From OncoLog, September 2012, Vol. 57, No. 9

Inflammatory Breast Cancer: Clinical Challenge, Research Enigma

By Sunita Patterson

Inflammatory breast cancer (IBC) stands apart from other cancers of the breast in its unusual clinical presentation, its aggressiveness, and its poor prognosis. Researchers and clinicians are working to clarify what distinguishes IBC from other breast cancers and to discover treatments that improve patient outcomes.

Although IBC accounts for only 2%–5% of breast cancers, it is responsible for 8%–10% of breast cancer–related deaths. “IBC has a strong tendency to metastasize. In fact, a third of patients have metastases at diagnosis,” said Naoto T. Ueno, M.D., Ph.D., a professor in the Department of Breast Medical Oncology and executive director of the Morgan Welch Inflammatory Breast Cancer Research Program and Clinic at The University of Texas MD Anderson Cancer Center. The IBC program at MD Anderson was the first clinic in the world devoted to IBC and is the largest today, treating about 100 patients each year.

Symptoms and diagnosis

Because IBC is rare and its symptoms differ from those of more typical breast cancers, misdiagnosis and less-than-optimal treatment are common, both of which diminish survival outcomes.

The first challenge that IBC presents clinicians is that it does not look like a typical breast cancer. It often appears to be and is misdiagnosed as an infection or a rash. The primary symptoms are usually rapid breast enlargement and erythema covering most of the breast; there may not be any lump.

For most patients with breast irritation and redness, mastitis is the problem, and an antibiotic will help. However, according to Dr. Ueno, if there is no response to the antibiotic in 1–2 weeks and the breast remains red, the physician should suspect IBC and order a biopsy right away. “We don’t want to waste a lot of time with this disease,” Dr. Ueno said, “because it increases the chance of metastasis.”

Both a core needle biopsy and a punch biopsy of the skin should be done. When there is no clearly defined mass, Dr. Ueno recommends directing the needle where the most swelling and redness exist. In patients with IBC, the skin specimen will often show extensive dermal lymphatic invasion. However, in the presence of persistent symptoms, negative biopsies do not rule out cancer completely.

Along with the biopsies, the patient should undergo mammography. If the results are negative, magnetic resonance imaging and ultrasonography should be considered.

Treatment

“Many community physicians will just see one case of IBC in their entire practice,” Dr. Ueno said. For this reason, he strongly recommends that patients with IBC be referred to a clinic specializing in IBC treatment. “These patients need a specific workup and a multidisciplinary care team,” he said.

The MD Anderson IBC clinic usually sees patients within 48 hours of their referral or self-referral. Typically, patients initially come to MD Anderson for 10–14 days of testing and meeting with medical, surgical, and radiation oncologists. The workup consists of repeat breast imaging (mammography, magnetic resonance imaging, and ultrasonography), remapping of the lymph nodes, blood tests, a pathologic review, and sometimes a positron emission tomography–computed tomography scan or a computed tomography scan with a bone scan.

Treatment of nonmetastatic IBC differs from that of other breast cancers in that systemic therapy is given preoperatively to debulk the disease as much as possible. Surgery and radiation therapy follow. Because treatment usually begins with chemotherapy, a medical oncologist is usually consulted first. But Dr. Ueno recommends that surgical and radiation oncologists with expertise in IBC also be involved from the beginning. “The optimal extent of local treatment can be difficult to judge when there isn’t a clear mass and the redness is diffuse,” he said, adding that coordinated care by an experienced team can reduce the possibility of errors.

The typical treatment course takes 6 months. The standard chemotherapy regimen involves treatment with paclitaxel and the combination of 5-fluorouracil, either doxorubicin or epirubicin, and cyclophosphamide over a period of 24 weeks. Patients with HER2-positive disease also receive trastuzumab. Many patients can receive chemotherapy in their own communities and return to Houston every 6 weeks for evaluation. “Our patients come from all over the country, and some aren’t able to stay in Houston for 6 months,” Dr. Ueno said. “But we highly recommend that our patients receive their surgery and radiation therapy at MD Anderson.” Patients who are eligible for a clinical trial are encouraged to receive all their treatment at MD Anderson.

Patients whose IBC responds to chemotherapy typically undergo mastectomy with complete axillary lymph node dissection. Patients whose disease does not respond to chemotherapy, particularly if negative surgical margins are unlikely to be achieved, are not good candidates for surgery. These patients may undergo additional chemotherapy and/or radiation therapy and later be reevaluated for surgery.

Radiation therapy for IBC targets the chest wall and the lymph nodes in the axillary, infraclavicular, supraclavicular, and internal mammary regions with a combination of electron and photon tangent fields or matched electron fields to minimize the risk to nearby organs. Treatment doses and schedules vary among institutions, but at MD Anderson, an aggressive twice-daily schedule and a total dose of up to 66 Gy are preferred. Radiation therapy may last 5–8 weeks.

A final component of treatment for patients with hormone receptor–positive disease is endocrine therapy for 5 years, beginning after surgery.

Follow-up is recommended at intervals of every 3 months for 2 years after the completion of radiation therapy, then every 6 months for 2–3 years, and then once a year. The follow-up appointment consists of symptom evaluation, a physical exam, and basic blood tests. “We’ve cut back on imaging during follow-up visits,” Dr. Ueno said. “It hasn’t proven to improve long-term outcomes.” Of course, if symptoms are suggestive of metastasis, a full workup, including imaging studies, is done.

The best outcome is seen in patients who have a pathologic complete response
 in the surgical specimen. “Unfortunately,” Dr. Ueno said, “most patients have some extent of residual disease.” Although the addition of neoadjuvant systemic therapy has improved the survival rate significantly, it is still only 30%–40% at 5 years.

