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INCIDENCE 712

MORTALITY 712
EPIDEMIOLOGIC FACTORS 712
INFLAMMATORY
BREAST CANCER
Windy Marie Dean-Colomb
Massimo Cristofanilli
EPIDEMIOLOGY 712
711
C H A P T E R
26
MOLECULAR TARGETS OF INFLAMMATORY BREAST CANCER 726
CURRENT THERAPEUTIC STRATEGIES AT MD ANDERSON 726
CANCER CENTER
CONCLUSION 727
MACROSCOPIC PATHOLOGY 715
MICROSCOPIC PATHOLOGY 715
DIFFERENTIAL DIAGNOSIS 716
TUMOR-NODE-METASTASES (TNM) 716
SYSTEM
POUSSE VOLUTIVE (PEV) SYSTEM 716
SURGERY 723
RADIOTHERAPY 723
NEOADJUVANT CHEMOTHERAPY 723
Anthracyclines / 724
Taxanes / 725
MULTIMODALITY TREATMENT 725
MAMMOGRAPHY 718
ULTRASOUND 718
MAGNETIC RESONANCE IMAGING 720
COMPUTERIZED TOMOGRAPHY 721
POSITRON EMISSION 721
TOMOGRAPHY
FAMILY HISTORY 713
REPRODUCTIVE HISTORY 713
BODY MASS INDEX, BLOOD 713
TYPE, AND GEOGRAPHIC
LOCATION
IMMUNOLOGIC FACTORS 714
RISK FACTORS 713
MOLECULAR DETERMINANTS OF INFLAMMATORY BREAST CANCER 716
EVOLVING ROLE OF IMAGING MODALITIES IN INFLAMMATORY 718
BREAST CANCER
THE MULTIDISCIPLINARY TREATMENT OF INFLAMMATORY 722
BREAST CANCER
PATHOLOGICAL ASPECTS OF INFLAMMATORY BREAST CANCER 714
STAGING OF INFLAMMATORY BREAST CANCER 716
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712 Breast Cancer PART VII
Inflammatory breast carcinoma (IBC) represents a
rare but very aggressive subtype of breast cancer. It is a
clinicopathologic entity that is characterized by distinct
skin changes suggestive of infection or inflammation,
usually of fairly abrupt onset and rapid progression. The
breast often appears red, swollen, and inflamed, hence
the term inflammatory breast cancer. Since IBC has
historically been a clinical diagnosis, its true incidence
has been hard to quantify based in large part on a lack
of consensus about a case definition for IBC. Acknowl-
edging variations in the case definitions for IBC in
population-based registries, it is estimated that IBC
accounts for almost 2% of all breast cancer cases here in
the United States (1).
Because of its unique appearance, IBC has often
been confused with locally advanced breast cancer
(LABC). However, emerging epidemiologic and mole-
cular evidence indicates that IBC is not a part of the
spectrum of LABC, but is in fact a separate entity (2).
Furthermore, a distinction must be made between pri-
mary IBC, which is the simultaneous development of
inflammatory skin changes and carcinoma in a previ-
ously healthy breast, and secondary IBC, which is
the development of inflammatory changes in a breast
known to have had a prior malignancy; the outcomes
from these two diseases are quite different. Patients
with primary IBC usually have a relatively short dura-
tion of symptoms prior to diagnosis, usually less than
3 months. Patients that have had symptoms for more
than 3 months are a more heterogeneous group and
include patients with previous non-IBC that develop a
new primary tumor or recurrence with clinical charac-
teristics of IBC.
EPIDEMIOLOGY
INCIDENCE
Worldwide, the incidence of IBC appears to be higher
than in the United States, ranging from 2.1% in Turkey
to as high as 50% in Tunisia (3). In fact, much of the
information about IBC was initially derived from studies
in Tunisia where about half of the breast cancer cases
were attributed to IBC (4). More recent and updated
data from Tunisia and other North African Countries
now suggest a lower incidence using the criteria of the
American Joint Commission for Cancer (AJCC) (5).
Data from the National Cancer Institutes Surveillance,
Epidemiology, and End Results (SEER) program demon-
strate that while there has been a steady decline in non-
IBC in general in the United States, the incidence of
IBC has been on the rise over the last three decades.
From 1973 to 2002, IBC has increased at an annual
rate ranging from 1.23 to 4.35% per year, depending
on the specific database analyzed and the case defini-
tion (1,3,6).
MORTALITY
IBC is an aggressive and usually lethal form of breast
cancer. Women diagnosed with IBC have statistically
significantly poorer survival than women with either
LABC or non-T4 breast cancer (p< 0.001), with a median
overall survival (OS) of 2.9 years (1,11). Additionally,
although IBC accounted for only 2.5% of all breast
cancer cases in the period 1988 to 2000, it led to 7%
of all breast cancerspecific deaths during that time-
frame (1).
As with non-IBC, overall mortality rates for IBC
have been declining. A modest trend for improved sur-
vival (8.4 months) was noted from 1988 to 1999 in a study
reported by Hance et al. (1) This trend toward improved
survival is supported by retrospective data from the
University of Texas, MD Anderson Cancer Center
(MDACC). We reviewed the outcomes of 635 patients
with locally advanced breast cancer, including IBC, with
a median follow-up of 90 months. The 2-year OS rates
of a historical control group of 178 patients treated with
anthracycline-based protocols compared with patients
treated on a paclitaxel-containing regimen were 71 and
74%, respectively. This suggested a marginal, but
not statistically significant, difference in favor of the
paclitaxel-containing regimen (7). The trend in decreasing
mortality from IBC may also be related to increasing
awareness of IBC, resulting in earlier diagnosis, and the
use of more effective multimodality treatments.
However, mortality rates from IBC continue to be
higher for African-American women with median
survival for African-American women at 2.0 versus
2.9 years for their Caucasian counterparts (p < .001) (1).
The early age at diagnosis and poor survival outcomes
observed in African-American patients with IBC sug-
gests that there are also race- or ethnicity-related bio-
logic determinants of this disease.
EPIDEMIOLOGIC FACTORS
Despite limited epidemiologic data regarding IBC,
several important epidemiologic factors have been
associated with IBC. First, there is a higher incidence of
IBC in African Americans compared to other ethnic
groups, with African Americans having at least a 50%
higher incidence than whites (3.1 versus 2.2 per 100,000
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CHAPTER 26 Inflammatory Breast Cancer 713
woman-years, p < .001) (1). Second, age of onset also
varies according to race or ethnicity with African
Americans having a younger age at onset (median
55.2 versus 58.1 years) and a poorer prognosis when com-
pared with Caucasians. Of note, Hispanic women have
the youngest mean age of onset of the disease (median
50.5 years) (8).
IBC appears to develop at a younger age (median
57 years) compared with non-IBC (61.9 years). There
are also differences between genders and age of onset
with men usually diagnosed 10 years later than women
(median 66.5 versus 57 years, p < .001) (3). Geographic
variations for IBC have also been noted. Using the
SEER program registries from 1992 to 2002, rates
ranged from 2.064 per 100,000 woman-years in Jose-
Monterey up to 3.042 cases per 100,000 in Los Angeles (3).
Tumor-specific factors include a higher tumor grade, an
equal proportion of estrogen receptorpositive and
negative tumors and an increased incidence of IBC over
time, which is in contrast to the decrease observed in
non-IBC (1).
