Update on the Management of Inflammatory
MASSIMO CRISTOFANILLI, AMAN U. BUZDAR, GABRIEL N. HORTOBÁGYI
Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center,
Houston, Texas, USA
Key Words. Inflammatory breast cancer · Targeted therapies
Inflammatory breast cancer (IBC) is the most aggres-
sive manifestation of primary breast carcinoma, with the
clinical and biological characteristics of a rapidly prolifer-
ating disease. The multidisciplinary management of IBC
has changed in the past 3 decades and is presently clearly
outlined in sequence, with preoperative or neoadjuvant
chemotherapy representing the mainstay of treatment.
Anthracyclines and taxanes are the most effective cyto-
toxic agents in the management of primary breast cancer
and should be the standard of treatment for women with
IBC. Locoregional treatment includes radiotherapy with
or without surgery and continues to play a major role
after appropriate medical treatment. The many investi-
gations into the particular molecular determinants of IBC
development have provided several interesting new ther-
apeutic targets. Combination regimens that include
angiogenic modulators, farnesyl transferase inhibitors,
and p53 modulators hold great promise in the medical
management of IBC. Future therapeutic approaches
should focus on these discoveries so that we can improve
the overall prognosis for women with IBC. The Oncologist
The Oncologist 2003;8:141-148
Correspondence: Massimo Cristofanilli, M.D., Department of Breast Medical Oncology, The University of Texas M.D.
Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 424, Houston, Texas 77030, USA. Telephone: 713-792-2817;
Fax: 713-794-4385; e-mail: firstname.lastname@example.org Received November 27, 2002; accepted for publication January
8, 2003. ©AlphaMed Press 1083-7159/2003/$12.00/0
Inflammatory breast carcinoma (IBC) is the most
aggressive manifestation of primary breast carcinoma. It is
relatively rare, with an incidence of only 1%-6% in the
U.S. . African Americans have a higher incidence of
IBC than do Caucasians and other ethnic groups (10.1%,
6.2%, and 5.1%, respectively). Furthermore, a review of
the Surveillance, Epidemiology, and End Results (SEER)
program data comparing trends and patterns for breast
cancer between 1975-1977 and 1990-1992 revealed that
the incidence of IBC increased from 0.3 to 0.7 cases per
100,000 person-years, a much larger increase than that
observed for noninflammatory forms of breast cancer during
the same period. .
After completing this course, the reader will be able to:
1. Recognize the differences in biology and clinical outcome of IBC compared with non-IBC.
2. Summarize the standard of care for IBC.
3. Identify molecular targets and novel agents for future treatments of IBC.
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Cristofanilli, Buzdar, Hortobágyi
The clinical presentation of IBC is quite characteristic
and has been extensively described [3-7]. Patients usually
present with a rapid onset of swelling of the involved breast.
The classic criteria for clinical diagnosis established by
Haagensen  include diffuse erythema, edema involving
more than two-thirds of the breast, peau d’orange, tender-
ness, induration, warmth, enlargement, and diffuseness of the
tumor on palpation. These symptoms usually progress
rapidly, and patients frequently have axillary node involve-
ment by the time they seek medical attention. Pathologically,
there is extensive lymphovascular invasion by tumor emboli
that involves the superficial dermal plexus of vessels in the
papillary and high reticular dermis .
Primary IBC is the simultaneous development of inflam-
matory skin changes and carcinoma in a previously healthy
breast, whereas secondary IBC is the development of inflam-
matory changes in a breast that has had a previous malignancy
or has a mastectomy scar or changes caused by irradiation.
However, the distinction between the two has been highly
controversial [10, 11]. Interestingly, Piera et al.  reported
that locally advanced disease associated with a clinically
detectable inflammatory component had a worse prognosis
than stage III cancer without associated skin changes.
A review of the SEER data that compared IBC with
non-IBC clearly showed that IBC had a statistically signifi-
cantly (p = 0.0001) lower overall survival (OS) rate .
