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Abstract
Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2.5% of all
breast cancer cases. It is characterized by rapid progression, local and distant metastases, younger age of onset,
and lower overall survival compared with other breast cancers. Historically, IBC is a lethal disease with less than a
5% survival rate beyond 5 years when treated with surgery or radiation therapy. Because of its rarity, IBC is often
misdiagnosed as mastitis or generalized dermatitis. This review examines IBC’s unique clinical presentation,
pathology, epidemiology, imaging, and biology and details current multidisciplinary management of the disease,
which comprises systemic therapy, surgery, and radiation therapy. CA Cancer J Clin 2010;60:351-375. ©2010
American Cancer Society, Inc.
To earn free CME credit or nursing contact hours for successfully completing the online quiz based on this article, go to
http://CME.AmCancerSoc.org.
Inflammatory breast cancer (IBC) is a clinicopathological entity characterized by rapid progression and aggressive behav-
ior from onset of disease. Historically, its prognosis has been very grim. Especially before the introduction of systemic
chemotherapy, attempts to control IBC with either surgery alone or surgery combined with radiation therapy resulted in
median survival times of less than 15 months and local recurrence rates as high as 50%.1 Although survival times have
increased with multimodal therapy, they are still around 35% to 40% and much lower than those for other breast cancers.
Because IBC is rare, clinicians are less familiar with it than with the more common types of noninflammatory breast
cancers (non-IBC). The purpose of this review is to describe the clinical diagnosis, epidemiology, imaging, biology, and
multidisciplinary treatment of IBC. We summarize both current practice and novel concepts under investigation.
1
Professor, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 2Professor, Department of Epidemi-
ology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 3Associate Professor, Department of Diagnostic Radiology, The University of Texas
M. D. Anderson Cancer Center, Houston, TX; 4Department of Breast Surgical Oncology, St Luke’s International Hospital, Chuo-ku, Tokyo, Japan; 5Research
coordinator, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 6Predoctoral fellow, Department of Epidemiol-
ogy, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 7Professor, Department of Pathology, The University of Texas M. D. Anderson Cancer
Center, Houston, TX; 8Associate Professor, Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 9Associate
Professor, Department of Imaging Physics, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 10Senior Research Scientist, Department of
Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 11Professor and Chair, Department of Pathology, The Ohio State
University College of Medicine and Public Health, Columbus, OH; 12Associate Professor, Department of Radiation Oncology, The University of Texas M. D.
Anderson Cancer Center, Houston; 13Professor and Chair, Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, TX;
14
Associate Professor, Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 15Professor, Department of Breast
Medical Oncology, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, TX; 16Professor and
Chairman, Department of Medical Oncology, G. Morris Dorrance, Jr, Endowed Chair in Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA.
Corresponding author: Massimo Cristofanilli, MD, Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111;
Massimo.Cristofanilli@fccc.edu
DISCLOSURES: The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The State of Texas Grant for Rare and Aggressive Cancers, and American
Airlines Susan G. Komen for the Cure Promise Grant KGO81287 provided support for this study.
We thank Sunita Patterson and Kathryn Hale (Department of Scientific Publications, The University of Texas M. D. Anderson Cancer Center) for editorial assistance and Nina Neal
(The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas M. D. Anderson Cancer Center) for editorial and technical assistance.
姝2010 American Cancer Society, Inc. doi: 10.3322/caac.20082.
Available online at http://cajournal.org and http://cacancerjournal.org
Medical History
Inflammatory breast cancer is
most frequently characterized by
a very rapid onset of clinical signs
and symptoms. Because of the
possibility of mistaking IBC for a
benign bacterial infection such as FIGURE 2. There are variations in clinical presentation of IBC. (A) This IBC patient presented with synchronous
mastitis, it is important to note bilateral erythema. (B) IBC patient with increased breast size, peau d’orange, and minimal erythema on a back-
ground of darker skin.
that IBC is not a true inflamma-
tory process and is generally not
associated with symptoms such as fever, localized Because IBC is relatively rare, some physicians might
pain, or leukocytosis. A careful medical history typi- interpret the lack of a palpable tumor as excluding a
cally contributes important information for discrimi- diagnosis of breast cancer. Furthermore, skin changes
nating the clinical signs of IBC, particularly the acute may vary in both color and pattern of distribution de-
onset of breast enlargement and heaviness.3 pending on the extent of disease at presentation (Fig.
1B). Early erythematous discoloration of the skin can
further progress to intense red or purple color involv-
Physical Examination ing the entire breast. Specifically associated skin man-
In the majority of patients with IBC, no discrete mass ifestation is the peau d’orange or orange peel
is palpable on clinical examination. Rapid breast en- appearance attributed to underlying skin edema.4
largement and changes in the skin overlying the breast From 55% to 85% of patients present with metasta-
are usually the first manifestations of the disease that ses to the axillary or supraclavicular lymph nodes that
bring patients to the attention of a physician (Fig. 1A). may be detectable on clinical examination.3 Fixed,
Differential Diagnosis
Few conditions are considered
in the differential diagnosis of
IBC, and those typically can
be excluded on the basis of an
accurate medical history and
diagnostic biopsy. Bacterial in-
fection, including mastitis and
FIGURE 3. Clinical presentation of secondary IBC is depicted. (A) This IBC patient presented with a chest-wall
rash. (B) An IBC patient has ulcerated nodules. abscess, is a common misdi-
agnosis. However, such infec-
tions are rare in nonlactating
palpable, ipsilateral, axillary nodes are a common find- women. Uncommon presentations of other cancers
ing.3 As with non-IBC, the presence of lymph node can mimic some or all of the clinical signs of IBC
involvement is a crucial piece of information in the but can be ruled out by biopsy results. Postradiation
staging of the disease and provides important prog- dermatitis, another cause of erythema, is sharply de-
nostic information. In the seventh edition of the marcated, whereas the erythema characteristic of
American Joint Committee on Cancer (AJCC) stag- IBC shows a diffuse distribution. Congestive heart
ing guidelines for breast cancer, IBC is classified as failure is a rare cause of unilateral breast edema,
Stage IIIB, IIIC, or even IV, depending on nodal sta- which should resolve when the underlying condi-
tus and evidence of distant metastasis.5 tion is appropriately treated. Primary lymphomas
Although nipple involvement is not described as a of the breast, mostly non-Hodgkin disease, are
diagnostically defining clinical feature of IBC, flattening, an extremely rare condition that may mimic IBC
retraction, crusting, or blistering may be frequently ap- and will be excluded on the bases of histopatholog-
parent. It is usual to photograph the condition of the ical features.
