Inflammatory Breast Cancer: What You Should Know

Editor's Note:
Inflammatory breast cancer (IBC) accounts for 1%-5% of all breast cancer cases but 10% of breast cancer deaths.^[1] Historically, 5-year survival in IBC has been less than 5% when treated with surgery or radiation therapy, increasing to 30%-40% with multimodal therapy that includes preoperative chemotherapy adequate to induce pathologic complete response (CR) before surgery.

Naoto T. Ueno, MD, PhD, Section Chief of Translational Breast Cancer Research and Executive Director of the University of Texas MD Anderson Cancer Center Morgan Welch Inflammatory Breast Cancer Program in Houston, Texas, spoke to Medscape about current IBC diagnosis and treatment.

New Data Show Statins Provide Benefit

Medscape: What do you see as the most significant advances in understanding and treatment of IBC in recent years?

Dr. Ueno: We are quite excited about data we reported at the 2012 San Antonio Breast Cancer Symposium, which showed an association between statin use and disease-free survival (DFS) in patients with IBC.^[2] We reviewed 724 patients in whom stage III IBC was diagnosed and treated at MD Anderson Cancer Center between 1995 and 2011, 74 of whom were using statins at the time of diagnosis. DFS was 1.76 years in those who did not take statins, 2.47 years in those who used lipophilic statins (atorvastatin, fluvastatin, lovastatin, or simvastatin), and 4.88 years in patients who used hydrophilic statins (rosuvastatin and pravastatin). This was only a retrospective study, but it provides a reason to look further at statin effects in IBC and in other cancers.

In related work, last year data from the Danish Breast Cancer Cooperative Group Registry showed reduced risk for recurrence in women with stage I-III breast cancer who had taken simvastatin.^[3] That study inspired us to look specifically at statins and IBC.

Is IBC Inflammatory or Not?

Medscape: Is the statin effect (if it exists) in IBC related to anti-inflammatory activity?

Dr. Ueno: Although this disease is called "inflammatory breast cancer," inflammation is not really proven. A related question is whether IBC really differs from noninflammatory breast cancer. IBC is currently more of a clinical diagnosis. Microarray analyses in triple-negative breast cancer show little difference between inflammatory and noninflammatory breast cancers, although the outcomes are, of course, very different. It is possible that this study was underpowered to detect a difference, but it also might be that the tumor-surrounding microenvironment -- not the tumor -- contributes to the difference in the behavior of the disease.

There is currently no molecular definition of IBC. We need analysis of a large, prospective collection of tissue samples to define this. We may find that IBC is not a separate entity, but is simply an accelerated form of other standard breast cancers. MD Anderson is investing a lot of money in this question, because IBC represents 8%-10% of breast cancer mortality and because if we can determine why IBC progresses so quickly, what we learn could be applied in non-IBC settings.

Medscape: Where does that leave the statins in IBC?

Dr. Ueno: We are planning a prospective randomized trial of statins in patients with IBC to further assess the impact on survival. This might be particularly important for IBC patients who do not achieve pathologic CR after preoperative chemotherapy, because they do not do very well after standard chemotherapy, surgery, and radiation and we have nothing else to offer them. The hope is that statins, which are a relatively benign intervention, might reduce the recurrence rate in these patients as well.

IBC Can Masquerade as Mastitis

Medscape: Is delayed or missed diagnosis still a problem in IBC?

Dr. Ueno: Yes. Most women who present to a family physician with typical IBC symptoms developing within about 3 months of erythema, edema in the breast, and exaggerated hair follicle pits are (quite reasonably) diagnosed with mastitis and treated with antibiotics. What is not reasonable is to order a second or third round of antibiotics if the first round does not solve the problem. That does not mean that every woman with a red breast should be sent to an oncologist, but if the condition does not improve after 1 round of antibiotics, it is time to order mammography and ultrasonography to see whether there is anything to be biopsied, and keep IBC in mind. Just repeating antibiotic therapy and hoping for the best is likely to result in IBC spread all over the place by the time we see the patient.

At the same time, we need to be careful not to overdiagnose. The patient with a lump that has been present and gradually enlarging for 3 years before the breast became red probably does not have IBC. She has delayed treatment of locally advanced breast cancer.

Medscape: What are the key steps in diagnosis of suspected IBC?

