This is a 60-year-old woman who has a history of right-sided breast cancer. The cancer is clinically of the inflammatory type with edema and redness, and the patient is also found to have an axillary lymph node at the time of diagnosis. This case of a patient presenting with what looks like clinical inflammatory breast cancer first needs to be approached with diagnostic confirmation. Typically, we would do an image-guided core biopsy of the mass and, in this case, given the imaging showing axillary adenopathy, probably a fine needle aspiration of the lymph node, as well. Of course, we confirm that this is carcinoma, as suspected, and obtain biomarker information: hormone receptor status and HER2 status.

The initial diagnostic studies with the core biopsy do confirm a high-grade carcinoma. The tumor is estrogen receptorpositive, progesterone receptor&ndash;negative, and HER2-positive. On that basis, given the fact that this patient has inflammatory breast cancer, the treatment generally would be neoadjuvant or preoperative therapy. As this is a HER2-positive breast cancer, our best treatment is going to be combination antibody therapy with trastuzumab and pertuzumab. This combination was actually approved in the neoadjuvant setting initially and, more recently, in the adjuvant setting. Of course, it has been approved in the metastatic setting for quite some time.

One of the more common regimens we use is the combination of docetaxel/carboplatin, along with trastuzumab and pertuzumab. This is a perfectly reasonable option that the patient receives. Other options would include anthracycline-based therapy: doxorubicin and cyclophosphamide, typically followed by a taxane with trastuzumab and pertuzumab.

Inflammatory breast cancer itself is not that common. It probably represents 2% or 3% of all cancers. However, node-positive breast cancer certainly is a common presentation. About a third of cases do present with positive nodes. In certain populations, younger populationsmaybe in urban populations&mdash;that number is even higher. Of all the cancers, about a fifth of them are HER2-positive. Inflammatory HER2-positive disease with all of those features may not be that common, but certainly the treatment paradigms that we use to treat these types of cancers can be applied here. The key issue in treating patients is the subtype of breast cancer based on hormone receptors and HER2 positivity, as well as the clinical and pathologic stage.

Reviewing a Case of HER2+ Inflammatory Breast Cancer

This patient does go on to receive doxorubicin and cyclophosphamide followed by docetaxel, trastuzumab, and pertuzumab and does have a clinical response at the time of surgery. In fact, she does have a complete pathologic response, which is defined by no invasive disease in either the breast or the lymph nodes.

Neoadjuvant therapy is typically used for patients with larger tumors or node-positive tumors or if there is an interest in breast-conserving surgery. The ability to use breast-conserving surgery is much greater in patients who have a significant response, and that&rsquo;s been shown very clearly in HER2-positive breast cancer.

Now, in this particular case, there&rsquo;s an additional important factor, and that is that the patient has inflammatory breast cancer. Historically, the outcome with surgery up front has been very poor. The recurrence rates are extremely high. For many, many years now, even before the advent of HER2-targeted therapies, we have been using preoperative chemotherapy for these patients because of the involvement of the dermal lymphatics. It&rsquo;s very difficult to know where the borders of the dermal lymphatics areif they are just involved right over the tumor or if they go further out&mdash;because the clinical changes are quite subtle, the redness and the swelling. So, it is very typical now for us to use neoadjuvant chemotherapy for these cases. Obviously, in the case of HER2-positive breast cancer, we would now add both antibodies, trastuzumab and pertuzumab.

The use of anthracyclines in the initial setting for HER2-positive breast cancer remains somewhat controversial. The data so far actually project equivalent outcomes from anthracycline or nonanthracycline therapy. If you look at the most important outcomes, which are disease-free survival and overall survival data from the older trials where anthracycline and nonanthracycline therapies were tested side by side, they show equivalent results. BCIRG-006 is the study that compared doxorubicin and cyclophosphamide followed by docetaxel along with trastuzumab to the nonanthracycline regimen of docetaxel, carboplatin, and trastuzumab. This was in the pre-pertuzumab era, but very clearly, the outcomes there were equivalent. At this point in time, there are some favorites. Some people like to use anthracyclines or feel that they might be more important for younger patients and for higher-stage disease. We don&rsquo;t really have clear, definitive proof that there&rsquo;s a right or wrong way to go when it comes to choosing anthracyclines or not.

HER2+ Inflammatory Breast Cancer: Neoadjuvant Approaches

The risk of recurrence in patients who have surgery up front is dictated mostly by their clinical stage, as well as other factors such as the grade of the tumor. In patients who receive neoadjuvant therapy, however, one of the strongest predictors is whether or not the patient achieves a complete pathologic response. Patients who achieve a complete pathologic response have a short-term 5-to-10-year outcome that&rsquo;s quite good. Maybe 10% to 15% of patients recur, so the disease-free survival typically tends to be about 90%.

