Volume 19, Number 4

October 2009

Introduction: Locally Advanced Breast Cancer

his is the most exciting time in the history of breast

cancer research and treatment. Advances occurring in all
disciplines of breast cancer care have had the positive effect of
improving survival and decreasing treatment side effects. For
example, screening and public educational efforts have significantly decreased the percentage of breast cancer cases that
present with locally advanced or metastatic disease. For those
who do present with locally advanced breast cancer, advances in surgical therapies have helped minimize treatmentrelated morbidity and improved the quality of life for survivors. With respect to systemic therapies, new cytotoxic
chemotherapies, new dose scheduling, and the introduction
of aromatase inhibitors have helped minimize the risk of
death from subsequent development of metastatic disease.
The understanding of breast cancer biology is also rapidly
changing, which has led to new therapeutics directed against
selective molecular targets, such as the HER2/neu receptor.
Finally, radiation treatments, which have been an integral
component of breast cancer management for over 6 decades,
have evolved. As a packet, these advances have made a real
difference for breast cancer patients. Specifically, breast cancer death rates in the United States and the United Kingdom
have shown a precipitous and consistent decline over the past
decade.1
Despite this background, there is still room for improvement. Over 40,000 women in the United States are predicted
to die of breast cancer each year.1 Many of the patients who
eventually die originally presented with lymph node-positive
disease and/or locally advanced breast cancer. In countries
without mammographic screening programs, the percentage
of patients diagnosed with locally advanced breast cancer and
the percentage of patients dying of disease are even more of a
pressing issue.
It is imperative that radiation oncologists and other specialists remain aware of the number of changes developing in
the understanding of locally advanced breast cancer and that
locally advanced breast cancer is a potentially curable disease. Moreover, each new systemic treatment advance that
increases the chance of eradicating micrometastases makes
the role of radiation for locally advanced breast cancer even
more critical. For example, patients treated for locally advanced breast cancer before the development of effective systemic treatments would often die of metastatic disease. Such
1053-4296/09/$-see front matter 2009 Published by Elsevier Inc.
doi:10.1016/j.semradonc.2009.05.002

patients received little benefit from radiation achieving eradication of persistent foci of local-regional disease after surgery. In contrast, with effective systemic treatment, failure of
eradication of persistent local-regional disease has been
shown to increase the risk of subsequent distant failures.
Using systemic therapy, radiation benefits can translate into
improved survival and cure rates.2
This issue of Seminars in Radiation Oncology provides the
reader with a broad overview of the current status of locally
advanced breast cancer. Newman updates the epidemiology
of locally advanced breast cancer and highlights how disparities in health care can influence the incidence of this disease
and its treatment success. Huber et al review how the evolving understanding of breast cancer biology is leading to an
improved classification of breast cancer. Locally advanced
breast cancer represents a spectrum of different biological
diseases that have distinct patterns of presentation, molecular
phenotypes, treatment responses to various agents, and prognoses. It is imperative that the radiation oncology community
become familiar with the new molecular lexicon of breast
cancer classifications and incorporate molecular features into
their therapeutic thought processes.
The optimal management of locally advanced breast cancer requires multidisciplinary care. As highlighted by Specht
and Gralow, neoadjuvant chemotherapy is now considered
the standard of care for these patients. This treatment is associated with high response rates, which can convert inoperable disease to an operable status and can allow for some
patients to be treated with breast conservation. With the
move to sequence chemotherapy before surgery, accurate
pretreatment assessment of disease is critical. Whitman and
Strom review the importance of a clear delineation of localregional disease status with appropriate diagnostic imaging
and examination before embarking on a course of neoadjuvant chemotherapy. Of particular value is the use of ultrasound with fine-needle aspiration to evaluate the extent and
location of regional adenopathy. The documentation of disease in lymph nodes before neoadjuvant chemotherapy can
frequently change clinical staging and affect subsequent local-regional treatment decisions.
One major potential advantage that neoadjuvant chemotherapy offers for selected patients with favorable disease
response is the opportunity of treating with breast-conserva193

T.A. Buchholz

194
tion therapy. Breast conservation after neoadjuvant chemotherapy requires close multidisciplinary coordination and
careful selection criteria to achieve optimal results. In this
issue, Alm El-Din and Taghian review the published outcome
data regarding breast conservation after neoadjuvant chemotherapy and help describe appropriate selection criteria for
consideration of this treatment approach.
Radiation treatments also play an important role as adjuvant therapy for patients treated with mastectomy. Postmastectomy radiation has been found to contribute to the survival of patients with locally advanced disease, and, as
systemic treatments improve, the benefits of local-regional
therapies on survival increase. Jagsi and Pierce review the role
of radiation after mastectomy and also discuss the published
data regarding the use of postmastectomy radiation in patients treated with neoadjuvant chemotherapy.
With survival probabilities increasing, it is critical that the
long-term risks of normal tissue injuries associated with radiation be minimized. Data from the Early Breast Cancer
Trialists Collaborative Group meta-analysis clearly show that
radiation can be associated with an increased risk of death
from cardiovascular disease.2 Modern treatment techniques
are available to minimize and potentially overcome this risk.
Furthermore, 3-dimensional image-guided radiation treatment planning can help ensure that the adequate dose is
delivered to important targets, which should help to improve
the efficacy of treatment. Moran and Haffty review modern
radiation treatment techniques to highlight some of these
advances.