TABLE 2. Selected Demographic Factors from the M. D. Anderson Inflammatory Breast Cancer Registrya
DEMOGRAPHIC FACTORS
SD indicates standard deviation; ER, estrogen receptor; PR, progesterone receptor; OCP, oral contraceptive pill.
a
n⫽70 at time of data analysis.
b
Parous women only.
Mammography Ultrasonography
Mammography, the gold standard for breast imaging, Ultrasonography is a cheap and rapid alternative imaging
has been largely unsuccessful in achieving the above- method that has shown success in delineating focal
stated roles for imaging IBC. Despite their median age breast parenchymal lesions in patients with IBC, facili-
of older than 51 years, more than 90% of women with tating tissue diagnosis of invasive cancer and permitting
IBC have nonfatty breast tissue, which may contribute evaluation of tumor markers.32-34 On an ultrasound im-
to poor observation of IBC features on mammog- age, IBC most frequently appears as an area of heteroge-
raphy, including breast masses or nodules and skin neous infiltration of the breast parenchyma or as a
changes.32 Mammographic breast abnormalities associ- conglomerate of masses within the breast with overlying
ated with IBC include a mass, architectural distortion, skin and subcutaneous edema (Figs. 8A, B).32,33 In a re-
and global skin and trabecular thickening, usually de- cent report, ultrasonography enabled detection of up to
scribed when already associated with overt clinical find- 93% of ipsilateral axillary nodal involvement and up to
ings (Fig. 7).32-34 Calcifications, a less common feature in 50% of infraclavicular, internal mammary, or supracla-
IBC, were noted in 33 (41%) of 80 patients in a recent vicular nodal involvement (N3 disease in the TNM clas-
series and in 47% of patients from a survey of 9 published sification system) in IBC patients (Fig. 8C).32 These
studies.32-34 Global skin and trabecular thickening are findings are useful for delineating regional nodal metas-
the most frequent mammographic abnormalities in IBC tases and may affect locoregional therapeutic planning
patients, but are nonspecific, as they can also be associ- that is based on initial disease involvement.35,36 Further-
ated with mastitis and LABC. There are currently no more, ultrasonography is extremely useful in evaluating
available data on early mammographic changes before response to induction chemotherapy of axillary nodes,
clinical diagnosis. with possible impact on timing of local therapy.
response to chemotherapy
in IBC, and the sample
sizes for both retrospective
trials were small (19 and 24
patients).40,42
Positron Emission
Tomography
Positron emission tomog-
raphy (PET) is a molecular
imaging technique that is
sensitive to functional or
FIGURE 9. (A) A 44-year-old woman has IBC (invasive ductal carcinoma). An axial T1-weighted VIBRANT MR image dem- metabolic changes in tis-
onstrates multiple parenchymal breast masses, with a large central dominant mass (arrows). (B) A 49-year-old woman has
IBC (invasive ductal carcinoma and ductal carcinoma in situ). An axial contrast-enhanced T1-weighted VIBRANT MR image sues. Because functional
demonstrates abnormal nonmass-like parenchymal enhancement (arrows).
changes precede anatomi-
cal changes, fluorine-18
significantly smaller than the LABC masses.38 fluorodeoxyglucose PET (F18-FDG PET) has the
Asymmetric nonmass-like enhancement is more potential to detect viable tumor tissue early through its
frequently associated with IBC than with non- level of glucose metabolism, which is higher than that
IBC, a finding concordant with the clinically ag- in surrounding normal tissues. Whole-body PET/
gressive and infiltrative behavior observed in this CT51 has the potential to clearly demonstrate—in a
disease and with the tendency for this carcinoma to single functional study—the extent of the disease, the
be multifocal and multicentric in its distribu- most likely sites for staging biopsies, and whether a
tion.32,38 The initial MRI peak-signal intensity given therapy is achieving its goal.51 Increasingly,
seen immediately after administration of intrave- F18-FDG PET is being used as a staging imaging
nous contrast is usually greater than 100% and has modality in women with LABC,52-54 and it has been
been reported to be higher in patients with IBC shown to be useful in detecting involvement of inter-
than in those with mastitis or LABC.38,39
nal mammary lymph nodes that is predictive of recur-
Other MRI findings that are predominantly re-
rence.55,56 A recent retrospective review on the role of
lated to the inflammatory components of IBC, such
PET/CT in the initial staging of IBC reported en-
as dilated lymphatic ducts, breast edema, or chest
couraging preliminary results in the diagnosis of lo-
wall edema, are best observed on a fat-suppressed
coregional and distant disease: 17% of 41 patients
T2-weighted sequence.41 The diffuse edematous
were shown to have unsuspected distant metastases at
pattern has been observed more commonly in IBC
than in LABC, whereas the focal peritumoral staging.57 Moreover, the conventional method of as-
edematous pattern has been reported in both.38 Skin sessing response to therapy in IBC is measuring tumor
abnormalities can be associated with mastitis, size. Because functional changes precede morpholog-
LABC, or IBC. Whereas normal skin thickness ical changes in tumors, much research has focused on
measures 3 mm or less on mammography and MRI, the role and efficacy of functional techniques in mea-
the thickness in patients with IBC frequently mea- suring response to therapy.58,59 Preliminary data on
sures up to 13 mm (Fig. 10).44 the monitoring of primary chemotherapy in LABC
DCE MRI has been used to monitor tumor re- show that FDG uptake is reduced after the first cycle
sponse to chemotherapy.42,45-48 Some reports have of treatment and that this decrease is a marker that
shown that, in LABC, tumor size after neoadjuvant may be valuable in predicting treatment response, and
chemotherapy, as observed on MRI, correlated better it will likely be able to correlate with overall
with actual residual disease than did measurements prognosis.60-62 In IBC, the absence of clinically iden-
by clinical examination, mammography, or ultra- tified masses to measure and track over time makes an
sonography. 45,46,49,50 Only 2 published studies have overall functional approach even more appealing for
evaluated the role of breast MRI in monitoring assessing response and managing therapy (Fig. 11).
radiation therapy. Magnetic resonance imaging and kinase inhibitor erlotinib. Because many poorly differ-
PET/CT have evolving roles in mapping locore- entiated non-IBC breast tumors also express HER2
gional disease and documenting distant metastases. and EGFR, it is probable that significant advances in
Molecular imaging offers a powerful tool for trans- prolonging overall survival of IBC patients will require
forming basic science research into clinical applica- identification of classes of therapeutic agents that tar-
bility by providing a way to assess and quantify get molecules other than ER/PR, HER2, and EGFR.