RISK FACTORS
Identifying risk factors associated with the develop-
ment of IBC has been challenging. However, when
studies involving IBC are combined with studies involv-
ing rapidly developing breast cancer, which includes
some cases of IBC, several interesting findings emerge
(Table 26-1).
FAMILY HISTORY
While clearly established risk factors have been associ-
ated with the development of non-IBC, this is not the
case with IBC, which is much less frequent and not con-
sistently defined. For example, while family history,
menopausal status, and age at menarche are important
risk factors for non-IBC, they have not been consis-
tently established as risk factor for the development
of IBC. In a study analyzing 68 patients with IBC and
143 patients with non-IBC seen at MDACC, 13% of
IBC patients reported a positive family history of breast
cancer, compared with 8% of non-IBC patients; this
was not statistically significant (9). However, in a
Pakistani study, 20% of patients with IBC reported a
positive family history of breast cancer, compared to
5% in the non-IBC group, which was statistically sig-
nificant (10).
REPRODUCTIVE HISTORY
Although IBC is diagnosed at a younger age than non-
IBC, there does not appear to be a consistent association
between IBC and premenopausal status. Of the patients
evaluated at MDACC, 49% of IBC patients were pre-
menopausal compared to 39% of non-IBC patients (9).
But again, in the Pakistani study, no significant differ-
ence in menopausal status was noted (10). Thus, larger
studies will be required to establish relationships between
IBC and menopausal status.
Early age at first birth has also been associated with
the development of IBC. Women with aggressive breast
cancer, including IBC, are more likely to have their first
child before the age of 20 when compared to patients
with non-aggressive breast cancer (3). In a study of
Tunisian patients with IBC as defined by the Pousse
volutive (PEV) System described later in the chapter,
14 out of 15 premenopausal women diagnosed with
IBC had their first births at the age of 18 or earlier (11).
These data are weakly supported by our study, in which
the lowest median age at first birth was seen among
the IBC patients, although this was not statistically
significant (9).
Many studies have also reported an association of
IBC with pregnancy and/or lactation. Although not
observed in the MDACC cohort, several other studies
from Tunisia and the United States have supported this
association. IBC accounts for approximately 21 to 26%
of breast cancer cases in patients that developed breast
cancer during or after pregnancy (11-13) No associa-
tion between oral contraceptive use and development of
IBC has been found (9).
BODY MASS INDEX, BLOOD TYPE, AND
GEOGRAPHIC LOCATION
Body mass index (BMI) and the risk of developing IBC
has also been studied. Usually, a high BMI is associated
with an increased risk of postmenopausal non-IBC.
We were among the first to evaluate the association
between IBC and high BMI. In our initial study, a case-
comparison between patients with IBC and non-IBC,
RISK FACTORS ASSOCIATED WITH THE
DEVELOPMENT OF INFLAMMATORY
BREAST CANCER
Early age at first birth
Pregnancy/lactation
Increased body mass index
Blood type A
Rural residency
T A B L E
26-1
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714 Breast Cancer PART VII
patients with IBC were heavier (median weight 77.6 kg)
than those with non-IBC (70.0 kg) or those having no
history of breast cancer (68.0 kg) (9). Additionally,
after adjusting for other factors, women with the
highest BMI (>26 kg/m
2
) had an increased risk for
development of IBC when compared to those with
non-IBC (odds ratio 2.54). This was irrespective of
menopausal status, age at menarche, or family history
of breast cancer.
We also evaluated whether obesity and meno-
pausal status had an impact on IBC survival in a cohort
of 177 female IBC patients seen from 1974 to 1993 at
MDACC. After adjusting for axillary lymph node
involvement and chemotherapy protocol, a modifying
effect of menopausal status at diagnosis was noted
on the association between obesity and IBC survival
(p = .02) (14). Relative to postmenopausal women,
premenopausal women had significantly worse sur-
vival (HR = 1.51). After stratifying by menopausal status,
premenopausal obese women had non-significantly
better survival than their leaner premenopausal coun-
terparts (HR = 0.63) while postmenopausal obese
women had significantly worse survival than their
leaner counterparts (HR = 1.86). These findings sug-
gest that factors associated with larger body size at
diagnosis may contribute to shorter IBC survival among
postmenopausal women but not premenopausal women,
who were found to have poorer survival regardless of
body size.
Finally, we retrospectively evaluated the associa-
tion and prognostic value of BMI at the time of initial
diagnosis in 602 patients with LABC, which included
a subset with IBC (18%). Obese patients were more
commonly associated with a diagnosis of IBC com-
pared with overweight and normal or underweight
groups (p = 0.01) (15). Additionally, patients with
LABC who were obese or overweight had a signifi-
cantly worse overall survival (OS) and relapse-free
survival (RFS), and a higher incidence of visceral
recurrence compared with normal/underweight patients.
In a multivariable model, BMI remained significantly
associated with both OS and RFS for the entire cohort.
The interactions between BMI and LABC subsets and
between BMI and menopausal status were not statisti-
cally significant.
Other factors that have been associated with the
development of IBC include blood type and area of resi-
dence. A higher proportion of Tunisian patients with
IBC have blood type A. Additionally, a larger propor-
tion of them live in rural locations (11). Smoking and
alcohol use were not associated with a risk of develop-
ing IBC (9).
IMMUNOLOGIC FACTORS
Given its rapid progression and its clinicopathologic
appearance, there have been efforts to identify immuno-
logic factors that may be important in the develop-
ment of IBC. Delayed hypersensitivity studies have
shown that IBC is not due to immune deficiency (16).
However, in Tunisian patients, a hyperimmune response
has been noted in patients with rapidly progressive
breast cancer (17).
Additionally, 81% of tumors from patients with
PEV3 (ie, clinicopathologic IBC) in Tunisia, were posi-
tive for a variant of the mouse mammary tumor virus
(MMTV). The percentage of patients with breast cancer
in Tunisia who were MMTV-positive were two-fold
higher than those here in the United States (74 versus
36%) (18). While these data are alarming, these
results are from cases diagnosed in the late 1970s,
when the incidence of IBC in this population was
reported to be as high as 55% (4,11). More recent
studies have shown that, as the incidence of IBC had
declined in this population, so has the prevalence of
MMTV-positive cancer cases (19). The relationship
between MMTV and IBC is currently being investi-
gated here in the United States.
PATHOLOGICAL ASPECTS
OF INFLAMMATORY BREAST
CANCER
The cancer we currently define as primary IBC was
first described in 1814 by Sir Charles Bell who noted a
condition where a purple color on the skin over the
tumor accompanied by shooting pains is a very unpro-
pitious beginning (20). However, the term Inflam-
matory Carcinoma of the Breast (ie, IBC) was not
coined until 1924 when Lee and Tannenbaum noted
that as the disease progresses, the skin becomes deep
red or reddish-purple, and to the touch is brawny and
infiltrated (21).
Despite the very early clinical identification of IBC,
the clinical case definition of this disease has continued
to be debated. Since 1924, several definitions for IBC
have emerged. Over time, the definition of IBC has
evolved with the eventual proposal of three subtypes of
IBC: (1) clinicopathologically apparent IBC, (2) clini-
cally apparent IBC, and (3) pathologic (ie, occult) IBC.
Of note, two population-based studies using this classi-
fication for IBC show that patients with occult IBC
have a better OS than patients with clinically apparent
IBC (22,23).
