBC, you can actually see that there is a heterogenous distribution. In fact, most of the commonly used SUM149 and Mary-X are triple negative or basal-like. SUM 149 is HER2-positive as well as 1IBC-3. And, the most recently established IBC01 is actually basal-like as well. So suggesting that somewhat the IBC phenotype is independent, at least regarding to the preclinical model from the subtype of the breast cancer.
So Mary-X is certainly the model that has allowed [us] to evaluate most of the initial observations for the biology of the disease, particular because of recapitulated tumor emboli of the disease. This is a typical patient with significant breast changes, edema, and ulceration related to the establishment of tumor emboli. This is a mouse with this established inflammatory breast cancer within the skin.
So this has allowed us to test various hypotheses. And we have evaluated the possibility that based on the increased expression of HDACs or histone deacetylases that histone deacetylase inhibitors would eventually differentiate the IBC cell line and make this disease less aggressive. So romidepsin after SAHA [suberoylanilide hydroxamic acid] has been tested in SUM149, SUM190, and compared to other cell lines to see if there is inhibition that is also present with the same cell line treated with Taxol®. And we have done also studies of the combination;
suggesting that it is possible to combine three preclinical models to get a synergistic effect for these two agents. And when we look at dosage, we saw that you can achieve up to 67%, in a dose-dependent fashion, inhibition of tumor volume reduction for the --- using romidepsin alone, and you can achieve 85% of using a higher dose of paclitaxel, 50 mg/kg.
So this translates in the design of a clinical trial where romidepsin in a Phase 1/Phase 2 [study] is combined with Abraxane® in these patients [with] metastatic HER2-negative inflammatory breast cancer.
The first phase has as the primary objective to assess the safety of this combination and to determine the maximum tolerated dose before moving to the Phase 2 that, in fact, will address the overall response rate, clinical benefit, and additional measures of efficacy.
This is the scheme of the study. These are patients with inflammatory metastatic disease being treated with two or three lines of previous therapies were --- will be enrolled first in the Phase 1 with an escalating dose of romidepsin, IV, over one hour, and Abraxane® would be a standard dose. The patients in Phase 2 after the maximum tolerated dose would be established, would be evaluated probably in the first or second line, in order to asses really the full benefit of this --- this disease treatment. At the same time we would have correlative studies looking at re-expression of markers of --- of differentiation, of particular, ER and other factors. And also would measure CDCs as a way to address rate of response.
So that protocol is going to be activated soon and will be available to patients. We also identified anaplastic lymphoma receptor tyrosine kinase [ALK] as a potential new target in inflammatory breast cancer.
Now the ALK is certainly not known to be a molecular target for breast cancer. It has been found, in fact, to [be] rearranged, mutated, amplified in los --- anaplastic large cell lymphoma, neuroblastoma, and non-small cell lung cancer. Only in a very small fraction of patients with triple negative breast cancer, mostly amplified or overexpressed.
So where in preclinical work in collaboration with Dr. Petricoin at George Mason University, we evaluated the protein expression level of this phospho-ALK. And we compared this with non-small cell lung cancer where this drug --- drugs for ALK targeting had been approved. We see the IBC actually clusters with non-small cell lung cancer different from the non-IBC breast cancer.
So we went back to our models and looked at the expression as well as the amplification level. We saw that ALK, for example, in the Mary-X is overexpressed and is a different copy number in Mary-X as well as IBC-01 and 02 new models being established for IBC.
This prompted [us] to go back to the tissue that had been collected at MD Anderson present in the database to look at the gene expression. This is very heterogenous and independent overall, appeared to be from the subtypes.
So we went back and used the IBC-01 tumor xenografts in order to establish --- some proof of concept that crizotinib can actually affect cell viability and survival and also can induce apoptosis in this particular tumor model.
So in conclusion, we showed that the histopathological characteristics of IBC is certainly characterized by extensive dermolymphatic invasion and the formation of tumor emboli, very critical for the lymphatic spreading in the metastatic process to be initiated. There are abnormal molecular pathways associated with angiogenesis, hypoxia, lymphangiogenesis, chemokines for the homing of cancer cells, growth factor receptors, and transcription factors. All of these represent an area for further investigation. For the standard treatment of HER2-positive patients, agents like lapatinib definitely show activity as a single agent, trastuzumab combination activity in primary recurrent IBC, representing now the standard neoadjuvant management of IBC patients. And novel targets are --- are being identified and it is possible that this will be translated very soon in promising clinical trials that can improve the overall prognosis and the outcome of these patients.
I want to acknowledge the support from the grant from the State of Texas, Rare Aggressive Breast Cancer Research, and the American Airlines support of Susan G. Komen Promise Grant to Fredika Robertson, who contributed most of this data and the new findings. And I welcome every one of you that wants to have any additional information about this terrible disease to contact us through our website. Thank you.
Inflammatory Breast Cancer: Biological Features video
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