Additional support for this observation comes from a more
recent analysis by Low et al.  who reported a long-term
follow-up study of 106 patients with locally advanced dis-
ease. Those authors retrospectively analyzed the outcome of
combination chemotherapy in patients with IBC compared
with patients with stage III non-IBC. The 10-year OS rates
for patients with non-IBC and those with IBC were 44.8%
and 26.7%, respectively (p = 0.031). Because of the relative
infrequency of IBC, no phase III trials have been reported
or performed, so all available knowledge is derived from
single-arm clinical trials and retrospective chart reviews.
We recently reviewed The University of Texas M.D.
Anderson Cancer Center’s experience treating 635 patients
with locally advanced breast cancer, including IBC with a
median follow-up of 90 months (unpublished data). The
median progression-free survival (PFS) and OS rates were
lower in the group with IBC (214 patients) than in the group
with stage III non-IBC (421 patients). Median PFS times were
24 months for IBC (95% confidence interval [CI], 19-29) and
35 months for non-IBC patients (95% CI, 25-45). Likewise,
the median OS times were 42 months for IBC (95% CI, 35-
49) and 60 months (95% CI, 47-73) for non-IBC patients. The
data from these studies show that IBC is a clinically aggres-
sive disease with an overall worse prognosis than non-IBC.
These findings suggest that the underlying molecular deter-
minants of the IBC phenotype will require more investigation
so that we can design more effective targeted treatments. This
review provides a summary of the traditional approaches used
for IBC and specifically addresses the new directions in the
management of this entity.
MULTIDISCIPLINARY TREATMENT OF IBC
The management of IBC has substantially evolved in the
past 3 decades . Surgery was the first therapeutic modality
used, but it had disappointing results . The mean survival of
patients treated with mastectomy alone ranged from 12 to 32
months. The addition of radiotherapy improved the locore-
gional control rate, but it had no significant effect on survival
[14-18]. Because IBC is a rare disease, patients with IBC were
usually treated with the same modalities as, and included in
clinical trials designed for, patients with noninflammatory
locally advanced breast cancer. The M.D. Anderson Cancer
Center has had the most experience of any cancer center in the
U.S. with the management of IBC, having treated a total of 242
consecutive patients in IBC-directed clinical trials between
1974 and 2001. Two hundred twenty-two patients were treated
in five studies (Table 1); the other 20 were enrolled in a recent
pilot study, which is described later.
Table 1. Summary of clinical responses in five consecutive clinical trials for patients with IBC [20-23]
Protocol A, n (%)
Protocol B, n (%)
Protocol C, n (%)
Protocol D, n (%)
Protocol E, n (%)
Abbreviations: PD = progressive disease; N/A = not applicable.
Novel Therapies for IBC
One hundred seventy-eight patients were treated as part
of four consecutive multimodality protocols between April
1974 and September 1993 [19-22]. Protocol A evaluated the
use of 5-fluorouracil/doxorubicin/cyclophosphamide (FAC)
as induction chemotherapy, followed by radiotherapy and
then further chemotherapy (FAC and/or cyclophos-
phamide/methotrexate/5-fluorouracil [CMF]). Protocol B
used the same induction regimen followed by mastectomy,
adjuvant FAC, and radiotherapy. In protocol C, vincristine
and prednisone were added to the FAC combination
(FACVP). Patients in the last group, protocol D, underwent
induction FACVP and surgery followed by FACVP in those
who experienced a complete response ([CR] defined as com-
plete disappearance of any clinical evidence of disease) dur-
ing induction chemotherapy and FACVP plus methotrexate
and vinblastine (MV) or MV alone in those who experi-
enced a partial response ([PR] clinical reduction of tumor
size by more than 50%) or minimal response ([MR] clinical
reduction of tumor size from 25%-50%) using bidimen-
sional criteria, respectively. This strategy was used to inves-
tigate the role of alternate therapy with potentially
non-cross-resistant drugs. The overall response rate for all
four groups combined was 72%, including a 12% clinical
CR rate [18, 22]. No significant differences were found in
the disease-free survival (DFS) or OS rates among the four
protocols. The addition of surgical treatment in protocols B
and C did not alter the risk of local recurrence in patients
with poorly responsive disease. The results of protocols C
and D indicate that the addition of vincristine and pred-
nisone and the introduction of non-cross-resistant MV had
no favorable effect on either DFS or OS [21, 22]. However,
the modest sample size of all four clinical trials suggests that
moderate differences in outcome might have gone unde-
tected. The median survival was 37 months for patients on
all four protocols combined (38, 38, 64, and 34+ months,
respectively). The estimated DFS rates for all 178 patients at
5, 10, and 15 years were 32%, 28%, and 28%, respectively.