pathways in animal models and patients to verify
that the pathways are similar in both scenarios.64-68 NFB Activation, Proinflammatory Cytokines,
and Chemokine Receptors in IBC
Pioneering gene-expression profiling studies were the
Evolving Concepts in the Biology of first to report that ER-negative IBC tumors are char-
Inflammatory Breast Cancer acterized by overexpression of multiple nuclear factor
kappa beta (NFB) target genes.80 While NFB acti-
Molecular Subtype of IBC
vation and stimulation of associated target genes is
Breast tumors are categorized into specific subtypes known to be involved in tumor progression, there are
on the basis of the presence or absence of estrogen currently no selective pharmacologic agents that target
receptors and progesterone receptors (ER/PR), the NFB. Curcumin and analogs of this natural product
level of expression of claudins, the presence and ex- derived from the Indian spice turmeric as well as the
tent of amplification of the Her2 oncogene, and the proteosomal degradation inhibitor bortezomib (Vel-
differential production of cytokeratins 5/6 and/or cy- cade®) have been evaluated for their ability to inhibit
tokeratins 8/18. Although IBCs may possess any NFB-mediated events. Studies have demonstrated
combination of hormone receptors and oncogenes, correlation among NFB activation, Toll-like recep-
they are most often classified within the Her2- tors, and hyperactivation of the mitogen-activated
amplified, basal-like, breast cluster and may also be protein kinase (MAPK) signaling pathways, which
low in claudin. This classification of IBC tumors is may be linked to overexpression of EGFR and/or
consistent with previous gene expression studies re- HER2. Other studies have demonstrated the coex-
porting that IBC tumors commonly lack ER/PR and pression of EGFR and the chemokine receptor
have Her2 oncogene amplification.77 Other character- CXCR4 in IBC patients, which was associated with
istics of IBC tumors include high expression of the significantly decreased overall survival.81 These sig-
tumor suppressor p53 and overexpression of the epi- naling pathways potentially offer new therapeutic tar-
dermal growth factor receptor (EGFR), which are gets for development of inhibitors of IBC.
both associated with poor prognosis.78,79
Molecular subtyping of breast cancers has provided Rho C GTPase and the Molecular Signature of
a tool to determine the potential utility of targeted IBC
therapeutics such as those that target Her2 and/or The majority of IBC studies have used the SUM149
EGFR. Results of clinical trials have reported a high cell line, which was developed from a primary IBC
response rate (39%) and efficacy of the dual tyrosine tumor.82 Differential display analysis was used to
kinase inhibitor lapatinib (Tykerb), which targets identify genes in this cell line and compare them to
both HER2 and EGFR in IBC patients with Her2- human mammary epithelial cells and normal lympho-
positive tumors. Although promising, the response of cytes; this approach identified 17 genes of interest, 8
IBC patients to lapatinib is not durable, with disease expressed in normal but not tumor tissue and 9 ex-
progression within 12 months and development of re- pressed only in SUM149 cells. One of the most highly
sistance. Studies are underway to identify the mecha- upregulated genes in IBC was the transforming onco-
nisms of lapatinib resistance and to identify agents gene Rho C GTPase,83,84 which encodes a member of
that may be combined with lapatinib to provide a du- the ras homology (Rho) GTPase family of proteins
rable response for IBC patients. Examples of other involved in cytoskeletal reorganization during inva-
targeted therapeutics being evaluated for their effects sion as well as regulation of angiogenic growth factors
in IBC include the anti-EGFR humanized monoclo- and production of inflammatory cytokines. Rho C
nal antibody panitumumab and the EGFR tyrosine GTPase was overexpressed in 90% of IBC tumors
examined. Interestingly, the IBC phenotype associ- tyrosine kinase.90,91 Furthermore, recent reports indi-
ated with Rho C GTPase is blocked by a farnesyl cated that administration of the antidiabetic agent
transferase inhibitor,85 which led to clinical studies metformin results in significantly greater frequency of
that are currently evaluating the effects of the farne- pathologic complete response to chemotherapy in di-
syl transferase inhibitor tipifarnib (Zarnestra®) in a abetic breast cancer patients than in those not treated
phase 2 clinical trial in patients with stage IIB-IIIC with metformin.92 The mechanism of action of met-
breast cancer.86 formin includes activation of the energy-sensing ki-
nase adenosine monophosphate-activated protein
Loss of WISP3/CCN6 and Cross Talk With kinase and blockade of protein translation regulated
Insulin-Like Growth Factor Signaling Pathways by the p70S6 kinase1/mammalian target of rapamy-
Other studies using the SUM149 IBC cell line iden- cin. Moreover, metformin blocks activation of the
tified the loss of Wnt-inducible signaling protein 3 phosphoinositide 3-kinase (PI3K)/Akt pathways in-
(WISP3/CCN6; LIBC [lost in inflammatory breast volved in survival and proliferation and abrogates ac-
cancer]). WISP3/CCN6 is a secreted protein with tu- tivation of ERKs.93 All of these pathways are known
mor suppressor functions that is a member of the to be dysregulated in breast cancer, and inhibitors
CCN protein family.87 Interestingly, CCN6 contains and/or antagonists are available for many of them.
a binding motif similar to one in insulin-like growth These studies, as well as other studies reporting the
factor (IGF) binding protein-related peptides convergence of insulin signaling with EGFR, ERKs,
(IGFBP-rp9). High levels of circulating IGF, with MAPKs, and proinflammatory cytokines, suggest that
loss of IGF binding proteins, have been associated these pathways may be crucial targets to explore for
with increased risk for development of multiple tumor their relevance in regulating the aggressive phenotype
types, including breast cancer.88 Microarray analysis of of IBC.
differential gene expression in IBC tumors compared
with non-IBC tumors revealed a distinct IBC molec- Cyclooxygenase-2 and Prostanoid Receptors
ular signature that includes genes involved in IGF sig- as Molecular Regulators of IBC Invasion and
naling, loss of IGF-binding genes, and increase in Metastasis
expression of genes belonging to the Rho guanyl- Studies using the SUM149 and SUM190 IBC cell
nucleotide exchange factor activity,80 consistent with lines document a role for prostaglandin endoperox-
the observations of a gain of Rho-GTPase and loss of ide synthase 2, also known as cyclooxygenase-2
WISP3/CCN6 as a signature of IBC. Insulin-like (COX-2), in the invasive and angiogenic phenotype
growth factor 1 stimulates production of the inflam- of IBC, which confirms previously reported results
matory cytokines interleukin-8 and interleukin-6 from gene-expression and tissue-microarray studies
through activation of extracellular signal-regulated ki- which were the first to identify Cox-2 overexpres-
nases (ERKs) and MAPK, suggesting that alterations sion in IBC tumors.94
in IGF-1 signaling in IBC have important conse- Overexpression of Cox-2 and elevated levels of its
quences in regulation of a “proinflammatory microen- enzymatic product prostaglandin E2 (PGE2) is a char-
vironment,” which may be sensitive to inhibitors of acteristic of invasive human breast cancers and is de-
ERKs and MAPK. Furthermore, clinical and epide- tectable at early stages of tumorigenesis.95 Cox-2 also
miological evidence indicates an important link be- directly regulates the P450 Cyp191A1 aromatase en-
tween insulin resistance, hyperinsulinemia, diabetes, zyme, thereby regulating estrogen production, and
and poor prognosis in breast cancer patients. These interacts with both HER-2 and EGFR. Cox-2 is one
observations are consistent with the clinical observa- of a group of genes that mediate tumor extravasation,
tions that there is a significant association between survival, and reinitiation at distant sites during me-
BMI and poor prognosis among patients with LABC, tastasis.96 Although nonsteroidal anti-inflammatory
including IBC.89 There are currently multiple agents agents and the coxibs, a class of selective Cox-2 inhib-
targeting the IGF-1 signaling pathway that have been itors, showed promise as therapeutic and chemopre-
evaluated in preclinical studies and are now in clinical ventive agents, the association with cardiotoxicity in
trials, including anti-IGF-1 receptor antibodies and some individuals led to discontinuation of the use of
small molecule inhibitors of the IGF-I receptor rofexocib and reduction in the use of celecoxib.