Dr. Ueno: Get a mammogram and ultrasonography. If you see a mass, biopsy it. If there is no mass but only skin changes, do a skin biopsy; there may be tumor emboli in the skin. If nothing is apparent on mammography or ultrasonography, a lesion or skin changes may be evident on MRI mammography. Even if imaging and biopsy show nothing, that does not rule out IBC. Because there is not a mass, needle biopsy may be from an area with no tumor at all.

You may have to rebiopsy. Use clinical judgment. One negative biopsy is not conclusive.

Pathologic Complete Response Is the Goal

Medscape: What is the standard for IBC treatment at MD Anderson?

Dr. Ueno: Our institution's standard is weekly paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) or 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for 4 cycles. You have to have a taxane, and you have to have an anthracycline regimen. If the patient is HER2-positive, trastuzumab is added.

The goal is to achieve pathologic complete response. I have recently seen regimens with 4 cycles of Taxotere® (docetaxel for injection) plus cyclophosphamide. It is difficult to say that this is a great regimen for IBC, because it does not achieve many pathologic CRs in locally advanced breast cancer. Giving only 2 cycles and going to surgery is also a mistake. You need to give plenty of systemic treatment so that you achieve pathologic CR before surgery. Otherwise, the outcome is not good.

We still see patients from surgical oncologists who do mastectomy up front in IBC. Other physicians give chemotherapy before surgery, but only for a very short period. Any patient who does not achieve pathologic CR to preoperative chemotherapy is unlikely to do well.

The surgery must be modified radical mastectomy, not segmental mastectomy or lumpectomy. Even if the redness and mass disappear with pathologic CR, we have no idea where the disease is sitting. It is scattered.

Patients should also be offered the possibility of entering a clinical trial. One change over the past 2 years is that several IBC-focused clinical trials are now recruiting patients. There are many reasons why patients might not participate in clinical trials, but lack of information should not be one of them.

Treatment May Take Different Pathways

Medscape: What is on the horizon for IBC?

Dr. Ueno: Our ongoing phase 2 study of panitumumab is going very well. Preclinical data suggest that the epidermal growth factor (EGF) pathway is very active in IBC, and epidermal growth factor receptor (EGFR) overexpression is a poor prognostic factor. We are seeing some very interesting early results with a fairly intensive regimen of panitumumab (Vectibix®), protein-bound paclitaxel (Abraxene®), and carboplatin. We will accrue up to 40 patients and are about halfway there. We are excited enough to think that this trial it should be continued. In general, pathologic CR after chemotherapy in IBC is about 15%, and we are seeing a much more interesting trend with this regimen.

We are trying double anti-HER2 therapy for patients with HER2-overexpressing IBC. We are also planning a new trial that suppresses inflammation in metastatic IBC with a regimen that suppresses both cytokines and angiogenesis. Finally, we have an ongoing phase 1/2 study of avatinib that should close accrual within 2 years.

Other new approaches that look interesting include targeting insulin-like growth factor 1 (IGF-1) pathways; determining why IBC is so aggressive even though E-cadherin levels are elevated; and targeting MAP kinase, which is highly elevated in IBC and in triple-negative breast cancers.

We also have a phase 1 study under way of lapatinib plus the histone deacetylase (HDAC) inhibitor entinostat, which modulates DNA replication. It is possible that lapatinib sensitivity could be enhanced by entinostat.

Medscape: How big is the MD Anderson team working on inflammatory breast cancer?

Dr. Ueno: We have 3 medical oncologists, 3 surgical oncologists, 2 radiation oncologists, 3 pathologists, 2 imaging specialists, and a couple of basic researchers.

Medscape: How is the MD Anderson IBC program supported?

Dr. Ueno: Patient advocates who work closely with us went to the Texas state legislature and obtained funding through a State of Texas Rare and Aggressive Breast Cancer Research Program Grant. This is a unique model and supports the Morgan Welch Inflammatory Breast Cancer Program, named for a young woman diagnosed with IBC who died quickly of the disease. The National Cancer Institute was reluctant to fund studies on IBC in the absence of a molecular definition. It became a chicken-and-egg situation. Consequently, all of our work is being supported by the State of Texas.

We are very proud of our advocates and how we work together. We try to be as open as possible about our program and to be accountable for how we use our support money. We recently had a community workshop to update our progress and get input from the advocates. We take it very seriously that patients, family, and advocates are involved and are stakeholders in the program. We don't just ask them for money. We have a very active social network system. We also want to make our staff known to people, so that they feel connected to the program, and our extensive use of social media, including Facebook and Twitter, are part of that effort.