Patients who experienced a CR or PR after induction
chemotherapy had an estimated 15-year DFS rate of 44% and
31%, respectively, and a 15-year OS rate of 51% and 31%,
respectively. Those patients who experienced an MR or sta-
ble disease (SD) had estimated 15-year DFS and OS rates of
7%, confirming the prognostic significance of response to
Protocol E was initiated in 1994 (Table 1) and incorpo-
rated, for the first time, paclitaxel in the management of IBC
. Forty-four patients were enrolled and treated with FAC
as induction and adjuvant chemotherapy. Paclitaxel was used
preoperatively to treat patients who achieved only an MR or
SD after undergoing FAC treatment and as adjuvant therapy
in all patients. Local treatment consisted of mastectomy after
induction chemotherapy and then radiotherapy at the com-
pletion of adjuvant chemotherapy. The overall response rate
was 77%, which was not significantly different from the rates
documented in previous studies. The 2-year OS rates of the
historical control group of 178 patients treated with anthra-
cycline-based regimens (protocols A-D) and the patients on
protocol E were 71% and 74%, respectively, showing a mar-
ginal, but not statistically significant, difference in favor of
the paclitaxel-containing regimen.
A subsequent pilot study was initiated to test the feasi-
bility of using the sequence of FAC plus weekly high-dose
paclitaxel as induction chemotherapy (protocol F) . This
sequence was followed by chemotherapy with cyclophos-
phamide, etoposide, and cisplatin (CVP) for bone marrow
mobilization followed by high-dose chemotherapy with
cyclophosphamide, carmustine (BCNU), and thiotepa (CBT)
and peripheral blood stem cell support (in patients who did
not experience a clinical CR). In the original design of the
study, the locoregional treatment consisted of radiotherapy
combined with paclitaxel. After the first three patients had
been treated, mastectomy was reintroduced as the primary
locoregional treatment. The protocol was completed after 20
patients had been enrolled. A preliminary analysis of the data
revealed that, of the 18 evaluable patients, seven (31%) expe-
rienced a clinical CR and 11 (61%) experienced less than a
CR (defined as clinical and radiological persistence of
disease). Thirteen patients underwent mastectomy; six (46%)
of those experienced pathological CR. These data are encour-
aging, but they are from a small pilot study, which limits their
use when developing standard-of-care recommendations for
patients with IBC.
To better clarify the role of paclitaxel in treating this
disease, we retrospectively compared the records of
patients with IBC who had been treated at our institution on
the basis of whether paclitaxel had been included in their
induction or adjuvant chemotherapy regimen . Two
hundred forty patients, all of whom had been included in
the earlier protocols, were included in this analysis; 178 had
been treated with anthracycline-based regimens (group A),
and 62 had been treated with paclitaxel (group B). The analy-
sis demonstrated that objective response rates (CR + PR) were
similar (A = 72% versus B = 79%). The 3-year OS and PFS
rates were higher in group B, but these differences did not
reach statistical significance (OS: A = 53% versus B = 71%,
p= 0.12; PFS: A = 39% versus B = 46%, p= 0.19). Moreover,
the 3-year OS and PFS rates were significantly higher in the
subgroups of patients with estrogen receptor (ER)-negative
tumors (OS: A = 43% versus B = 71%, p = 0.035; PFS: A =
31% versus B = 39%, p = 0.042). This analysis provides fur-
ther evidence that paclitaxel is an important agent in the
management of IBC.