Our studies demonstrate that antagonists of the pros- well as to the changes in skin texture that are the initial
tanoid receptor EP4, which block binding of PGE2, signs of IBC, although the association of these obser-
effectively inhibit the robust invasion and aberrant an- vations in terms of cause and effect has never been
giogenesis exhibited by IBC tumor cells.97 Interest- subjected to rigorous scientific evaluation. As one of
ingly, a study in canine inflammatory mammary the classical histopathological findings in IBC, tumor
carcinoma reported that the nonselective nonsteroidal emboli within the skin are skin lesions that have es-
anti-inflammatory drug (NSAID) piroxicam, used as caped the confines of the underlying breast. Whereas
a single agent, significantly increased the mean overall most human xenografts grow in mice as nodules with-
progression-free survival interval compared with out obvious lymphovascular invasion, the Mary-X xe-
treatment with doxorubicin-containing regimens.98 nograft model of IBC exhibits lymphovascular tumor
The roles of Cox-2 and the associated PGE2 prostan- emboli present in the skin overlying the breast, turn-
oid receptor family in the metastatic phenotype of ing the skin of the mouse bright red, thereby providing
IBC are currently under active investigation and rep- an appropriate model with which to study this phe-
resent important therapeutic targets in IBC. nomenon, one of the most well-characterized signa-
tures of IBC. Studies using IBC tumor spheroids in
ERBB2 Tyrosine Kinase Family of EGFRs vitro and IBC tumor emboli in vivo are providing in-
Another IBC cell line (KPL-4) that was isolated sight into molecular pathways and therapeutic targets
from the pleural effusion of an IBC patient has been that are vitally important to the intravasation and
characterized as overexpressing multiple members rapid metastasis exhibited by IBC. Furthermore, tu-
of the ERBB2 tyrosine kinase family of EGFRs.99 mor emboli that are the result of lymphovascular inva-
The KPL-4 cell line and the KPL-4 xenograft sion can be used as a therapeutic endpoint if the
model have been used primarily to evaluate the effi- Mary-X model of IBC is used.
cacy of agents that target these pathways, including Mary-X has a molecular subtype characteristic of the
the HER1/EGFR tyrosine kinase inhibitor erlo- majority of IBC tumors: it is ER/PR/HER-2 null but
tinib; a HER2-specific recombinant, humanized, expresses both p53 and EGFR.101 It is characterized by
monoclonal antibody, pertuzumab (Omnitarg™), aberrant overexpression of the calcium-dependent trans-
which prevents heterodimerization of HER2 with membrane glycoprotein E-cadherin, one of the hall-
other HERs; and the dual inhibitor of EGFR and marks of IBC tumors and tumor emboli, which is also
ErbB2 kinase, MP-412 (AV-412).100 present on the surface of circulating tumor cells isolated
Although both the SUM149 and KPL-4 cell lines from IBC patients.102,103,104 Interestingly, the tumor em-
can be injected into immunocompromised mice and boli of Mary-X overexpress E-cadherin with the con-
form primary tumors, with development of metastatic comitant loss of sialyl-Lewisx/a (sLex/a). An overactive
lesions (primarily to the lung), there are currently only intact E-cadherin/alpha,beta-catenin axis mediates ho-
2 in vivo xenograft models of IBC, the Mary-X and motypic aggregation of the cells comprising the tumor
the WIBC-9 models that recapitulate the tumor em- emboli, while sLex/a mediates binding of the tumor em-
boli that are the signature of human IBC. boli to the endothelium through E-selectin. The gain of
E-cadherin and loss of sLex/a results in tight aggregation
Overexpression of E-cadherin as a Molecular of cells within the tumor emboli while simultaneously
Signature of IBC preventing tumor emboli from binding to the surround-
The first clinical signs of IBC are the rapidly progress- ing endothelium. E-cadherin expression has been asso-
ing changes in the skin that are presumed to be sec- ciated with a normal breast cell phenotype, whereas loss
ondary to the presence of florid lymphovascular of E-cadherin and gain of N-cadherin have been re-
invasion. These changes in the skin have a unique mi- ported to occur during the epithelial-mesenchymal tran-
croscopic appearance and occur as compact clumps of sition (EMT) associated with tumor progression and
tumor cells that are retracted from the endothelial cell metastasis.105 Inflammatory breast carcinoma is a nota-
layer that lines the lymphovascular spaces of the der- ble exception to the common association between the
mis. The subsequent plugging of the lymphovascular loss of E-cadherin and subsequent acquisition of an
spaces by tumor emboli is believed to contribute to the EMT phenotype.102,104 This anomalous overexpression
tenderness, reddening, and swelling of the breast as of E-cadherin by the most aggressive and metastatic of
all breast cancers is provocative in light of the current demonstrated to have significant levels of gene expres-
thinking that loss of E-cadherin is a requirement for the sion of multiple genes associated with angiogenesis
process of EMT, which is associated with acquisition of and lymphangiogenesis, compared with non-IBC
a metastatic phenotype. This may represent a unique breast tumors. These same studies validated the pres-
mechanism by which tumor cells that have molecular ence of angiogenic growth factors and the associated
plasticity undergo metastatic progression, or alternatively receptors, by using tissue microarray and immuno-
it may represent a survival mechanism for cells within the chemistry, and validated the presence of increased
tumor emboli. lymphatic endothelial cell proliferation, suggest-
Studies focused on E-cadherin as a potential thera- ing that lymphangiogenesis has an important role in
peutic target have demonstrated that blockade of IBC tumors.94
E-cadherin by using anti-E-cadherin antibodies re- In addition to the classic angiogenic pathways asso-
sults in loss of homotypic aggregation of Mary-X ciated with endothelial migration, proliferation, and
spheroids in vitro. When injected via the intravenous organization to form new vessels, driven primarily by
route into animals bearing Mary-X tumors with vascular endothelial growth factor (VEGF) and its re-
known pulmonary metastasis, anti-E-cadherin anti- ceptors, IBC tumors exhibit vasculogenesis, which is
bodies induced dissolution of the metastatic lesions. the de novo formation of vessel-like structures that
In vitro, Mary-X spheroids containing a dominant- allow the flow of oxygen and nutrients in the absence
negative E-cadherin mutant (H-2K[d]-E-cad) lack- of endothelial cells. The ability of tumor cells to form