Finally, inflammatory breast cancer remains the most aggressive and malignant subcategory of locally advanced disease. Inflammatory breast cancer has unique clinical presentations, biological features, and natural histories. Woodward
and Cristofanilli highlight these unique features, discuss optimal therapeutic approaches, and review future directions of
research.
Advances in the management of locally advanced breast
cancer have significantly improved the outcome for patients,
and radiation treatments for this disease continue to complement the benefits of surgery and systemic therapy. The numerous advances in physics, imaging, and computer technologies have permitted radiation treatments to be much more
precise, which has the real potential to overcome many of the
limitations of the past. In addition, radiation oncologists
need to continue contributing to the understanding of breast
cancer biology and remain educated about the continuing
advances in other subspecialties. It is with this aim that we
dedicate this issue of Seminars in Radiation Oncology.
Thomas A. Buchholz, MD, FACR
Guest Editor

References
1. Cancer Facts & Figures 2008. Atlanta, GA, American Cancer Society,
2008, pp 2-8
2. Early Breast Cancer Trialists Collaborative Group: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on
local recurrence and 15-year survival: An overview of the randomised
trials. Lancet 366:2087-2106, 2005

Epidemiology of Locally Advanced Breast Cancer

Lisa A. Newman, MD, MPH, FACS
Locally advanced breast cancer refers to patients diagnosed with bulky primary cancers
and/or regional adenopathy. Its frequency has diminished greatly because of screening
mammography and early detection. However, impoverished and minority racial/ethnic
communities continue to experience disproportionately high breast cancer mortality rates
because of their high risk for being diagnosed with locally advanced disease.
Semin Radiat Oncol 19:195-203 2009 Published by Elsevier Inc.

ocally advanced breast cancer (LABC) is a relatively nonspecific term referring to bulky invasive tumors that may
have varying degrees of breast skin and/or chest wall involvement or cases with matted axillary and/or supraclavicular
nodal disease. More precise definitions have varied over time
in accord with modifications of the breast cancer staging
system and shifting clinical treatment approaches for breast
cancer. The classic work of Haagensen during the 1950s,
widely referred to as the Columbia Breast Cancer Staging
System, coined the term grave signs of LABC, which included (1) ulceration of the skin, (2) edema of the skin, (3)
tumor fixation to the chest wall, (4) axillary lymph nodes
measuring at least 2.5 cm, and (5) fixation of axillary nodes to
the skin or deep structures of the axilla. The presence of these
grave signs was used as a determinant of inoperability via
Halstedian radical mastectomy, which was the surgical standard of that era.1,2
The development of multicenter and population-based tumor registries led to the adoption of alternative and simplified
staging systems, such as the local-regional-distant schema used
by the surveillance, epidemiology, and end results (SEER) Program since its inception in 1973. With this categorization of
patients as having breast-only/node-negative (local, L) versus
node-positive (regional, R) or metastatic (distant, D) disease, the
identification of LABC cases is more challenging. LABC cases
identified through the publicly available SEER data are those
cases that have been characterized as regional disease at presentation. This clearly results in some overestimation of LABC frequency because some patients with small tumors will also be
found to have node-positive disease.
The American Joint Committee on Cancer (AJCC) Staging
system (edition 1 published in 1977) evolved concomitantly

Breast Care Center, University of Michigan, Ann Arbor, MI.

Address reprint requests to Lisa A. Newman, MD, MPH, FACS, Breast Care
Center, University of Michigan, 1500 East Medical Center Drive, Ann
Arbor, MI 48109. E-mail: lanewman@umich.edu

1053-4296/09/$-see front matter 2009 Published by Elsevier Inc.

doi:10.1016/j.semradonc.2009.05.003

with the contemporary era of clinical trials and outcome measurements in which it is essential that therapies and survival
rates are monitored as a function of well-defined extent of
disease categories. The TNM system refers to primary breast
tumor size (T), regional nodal status (N), and the presence
versus absence of distant organ metastases (M). Each of these
strata in turn is comprised of several clearly defined subsets
based on the available clinicopathologic measurements, and
the patient is assigned an overall stage based on the subset
groupings. Even with application of well-defined TNM categories, however, we continue to see variations in the groupings that are used to identify LABC cases. This variation is a
consequence of both improved breast cancer outcomes over
time and shifts in breast cancer treatment approaches. For
example, early editions of the AJCC breast cancer staging
system included supraclavicular nodal disease as distant metastasis (M1), and these patients were considered unresectable and generally incurable in the past. Advances in systemic
therapy for breast cancer (particularly with neoadjuvant chemotherapy approaches) have yielded markedly improved
survival rates for patients with supraclavicular nodal disease
as the isolated site of distant disease. The current AJCC staging system no longer considers these patients to have M1
disease, and supraclavicular nodal disease is now recognized
as another form of LABC; a high-risk form of breast cancer
but a form that benefits greatly from aggressive is multimodality therapy.
Neoadjuvant systemic therapy protocols have also impacted on the way LABC cases are identified. Historically,
preoperative chemotherapy was developed as a strategy for
controlling unresectable breast cancer and then became
adopted for improving the ease of resecting bulky disease.
Therefore, the early neoadjuvant chemotherapy protocols for
LABC of the 1970s and 1980s defined eligibility as cases of
large-diameter (T3, at least 5 cm) tumors or those with skin
and/or chest wall involvement. Appreciation for the tumor
downstaging benefits of neoadjuvant chemotherapy grew
195

L.A. Newman

196

Figure 1 The proportion of breast cancer patients diagnosed with stage III disease (as per NCDB4) or regional/nodepositive disease (as per SEER5) stratified by race/ethnicity.

during the 1990s, leading to expanded definitions for LABC

protocol eligibility. For example, the classic Bonnadona et al3
article of 1990 refers to primary (neoadjuvant) chemotherapy to avoid mastectomy in patients with primary tumors
measuring at least 3 cm.
The remainder of this article summarizes registry data and
published studies of LABC defined as stage III breast cancer;
tumors measuring at least 5 cm (T3 tumors) with positive
axillary lymph node(s); cases of bulky, fixed axillary adenopathy (N2 disease); cases with breast skin involvement (satellite lesions or ulceration; T4b disease); and/or cases with
chest wall fixation (T4a disease). The so-called neglected
LABC may have secondary inflammatory changes, and these
cases are more frequently seen among impoverished communities that lack resources for appropriate breast cancer
screening and treatment. True de novo inflammatory breast
cancer (T4d) probably has a distinct biological identity and is
excluded from this discussion.