Aside from the availability of coordinated multidisciplinary care, another advantage of patients’ being treated at a comprehensive cancer center is the access to clinical trials. Because of the low survival rates for IBC patients, Dr. Ueno recommends considering initial treatment in a clinical trial. “Of course, a trial is always experimental,” he said. “But a standard treatment that’s not fully effective is also not the ideal treatment.”

Researching causes and cures

Discovering better treatment strategies is a driving force behind the research component of MD Anderson’s IBC program. “There are three research questions we’re trying to answer,” Dr. Ueno said. “What are the differences between IBC and other breast cancers? Can we identify an IBC-specific target for targeted therapy? What are the molecular risk factors for developing IBC?”

Currently, IBC is a clinical diagnosis based on the patient’s symptoms; pathologic results consistent with IBC are not a requirement for the diagnosis. To identify molecular differences between IBC and noninflammatory breast cancers, Dr. Ueno’s research group has been looking at differences between the DNA, RNA, and protein levels in IBC and noninflammatory breast cancer specimens.

“So far, there hasn’t been a clear-cut difference in tumor mRNA levels between IBC and other breast cancers,” Dr. Ueno said. This raises the question: Is IBC a distinct entity that has an aggressive, metastatic phenotype, or are IBC and noninflammatory breast cancer the same biological entity that can grow either rapidly and aggressively or more slowly?

One challenge in the past was that the rareness of IBC made it difficult to obtain enough specimens for meaningful analyses. This need prompted the formation of an IBC registry at MD Anderson in 2006. The registry collects tumor, blood, and skin specimens from around the world, along with epidemiological data. The collection of specimens and data led to the definition of universal diagnostic criteria for IBC by participating institutions in 2008.

Forty samples from the registry are now being submitted to the International Cancer Genome Consortium for whole-genome sequencing. Dr. Ueno is hopeful that the information gained will suggest appropriate targets for treatment.

Possible treatment targets

As in other cancers, one avidly investigated treatment strategy involves targeting genes or proteins that are highly expressed in tumor cells with an agent that inhibits that gene or protein and thereby blocks tumorigenesis or metastasis. One such target that Dr. Ueno’s group is investigating is epidermal growth factor receptor (EGFR). In an MD Anderson study, EGFR was found to be overexpressed in 30% of IBC tissue specimens, and EGFR overexpression was associated with poor prognosis. Preclinical studies demonstrated that EGFR inhibition was a promising anti-IBC strategy. This work has advanced to a phase II clinical trial of the EGFR-targeting antibody panitumumab in patients with IBC. Other MD Anderson clinical trials are testing the targeting of histone deacetylase with the inhibitor entinostat and the targeting of fibroblast growth factor receptor 3 and vascular endothelial growth factor receptor with the inhibitor dovitinib.

An alternative hypothesis is being pursued by a team of researchers led by James Reuben, Ph.D., a professor in the Department of Hematopathology, and Wendy Woodward, M.D., Ph.D., an associate professor in the Department of Radiation Oncology. These investigators, with Dr. Ueno, are looking at whether the lethal potential of IBC lies not in the tumor cells themselves but in the microenvironment. It may be that immune system or inflammatory factors present in some patients induce tumor cells to act more aggressively.

This line of research has led to investigation of cyclooxygenase 2 (COX2), an enzyme associated with inflammation. The group, with Peiying Yang, Ph.D., an assistant professor in the Department of General Oncology, tested fish oil, which acts as a COX2 inhibitor, in vitro and saw a reduction in both the proliferation of IBC cells and the formation of mammospheres, an indicator of the presence of cancer stem cells. “Fish oil doesn’t have a lot of side effects, so we’re trying to develop this as a clinical trial,” Dr. Ueno said.

Statins are another avenue of exploration. This class of drugs, commonly used for patients with high cholesterol or triglyceride levels, is also thought to modulate inflammation. “If inflammation is a clinically relevant target, statins or COX2 inhibitors or fish oil could be a future therapy,” Dr. Ueno said. “It’s a matter of determining which pathway is best to target.” He anticipates a clinical trial in 1–2 years.

The IBC research group has been testing a new strategy for phase I clinical trials. An experimental drug is given to patients who previously received standard therapy and still have circulating tumor cells, or micrometastases, in the blood or bone marrow. A test for measuring these cells was developed by Dr. Reuben. The researchers hypothesize that the persistence of circulating tumor cells after treatment for IBC identifies patients at higher risk of recurrence or metastasis. If a drug eradicates those cells, it may be successful in preventing recurrence, and thus a larger trial with traditional disease outcome measures would be warranted.

Potential impact

Dr. Ueno is passionate about the need to study IBC even though it’s “rare.” “People keep asking, why are we investing so much effort in an ‘orphan’ disease?” he said. “It’s true that IBC is rare in terms of incidence. But from the mortality perspective, IBC isn’t rare. It’s a killer.”

For more information, call Dr. Naoto Ueno at 713-792-8754.

ADDITIONAL RESOURCES

Dr. Naoto Ueno recently co-edited a textbook about IBC treatment and research: Inflammatory Breast Cancer: An Update (Ueno NT, Cristofanilli M, eds.). Springer, 2012.

The MD Anderson IBC program hosts a Web page, Facebook page, and Twitter account with research updates and patient information:

• www.mdanderson.org/IBCProgram
• www.facebook.com/InflammatoryBreastCancer
• www.twitter.com/InflammatoryBCa

Dr. Ueno posts information for patients, clinicians, and researchers on Facebook and Twitter:

• www.facebook.com/ntueno
• www.twitter.com/teamoncology