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CHAPTER 26 Inflammatory Breast Cancer 715
MACROSCOPIC PATHOLOGY
The classic criterion for diagnosis of IBC established by
Haagensen in 1971 included diffuse erythema and edema
involving more than two-thirds of the breast, tenderness,
induration, warmth, enlargement, and a diffuse tumor
revealed on palpation (24). Indeed, the gross pathology
of IBC tends to correspond with its clinical character-
istics. One of the commonly described changes associ-
ated with IBC is erythema. The extent of the erythema
can vary from merely a flush of pink to red to bronze.
Comparison with the contralateral, unaffected breast is
therefore important to clearly identify the erythema
(Fig. 26-1A-B). The erythema may also be associated
with a sensation of heat in the affected breast.
Subsequently, the breast begins to enlarge rapidly,
sometimes increasing in size two- to three-fold in a period
of a few weeks. The thickening of the skin is usually sig-
nificant and can measure up to 1 cm. The increased size
of the breast is the result of edema caused by obstruction
of the lymphatic channels. The edema is associated with
exaggerated hair follicle pits, causing a characteristic
orange peel (peau dorange) appearance to the skin.
In African and African-American women, where ery-
thema may be more difficult to distinguish, peau dorange
changes may be easier to identify (Fig. 26-1C).
It is important to mention that the rapid rate of pro-
gression, along with the diffuse erythema of more than
one-third of the skin overlying the breast, should be
used as criteria to distinguish IBC from neglected
locally advanced breast cancer with skin involvement.
These gross skin changes associated with IBC become
less prominent following neoadjuvant chemotherapy.
MICROSCOPIC PATHOLOGY
In conjunction with the clinical features associated with
IBC, several histopathological features have also been
identified. Histologically, IBC does not correspond to
any specific breast carcinoma subtype. IBC tumors are
generally characterized by higher-grade, ductal-type
breast tumors with significant angiolymphatic invasion
(25). In 1887, Thomas Bryant observed that the marked
swelling of the breast and inflammatory signs were
probably related to tumor invasion of the dermal lym-
phatics causing obstruction (Fig. 26-1D) (26). In fact
FIGURE 26-1. Clincal appearance of inflammatory breast cancer. A. Erythema and enlargement noted when compared to normal breast;
B. Diffuse erythema of the left breast in a woman with prior history of right breast cancer. C. Peau dorange appearance of the skin of the
right breast. D. Photomicrograph of breast biopsy from a woman with inflammatory breast cancer showing normal appearing epidermis
(bottom of figure) with tumor cells infiltrating the lymphatic channels of the dermis.
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716 Breast Cancer PART VII
dermal lymphatic invasion (DLI) was considered to
offer pathologic proof of IBC (27). However, in 1974,
Saltzstein described a form of IBC he identified as clin-
ically occult inflammatory carcinoma of the breast in
which DLI was pathologically present, but there was no
clinical signs of IBC (28). Nonetheless, although the
presence of DLI is the histological hallmark of IBC and
responsible for the clinical inflammatory signs of IBC
invasion, it is not required for diagnosis.
The metastatic potential of IBC has been attributed
to DLI and the molecular basis for DLI has been evalu-
ated in several studies. E-cadherin overexpression
appears to contribute to the development of this condi-
tion. E-cadherin in normally thought to be a tumor sup-
pressor protein, with its loss associated with disease
progression in most malignancies. However, in IBC,
overexpression of E-cadherin has been shown to be nec-
essary for tumor emboli formation by enhancing tumor
cell-cell contact (29).
Its rapid onset, progression, and name, all suggest
an inflammatory process as part of the underlying
cause of IBC. However, infiltration of the affected
breast tissue by inflammatory cells is rare. Moreover,
there is no significant increase in the levels of inflam-
matory cytokines produced by the tumor cells. In fact,
similar mRNA expression levels for the more common
inflammatory cytokines were noted in both IBC and
non-IBC tumors (30).
DIFFERENTIAL DIAGNOSIS
The aggressive and lethal nature of IBC calls for its
early and accurate diagnosis. The most common misdi-
agnosis for inflammatory cancer is acute mastitis (AM).
This condition occurs during lactation and is character-
ized by acute inflammation of the breast, with swelling,
redness, and breast pain. Mastitis usually resolves in
several days, but if left untreated, mastitis may become
a breast abscess requiring surgical drainage. Thus, the
acute nature, along with the clinical scenario and other
constitutional symptoms, should help in distinguishing
IBC from mastitis. Other infectious entities that can
mimic IBC include erysipelas, which is usually caused
by group A streptococcus.
Various other cancers can also mimic IBC, including
LABC, sarcoma, inflammatory metastatic melanoma
and lymphoma. In these instances, biopsy with appro-
priate differential staining is important. Paget disease of
the nipple can also mimic IBC, but generally develops
more slowly and is usually associated with destruction
of the nipple. Radiation dermatitis, in its acute phase,
may also appear to be IBC, however, desquamation of
the skin usually occurs with resolution of skin changes
in 2 to 3 weeks.
STAGING OF INFLAMMATORY
BREAST CANCER
TUMOR-NODE-METASTASES (TNM)
SYSTEM
In the United States, the most widely used case defini-
tion for IBC is that of the AJCC which states that
inflammatory carcinoma is a clinicopathologic entity
characterized by diffuse erythema and edema of the
breast (peau dorange), often without an underlying
mass. These clinical findings should involve the major-
ity of the breast. Involvement of the dermal lymphatics
alone does not indicate inflammatory carcinoma in the
absence of clinical findings (31). Based upon this defi-
nition, IBC is designated as a T4d tumor in TNM classi-
fication (32). Thus patients with IBC will have at least
stage IIIB disease (Table 26-2).
POUSSE VOLUTIVE (PEV) SYSTEM
While the AJCC definition of IBC is clinically appro-
priate, it does not cover the entire spectrum of IBC since
it restricts the diagnosis of IBC to only those cases with
clinical involvement of more than half the breast and
does not include occult IBC. This limited definition is
problematic since previous population-based registries
have included patients with occult IBC or tumors
involving less than 50% of the breast (1,8,33).
Thus, a system that encompasses the entire spec-
trum of IBC has been proposed. This system was
devised in 1959 in France in an effort to describe a
rapidly progressive breast cancer with inflammatory
features (Table 26-2). Using this French PEV breast can-
cer classification, PEV2 (inflammatory signs involving
less than half the breast) and PEV3 (inflammatory signs
involving more than half the breast) would coincide with
IBC here in the United States. When utilizing this classi-
fication, approximately 50% of the breast cancer cases
in Tunisia have been attributed to IBC (11,34).
MOLECULAR DETERMINANTS OF
INFLAMMATORY BREAST CANCER
Notwithstanding the obstacles noted in making a clini-
cal diagnosis of IBC, our knowledge of the molecular
basis of IBC has expanded tremendously in the past
several decades. Development of in vivo and in vitro
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CHAPTER 26 Inflammatory Breast Cancer 717
models of IBC has also allowed for molecular profiling.
This has led to the identification of two IBC signatures
(30,35-38). While IBC shares some of the molecular
characteristics associated with breast cancer in general,
some very distinct differences have been noted. For
example, as would be expected in highly aggressive
tumors, IBC tumors are usually of higher grade (10).