Incidence: United States

Large-scale data on the cancer burden of the American population are available through the National Cancer DataBase
(NCDB) and the SEER Program. The NCDB is jointly maintained by the American College of Surgeons and the American Cancer Society, and since 1990 it has collected data from
hospital-based tumor registrars on cancer diagnosis and
treatment patterns on an estimated 80% of cases in the
United States. Publicly available NCDB statistics on breast
cancer stage distribution are available as AJCC TNM classifications. The SEER Program is a population-based registry

that has documented the cancer burden of the United States

since 1973. The SEER program was initially established to
collect cancer statistics from 7 sites (5 states, Connecticut,
Iowa, New Mexico, Utah, and Hawaii, and 2 metropolitan
areas, Detroit and San Francisco-Oakland) that were considered to be representative of the American population. It has
been expanded several times over the past 25 years, specifically with the intent of becoming more appropriate in reflecting the diverse American cancer population in terms of race/
ethnicity, culture, and rural versus urban geography. The
current SEER program collects data using the local-regionaldistant staging system from 17 registries and is estimated to
cover approximately 26% of the US population. Web-based,
publicly available statistics on the frequency of advanced
stage breast cancer among American women can be retrieved
as regional disease from the SEER program and as stage III
breast cancer from the NCDB.
Figure 1 shows the stage distribution of 178,764 cases of
breast cancer accessioned into the NCDB for the year 2006
(including cases of in situ disease), revealing 9.1% diagnosed
as stage III disease.4 If the 33,716 cases of stage 0 (in situ)
cancers are excluded from consideration, 11.2% of American
women with invasive breast cancer were diagnosed with
stage III disease. SEER data show that 33% of American
women were diagnosed with regional stage disease in the year
2000.5 As noted previously, the frequency of regional stage
disease will represent a notable overestimation of the proportion of cases presenting as true locally advanced, bulky breast
cancer. As shown in Figures 1 and 2 the proportion of breast
cancers diagnosed as LABC is higher among younger women

Epidemiology of locally advanced breast cancer

197

Figure 2 The proportion of breast cancer patients within age categories diagnosed with stage III disease stratified by
race/ethnicity from the NCDB.4

and among racial-ethnic minorities (especially African Americans).

Survival
SEER data reveal 5-year survival rates of 98% for patients
with localized disease, 84% for patients with regional disease,
and 27% for distant-stage disease at presentation. Outcome
based on size alone yields survival rates of 5-year survival
rates of 94%, 80%, and 66% for patients with T1, T2, and T3
tumors at diagnosis, respectively. Combining size and nodal
status through the TNM staging system provides the most
refined prognostic estimates: 95%, 85%, 70%, 52%, 48%,
and 18% for patients presenting with stage I, IIA, IIB, IIIA,
IIIB, and IV disease, respectively.6 Improvements in outcome
for LABC over the past few decades have primarily been
related to both improvements in systemic treatments and
enhanced control of locoregional disease because of multimodality therapy, including the application of neoadjuvant
systemic therapy and delivery of postsurgical locoregional
radiation therapy. Prospective randomized trials of neoadjuvant compared with adjuvant/postoperative chemotherapy
have consistently revealed overall survival equivalence, but
preoperative tumor downsizing clearly improves rates of resectability for cases of bulky chest wall disease and this sequence also increases opportunities to offer successful breastconserving surgery.7 Therefore, neoadjuvant chemotherapy
is now widely considered the standard of care for managing
LABC.
Advances in our understanding of breast cancer subtypes,
with the development of targeted therapy based on individual tumor markers is likely to be a more successful strategy in
achieving increased overall survival for LABC patients. The
importance of individualized tumor profiling in planning
systemic therapy is already apparent in studies of the
OncotypeDx Recurrence Score.8 This reverse transcriptase poly-

merase chain reaction based multigene assay stratifies the risk

of distant recurrence in tamoxifen-treated patients with
node-negative, estrogen receptorpositive breast cancer. It is
used to determine the extent of benefit from endocrine therapy alone versus endocrine therapy plus chemotherapy, and
its predictive value is independent of primary tumor size.
Therefore, it is applicable in cases of T3 disease that previously would have been considered LABC tumors and therefore automatic candidates for chemotherapy on the basis of
primary cancer size alone. Also, studies of trastuzumab therapy to target HER2/neu-positive disease are now showing improved outcomes for these biologically aggressive cancers, even
when they present as bulky LABC tumors.

Health Care Disparities

The frequency of LABC is largely dependent on the effectiveness of mammography screening programs. Before the implementation of breast cancer awareness and early detection
programs, breast cancer presentation as LABC was commonplace. Surveillance mammography has resulted in dramatic
increases in the number of breast cancers diagnosed as in situ
disease or nonpalpable T1 or T2 tumors, with a corresponding decrease in the proportion of women presenting with
bulky, locally advanced tumors. Selected population subsets
will be characterized by less effective breast cancer early detection, such as women younger than age 40 years in whom
screening mammography is not routinely recommended and
racial/ethnic minorities in whom socioeconomic disparities
result in barriers to accessing the health care system. Examples of differences in the stage distribution of breast cancer by
age and racial/ethnic background are shown in Figures 1 and
2 and Table 1. Approximately 12% of African American and
Hispanic/Latina breast cancer patients are diagnosed with
stage III disease compared with only 8% of white American
cases. For women age 30 to 39 years diagnosed with breast