ing the extracellular binding domain but retaining the tube-like structures is defined as vasculogenic mimicry
-catenin binding domain similarly resulted in loss of (VM) and was first described in uveal malignant mel-
homotypic aggregation. In mice, these dominant- anoma.109 In addition to being a characteristic of em-
negative mutant constructs were only weakly tu- bryonic stem cells, VM is a hallmark of very aggressive
morigenic and did not form tumor emboli.104,106 tumor types that display phenotypic plasticity.110
Other studies using the SUM149 IBC cell line Studies in melanoma suggest that tumor cells capable
demonstrated that the presence of dominant nega- of undergoing VM exhibit the ability to undergo epi-
tive E-cadherin (H-2kd-E-cad) cDNA blocked genetic reprogramming and can remodel their micro-
the robust invasion of SUM149 cells in vitro, which environment. The observations that IBC tumors
was associated with decreased expression of the exhibit VM are consistent with observations that IBC
matrix metalloprotease (MMP) enzymes MMP-1 tumors are more angiogenic, lymphangiogenic, and
and MMP-9. These studies suggest that the pro- vasculogenic than non-IBC breast tumors and that
cess of invasion and intravasation by IBC tumor IBC tumor cells express genes associated with survival
emboli was mediated by both E-cadherin and en- under hypoxic conditions, even in a normoxic
hanced proteolytic enzyme activity.107 In support of environment.
the role of E-cadherin and related molecules in IBC The WIBC-9 xenograft model was used to first
are recent studies demonstrating that blockade of demonstrate a role for VM in IBC.111 The Mary-X
p120-catenin, which anchors E-cadherin, or inhi- model of IBC also exhibits a type of VM, whereby
bition of the translation initiation factor eIF4GI, mesenchymal stem cells form vascular channels that
which regulates translation of specific mRNAs encircle tumor emboli in dermal lymphatics (unpub-
such as p120, results in loss of integrity of SUM149 lished observations, S. H. Barsky). Studies in dogs
tumor spheroids.108 with inflammatory mammary carcinoma have also re-
These findings collectively suggest that the ported that these tumors are highly angiogenic, ex-
E-cadherin molecule is central to the intravasation of hibit lymphangiogenesis, and contain capillary-like
IBC tumor emboli and represents an important target structures.112 Evaluation of molecules and pathways
for effective treatment of IBC. that are known to regulate lymphangiogenesis and
vasculogenesis as well as pathways that regulate tumor
Angiogenesis, Lymphangiogenesis, and hypoxia through hypoxia-inducible factor-1 alpha
Vasculogenic Mimicry in IBC represent new opportunities for understanding the
In studies using real-time quantitative reverse trans- spectrum of angiogenic pathways that are crucial to
criptase polymerase chain reaction, IBC tumors were the distinct molecular signature of IBC.
Cancer Stem Cells and IBC durations of disease-free survival and overall survival
Some of the most exciting opportunities in IBC re- of IBC patients. Signaling pathways, transcription
search come from converging evidence from the areas factors, and molecules that regulate survival, self-
of stem cell biology, developmental biology, and can- renewal, and multipotency of CSCs, which in some
cer biology, which suggest that aggressive metastatic cases overlap with those used by normal stem cells in-
tumor types exhibit phenotypic plasticity and are en- cluding the Notch, Wnt, and hedgehog signaling
riched for a subpopulation of cells that have unique pathways, are currently being evaluated for their utility
characteristics consistent with their activities as as targets for development of effective therapeutics
“tumor-initiating” or cancer stem cells (CSCs).113 In a for IBC.
manner similar to embryonic stem cells, CSCs can un-
IBC and the Epithelial-Mesenchymal Transition
dergo self-renewal, providing a means of limitless rep-
Further support for the potential role of CSCs in the
lication, and are multipotent, giving rise to more
aggressive phenotype of IBC comes from observations
differentiated cells of other lineages. Established
that CSCs are linked to tumor progression through
breast cancer cell lines contain CSCs that can be cul-
their ability to undergo the process of epithelial-
tivated by using specific culture conditions, providing
mesenchymal transition (EMT).119 This ability is reg-
the foundation for developing in vitro models to eval-
ulated by transcription factors that also orchestrate
uate the role and function of CSCs.114,115 SUM149 critical steps of organ development during embryo-
IBC cells were documented to express the putative genesis. The EMT is associated with a change in can-
stem cell surface markers CD44⫹/CD24⫺/low and to cer cells from epithelial morphology to acquisition of
have aldehyde dehydrogenase (ALDH-1) enzyme ac- mesenchymal morphology with an associated gain of
tivity, believed to be a marker of tumor-initiating ac- motility. Recent studies demonstrate that breast can-
tivity.116 CSCs that possess both CD44⫹/CD24⫺ and cer cells that undergo EMT acquire characteristics of
ALDH-1 activity have been demonstrated to be CSCs.120 There is currently great interest in agents
highly tumorigenic when injected into mice, whereas and molecular strategies that reverse the EMT pro-
bulk tumor cells that lack these stem cell markers have cess, which would result in the loss of invasive and
lower tumorigenic potential. CSCs are relatively qui- metastatic potential. One study demonstrated that the
escent and undergo replication very slowly and, thus, SUM149 IBC cell line, which expresses high levels of
are defined as label-retaining cells. This characteristic EGFR and undergoes EMT, was sensitive to the in-
renders CSCs less susceptible to the cytotoxic effects hibitory effects of either EGFR small interfering
of conventional chemotherapeutic agents, which pri- RNA or erlotinib, an inhibitor of the EGFR tyrosine
marily target actively proliferating cells. CSCs also ex- kinase. Targeting EGFR through the ERK1/2 path-
press cassettes of multidrug transporters responsible way blocked SUM149 invasion in vitro; interestingly,
for the rapid efflux of lipophilic and chemotherapeutic low doses of erlotinib, which had no effect on primary
drugs, which provide additional mechanisms for tumor growth, inhibited development of pulmonary
CSCs to resist effects of cytotoxic therapies used to metastases.121 These results suggest that EGFR and
treat the majority of breast cancers. CSCs have also the associated ERK signaling pathway may be impor-
been shown to activate survival pathways, such as the tant targets in the strategy of reversing the process of
PI3K/Akt signaling pathway, that mediate resistance EMT in IBC.