Additionally, IBC tumors are more likely to be estrogen
receptornegative when compared to non-IBC tumors
(66 versus 36%) (39). Furthermore, overexpression of
c-erB1/ ErbB1/EGFR and c-erB2/ErbB2/Her2-neu has
been noted, with 42 to 57% of IBC tumors noted to be
Her2-positive (40,41).
Not surprisingly, IBC is a very vascular tumor
with overexpression of lymphangiogenic factors
such as VEGF and Flt-4 (29,42). Additionally, a signifi-
cantly higher intratumoral microvessel density has
been reported in IBC tumors when compared to non-
IBC tumors (43). Furthermore, increased expression of
E-cadherin and non-sialylated mucin-1 (MUC1) have
also been identified in IBC tumors. In one study, 100%
of IBC tumors were positive for E-cadherin compared
to 68% in non-IBC tumors (44). In another study using
a xenograft model, a 10- to 20-fold increased expres-
sion of E-cadherin and MUC-1 was noted and thought
to contribute to the passive dissemination of tumor
emboli in IBC (45). Dual overexpression of these two
proteins in IBC is thought to play a role in the aggres-
sive, invasive nature of this disease (46,47).
Studies evaluating p53 overexpression in IBC have
also yielded interesting findings. In a study performed
at MDACC evaluating 48 patients with IBC, p53 over-
expression was noted in 58% of IBC tumors (48). In this
study, patients who had p53 overexpression were found to
have lower 5-year progression-free survival (PFS) rates
(35 versus 55%; p = .3) and 5-year OS rates (44 versus
54%; p = .4). This is supported by another study in
which p53 overexpression was also associated with a
poorer prognosis, with an 8.6-fold increased risk of
death in patients with IBC (49).
Other studies have described increased chromoso-
mal instability in patients with IBC and resulted in
the identification of two distinct genotypes of IBC (36).
RhoC GTPase, a novel transforming oncogene in human
mammary epithelial cells that partially mimic the
inflammatory breast cancer phenotype has been shown
to be overexpressed in IBC tumors more frequently
than in non-IBC tumors (91 versus 38%) (50). The
overexpression of RhoC GTPase has been associated
with increased mRNA expression of cyclin D1, VEGF,
fibronectin, and caveolin-2, proteins which are impor-
tant in tumor invasion (50,51). It is believed that the
CLASSIFICATION SYSTEMS USED IN THE DIAGNOSIS OF INFLAMMATORY
BREAST CANCER
A. POUSSE VOLUTIVE (PEV) CLASSIFICATION
Tumor Classification Definition
T4 Any size tumor growing into the chest wall or affecting the skin
T4a Extension of tumor to the chest wall
T4b Edema (including peau dorange), ulceration of the skin or satellite skin nodules confined to the
same breast
T4c Both 4a and 4b
T4d Inflammatory breast carcinoma
B. POUSSE VOLUTIVE (PEV) CLASSIFICATION
PEV Classification Clinical Presentation
PEV-0 A tumor without recent increase in volume and without inflammatory signs
PEV-1 A tumor showing marked increase in volume during the previous 2 months but without inflammatory
signs
PEV-2 A tumor in which breast tissue, particularly the skin, is affected by subacute inflammation and
edema involving less than half of the breast surface
PEV-3* A tumor with actue and subacute inflammation and edema involving more than half of the breast
surface
TNM, tumor, nodes, metastasis.
*PEV-3 is equivalent to T4d AJCC classification for IBC.
T A B L E
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718 Breast Cancer PART VII
overexpression of RhoC GTPase, combined with the
loss of WISP3/WINT-1, another tumor suppressor
gene, is largely responsible for the aggressive pheno-
type of IBC (52). The expanded knowledge gained from
these studies about the biological basis of IBC has
resulted in several potential molecular targets for
directed therapy (Table 26-3).
EVOLVING ROLE OF IMAGING
MODALITIES IN INFLAMMATORY
BREAST CANCER
Although IBC is a clinicopathologic entity, the use of
modern imaging modalities has played a key role in the
diagnosis and staging of this disease. In fact, multi-
modality imaging comprised of mammography, sonog-
raphy, and magnetic resonance imaging is considered
the minimal imaging needed to diagnose IBC, and to
adequately stage it.
MAMMOGRAPHY
Mammographic findings in patients with IBC can be quite
subtle, with the mammogram often read as negative.
In fact, in a retrospective analysis of various imaging
modalities in the diagnosis of IBC, mammography was
found to be the least sensitive and effective method,
detecting only 43% of primary breast parenchymal
lesions (53). The most common sign of IBC noted on
mammogram is skin thickening (Fig. 26-2) (54).
Although it is usually always present in patients with
IBC, it is often missed on mammograms based on low
levels of suspicion. Diagnosis is often not made without
comparison to the contralateral breast.
The most variable mammographic finding in patients
with IBC is that of a visible mass. While often not
visible on mammograms, a palpable mass has been
reported in 82% of cases of IBC, calling into question
the clinical diagnoses in those patients (see criteria for
clinical diagnosis of IBC) (55). The lack of a visible
mass on mammogram has been attributed to the
increased density of the breast in patients with IBC,
which often obscures the underlying mass. Calcifications
are also less common in patients with IBC and typi-
cally only become apparent after therapy, when there
has been a decrease in breast density (55). Further-
more, in some instances, the only mammographic find-
ing of IBC may be that of axillary lymphadenopathy.
This finding is often useful in distinguishing IBC
from other breast abnormalities such as postradiation
change.
In our retrospective study evaluating the mammo-
graphic findings of 26 women with IBC, 92% of them
had skin thickening, 81% had diffusely increased breast
tissue density, 62% had trabecular thickening, 58% had
axillary lymphadenopathy, 50% had architectural dis-
tortion or focal asymmetric density, and 38% had nipple
retraction.
ULTRASOUND
Information regarding the role of ultrasound in the diag-
nosis of IBC is limited. As with non-IBC, ultrasound is
very useful in localizing sites for biopsy in patients
with masses. In a series evaluating 142 women with
histologically proven IBC, in contrast to mammography,
SUMMARY OF POTENTIAL BIOLOGICAL TARGETS IN THE TREATMENT OF
INFLAMMATORY BREAST CANCER
Category Molecular Marker Agents
Oncogenes (40,41,51,100) Her-2/neu mAbs, TKIs
EGFR TKIs
RhoC GTPase FTIs
Tumor suppressor genes (10,48,49,101) p53 Gene therapy, p53-stabilizing agents
PTEN Proteasome inhibitors, PI3K-inhibitors
Angiogenesis modulators (29,44,45,47) Tie-2 Tie-2 kinase inhibitor
VEGF Angiogenesis inhibitors
Flt-1/Flk-1 TKIs, mAbs
E-cadherin E-cadherin inhibitors
MUC-1 MUC-1 inhibitors, PIAS
RhoC GTPase FTIs
FTIs, farnesyltransferase inhibitors; mAbs, monoclonal antibodies; MUC1, mucin-1; PIAS, protein inhibitor of activated signal transducer and
activator of transcription; PI3K, phosphatidylinositol-3-kinase; TKIs, tyrosine kinases inhibitors; VEGF, vascular endothelial growth factor.