198

Table 1 Results of Selected Studies Comparing LABC in Racial/Ethnic Subsets of the United States Population
Study
Chlebowski et
2005

Hance et al,12
2005

Joslyn et al,13
2005

Li et al,33 2003

al,9

Dataset

Feature

WHI postmenopausal

n
Mean tumor size (cm)
Proportion with T3 tumors
ER-negative (%)
Proportion with node-positive disease
Mortality hazard (95% confidence interval);
adjusted for age, BMI, and stage
N (number LABC cases analyzed)
Incidence rate for LABC (age-adjusted, per
100,000 woman years)
Breast cancerspecific median survival
from LABC
N
Age-specific incidence rates for regional
stage disease (per 100,000 population)
40-44
45-49
50-54
55-59
60-64
N
Proportion with stage III breast cancer
Proportion with T3 tumors

SEER, 1988-2000

NAACCR, 1994-1998

SEER, 1992-1998

White
Americans

African
Americans

Hispanic
Americans

Am Ind/Alas
Nat

3455
1.56
2%
13%
22%
1.0 (Ref)

242
1.60
2%
29%
28%
1.79 (1.05-3.05)

103
1.89
1%
17%
27%
NR

11
1.64
0%
11%
36%
NR

2892
2.1

535
3.8

NR
NR

NR
NR

NR
NR

7.5 Years

3.1 Years

NR

NR

NR

NR
45.15
46.39
58.39
74.80
322
10.9%
11.5%

35.69
53.14
57.70
69.56
68.24
8834
6.7%
10.0%

Asian/PI
88
1.95
0%
13%
22%
NR

363,801

41.82
66.67
80.62
89.02
95.54
97,999
6.8%
8.0%

47.65
71.18
85.91
93.25
89.14
10,560
11.0%
15.0%

33.91
51.96
53.46
57.50
66.98
7219
9.6%
13.9%

NAACCR, North American association of central cancer Registries; WHI, Womens Health Initiative; PI, Pacific Islander.

L.A. Newman

Epidemiology of locally advanced breast cancer

199
33%

35%
30%
25%

28%

27%
24%
22%
19%

20%

White American

18%

African American
Hispanic/Latino American

15%
10%

8%

10%

American Indian/Alaskan Native

11%

Asian American

5%
0%
Proportion with Income
Below Poverty Level

Proportion with No
Medical Insurance

Figure 3 Proportions of impoverished and medically uninsured among ethnic subsets of the American population.11,14,32 (Color version of figure is available online.)

cancer, 15% of white Americans are diagnosed with stage III

disease, and this frequency increases to 18% and 19% for
African American and Hispanic/Latina patients, respectively.
Appropriate and standardized oversight of health care can
lower the frequency of LABC in women of all racial/ethnic
backgrounds. This is shown by follow-up studies of the
closely monitored postmenopausal women participating in
the Womens Health Initiative: of the breast cancers that were
diagnosed in these prospectively followed women; only 1%
to 2% were detected as T3 tumors in the white American,
African American, and Hispanic American participants. Some
race/ethnicity-associated disparities in breast tumor biology
persisted, however, with African American women still being
more likely to present with node-positive and estrogen receptornegative disease.9

High-Risk/LABC
and African American Women
Race/ethnicity-associated disparities in breast cancer burden
have been studied most extensively for African Americans
compared with white Americans. Poverty rates and lack of
health care insurance are the 2 metrics most commonly cited
as a means of assessing socioeconomic status, and African
Americans are notably overrepresented among both of these
disadvantaged communities. Twenty-four percent of the African American population live below the poverty level compared with 8% of the white American population; and 19% of
African Americans have no medical insurance compared with
11% of white Americans (Fig. 3).10,11 These socioeconomic
inequities will clearly lead to delays in breast cancer diagnosis
as well as appropriate and timely treatment.
Hance et al12 evaluated SEER-based trends in detection
and outcome from inflammatory, locally advanced and nonLABC recently and reported interesting ethnicity/race-related
patterns. Incidence rates for both inflammatory breast cancer
and LABC were higher for African American compared with
white American women (3.1 v 2.2 per 100,000 for inflammatory disease and 3.8 v 2.1 per 100,000 for LABC). The

African American women with these high-risk breast cancers

also tended to be younger than their white American counterparts, and they had poorer survival rates.
African American women have been shown repeatedly
through single-institution, population-based, and multicenter studies to present with more advanced stages of disease. Recently, Joslyn et al13 reported findings from the North
American Association of Central Cancer Registries, showing
that this statistically significant increased risk for more advanced stage disease is seen at nearly all age ranges for African
American women. The lower frequency of early-stage disease
is consistent with suboptimal breast cancer screening practices among African American women; however, data from
the American Cancer Society, based on the National Health
Interview Study14 and others,15 have documented only modest magnitude differences in the use of mammography
screening between African American and white American
women (averaging at approximately 70% for white Americans and 67% for African Americans). Other factors, such as
access to the health care system for diagnostic biopsy and
treatment interventions, are probably also contributing to
these stage distribution differences. Gorin et al16 found that
African American breast cancer patients were more likely to
experience diagnostic as well as treatment delays when compared with all other racial-ethnic subsets of the American
female breast cancer population aged 65 and older. This
study was based on analysis of SEER and Medicare data.
Table 1 summarizes the results of several studies that have
compared stage distribution, hormone receptor status, and
other tumor features among African American versus white
American breast cancer patients. The increased prevalence of
high-grade, hormone receptornegative disease is shown
consistently by various investigators. Anderson et al17 have
documented lower population-based incidence rates of
estrogen receptorpositive disease for African American
women within all age deciles of life. Hance et al12 analyzed
population-based incidence rates for estrogen receptorpositive disease after stratifying by stage of disease. Incidence
rates for estrogen receptornegative disease were higher for