to ionizing radiation.117
By using the Mary-X model of IBC, tumor sphe-
roids were found to express surface markers CD44⫹/
New Tools to Elucidate the Biology of
CD24⫺/low, to have ALDH-1 activity and, most
IBC
uniquely, to express CD133, which is consistent with New technologies will prove invaluable for unraveling
Mary-X having characteristics of CSCs.118 the complexities of the biology of IBC. Next genera-
Evidence that IBC tumors may be enriched for tion sequencing, for example, will provide first-time
CSCs could provide an explanation for the observa- definition of single nucleotide polymorphisms, dele-
tions that targeting proliferation of IBC tumors has tions/insertions, translocations, and copy-number
not been successful in terms of increasing the variations in IBC tumors and cell lines. Coupled with
series of 44 patients with IBC, investigators from be overexpressed and/or amplified with greater fre-
M. D. Anderson noted that 7 of 16 patients who had quency (36%-60%) in IBC than in non-IBC.79,134,135
crossover treatment from anthracycline-based in- Trastuzumab has been investigated in 5 prospective
duction chemotherapy to paclitaxel achieved a partial trials with systemic chemotherapy for LABC, includ-
response and were able to undergo mastectomy.125 ing IBC.136 In that study of the combination of neo-
With this experience, the same investigators com- adjuvant docetaxel, cisplatin, and trastuzumab, 48
pared a cohort of 178 patients with IBC who re- patients with HER2-positive LABC, including IBC,
ceived CAF alone with 62 patients who received CAF had a 17% pathologic complete response.136 Among
followed by paclitaxel. Patients who received pacli- those who had a pathological response, 4-year
taxel had a higher pathologic complete response progression-free and overall survival rates were 100%.
rate (25% vs 10%; P ⫽ .012), median overall survival In a second study, 22 patients (9 with IBC) were
rate, and progression-free survival rate than patients
treated with neoadjuvant docetaxel and trastu-
who did not receive paclitaxel.126 Thus, combination
zumab.137 The investigators noted 40% complete re-
of a taxane with an anthracycline increased the re-
sponse and 77% objective clinical response rates. With
sponse rate to primary systemic chemotherapy and
a combination of docetaxel, vinorelbine, and trastu-
improved prognosis.
zumab, 31 patients with HER2-amplified cancers, in-
It is important to note that, in these preoperative
cluding IBC, had clinical and pathological response
chemotherapy studies, the response to preoperative
rates of 94% and 34%, respectively.138 In a pilot study
chemotherapy was the most important prognostic fac-
of the combination of paclitaxel and trastuzumab, 40
tor. In evaluating a cohort of 372 patients with LABC
patients (6 with IBC) had complete clinical and
(including IBC) who were enrolled in 2 prospective
pathological response rates of 30% and 18%, respec-
trials, investigators at M. D. Anderson observed sig-
tively. The largest series of patients with IBC was re-
nificantly better outcomes in the group of patients
ported in the preliminary data from the NOAH
who achieved a pathologic complete response than in
(neoadjuvant trastuzumab) phase 3 trials. In 76 pa-
the patients with residual disease (5-year overall sur-
tients with HER2-positive IBC, a significantly higher
vival rates, 89% vs 64%, respectively; 5-year disease-free
pathologic complete response rate (54.8%) was noted
survival rates, 87% vs 58%, respectively).127 In a retro-
in women who received standard doxorubicin, pacli-
spective study with a long-term outcome for 54 patients
taxel, and cyclophosphamide chemotherapy with tras-
with IBC, patients who achieved a pathologic complete
tuzumab than in women who received standard
response had a longer 10-year survival rate than pa-
therapy without trastuzumab (19.3%).139
tients with residual disease (45% vs 31%, respectively;
These investigations, demonstrating the success of
P ⫽ .09).128 In a study of 61 IBC patients with cytologic
trastuzumab in combined systemic chemotherapy reg-
confirmed axillary lymph node metastases treated with
imens for HER2-positive breast cancer, suggest that
neoadjuvant anthracycline- and taxane-based chemo-
trastuzumab may be an essential drug in such regi-
therapy, patients who had a pathologic complete re-
mens for patients with HER2-positive IBC. Further
sponse in the axillary lymph nodes had better overall
study is warranted in a large cohort of patients with
survival and disease-free survival rates than patients with
IBC to confirm this efficacy and to find the most ef-
residual axillary disease (overall survival rates, 82.5% vs
fective combination of chemotherapy plus trastu-
37.1%, respectively; disease-free survival rates, 78.6%
zumab in IBC.
vs 25.4%, respectively).129 Taken together, these data
demonstrate that primary systemic therapy plays Surgery
an important initial role and that tumor response to Surgery plays an important role in the multimodality
that therapy defines the long-term outcome for patients treatment of IBC. Historically, mastectomy alone
with IBC. failed to achieve any survival benefit as a primary treat-
Trastuzumab is a humanized monoclonal antibody ment.140 In contrast, however, several retrospective
targeted against the HER2 protein that has been studies have shown that surgery improved the local
shown effective in combination with chemotherapy control rate and survival duration for patients whose
for breast cancer in the neoadjuvant, adjuvant, and disease responded well to primary chemotherapy.141
metastatic settings.130-133 HER2 has been observed to The optimal surgical procedure for those whose
disease responds to neoadjuvant chemotherapy is strategy requires that patients be seen by all multimo-
mastectomy with axillary lymph node dissection. dality team members before initiation of treatment.
Data showing poorer prognosis for patients with Radiation treatment schedules (once or twice daily)
positive margins than for those with negative mar- and treatment doses vary among institutions. At
gins indicate that surgery should aim for complete M. D. Anderson, a treatment schedule of twice a day
resection of residual gross disease with negative sur- and a total dose of up to 66 Gy has been our standard
gical margins.142,143 Axillary lymph node involve- approach to IBC for about 15 years. We have recently
ment at the time of presentation is noted in about identified lower risk IBC subgroups for whom stan-
55% to 85% of patients with IBC. Lymph node sta- dard dose and fractionation of radiation may be suffi-
tus remains an important prognostic indicator; cient (see the section on accelerated hyperfractionated
thus, complete axillary lymph node dissection is the radiation therapy). Outside M. D. Anderson, once
standard of care for IBC patients. daily radiation is typical. Although not much compar-
The surgeon must exercise careful judgment in de- ative information is available about dose, a total dose
termining which patients will benefit from mastec- of 55 Gy to 66 Gy can be used.
