Inflammatory Breast Cancer: Clinical Challenge, Research Enigma
By Sunita Patterson
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.
“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.
|Inflammatory breast cancer can closely resemble mastitis. Common symptoms, often rapid in onset, are erythema, engorgement, induration, (left) and peau d’orange (dimpling resembling an orange peel; right).
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
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
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
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.
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
information, call Dr. Naoto Ueno at 713-792-8754.
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:
Dr. Ueno posts information for patients, clinicians, and researchers on Facebook and Twitter:
articles in OncoLog, September 2012 issue:
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