L.A. Newman

200
Table 2 Frequency of Triple-Negative Breast Cancer in African American Women

Frequency of Triple-Negative Breast Cancer

Study
Carey et

al,34

Dataset/Sample Size
2006

Morris et al,35 2007

Lund et al,36 2008
Lund et al,37 2008
Moran et al,38 2008

97 Premenopausal AA v 164 premenopausal

non-AA women from Carolina Breast
Cancer Study
2230 Thomas Jefferson University Hospital
pts and 197,274 SEER patients
Population-based Atlanta, GA cohort of 116
AA, 360 WA cases
167 AA and 23 WA cases from Grady
Hospital; urban Atlanta, GA
99 AA and 968 WA breast conservation pts
from Yale University School of Medicine

African
Americans (%)

White
Americans (%)

P Value

39 (basal subtype)

16 (basal subtype)

<.001

20.8

10.4

<.0001

46.6

21.8

<.001

29.3

13.0

.05

<.0001

21

AA, African American; WA, White American.

African American women compared with white American

women regardless of age and regardless of whether the breast
cancer was diagnosed as early stage, LABC, or inflammatory
breast cancer. Furthermore, several studies have shown that
African Americans are also more likely to be diagnosed with
triple-negative breast cancer, tumors that lack expression of
the estrogen receptor, the progesterone receptor, and the
HER2/neu marker. These studies are summarized in Table 2.
Disentangling the confounding effects of breast cancer
subtype, stage distribution, and socioeconomic status is critical for investigations of race/ethnicity-related breast cancer

disparities. Endocrine-resistant and triple-negative tumors

are biologically aggressive and will be more likely to present
as LABC. Therefore, racial/ethnic ancestry associated with
hereditary susceptibility for high-risk breast cancer subtypes
could account for the higher frequency of LABC observed in
African American women. By contrast, as noted previously,
African Americans are overrepresented among the impoverished in the United States, and socioeconomic deprivation is
associated with an increased risk of LABC because of inadequate screening and delayed diagnoses. It has also been postulated that poverty might somehow be an independent risk

Figure 4 Meta-analysis of breast cancer survival studies in African American and 2hite American patients adjusted for
socioeconomic status, age, and stage at diagnosis. Pooled mortality hazard ratio 1.27 (95% confidence interval).
(Mortality hazard relative risk for mortality, African American compared with White American breast cancer
patients) from Newman et al.20 *Outcome data in Simon study stratified by age less than 50 versus 50 years and older.
**Outcome data in Albain study stratified by menopausal status. Premen, premenopausal; postmen, postmenopausal.

Epidemiology of locally advanced breast cancer

201

Figure 5 Age-standardized breast cancer incidence and mortality rates with corresponding mortality:incidence ratios.

factor for the development of estrogen receptornegative disease.18 However, NCDB data show persistently higher proportions of estrogen receptornegative tumors among African American women compared with white American
women, even after controlling for age, stage, and income
level.19 Also, a meta-analysis by Newman et al20 involving
more than 15,000 African American breast cancer patients
and more than 75,000 white American breast cancer patients
showed that African American race/ethnicity is an independent, adverse prognostic factor for breast cancer mortality
even after accounting for socioeconomic status (Fig. 4). Furthermore, international studies (in which the confounding
effects of African American race/ethnicity and socioeconomic
status are nonexistent) have shown no correlation between
poverty versus affluence and frequency of estrogen receptor
negative breast cancer.21,22

International Patterns
As shown in Figure 5, countries that are less well developed
(eg, many countries in Africa and Asia) tend to have relatively
low incidence and mortality rates for breast cancer. This diminished breast cancer burden is a consequence of several
factors including reproductive patterns that lower the lifetime estrogen exposure of mammary tissue (early and more
frequent childbearing and prolonged lactation); competing
mortality risks, especially from infectious causes; and lack of

breast cancer documentation because of limited screening as

well as biopsy capability. Scanty health care resources preclude support for tumor registries, and so it is more difficult
to accurately report the frequencies of LABC in these parts of
the world. However, the limited breast cancer surveillance
results in few screen-detected tumors and larger proportions
of advanced-stage disease with correspondingly higher mortality rates. Therefore, it is reasonable to resort to the use of
mortality-to-incidence ratios as a proxy for estimating the
burden of LABC in countries that lack well-developed tumor
registry data. Figure 5 depicts the incidence and mortality
data estimated by the Globocan 2002 Database23 (which in
turn is generated and maintained by the Descriptive Epidemiology Group of the International Agency for Research on
Cancer) as well as the mortality-to-incidence ratios. These
ratios are highest in the less developed nations of Africa and
Asia (where incidence rates are lowest, but the screening and
treatment opportunities are most limited), and they are lowest in westernized, industrialized nations (where breast cancer incidence is highest, but early detection and treatment
options are most advanced).
The limited reported data in the published literature on
breast cancer burden in populations of developing nations
have confirmed the higher proportions of cases presenting as
clinically overt, nonscreen-detected LABC. In most of these
studies, the reported range of breast cancers presenting as
LABC is 20% to more than one half of cases. This more