T A B L E
26-3
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CHAPTER 26 Inflammatory Breast Cancer 719
ultrasound was able to detect an additional 24 masses
(18%) obscured by edema, when compared to mammo-
gram alone (56). The greatest benefit of ultrasound may
be its potential to provide comprehensive evaluation of
the nodal stations and pectoral muscle invasion. In this
same series, ultrasound was able to detect axillary lym-
phadenopathy in the majority (73%) of these patients
and pectoral muscle invasion in 10%. These findings
have been confirmed in our series, in which sonography
found a parenchymal breast lesion and skin thickening
in 95% of patients and regional axillary nodal disease in
93% of cases (Fig. 26-3) (54).
FIGURE 26-2. Bilateral mediolateral oblique
mammograms in a 54-year-old female show
global skin and trabecular thickening (short
arrows) of the right breast with associated right
axillary adenopathy (long arrow). No visible
primary breast parenchymal lesion is noted in
the right breast. (Reproduced, with permission,
from Yang WT, Le-Petross HT, Macapinlac H,
et al. Inflammatory breast cancer: PET/CT,
MRI, mammography, and sonography findings.
Breast Cancer Res Treat 2008;109:417-426.)
FIGURE 26-3. Ultrasound images of the right breast from patient
described in Fig. 26-2. (A) Extended-field-of-view ultrasound of
the right breast in the patient of Fig. 26-2 showing marked diffuse
skin thickening and subcutaneous edema (short arrows) and a
focal solid hypoechoic mass (long arrow) representing primary
breast parenchymal lesion. (B) Transverse ultrasound with power
Doppler imaging of the primary mass in the right breast shows
marked internal hypervascularity. (C) Transverse ultrasound of
the right supraclavicular region shows a solid hypoechoic node
that showed metastatic carcinoma on biopsy. (Reproduced, with
permission, from Yang WT, Le-Petross HT, Macapinlac H, et al.
Inflammatory breast cancer: PET/CT, MRI, mammography, and
sonography findings. Breast Cancer Res Treat 2008;109:417-426.)
26_Kantarjian_Ch26_p711-730.qxd 2/28/11 10:04 AM Page 719
720 Breast Cancer PART VII
FIGURE 26-4. (A) Sagittal T2-weighted fast spin-echo image with fat suppression shows a dominant heterogeneous mass in the superior
right breast (long arrow), global skin and subcutaneous edema (medium arrows), and right axillary adenopathy (broad arrow). (B) Sagittal
fat suppressed 3D spoiled gradient-recalled-echo sequence with parallel imaging at 2 min post-contrast administration demonstrates multi-
ple rim enhancing tumor masses (arrows) in the right breast and malignant-appearing necrotic right axillary lymph nodes (broad arrow).
(C) Delayed axial fat suppressed contrast-enhanced 3D fast spoiled gradient-recalled echo MR image reveals multiple heterogeneously
enhancing masses in the central and lateral right breast (arrows), and right axillary adenopathy (broad arrow). (Reproduced, with permission,
from Yang WT, Le-Petross HT, Macapinlac H, et al. Inflammatory breast cancer: PET/CT, MRI, mammography, and sonography findings.
Breast Cancer Res Treat 2008;109:417-426.)
MAGNETIC RESONANCE IMAGING
The use of magnetic resonance imaging (MRI) in the
diagnosis of breast cancer has steadily increased over
the past several decades based on its superior sensitivity
and lack of ionizing radiation. However, only a few
studies have evaluated its use in the diagnosis of IBC.
Nevertheless, it is clear that MRI plays an important
role in the diagnosis of IBC, with 90-100% of patients
noted to have skin thickening on MRI and 75% of
patients also having axillary lymphadenopathy (53,54,
57,58). A discreet mass could also be seen in up to 38%
of the cases (57,59). Thus, MRI is considered by some
to be the imaging modality of choice in the diagnosis of
IBC (Fig. 26-4).
MRI use in differentiating between AM and IBC has
also been evaluated. For the most part, the MRI findings
with AM and IBC were very similar with edema and
skin thickening noted in both (59,60). However, in a
recent study evaluating 90 patients (48 with IBC and 42
with AM), MRIs of the breast were able to statistically
26_Kantarjian_Ch26_p711-730.qxd 2/28/11 10:04 AM Page 720
CHAPTER 26 Inflammatory Breast Cancer 721
detect more T2-hypodense masses, infiltration of pec-
toralis major muscle, and pectoralis edema (60). Addi-
tionally, MRI has been shown to be useful in follow-up
of AM by evaluating success of antibiotic treatment
and diagnosis of coexisting or confounding inflamma-
tory carcinoma (59).
Breast MRI has also been used to monitor response to
therapy with correlation with pathologic size ranging
from 0.75 to 0.89 (61,62). Several studies have shown that
pathologic complete response (pCR) was the strongest
prognostic factor for IBC and in a recent study by Chen
et al., the accuracy of complete clinical response on
MRI to predict pCR was 69% (11 of 16), with a sensitivity
of 58% (7 of 12), specificity of 92% (11 of 12), and a false-
negative rate of 21% (5 of 24) (63). These results suggest
that interpretation of and future treatment decisions based
upon MRI findings should be done with extreme caution,
especially in cases where no discrete mass was identified,
since cases with no identifiable discrete mass accounted
for 80% of the false-negative cases (4 of 5).
COMPUTERIZED TOMOGRAPHY
The utility of helical computerized tomography (CT)
which provides high-resolution thin cuts has also been
investigated in the diagnosis of IBC. In a study by
Mogavero et al., as with MRI, skin thickening was found
in 100% of the patients with IBC (Fig. 26-5). However,
unlike mammography, axillary lymphadenopathy was
found in 82% of patients and distant metastases noted in
64% of patients (64). Helical CT has also been evalu-
ated for its ability to monitor response to therapy in
patients with IBC. When compared to clinical examina-
tion and mammography, breast helical CT was found to
be very useful in the quantitative assessment of response
to neoadjuvant chemotherapy and preoperative deter-
mination of residual tumor volume in patients with
round opacities (correlation coefficients of 0.97) (65).
However, it was not as reliable for tumors with diffuse,
scattered or multinodular opacities (correlation coeffi-
cient 0.60). Thus some have been cautious about the
role of helical CT in determining the extent of residual
disease following neoadjuvant chemotherapy (66).
POSITRON EMISSION TOMOGRAPHY
The data regarding the role of positron emission
tomography(PET) in the diagnosis of IBC is very limited.
In one study that evaluated PET in seven patients with
IBC, skin enhancement was noted in 100% of the
patients, with axillary lymphadenopathy in 85%, and
skeletal metastases in 14% (Fig. 26-6). Postchemother-
apy PET scans performed in four patients showed
response in the primary tumor, axillary lymph nodes,
and skeletal metastases (67). Given that 20 to 35% of
patients with IBC have distant metastases at the time of
diagnosis, PET, and increasingly PET/CT may have a
useful role in staging.
FIGURE 26-5. (A) PET/CT shows multicentric hypermetabolism in the right breast (arrow) associated with hypermetabolic diffuse skin
thickening. (B) PET/CT shows a solitary focal hypermetabolic focus in the right lobe of the liver (arrows) that showed a maximum SUV
of 5.7. Corresponding CT of the liver shows a focal hypoechoic mass with indistinct margins. (C) PET/CT shows a solitary focal hyperme-
tabolic focus in the left proximal femur (arrows) that showed a maximum SUV of 7.7. Corresponding CT of the proximal femur shows this
area of hypermetabolism to be within the marrow (whole body bone imaging was negative in this patient). (Reproduced, with permission,
from Yang WT, Le-Petross HT, Macapinlac H, et al. Inflammatory breast cancer: PET/CT, MRI, mammography, and sonography findings.