In the case of inflammatory breast cancer, however, our experience is more limited given the rarity of this type of cancer. The data seem to show that the long-term outcomes, even in patients who achieve a complete pathologic response, may not be as favorable. Maybe 20% or 25% of these patients may still recur. The pathologic complete response rate is also lower in inflammatory breast cancer to start with.

Although pathologic complete response rate does predict a better outcome, and patients who do not have a complete pathologic response do have a worse outcome, the outcome is serially worse depending on how much residual disease there is. Especially if there are multiple nodes involved, these patients may have as high as a 30%, 40%, or 50% long-term risk of metastatic recurrence.

Following surgery and the determination of pathologic response, this patient who presented with inflammatory breast cancer that&rsquo;s stage T4d, as well as node-positive, would clearly have an indication for chest-wall radiotherapy to include the regional nodes, which is what the patient receives. Following that, because the tumor was hormone receptorpositive, the patient would have gone on endocrine therapy. The typical endocrine therapy for a postmenopausal patient would be an aromatase inhibitor.

In addition to hormonal therapy following radiation and even during radiation, the continuation of a maintenance antibody would be given. The optimal therapy is to continue both antibodies, trastuzumab and pertuzumab, for completion of a full year, including what was given with the chemotherapy.

Typically, a patient who receives neoadjuvant therapy does not receive additional cytotoxic therapy. They obviously do get maintenance therapy with antibodies. We don&rsquo;t have much experience in how to handle these patients. Many times, if a patient receives nonanthracycline therapy, they may then be given additional anthracycline therapy if they have significant residual disease. That&rsquo;s the case, at least with chemotherapy. Now, with biological therapy, as I mentioned, we always give maintenance therapy with trastuzumab alone in lower-risk cases. But in higher-risk cases, pertuzumab and trastuzumab are now indicated, and they&rsquo;re given in the maintenance setting.

Recently, there has also been a demonstration that the tyrosine kinase inhibitor neratinib can add a further reduction in the risk of recurrence when it&rsquo;s given after the completion of maintenance trastuzumab. This is from the ExteNET study, which compared neratinib to placebo and found that there was a reduction in the risk of recurrence in higher risk patients who were given neratinib. That is another adjuvant option, especially for higher-risk patients.

Certainly, in the adjuvant setting for this patient, the maintenance antibody should definitely be continued. That&rsquo;s a standard part of care. After the completion of antibody, the patient would then probably be on hormonal therapy because the patient&rsquo;s tumor is ERpositive. That, after the completion of antibody therapy, is when one would also consider the use of neratinib along with, in this case, hormonal therapy. That would typically start as soon as the antibody is over. The clinical trial that looked at neratinib, the ExteNET trial, initially enrolled within the first 2 years, but then the protocol was amended, and patients had to go on therapy within a year of completing adjuvant antibody therapy.

HER2+ Inflammatory Breast Cancer: Adjuvant Strategies 

The APHINITY trial was designed to test the addition of pertuzumab to a standard nonanthracycline or anthracycline-containing chemotherapy backbone along with trastuzumab. Patients were randomized to get standard chemotherapy with trastuzumab, and that was given either with or without pertuzumab during the chemotherapy phase, overlapping with the taxane, as well as during the maintenance phase.

The study enrolled patients who had higher-risk node-negative cancers, defined as cancers that were greater than 1 cm. Or, if they were in the 0.5-cm to 1-cm range, they had to be high grade or hormone receptornegative. Of course, it also included node-positive patients. Both hormone receptor statuses were included. The main outcome measure here was the standard invasive-disease&ndash;free survival. The study did meet its endpoint, showing a statistically significant improvement in disease-free survival. The core take-home message of this trial was that pertuzumab does indeed add benefit. It was a statistically significant difference. The absolute difference was rather small in the lower-risk patients, but I think all of us would agree that in higher-risk patients, the use of pertuzumab is clearly justified.

Fortunately, there didn&rsquo;t seem to be added risks in terms of cardiotoxicity, which is one of the risks that we&rsquo;re always concerned about with HER2-targeted therapy. The number of patients who had cardiac events was no higher in the pertuzumab-containing arm. There were some toxicities that were more frequent. Most notable was diarrhea, which is a known side effect of adding pertuzumab, particularly to the chemotherapy part. That was seen at a higher rate.