Cristofanilli, Buzdar, Hortobágyi
MOLECULAR DETERMINANTS OF IBC DEVELOPMENT:
FUTURE OF TARGETED THERAPIES
IBC is often characterized by invasive carcinoma of
high histological grade and the presence of molecular mark-
ers of aggressive disease, including high S phase, aneu-
ploidy, absent ER expression, and high expression of p53
and epidermal growth factor (EGF) .
Aziz et al. compared the expression levels of several
prognostic markers, including p53 and erbB-2, in 40 IBC
patients with those from 40 matched patients with non-IBC
. p53 was expressed in 70% of tumors in the IBC group
and 48% in the control group (p = 0.0238). No statistically
significant difference in expression was detected for erbB-
2 (38% in the IBC group versus 35% in the control group).
Other authors have investigated the incidence of erbB-2
overexpression in IBC, and, while some controversies per-
sist, most have found that the incidence in IBC does not dif-
fer significantly from the incidence in non-IBCs [26, 28].
The subset of patients with erbB-2 overexpression might
benefit from trastuzumab-based therapies [29, 30]. Patients
with IBC are commonly included in clinical trials that enroll
patients with erbB-2-overexpressing locally advanced
Regarding the role of p53 in IBC, some authors have
found a process of nuclear exclusion and cytoplasmic
sequestration as the predominant mechanism of protein func-
tion inactivation, which clearly differs from the most com-
mon explanation that the inactivation is caused by missense
gene mutations [32, 33]. The process of p53 inactivation by
nuclear exclusion is a phenomenon that has been found in
37% of IBCs and in approximately 95% of undifferentiated
neuroblastomas . Further studies have clarified that the
formation of cytoplasmic aggregates is mediated by the C-
terminal domain of p53 and results in high molecular weight
complexes with half-lives of about 6 hours.
The functions of Mdm2 and PTEN are thought to be crit-
ical to the regulation of p53 function . In fact, the level of
p53 activity is regulated in part by the Mdm2 oncoprotein.
Mdm2 shuttling from the cytoplasm to the nucleus promotes
p53 protein degradation through the ubiquitin-dependent
proteasome pathway [34, 35]. PTEN has been shown to
inhibit the phosphatidylinositol 3-kinase/Akt signal that reg-
ulates translocation of Mdm2 into the nucleus, resulting in
persistent p53 activation . PTEN is a tumor-suppressor
gene localized to chromosome 10q23 that regulates cell
migration, growth, and survival by dephosphorylating phos-
phatidylinositol 3-kinase second messengers and signaling
phosphoproteins . Through this mechanism, PTEN also
inhibits the nuclear entry of Mdm2, causing its degradation
by the proteasome and increasing the cellular content of p53
[35, 37]. Loss of PTEN has been found in invasive breast
cancer and has been associated with a poor prognosis [38,
39]. These findings suggest the possibility that mechanisms
that inhibit Mdm2 function or control cytoplasmic degrada-
tion of the p53 protein may be an alternative and indirect
approach to overcoming the effects of p53 inactivation.
These data also support the use of more direct therapeutic
approaches aimed at restoring p53 function with agents that
act directly on the p53 protein [40, 41].
Recent studies with human xenograft models have pro-
vided some insight into the pathogenesis of IBC and suggest
that angiogenesis may be a novel therapeutic target. Two
groups of investigators recently reported the establishment of
a human xenograft model of IBC [42, 43]. Alpaugh et al.