L.A. Newman

202
advanced breast cancer stage distribution has been documented in underprivileged populations of Singapore,24 Egypt
and Northern Africa,25,26 India,27 and sub-Saharan Africa.28,29
The Breast Health Global Initiative convened a meeting of
their Global Initiative Systemic Therapy Focus Group in October 2007 in which this extensive burden of LABC in developing nations was discussed extensively. The group stressed
the fact that neoadjuvant chemotherapy is simply not feasible
for most LABC patients in developing countries because of
financial constraints; proceeding to primary modified radical
mastectomy is therefore the only option in these situations.30
The focus group also discussed the need to improve the availability of efficient pathology laboratory resources because
many facilities in underdeveloped countries are unable to
perform basic molecular marker studies such as estrogen receptor, progesterone receptor, and HER2/Neu imunohistochemistry.
Changes in the breast cancer burden of transitional populations within rapidly developing nations have been documented by Fan et al31 based on their study of the populationbased Shanghai Cancer Registry in China. This registry was
created in 1963, and it has therefore chronicled the evolution
of breast cancer incidence and mortality among Chinese
women in Shanghai related to industrialization and adoption
of westernized child-bearing/reproductive patterns, implementation of breast cancer screening programs, and improvements in health care delivery systems. As expected,
age-adjusted breast cancer incidence rates have steadily risen
in this population over the past several decades, from 17 per
100,000 in 1975 to 40 per 100,000 in 2004. The proportion
of cases presenting as LABC/stage III disease has steadily
declined, from nearly 25% before 1990 to less than 10% in
2007. Other trends were identified over time in this study
including increasing use of breast-conserving surgery, breast
reconstruction, and adjuvant chemotherapy.
It is clear that global incidence rates for breast cancer are
likely to increase progressively because the reproductive and
dietary lifestyles of industrialized societies are more widely
adopted worldwide. Therefore, we have an obligation to aggressively expand mammography screening/early detection
and multidisciplinary treatment programs so that breast cancer mortality rates do not rise disproportionately.

Conclusions
Breast cancer surveillance through screening mammography
programs has been successful in achieving earlier detection of
disease and decreasing rates of LABC. Nonetheless, approximately 10% of American breast cancer patients are diagnosed with LABC. Younger/premenopausal women and African Americans are more likely to present with LABC
compared with older white American women. Underdeveloped nations also have higher rates of LABC compared with
industrialized countries. When feasible, neoadjuvant chemotherapy is the standard of care for managing LABC. This
strategy improves rates of margin-negative resectability and
breast conservation, but this multimodality treatment sequence has limited value in underdeveloped countries be-

cause of cost issues. Ongoing research of LABC will focus on

studies to disentangle the potential association between racial-ethnic ancestry and susceptibility for high-risk disease,
improvements in targeted therapy so that the management of
LABC can be tailored to match the individual tumor biology,
and international studies to improve screening and treatment
opportunities in populations of developing countries that are
experiencing increases in breast cancer incidence.

References
1. Haagensen C, Stout A: Carcinoma of the breast II. Criteria of operability. Ann Surg 118:859, 1943
2. Haagensen CD: Diseases of the Breast. Philadelphia, Saunders, 1956
3. Bonadonna G, Veronesi U, Brambilla C, et al: Primary chemotherapy to
avoid mastectomy in tumors with diameters of three centimeters or
more. J Natl Cancer Inst 82:1539-1545, 1990
4. Benchmark Reports, V. 9.0. National Cancer Data Base, Commission
on Cancer, American College of Surgeons, 2009. Available at: http://
www.facs.org/cancer/publicncdb.html. Accessed May 1, 2009
5. Ries L, Melbert D, Krapcho M, et al: SEER cancer statistics. ReView,
1975-2005. Posted to SEER website. Available at: http://seer.cancer.
gov/csr/1975_2005. Accessed May 1, 2009
6. American Cancer Society: Breast Cancer Facts and Figures 2007-2008.
Atlanta, GA, American Cancer Society, Inc, 2009
7. Wolmark N, Wang J, Mamounas E, et al: Preoperative chemotherapy in
patients with operable breast cancer: Nine-year results from national
surgical adjuvant breast and bowel project B18. J Natl Cancer Inst
Monogr 30:96-102, 2001
8. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of
tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:
2817-2826, 2004
9. Chlebowski RT, Chen Z, Anderson GL, et al: Ethnicity and breast
cancer: Factors influencing differences in incidence and outcome.
J Natl Cancer Inst 97:439-448, 2005
10. Ward E, Jemal A, Cokkinides V, et al: Cancer disparities by race/ethnicity and socioeconomic status. CA Cancer J Clin 54:78-93, 2004
11. US Census Bureau, Population Division: Population Projections
Branch, Maintained by Information and research services. Available at:
http://www.census.gov/ipc/www/usinterimproj/. Accessed May 1,
2009
12. Hance KW, Anderson WF, Devesa SS, et al: Trends in inflammatory
breast carcinoma incidence and survival: The Surveillance, Epidemiology and End Results Program at the National Cancer Institute. J Natl
Cancer Inst 97:966-975, 2005
13. Joslyn SA, Foote ML, Nasseri K, et al: Racial and ethnic disparities in
breast cancer rates by age: NAACCR breast cancer project. Breast Cancer Res Treat 92:97-105, 2005
14. Ward E, Jemal A, Cokkinides V, et al: Cancer disparities by race/ethnicity and socioeconomic status. CA Cancer J Clin 54:78-93, 2004
15. Clegg LX, Li FP, Hankey BF, et al: Cancer survival among US whites
and minorities: A SEER (surveillance, epidemiology, and end results)
program population-based study. Arch Intern Med 162:1985-1993,
2002
16. Gorin SS, Heck JE, Cheng B, et al: Delays in breast cancer diagnosis and
treatment by racial/ethnic group. Arch Intern Med 166:2244-2252,
2006
17. Anderson WF, Chatterjee N, Ershler WB, et al: Estrogen receptor breast
cancer phenotypes in the surveillance, epidemiology, and end results
database. Breast Cancer Res Treat 76:27-36, 2002
18. Thomson CS, Hole DJ, Twelves CJ, et al: Prognostic factors in women
with breast cancer: Distribution by socioeconomic status and effect on
differences in survival. J Epidemiol Community Health 55:308-315,
2001
19. Lee MC, P-PLB, KI, et al: Increased Frequency Estrogen Receptor (ER)
Negative and Aneuploid Breast Cancer in African American Women at
All Stages of Disease: First Analysis From the National Cancer Database.
New York, NY, Society of Surgical Oncology, 2007