I think that the APHINITY trial was really an adjuvant trial, where patients had surgery first. There, it&rsquo;s a little more defined. I think for the most part, it was stage 2 disease or higher. Even stage 1 patients were included in the study, but they were at higher risk. That&rsquo;s probably where the controversy iswhere you&rsquo;d draw the risk line. But certainly for higher risk, node-positive, or even stage 2A disease, that would be an appropriate therapy. These patients are at higher risk of recurrence.

The additional thing I would say, though, is that patients who got neoadjuvant therapy were not included in the APHINITY trial, but we also know what their risk is. Those patients already had pertuzumab approved by the FDA on the basis of a higher complete pathologic response rate, and it was approved specifically with chemotherapy. But as you look at the NeoSphere trial and the TRYPHAENA trialthose were the 2 neoadjuvant trials that led to the approval of pertuzumab in the neoadjuvant setting&mdash;and you combine them with the findings of the APHINITY trial, I would say that our standard is now going to be to use both trastuzumab and pertuzumab with chemotherapy, and then to use them for the maintenance phase as well.

We do not have a randomized trial that really tests just the maintenance phase, where, for example, patients might get trastuzumab and pertuzumab along with chemotherapy, and then one group gets just trastuzumab and the other group gets both antibodies for maintenance. We don&rsquo;t have that study, so my default is really to use both antibodies for the duration.

What it really boils down to is, what is the residual risk you&rsquo;re predicting for this patient? We know that the odds of recurrence were reduced by about a third. A third of a very small residual number is going to be a small number indeed. If the patient just has a 3%, 4%, or 5% risk of recurrence, they&rsquo;re just lowering it by maybe 1%. However, with any number that&rsquo;s higher than that, you now get into reasonable numbers in terms of a difference between recurrence or not. Really, the best metric to useof course, this an estimation&mdash;is the literature to guide you in predicting what is the residual risk that this patient has. I would say that someone with inflammatory breast cancer, even someone who did achieve a complete pathologic response, still has a good 20%, 25%, or maybe even as high as 30% risk of recurrence, despite having a PCR.

APHINITY Trial: Adjuvant Pertuzumab and Trastuzumab

Neratinib is also used in the setting of higher-risk disease. Like other therapies, we try to project, what is this patient&rsquo;s risk of recurrence? And then, based on the hazard rate reduction that we project with that drug based on the clinical trials, we calculate what their absolute benefit would be. In this patient, I believe they have a high enough residual riskeven with all the therapy they&rsquo;re receiving&mdash;such that the addition of neratinib may add a few more percentage points in lowering the risk of recurrence.

There are several different directions that are being taken to improve outcomes in HER2-positive breast cancer. Metastatic recurrences remain incurable, so our goal really needs to be to keep that number as low as possiblewith an acceptable risk profile, of course. The addition of other therapies that may complement these drugs is always going to be important. But then, we also have to realize that these drugs have side effects, there are costs, and there are convenience issues.

We don&rsquo;t want to just keep piling on more and more drugs. We would like to be at a point where we can personalize therapy and know which patients do or do not need drugs. That falls into 2 general areas. One is understanding and discovering biomarkers that may predict who will respond to specific drugs. One example of a biomarker is PI3 kinase mutations, which seem to indicate some degree of resistance to trastuzumab and maybe to pertuzumab. They&rsquo;re not really clinically used right now, but we need more biomarkers like that, and they need to be validated. Of course, we also need to look at other factors that predict who might be at higher risk of recurrence, whether it&rsquo;s the stage or other clinical features, and this will help us be more precise.

The other movement that&rsquo;s going on in this area is, are there patients in whom you can deescalate therapy? Someone who looks like they&rsquo;re going to have an absolutely good outcome might not need the full year of antibody therapy. At this point, we don&rsquo;t know that, but there are some discussions about identifying patientsnot with inflammatory cancers, but maybe who start off with node-negative cancers&mdash;who have a complete pathologic response and maybe don&rsquo;t need to complete the full year of maintenance antibodies. Those kinds of studies are being discussed, as well.

Optimizing the Management of HER2+ Inflammatory Breast Cancer

Reviewing a Case of HER2+ Inflammatory Breast Cancer

HER2+ Inflammatory Breast Cancer: Neoadjuvant Approaches

HER2+ Inflammatory Breast Cancer: Adjuvant Strategies

APHINITY Trial: Adjuvant Pertuzumab and Trastuzumab

HER2+ Inflammatory Breast Cancer: Addressing Unmet Needs