Breast Cancer Res Treat 2008;109:417-426.)
26_Kantarjian_Ch26_p711-730.qxd 2/28/11 10:04 AM Page 721
722 Breast Cancer PART VII
For example, in studies performed at MDACC,
PET/CT was able to identify patients with distant
metastases at diagnosis. In one study in which PET/CT
was performed on 24 patients with IBC, 63% of patients
were noted to have multicentric disease, 88% noted to
have regional nodal disease, and 38% found to have dis-
tant metastases (53,54,58,68). In more recent studies,
up to 98% of patients were found to have parenchymal
breast lesions on PET/CT (54,58,68). Additionally,
when PET/CT was used in initial staging of IBC, 17%
more cases of distant metastases were identified in
patients who were not previously known to have
metastases (68). However, further studies are needed to
determine the cost-benefit utility of this diagnostic
modality.
THE MULTIDISCIPLINARY
TREATMENT OF INFLAMMATORY
BREAST CANCER
There have been significant advances in the care of the
IBC patients over the last 40 years. While once consid-
ered a uniformly fatal disease, with fewer than 5% of
patients alive at 5 years, the introduction of primary sys-
tem chemotherapy in combination with other treatment
Perform multidisciplinary assessment and treatment
planning
Obtain skin biopsy and ultrasound guide core biopsy
Imaging with mammogram, ultrasound and MRI
PET/CT
Obtain photograph to establish baseline clinical
appearance
Obtain history and perform physical examination
Neoadjuvant doxorobin- and taxane-based
chemotherapy
Multidisciplinary evaluation of response
PR or CR
Operable disease
<PR
Inperable disease
Mastectomy XRT
XRT TAM or AI if ER+
TAM or AI if ER+
Clinical trial
targeted therapy
FIGURE 26-6. Schematic representation of the proposed optimal sequence of treatment for newly diagnosed IBC. XRT, radiotherapy;
TAM, tamoxifen; AI, aromatase inhibitor. (Modified, with permission, from Cristofanilli M, Buzdar AU, Hortobagyi GN: Update on the
management of inflammatory breast cancer. Oncologist 8:141-8, 2003.)
26_Kantarjian_Ch26_p711-730.qxd 2/28/11 10:04 AM Page 722
CHAPTER 26 Inflammatory Breast Cancer 723
modalities has drastically altered the survival outcomes
compared to locoregional treatments alone.
SURGERY
Historically, surgery was the primary modality for IBC,
but it yielded poor results. In fact, the inadequacy of
surgery to provide local control or increase survival was
first noted in the 1920s when Lee and Tannenbaum
observed an almost immediate recurrence following
radical surgery for IBC, thus making them certain of
the inefficiency of surgery in this disease (21). In a
review article evaluating the efficacy of surgery in the
treatment of IBC from 1924 to 1981, a median survival
of 19.8 months was noted, with a 5-year OS less than
5% (69). Upfront surgery for IBC also provides poor
local control with a local recurrence rate around 50%
(21,70-72). As it became apparent that nearly all the
patients with IBC died despite surgery, this treatment
was abandoned. Thus, by the 1950s, the only indica-
tion for surgery was to establish a diagnosis with
biopsy.
However, as multimodality treatment became the
standard of care for patients with IBC, the role of
surgery expanded (69). In a study examining the treat-
ment of 485 patients with IBC, there was an increase in
the use of mastectomy from 11 to 69%, with a concur-
rent decrease in the number of patients having no
surgery from 67 to 22% (73). During this time the
sequencing of surgery also changed with mastectomy
occurring following neoadjuvant chemotherapy.
A more recent study of 178 women with IBC treated
with neoadjuvant chemotherapy showed that the addi-
tion of mastectomy to combination chemotherapy plus
radiotherapy improved local control in patients with IBC.
Furthermore, the addition of mastectomy to chemother-
apy plus radiotherapy improved distant disease-free
survival (DFS) and OS in patients with a clinical com-
plete response (CR) or partial response (PR) to induc-
tion chemotherapy (74). Patients are now considered
candidates for a modified radical mastectomy when
there has been complete resolution of inflammatory
skin changes.
RADIOTHERAPY
Since initial studies indicated that IBC was not a disease
amendable to surgical intervention, studies evaluating
the benefit of radiation in local control emerged with
radiotherapy alone being the treatment of choice (33).
Although treatment with radiotherapy yielded better
overall responses with 50% local control, which was the
best rate reported at the time, survival was still poor
with less than 5% of patients alive by 5 years (75). Even
in more recent studies evaluating radiotherapy alone in
the treatment of IBC, local control remains a problem.
For example, in a 1980 study in which 62 patients with
localized clinical IBC were treated with radiotherapy to
the breast and draining lymphatics, 69% of the patients
developed local and regional recurrence (76).
To improve these results, studies using different
radiotherapy regimens were investigated. A team
from MDACC was the first to use hyperfractionated
radiotherapy in the treatment of IBC. Locoregional
recurrence was decreased from 47% in patients with
once-daily radiation therapy to 27% with twice-daily
administration.
Other studies have shown improved survival with
radiotherapy especially with the use of dose escalation.
For example, at MDACC, in a study evaluating 115
nonmetastatic patients with IBC from 1977 to 1993
treated with curative intent, twice-daily postmastec-
tomy radiation to a total dose of 66 Gy, resulted in sig-
nificant improvements in rates of locoregional control
(p = 0.03) and OS (p = .03), and a trend toward better
DFS (p = .06) (77).
NEOADJUVANT CHEMOTHERAPY
Despite the ability of radiation therapy to provide some
improvement in locoregional control, the development
of distant metastatic disease has remained a challenge,
and for many years, no standard chemotherapeutic regi-
men existed for IBC. The rarity and poor overall prog-
nosis associated with IBC often resulted in these
patients being excluded from most clinical trials. As a
result, most patients with IBC were previously treated
with regimens intended for those with non-IBC cancer.
More recently, clinical trials of chemotherapy specifically
designed for patients with IBC have been conducted.
Importantly, based upon emerging data showing that
response to neoadjuvant chemotherapy had prognostic
significance, studies were designed using neoadjuvant
chemotherapy in the treatment of IBC. For example, in
a study evaluating 372 patients with LABC treated with a
doxorubicin-containing regimen showed that neoadju-
vant chemotherapy was able to completely clear the
breast and axillary lymph nodes of invasive tumor
before surgery. Furthermore, patients with LABC who
have a pCR in the breast and axillary nodes have a sig-
nificantly improved DFS rate (78). Therefore, treat-
ment with doxorubicin-containing regimens in the
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724 Breast Cancer PART VII
neoadjuvant setting became the standard for treatment
of IBC.