established the first transplantable human IBC xenograft,
MARY-X, in severe combined immunodeficient (SCID)
mice . Unlike other human xenografts that grow as iso-
lated subcutaneous nodules, MARY-X grows exclusively
within murine lymphatics and blood vessels and exhibits
striking erythema of the overlying skin, and its molecular
markers mirror those of human IBC—ER and progesterone
receptor negative, HER-2/neu negative, and p53 and EGF
receptor positive. Shirakawa et al. [43, 44] also established
an IBC xenograft, WIBC-9, that is transplantable into SCID
mice. WIBC-9 exhibits erythema of the overlying skin, and
histological studies showed that WIBC-9 has a hypervascu-
lar structure of solid tumor cell nests and marked lymphatic
permeation in the overlying skin. A comparative analysis of
WIBC-9, three established non-IBC xenografts, and a human
breast cancer cell line showed that certain human and murine
genes (interleukin-8 [IL-8], vascular endothelial growth fac-
tor [VEGF], basic fibroblast growth factor [bFGF], angiopoi-
etin 13, Flt-1, Tie-2, Tie-1, integrin-αVβ3, and CD31) are
overexpressed in IBC. Many of these factors mediate angio-
genesis. In another study, Shirakawa et al.  found that
murine VEGF exhibits a more than 30-fold amplification of
expression in WIBC-9. Furthermore, WIBC-9 tumors have a
higher population of tumor-infiltrating endothelial cells and
endothelial precursor cells than non-IBC tumors. Moreover,
Shirakawa et al. also have described a particular pattern of
neovascular growth in IBC [45, 46]. The phenomenon of
“vascular mimicry” indicates a condition in which blood ves-
sels within cancer tissue do not have a lining of endothelial
cells. In subsequent experiments, the therapeutic use of
agents that target VEGF receptors proved, as predicted, to be
more effective in the human IBC xenograft model .
Cadherins are transmembrane components that play
crucial roles in epithelial morphogenesis and mediate inter-
cellular adhesion . These receptors bind catenins and
are involved in signal transduction pathways that regulate
cell growth and apoptosis. Epithelial cadherin (E-cadherin)
is a potent tumor suppressor in breast cancer, and loss of
Novel Therapies for IBC
E-cadherin expression has been found to correlate with
poor prognosis [48, 49]. The E-cadherin gene (CDH1) is
located on human chromosome 16q22.1, a region fre-
quently affected by loss of heterozygosity in sporadic breast
cancer . Overexpression of E-cadherin has been
described as characteristic of IBC . Subsequent investi-
gations demonstrated that IBC is associated with intact and
overexpressed E-cadherin/αβ catenin and the lack of sialyl-
Lewis (x/a) carbohydrate ligand-binding epitope [51, 52].
These two biological characteristics explain the presence of
diffuse lymphovascular tumor emboli and the lack of
endothelial adherence of the cells constituting it. Together,
these unique molecular features suggest that angiogenesis
has an important role in IBC and indicate that angiogenesis
modulation may be an important therapy.
van Golen et al.  recently identified two additional
molecular targets for IBC therapy. These investigators used
differential display and Northern blot analysis to screen a cell
line from a primary IBC and cells lines from non-IBCs. They
identified two transcripts with distinct expressions in IBC: a
novel low-affinity insulin-like growth factor binding protein,
LIBC (lost in inflammatory breast cancer), and RhoC guano-
sine triphosphatase (GTPase). In situ hybridization of
archival material showed that LIBC was absent in 80% of
IBCs but only 21% of non-IBCs (p = 0.0013). RhoC GTPase
was overexpressed in 90% of IBCs compared with only 38%
of non-IBCs (p = 0.0095).
LIBC has subsequently been demonstrated to have
tumor suppressor activity in in vivo studies in which mice
injected with an IBC-derived cell line (SUM149) transfected
with LIBC survived longer than did mice injected with the
same cell line transfected with a vector control .
Because further studies were necessary to determine the
oncogenic potential of RhoC in IBC, the same investigators
[55, 56] transfected RhoC GTPase in nontransformed,
immortalized HME cells. The transfection was associated
with malignant transformation, growth under anchorage-inde-
pendent conditions, and the ability to produce tumors in nude
mice. RhoC GTPase overexpression was also associated with
increased levels of VEGF, bFGF, IL-6, and IL-8 in condi-
tioned media, suggesting modulation of angiogenic factors.