tomy. In one study, patients who had a complete or
Standard Treatment of Metastatic IBC
partial clinical response to primary chemotherapy de-
There are currently no standard IBC-specific treat-
rived local control and survival benefits from mastec-
ments for patients with advanced disease; therefore,
tomy (followed by radiation therapy), whereas
enrollment in available clinical trials, including those
patients whose disease did not respond to induction
of novel targeted therapies, is strongly recommended
chemotherapy derived no such benefits.141 Patients
for IBC patients.
whose disease does not respond to induction chemo-
One area of controversy is whether patients with
therapy should be considered for radiation therapy newly diagnosed metastatic IBC should undergo local
and then re-evaluated for operability. resection. As standard care, locoregional management
Radiation Therapy of metastatic disease is challenging and plays a limited
As a standard approach, most IBC patients who re- role. There is some anecdotal evidence that debulking
quire radiation therapy have undergone mastectomy the primary tumor will prolong overall survival.
after primary chemotherapy.144,145 The chest wall and Whether this concept truly applies for IBC is com-
the lymph nodes within the axillary, infraclavicular, pletely unknown. Therefore, we generally recommend
supraclavicular, and internal mammary regions are that patients with metastatic IBC undergo systemic
targeted for radiation therapy. For patients with IBC, therapy first and then local therapy (radiation and/or
surgery) for palliative purposes. A prospective study is
the most important field is the chest wall, so enough
needed to address whether local therapy is indicated in
coverage of potential tumor emboli within dermal
the IBC setting, and its impact on prolongation of
lymphatics is assured. To achieve broad chest-wall
disease control.
coverage and minimize intrathoracic organ risk, a
combination of electron and photon tangent fields or
matched electron fields is used. Novel Local and Systemic Therapies
It is vitally important to have comprehensive pre- For the 70% of patients with IBC who present with
treatment images, including mammograms, sono- distant metastatic disease during the course of their
grams, medical photographs, and MRI scans, to disease,146 there is a strong need for novel approaches.
correlate with postchemotherapy and/or postsurgery Approaches that have been or are currently being eval-
CT scans for radiation treatment planning. Areas with uated for IBC include targeted systemic therapy and
pretreatment skin involvement also should be consid- novel approaches to surgery and radiation therapy.
ered for radiation treatment because there is a high
risk of local recurrence. Radiation treatment planning, Targeted Systemic Therapy
including the design of fields and the choice of dose, Several potential molecular targets have been identi-
should take into account the degree of treatment re- fied for the treatment of IBC.147 It is important to
sponse and extent of surgical resection. This treatment recognize that the novel and unique targets that drive
IBC in a clinical setting have not yet been established. monoclonal antibody against VEGF, was evaluated in
While HER-targeted therapy has been investigated a pilot trial in combination with neoadjuvant doxoru-
largely on the basis of clinical hypotheses, recent ex- bicin and docetaxel in 21 previously untreated patients
tensive work with experimental models and molecular with LABC, 20 of whom had IBC.47 The overall re-
profiling has identified additional genes and pathways sponse rate was 67%, and a significant decrease in the
potentially involved in the development of IBC and/or level of phosphorylated VEGF receptor-2 (VEGFR-2)
responsible for the rapid progression of this disease.148 in tumor cells was noted after a single cycle of bevaci-
Therapy Targeting HER2 zumab. This result might indicate that anti-VEGF
therapy could have not only an antiangiogenic effect
Targeted therapy against HER2—trastuzumab and
but also a direct antitumoral effect through VEGFR-
lapatinib—is one promising strategy for treatment of
2.151 In a preliminary report of a phase 2 trial of dose-
IBC, and it has been extensively investigated in the
dense doxorubicin and cyclophosphamide followed by
clinic. The success of trastuzumab in breast cancer,
weekly carboplatin and paclitaxel with bevacizumab
described in detail already, has led to investigations of
for HER2-negative large or inflammatory breast tu-
lapatinib in breast cancer. Lapatinib is an oral, dual,
tyrosine kinase inhibitor against EGFR and HER2. mors, 3 of 10 patients in the study had a pathologic
Inflammatory breast cancer is known to overexpress complete response.152
HER2 frequently; furthermore, EGFR expression is Semaxanib (SU5416), a small-molecule inhibitor
associated with poor prognosis.81 Clinical trials have of VEGFR-2, was investigated in a phase 1 trial in
shown that lapatinib is effective in HER2-positive combination with doxorubicin in 18 patients with
breast cancer and has efficacy similar to that of trastu- IBC.153 Decreased tumor blood flow after treat-
zumab in such patients. ment was shown on DCE MRI. Unfortunately,
The preliminary results from a phase 2 trial of lapa- 4 (22%) of the 18 patients experienced a significant
tinib and paclitaxel as neoadjuvant therapy in patients decrease in cardiac function after completion of
with newly diagnosed IBC showed that 95% of treatment. These adverse events precluded further
HER2-positive cases had a clinical response.149 In a investigation of this combination.
phase 2 trial of lapatinib monotherapy for heavily Pazopanib is an oral angiogenesis inhibitor that has
treated patients with IBC, the response rate was 50% been investigated in an ongoing phase 3 clinical trial in
among the 30 patients with HER2-positive tumors combination with lapatinib.154 Further investigation
but only 7% among the 15 patients with HER2- is needed to conclude whether angiogenesis is a clini-
negative/EGFR-positive tumors.154 Currently, the cally relevant target in IBC.
European Organization for Research and Treatment Lymphangiogenesis and vasculogenesis. Lymphangio-
of Cancer (EORTC) is conducting a randomized genesis can lead to tumor cell dissemination through
phase 1/2 trial of docetaxel and lapatinib as neoadju- lymph vessels. Tumors can induce formation of a
vant therapy in patients with HER2-positive LABC, new lymph vessel network, a process called tumor-
IBC, or resectable breast cancer.150 At M. D. Ander- induced lymphangiogenesis, and thereby promote tu-
son, a phase 2 study of neoadjuvant lapatinib plus che- mor spread.155 Vasculogenesis is the formation of
motherapy (sequential 5-fluorouracil, epirubicin, and new vascular channels due to de novo production of
cyclophosphamide and paclitaxel) in patients with endothelial cells by tumor cells.156 Although lym-
HER2-positive IBC is in progress. phangiogenesis and vasculogenesis is one potential
mechanism for tumor progression, both mechanisms
Therapy Targeting Vasculolymphatic Pathways—
Angiogenesis, Lymphangiogenesis, and must be studied further before vasculogenesis can be
Vasculogenesis confirmed as a potentially useful target for treatment
Molecular targets in vasculolymphatic processes—an- of IBC.