The largest experience to date on the systemic man-
agement of IBC comes from MDACC. From 1974 to
2001, we treated 242 IBC patients on clinical trials
designed solely for this disease (Table 26-4). These trials
established the need for neoadjuvant chemotherapy to
improve DFS and OS in patients with IBC. Additionally,
they showed that response to neoadjuvant chemotherapy
was a surrogate marker of long-term outcome in patients
with IBC. In a retrospective study examining 489 patients
(7.5% with IBC) that received an anthracycline-based
chemotherapy as their primary mode of treatment,
patients with IBC were found to have lower RFS rates
and a greater hazard of death than patients with clini-
cal stage I/II/IIIA disease. Additionally, patients with
IBC who failed to achieve CR with primary systemic
chemotherapy also had decreased OS (79). Thus, not
only did neoadjuvant chemotherapy become a mainstay
in the treatment of IBC, but trials to identify the
chemotherapeutic regimen that yielded the best patho-
logical response were also begun.
Anthracyclines
Four consecutive protocols took place at MDACC
between 1974 and 1993 (80-83). The first protocol
evaluated the use of 5-fluorouracil, doxorubicin, and
cyclophosphamide (FAC) as induction/neoadjuvant ther-
apy, followed by radiation and further chemotherapy
with FAC or cyclophosphamide, methotrexate, and 5-FU
(CMF). A second protocol investigated the same induc-
tion regimen followed by mastectomy, adjuvant FAC,
and radiation, while a third protocol investigated the
addition of vincristine and prednisone to FAC (FACVP).
Finally, a fourth study gave IBC patients induction
chemotherapy with FACVP and surgery followed by
FACVP for those who had a CR after induction with
FACVP. Patients who achieved a PR with a clinical
reduction in tumor size of more than 50% received post-
operative treatment with FACVP plus methotrexate and
vinblastine (MV); those who achieved a minimal
response (MR) of a 25 to 50% decrease in tumor size
were treated postoperatively with MV alone.
The ORR for all four trials was 72%, with a 12%
clinical CR rate. There were no significant differences
in DFS or OS between the four protocols. Of note, the
use of surgery did not alter the risk of local recurrence
for those with poorly responsive disease. Results from
the fourth protocol showed that the vincristine and pred-
nisone and methotrexate and vinblastine had no effect
on DFS or OS. Importantly, the rarity of IBC resulted in
modest sample sizes for all four trials. Nevertheless, for
all 178 patients treated on these protocols, the DFS
ranged from 32% at 5 years to 28% at 15 years, with a
median survival of 37 months.
A 20-year follow-up regarding these initial 178
patients reported by Ueno et al. showed among those
patients with recurrence, 20% of patients had local failure,
39% systemic failure, and 9% CNS recurrence (83).
Initial response to induction chemotherapy was found
to be an important prognostic factor. DFS at 15 years
was 44% in patients who had a CR to induction
chemotherapy, 31% in those who had a partial response
(PR), and 7% in those who had less than a PR. There
was no improvement in OS or DFS among patients who
underwent alternate chemotherapy (MV) compared
with those who did not. Using surgery and radiotherapy
as opposed to radiotherapy alone as local therapy did
not have an impact on the DFS or OS rate.
These long-term follow-up data showed that with a
combined-modality approach, a significant fraction of
SUMMARY OF CLINICAL RESPONSES IN FIVE CONSECUTIVE CLINICAL
TRIALS CONDUCTED AT MDACC FOR PATIENTS WITH INFLAMMATORY
BREAST CANCER (81-83,86)
Protocol A Protocol B Protocol E Protocol C Protocol D
Clinical Response N (%) N (%) N (%) N (%) N (%)
CR 6 (15) 3 (13) 3 (7) 9 (13) 3 (7)
PR 26 (65) 10 (44) 25 (58) 45 (63) 31 (70)
MR 6 (15) 8 (35) 11 (26) 13 (18) 0 (0)
SD 1 (3) 0 (0) 0 (0) 2 (3) 1 (2)
PD 1 (3) 2 (9) 0 (0) 1 (1) 6 (14)
N/A 0 (0) 0 (0) 4 (9) 2 (3) 3 (7)
Total 40 (100) 23 (100) 43 (100) 72 (100) 44 (100)
N/A, not applicable; PD, progressive disease.
T A B L E
26-4
26_Kantarjian_Ch26_p711-730.qxd 2/28/11 10:04 AM Page 724
CHAPTER 26 Inflammatory Breast Cancer 725
patients (28%) remained free of disease beyond 15 years
compared to 5% following single-modality treatments.
These findings have helped to establish combined-
modality treatment (anthracycline-based neoadjuvant
chemotherapy, then mastectomy, then adjuvant chemother-
apy and radiotherapy) as the standard of care for treat-
ment of inflammatory breast carcinoma.
Taxanes
The importance of achieving a pCR following neoadju-
vant chemotherapy has been observed in patients with
IBC as it has been for those with non-IBC. In a study of
175 patients with IBC that were treated with neoadju-
vant chemotherapy, 61 were found to have residual dis-
ease in the axillary lymph nodes. These patients were
noted to have a lower 5-year RFS (82.5 versus 37.1%)
and 0S (78.6 versus 25.4%) when compared to patients
who attained a pCR. Thus, the significance of a pCR to
induction chemotherapy as an important prognosticator
of survival has led to the investigation of novel chemother-
apeutic regimens that might increase pCR rates.
In 1994, a fifth protocol opened at MDACC, which
evaluated the use of paclitaxel in the treatment of IBC.
A total of 44 patients were enrolled. All patients were
treated with FAC for induction and adjuvant chemother-
apy. Paclitaxel was given preoperatively to those
patients who achieved only a minimal response or sta-
ble disease after receiving FAC and it was delivered to
all patients in the adjuvant setting. The treatment course
consisted of neoadjuvant chemotherapy, mastectomy,
adjuvant chemotherapy, and radiation therapy. While this
approach was promising with higher objective response
rates compared with the four prior trials (81 versus 72%)
and better OS rates (46 versus 37 months), the results
were not statistically significant (84).
Thus a sixth trial involving 18 IBC patients was
begun, which was designed to determine the effect of
FAC plus high-dose weekly paclitaxel as induction
chemotherapy. Postoperative therapy then consisted of
cyclophosphamide, etoposide, and cisplatin (CVP). This
treatment was followed by bone marrow mobilization,
high-dose chemotherapy with cyclophosphamide, car-
mustine (BCNU), and thiotepa, and subsequent periph-
eral blood stem cell support. Analysis of the data
showed that 31% of patients achieved a clinical CR and
72% of patients proceeded to mastectomy (84).
More recently, a retrospective study evaluated the
outcomes of 240 patients with IBC treated on these six
MDACC protocols. Patients were stratified on the basis
of whether they had received paclitaxel as part of either
their induction or adjuvant chemotherapy. There was a
trend toward an increased objective response rate
(ORR) for the paclitaxel regimens (79%) compared
with anthracycline-based therapy (72%) and increased
3-year OS rates (71 versus 53%, respectively). While, sta-
tistical significance was not reached in the general analy-
sis, subset analysis of the ER-negative group of patients
did reveal a significantly higher 3-year OS (54 versus
32 months, p= .03) and PFS (27 versus 18 months, p= .04).
Additionally, a significantly higher pCR rate was noted
with the addition of paclitaxel compared with treatment
using FAC alone (25 versus 10%, p = .012) (85).
These results established the addition of paclitaxel
to anthracycline-based therapy in the treatment of
patients with ER-negative IBC. Furthermore, these
results indicate that anthracyclines and taxanes are the
most effective chemotherapeutic agents in the treatment
of IBC, thus securing their use in the frontline setting.