Epidemiology of locally advanced breast cancer

20. Newman LA, Griffith KA, Jatoi I, et al: Meta-analysis of survival in
African American and white American patients with breast cancer:
Ethnicity compared with socioeconomic status. J Clin Oncol 24:13421349, 2006
21. Carnon AG, Ssemwogerere A, Lamont DW, et al: Relation between
socioeconomic deprivation and pathological prognostic factors in
women with breast cancer. BMJ 309:1054-1057, 1994
22. Halmin M, Bellocco R, Lagerlund M, et al: Long-term inequalities in
breast cancer survivalA ten year follow-up study of patients managed
within a National Health Care System (Sweden). Acta Oncol 47:216224, 2008
23. Globocan: International Agency for Research on Cancer. Available at:
http://www.isradiology.org/education/globocan%202002%20database/
view.htm. Accessed May 1, 2009
24. Tan EY, Wong HB, Ang BK, et al: Locally advanced and metastatic
breast cancer in a tertiary hospital. Ann Acad Med Singapore 34:595601, 2005
25. Omar S, Khaled H, Gaafar R, et al: Breast cancer in Egypt: A review of
disease presentation and detection strategies. East Mediterr Health J
9:448-463, 2003
26. El Saghir NS, Khalil MK, Eid T, et al: Trends in epidemiology and
management of breast cancer in developing Arab countries: A literature
and registry analysis. Int J Surg 5:225-233, 2007
27. Agarwal G, Pradeep PV, Aggarwal V, et al: Spectrum of breast cancer in
Asian women. World J Surg 31:1031-1040, 2007
28. Bird PA, Hill AG, Houssami N: Poor hormone receptor expression in
East African breast cancer: Evidence of a biologically different disease?
Ann Surg Oncol 15:1983-1988, 2008
29. Fregene A, Newman LA: Breast cancer in sub-Saharan Africa: How does

203

30.

31.

32.
33.

34.

35.

36.

37.
38.

it relate to breast cancer in African-American women? Cancer

103:1540-1550, 2005
El Saghir NS, Eniu A, Carlson RW, et al: Locally advanced breast cancer:
Treatment guideline implementation with particular attention to low- and
middle-income countries. Cancer 113:2315-2324, 2008 (suppl)
Fan L, Zheng Y, Yu KD, et al: Breast cancer in a transitional society over
18 years: Trends and present status in Shanghai, China. Breast Cancer
Res Treat 2009 [Epub ahead of print]
US Census Bureau: Current population survey, 2002-04. Annual Social
and Economic Supplements, Washington, D. C., 2004
Li CI, Malone KE, Daling JR: Differences in breast cancer stage, treatment, and survival by race and ethnicity. Arch Intern Med 163:49-56,
2003
Carey LA, Perou CM, Livasy CA, et al: Race, breast cancer subtypes, and
survival in the Carolina breast cancer study. J Am Med Assoc 295:24922502, 2006
Morris GJ, Naidu S, Topham AK, et al: Differences in breast carcinoma
characteristics in newly diagnosed African-American and Caucasian
patients: A single-institution compilation compared with the National
Cancer Institutes surveillance, epidemiology, and end results database.
Cancer 110:876-884, 2007
Lund MJ, Trivers KF, Porter PL, et al: Race and triple negative threats to
breast cancer survival: A population-based study in Atlanta, Ga. Breast
Cancer Res Treat 113:357-370, 2009
Lund MJ, Butler EN, Bumpers HL, et al: High prevalence of triplenegative tumors in an urban cancer center. Cancer 113:608-615, 2008
Moran MS, Yang Q, Harris LN, et al: Long-term outcomes and clinicopathologic differences of African-American versus white patients
treated with breast conservation therapy for early-stage breast cancer.
Cancer 113:2565-2574, 2008

Breast Cancer Molecular Subtypes in Patients With

Locally Advanced Disease: Impact on Prognosis,
Patterns of Recurrence, and Response to Therapy
Kathryn E. Huber, MD, PhD,*, Lisa A. Carey, MD, and David E. Wazer, MD*,
Gene expression profiling has led to the discovery of 4 distinct molecular subtypes of
breast cancer: luminal A, luminal B, basal like, and HER2 enriched. Investigation of these
subtypes in women with breast cancer has given insight into the heterogeneous biology
and outcomes in patients with locally advanced disease. These subtypes have been found
to be predictors for survival, response to systemic therapy, and locoregional recurrence.
This review discusses the biology of locally advanced breast cancer and the available data
on how molecular subtype may provide information regarding response to treatment and
prognosis of women with locally advanced breast cancer.
Semin Radiat Oncol 19:204-210 2009 Elsevier Inc. All rights reserved.

ocally advanced breast cancer (LABC) is a diverse disease

that includes a wide range of clinical presentations, including advanced primary tumors or extensive regional
nodal involvement without systemic metastasis. An elderly
woman whose breast cancer has become inoperable after
years of neglect as well as a young woman with rapidly growing, aggressive breast cancer that developed between her annual screening mammograms would both be described as
having locally advanced disease. However, even though they
both represent LABC, these 2 scenarios show divergent biological processes. The elderly woman in the first scenario may
have a biologically indolent tumor that is characterized by
responsiveness to hormonal treatment, high estrogen receptor (ER) expression, low grade, and a low proliferative index.1
In contrast, the young woman who presented with locally
advanced disease within the interval of time between annual
screening is more likely to have an ER-negative, high-grade
tumor with a high proliferative index. Despite the fact that
they both present with locally advanced disease, the biology
of their breast cancer will confer strikingly dissimilar prog-