giogenesis, lymphangiogenesis, and vasculogenesis— Therapy Targeting Overexpression of RhoC GTPase
have shown greater potential in IBC than in non-IBC. and Loss of WISP3
Angiogenesis. Angiogenesis, the formation of new RhoC is an important player in signal transduction as
vessels from pre-existing vessels, is necessary for tu- a member of the Ras superfamily and is involved in
mor growth and metastasis. Bevacizumab, a human regulation of the cytoskeleton.83,157,158 Farnesyl
transferase inhibitor treatment to modulate RhoC ex- lymphatic invasion can make it difficult to achieve the
pression159,160 has been investigated in the preclinical negative margins that are so important in IBC, as dis-
setting. Although further investigation is required in cussed already. Moreover, because postmastectomy
the clinical setting, farnesyl transferase inhibitors may radiation therapy is required in patients with IBC, im-
be a potential novel targeted therapy for tumors that mediate reconstruction is not recommended.
overexpress RhoC, including IBC. Just recently, a
phase 2 clinical trial of the farnesyl transferase inhibi- Radiation Therapy
tor tipifarnib combined with doxorubicin and cyclo- Accelerated Hyperfractionated Radiation Therapy
phosphamide for LABC, including IBC, was Accelerated hyperfractionation has been investigated
completed.161 Results are eagerly awaited. to achieve better local control than standard radiation
therapy for this aggressive disease. One reason that
High-Dose Chemotherapy
tumors develop resistance to standard radiation ther-
Several investigators have tried high-dose chemother- apy is the rapid repopulation of IBC tumor cells be-
apy (HDCT) with autologous stem cell support to im- tween radiation doses. To circumvent this rapid cell
prove response in patients with IBC. Although the use growth, an accelerated hyperfractionated schedule has
of HDCT for breast cancer remains controversial, re- been studied.
cent studies show encouraging results in IBC.162-163 To evaluate the effect of a higher radiation dose,
Although HDCT has produced some better re- outcomes for 32 patients treated with twice-daily ra-
sponses than conventional chemotherapy in patients diation to a total dose of 60 Gy were compared with
with IBC, HDCT is associated with more toxicity and outcomes for 39 patients treated twice daily to a total
poorer quality of life. The definitive benefit of HDCT dose of 66 Gy. Significantly better rates of locore-
has not been established yet, and a large clinical trial is gional control were achieved in the high-dose group
warranted to assess its efficacy and safety for patients than in the standard-dose group (84% vs 58% at 5
with IBC. At M. D. Anderson, we are currently con- years, 77% vs 58% at 10 years; P ⫽ .04).164 Although
ducting a HDCT study in which circulating tumor data have demonstrated the effectiveness of postmas-
cells are removed by using a CD34-positive selection tectomy accelerated hyperfractionated radiotherapy,
process during apheresis. an updated review of this approach showed that the
benefit appeared highest in cases at high risk of recur-
Surgery rence: those that have a poor response to chemother-
Two approaches to surgery have been evaluated re- apy, those with close or positive surgical margins,
cently for patients with breast cancer, but they are not those involving 4 or more nodes after neoadjuvant
recommended for patients with IBC. chemotherapy, and those in patients younger than age
Sentinel LymphNode Biopsy 45 years. In the same analysis, short-term and long-
Although sentinel lymph node biopsy (SLNB) has term toxic reactions to this treatment were examined.
been accepted as the standard of care for evaluating Although the degree of acute skin reaction is thought
axillary lymph node status in patients with early breast to correlate with local disease control, such reactions
cancer, it is not recommended for patients with IBC. were significant and sometimes required analgesics. A
One significant reason is that lymphatic blockage by higher risk of developing grade 3 to 4 late complica-
tumor cells is a feature of IBC, and such blockage tions was observed in the high-dose group than in the
could prevent the dye or radioactive isotope used for standard-dose group (29% vs 15%, respectively;
this procedure from being carried to sentinel lymph P ⫽ .08).143 As such, this approach is reserved for pa-
nodes. There has also been a concern that SLNB after tients with features suggesting high risk of recurrence.
neoadjuvant therapy would not be reliable for evaluat- Preoperative Radiation Therapy
ing axillary lymph node involvement. In other malignancies, radiation therapy has been in-
Skin-Sparing Mastectomy with Immediate vestigated as a preoperative modality. Although this
Reconstruction strategy has not been thoroughly explored in breast
Skin-sparing mastectomy is not recommended for pa- cancer, there may be a benefit in the aggressive IBC.
tients with IBC. This disease’s high rate of dermal In an M. D. Anderson review of preoperative
radiation treatment in 42 patients with IBC, the erythema, edema, breast induration, and pain. Al-
5-year local control and distant metastasis-free sur- though dermal lymphatic invasion is a pathological
vival rates were 75% and 20%, respectively, and 8 pa- hallmark of IBC, it is not required for diagnosis.
tients survived without distant metastasis for more Epidemiological observations have suggested geo-
than 40 months (unpublished data). However, higher graphic differences in the incidence of IBC but have
complication rates have been reported in patients who not resulted in identification of risk factors. An ongo-
received preoperative radiation than in those who did ing international prospective registry is being con-
not. One study reported wound necrosis in 6 (21%) of ducted at The University of Texas M. D. Anderson
29 patients with IBC who received preoperative radi- Cancer Center that will further elucidate the etiology
ation at a dose between 44.2 and 50.4 Gy.165 With and risk factors for IBC.
these results in mind, until the safety and efficacy of The descriptions of advanced imaging approaches
preoperative radiation therapy have been demon-
and modalities herein are not exhaustive and are not
strated, surgical candidates should undergo surgery
necessarily specific to IBC, but they are based on our
before radiation therapy.
current experience and represent some promising ar-
Concurrent preoperative chemoradiation has not
eas for improving the characterization and pluridisci-
been used as effectively in breast cancer as in other
plinary management of this complex disease.
cancers. At M. D. Anderson, concurrent capecitabine
The ability to identify new therapeutic targets that
and radiation therapy resulted in 91% of “inoperable”
breast cancers becoming operable. The clinically com- regulate the aggressive phenotype of IBC will be cru-
plete response and overall response rates were 33% and cial. There are currently new classes of agents that dis-
22%, respectively. play novel mechanisms of action, and early
experiments suggest that these drugs may be effective
in IBC. Emerging concepts in the areas of stem cell
Summary biology and cancer biology may revolutionize our un-
Inflammatory breast cancer has proven to be distinct derstanding of the molecular basis of IBC while pro-
from LABC and is managed as such. Clinical pre- viding opportunities to discover new molecular targets
sentation of IBC consists of acute onset of diffuse and useful diagnostic biomarkers for IBC.
breast cancer. In: Pazdur R, Coia L, 16. Meyer AC, Dockerty MB, Harrington SW.
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