We find it interesting that the use of farnesyl transferase
inhibitors (FTIs), which inhibit RhoC proteins, decreased
angiogenesis in some animal studies . FTIs inhibit Rho
protein function by inhibiting its posttranslational modifica-
tion [57, 58]. Although FTIs were designed to inhibit Ras,
subsequent studies have shown that Ras may not be the only
target of FTIs, and other studies suggest that inhibition of
Rho proteins may mediate their therapeutic effects. These
data suggest that RhoC may be an excellent target in the
treatment of IBC.
SUMMARY AND CONCLUSIONS
IBC is the most aggressive manifestation of primary
breast carcinoma, with the clinical and biological characteris-
tics of a rapidly proliferating disease. The management of
IBC has changed in the past 3 decades and, presently, the
standard of care requires having a team of dedicated and
experienced specialists (e.g., pathologist, surgeon, radiothera-
pist, diagnostic imager, and medical oncologist) involved in
the complex management of this entity. The multidisciplinary
treatment of IBC is clearly outlined in sequence, with preop-
erative or neoadjuvant chemotherapy representing the main-
stay of treatment (Fig. 1). Locoregional treatment includes
radiotherapy with or without surgery and continues to play a
major role after appropriate systemic treatment. Its sequence
is greatly dependent on the quality of objective response
achieved with induction chemotherapy. In the majority of
cases, after optimal remission, defined as partial objective
clinical disease remission with resolution of the characteristic
skin changes, patients are considered surgical candidates and
a modified radical mastectomy is recommended followed by
Anthracyclines and taxanes are the most effective cyto-
toxic agents in the management of primary breast cancer and
have demonstrated their importance in the management of
early breast cancer and IBC as well [23-25]. The use of a
sequence including an anthracycline-containing regimen (e.g.,
AC, FAC) followed by a taxane (either docetaxel or paclitaxel)
is associated with a higher probability of objective remission
and should be used routinely as standard of care . The
Figure 1. Schematic representation of the proposed optimal sequence of
treatment for newly diagnosed IBC. Abbreviations: XRT = radiotherapy;
TAM = tamoxifen; AI = aromatase inhibitor.
evaluation of response
PR or CR
TAM or AI if ER+
TAM or AI if ER+
Cristofanilli, Buzdar, Hortobágyi
optimal schedule of administration of paclitaxel remains to be
established, but several trials suggest that a weekly schedule is
associated with a higher pathological CR rate [24, 60]. Patients
who undergo modified radical mastectomy and who are found
to have extensive residual disease after optimal preoperative
chemotherapy have a grim prognosis, and the role of alternate
further adjuvant chemotherapy remains to be established. For
patients who do not achieve an optimal debulking response,
radiotherapy (alone or followed by surgical resection) repre-
sents an adequate locoregional treatment .
The many investigations into the particular molecular
determinants of IBC development have provided several
interesting new therapeutic targets (Table 2). Combination
regimens that include angiogenic modulators and FTIs hold
great promise in the medical management of IBC. The use of
agents or modalities that are able to restore p53 function could
also lead to dramatic improvements in objective response.
Researchers in that field should direct future therapeutic
approaches so that we can improve the overall prognosis of
women with IBC.
The authors want to acknowledge the invaluable support
of Shu-Wan Kau in providing the statistical analysis of our
database. Furthermore, we want to thank the physicians and
research nurses who have contributed through the years to
the several clinical trials. Lastly, and most importantly, a
thanks and a dedication to the women with IBC participating
in our studies and helping to increase our knowledge of this
Table 2. Summary of biological targets in IBC
Oncogenes [26, 28, 53]
Gene therapy, p53-stabilizing agents
Proteasome inhibitors, PI3K-inhibitors
Tie-2 kinase inhibitor
Tumor suppressor genes [27, 32, 34, 37]
Angiogenesis modulators [42, 43, 50-53]
Abbreviations: mAbs = monoclonal antibodies; RTKs = receptor tyrosine kinases; PI3K = phosphatidylinositol-3-kinase; VE = vascular endothelial.
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