MULTIMODALITY TREATMENT
As outcomes in patients with IBC began to improve fol-
lowing the introduction of primary systemic chemother-
apy, combining this treatment with local therapies such
as radiation therapy and surgery became more common.
One of the first studies evaluating multimodality treat-
ment of IBC was performed at MDACC. Thirty-two
patients with inflammatory breast cancer were treated
with a combined modality approach consisting of FAC,
followed by radiation therapy and compared with 32
patients with inflammatory breast cancer treated with
irradiation without systemic therapy at our institution in
the past. After a median follow-up of 62 months (range
42-76 months), 11 patients in combined modality group
and 3 patients in the irradiation group were free of disease.
Overall median disease-free interval was 22.8 months
for the combined modality group and 9 months for the
irradiation group, with a median survival of 30.1 months
and 18 months, respectively. In subgroup analysis, this
treatment was effective in prolonging the disease-free
interval and survival of patients greater than or equal to
50 years of age, with an estimated 45% of the patients
surviving free of disease beyond 42 months. However,
in patients <50 years old, although an improved disease-
free interval was still noted, survival of this subgroup
was not significantly improved (86).
To reexamine the benefit of surgery in IBC, Fleming
et al. performed a retrospective analysis of 178 patients
that had received multimodality treatment between
1974 and 1993. They found that the addition of mastec-
tomy to combination chemotherapy plus radiotherapy
improved local control, distant DFS and OS in IBC
patients with a clinical complete or partial response to
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726 Breast Cancer PART VII
induction chemotherapy (74). These studies laid the
foundation for the multimodality treatment for IBC (87).
As improved responses to chemotherapy in combi-
nation with local therapies were noted, questions regard-
ing the best sequencing of these modalities emerged.
Thus, studies were performed combining chemotherapy
with radiation, with the addition of surgery, depending
on response to chemotherapy. The efficacy of neoadju-
vant chemotherapy was shown in a study that retrospec-
tively examined 179 patients with nonmetastatic IBC
treated with curative intent. Patients who received mul-
timodality treatment with neoadjuvant chemotherapy,
surgery, and radiation had a higher 5-year DFS (40%),
when compared to patients who received only defini-
tive radiation (6%), surgery with radiation (24%), or
chemotherapy with radiation (6%) (88). Similar results
were seen at 10 years and this improvement has been
confirmed by other studies.
The use of high-dose chemotherapy (HDCT) sup-
ported by stem cell transplantation (SCT) as a compo-
nent of multimodality therapy regimens has also been
assessed. Several small phase II trials have shown a sur-
vival benefits for patients with IBC treated with HDCT
with SCT. These trials generally reported 3 to 4 year OS
rates of 52 to 89% and DFS rates of 45 to 65%, which
were favorable compared to historical survival data
with standard-dose chemotherapy (89-92). However, in
the absence of definitive, prospective, randomized trials,
the use of HDCT remains controversial.
MOLECULAR TARGETS OF
INFLAMMATORY BREAST
CANCER
With the identification of molecular determinants of
IBCs, focus then turned to the introduction of novel bio-
logic therapies to the primary systemic chemotherapy.
The identification of Her2 overexpression in IBC soon
led to the incorporation of trastuzumab, a humanized
monoclonal antibody against Her2, to anthracycline/
taxane-based chemotherapy regimes. To date, at least
four prospective trials have added trastuzumab to pri-
mary systemic therapy in the treatment of IBC. In a
study by Hurley et al., 48 patients with Her2-positive
LABC (including IBC) were treated with docetaxel,
cisplatin, and trastuzumab, followed by surgery, adjuvant
chemotherapy, and radiation. An OS rate of 100% was
noted in those who attained a pCR, compared to 76 to
83% for those who had residual disease (93).
In another study by of 22 patients with LABC, 9 of
whom had IBC, treated with docetaxel and tratuzumab,
a complete response rate of 40% was observed (94).
Other studies have yielded similar results, with pCR
rates of 18 to 39% (95,96). Taken together, these studies
showed that the addition of trastuzumab contributed to
higher rates of pCR in patients with Her2-positive IBC.
Encouraging results have also been obtained with
lapatinib, a dual-action Her1 and Her2 tyrosine kinase
inhibitor, in Her2-positive IBC. The combination of
lapatinib and paclitaxel in 21 patients with Her2-positive
IBC resulted in a 95% clinical response rate (97). These
results are currently undergoing prospective validation.
Several other novel agents have been or are currently
being studied in the treatment of IBC. The identification
of increased expression of VEGF has led to the investiga-
tion of angiogenesis as a therapeutic target. Bevacizumab,
a VEGF inhibitor, has been evaluated in combination with
primary system chemotherapy in IBC. Thus far, results
have been disappointing, but other multitargeted tyrosine
kinase inhibitors of angiogenesis such as pazopanib are
now being investigated (98).
The discovery that low-affinity insulin-like growth-
binding protein (LIBC/WINT1) and RhoC GTPase,
which are part of the Ras pathway, are respectively
absent and overexpressed in IBC, leading to their evalu-
ation as potential targets in the treatment of IBC (51). It
has been shown that farnesyl transferase inhibitors
(FTIs), which inhibit RhoC proteins, decrease angio-
genesis, and therefore RhoC-targeted therapy merits
further investigation in the treatment of IBC (99).
CURRENT THERAPEUTIC
STRATEGIES AT MD ANDERSON
CANCER CENTER
Multimodality therapy for IBC is of utmost importance
with neoadjuvant chemotherapy acting as the backbone.
Anthracyclines and taxanes are the cytotoxic agents of
choice for the management of IBC. Our standard of
care is the use of an anthracycline-containing regimen
(FAC) followed by a taxane (paclitaxel or docetaxel).
For paclitaxel, the data suggest that a weekly schedule
may be more beneficial, with achievement of a higher
pCR rates. Patients are deemed to have a poor prognosis
if extensive residual disease is present after induction
chemotherapy.
Locoregional treatment after neoadjuvant chemother-
apy consists of radiation therapy with or without surgi-
cal intervention. After resolution of the characteristic
skin changes associated with IBC, most patients are
considered to be appropriate candidates for a modified
radical mastectomy and subsequent radiation treatment.
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CHAPTER 26 Inflammatory Breast Cancer 727
Radiation therapy alone is an adequate method of locore-
gional treatment for patients who have not achieved
sufficient debulking. Increased complete pathologic
response rates are currently being evaluated by combin-
ing chemotherapy with biologically directed agents.
Our recommended schema for multimodality treatment
of IBC is presented in Fig. 26-6.
CONCLUSION
IBC is an aggressive and often lethal form of breast can-
cer. Thus, early and accurate diagnosis is essential.
Although IBC is a clinicopathologic entity, imaging
modalities such as mammography, ultrasound, MRI,
CT, and PET/ CT have been useful in diagnosing and
staging this disease. While primary systemic chemother-
apy with anthracycline- and taxane-based regimens are
the mainstay of therapy, a multidisciplinary approach
using adjuvant chemotherapy, radiation, and/or surgery
is of critical importance. This multidisciplinary approach
to the treatment of IBC has resulted in significant
increases in survival over the past four decades, with OS
up from less than 5 to 44% at 15 years in patients who
achieve a pCR. As our knowledge of the biological basis
of IBC continues to expand, one would expect further
improvement in survival as targeted therapies are added
to these regimens.
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