*Department of Radiation Oncology, Tufts University School of Medicine

and Tufts Medical Center, Boston, MA.
Rhode Island Hospital, Brown University School of Medicine, Providence,
RI.
Department of Medicine, Division of Hematology/Oncology, Lineberger
Comprehensive Cancer Center, University of North Carolina, Chapel
Hill, NC.
Address reprint requests to Kathryn E. Huber, MD, PhD, Department of
Radiation Oncology, Tufts Medical Center, 800 Washington Street, Box
359, Boston, MA 02111. E-mail: khuber@tuftsmedicalcenter.org

204

1053-4296/09/$-see front matter 2009 Elsevier Inc. All rights reserved.

doi:10.1016/j.semradonc.2009.05.004

noses. The elucidation of the mechanisms of these biological

differences is the focus of considerable ongoing investigation.
Inferior access or use of breast cancer screening can lead to
a postponement in the detection of a breast tumor until it
becomes symptomatic, which increases the likelihood that it
will be locally advanced at the time of diagnosis. The widespread use of screening mammography resulted in an initial
rise in breast cancer incidence with a proportional decrease
in the amount of LABC diagnosed, although the number of
LABC cases remained fairly constant. Recent trends in breast
cancer in the United States have shown a decline in overall
breast cancer incidence starting in the year 2000; however,
the rate of patients with larger tumors at the time of diagnosis
has not shown the same effect.2,3 These observations might
suggest that there is a biologically distinct subset of tumors
that either have a rapid growth rate allowing them to become
large tumors in the interval between screening mammography or have radiographic characteristics that limit earlier detection.4-6 In addition, hormone receptor (HR)-negative
breast cancer is disproportionately overrepresented in interval tumors diagnosed outside of screening, highlighting that
tumor biology may limit the impact of screening in some
subtypes.7,8
Inflammatory breast cancer (IBC) is an aggressive subset of
LABC that is clinically defined by its rapid onset of symptoms
including breast edema, erythema, warmth, and induration.
Patients with IBC have a worse clinical outcome compared to
stage-matched noninflammatory LABC.9 Biological characteristics of IBC include high nuclear grade, lower ER expression, and higher expression of markers associated with ag-

Breast cancer molecular subtypes

205

gressive pathology, such as p53, HER2 epidermal growth

factor receptor, and RhoC GTPase.10,11 Although considered
a form of LABC, IBC appears to have distinct biology, with
marked dysregulation of growth pathways, cellular adhesion,
and interaction molecules. However, IBCs are still quite heterogeneous and can be distinguished by the same molecular
subtypes that have been defined in non-IBC.12,13 A detailed
description of IBC is comprehensively covered in another
review in this issue of Seminars in Radiation Oncology.
The advent of genomic technology has allowed for molecular analysis of breast cancers, showing that the molecular
profiles of the tumors from the 2 patients discussed previously are likely to be quite different from one another. The
tumors molecular fingerprint may have within it information regarding prognosis and response to therapy that will
help us better treat LABC. The goal of this review was to
discuss LABC from the standpoint of molecular subtyping,
with regard to its diversity in prognosis and response to therapy.

sion within breast cancer: those that were ER-positive and

respond to antiestrogens and those that are ER-negative and
are refractory to hormonal manipulation.16 This crucial biological distinction is mirrored in noninflammatory LABC;
neglected disease is more likely to be ER-positive, whereas
the more aggressive forms of LABC are more likely to be
ER-negative. Another biologically distinct subset of breast
cancer was discovered by novel work investigating the amplification of the HER2/neu oncogene in breast cancer.17 The
analysis of 189 primary breast tumors showed that the amplification of the HER2/neu oncogene occurred in 25% to
30% of the specimens and that this genomic alteration predicted poor clinical outcome, even after adjustment for other
prognostic variables. Similar to the earlier breakthrough investigations of HRs in breast cancer, this finding led to the
development of targeted therapy and has had a significant
impact on the outcome of women with HER2 overexpressing
tumors.18,19

Heterogeneity of Breast Cancer

Molecular
Subtypes of Breast Cancer

Breast cancer is a heterogeneous collection of diseases with

various histologically defined subsets, clinical presentations,
responses to treatment, and outcomes. Several clinical and
histologic factors have prognostic value, such as the presence
and extent of lymph node metastasis, age at diagnosis, tumor
grade and histology, and size of the primary tumor. The earliest observations of the heterogeneity of breast tumors led to the
histopathologic classification of these tumors based on their
morphologic features. Currently, 15 distinct histopathologic
forms of breast cancer are recognized by the American Joint
Committee on Cancer.14 A few of these subsets are associated
generally with favorable (pure tubular or medullary) or unfavorable (metaplastic or undifferentiated) prognoses; however, most of the histologic forms have considerable variation
in their behavior. In addition, the development of LABC does
not correlate with a particular histologic subtype and most
LABCs, like most non-LABC primary breast cancers, are invasive ductal and/or lobular cancers. Further characterization of microscopic cellular heterogeneity in breast cancer,
such as nuclear pleomorphism, tubule formation, and mitotic index, has led to widely used tumor grading systems
that show a strong correlation with prognosis.15 However,
although LABC can be associated with high grade, this association is not consistent. The limitations in the prognostic
value of these clinical and microscopic variables have driven
the exploration of the molecular diversity of this disease with
the anticipation that it will help identify patients with poor
prognosis and lead to the development of novel treatments
that will target the specific aberrant biology of their cancer.
The first molecular distinction made in breast cancer was
from the work in the 1960s and 1970s that identified and
characterized estrogen and progesterone receptor expression
on breast cancer cells. This discovery quickly led to the development of antiestrogen therapies. Responsiveness of the
tumor to hormonal therapy correlated directly with receptor
expression and identified an important biological subdivi-

Gene expression profiling, which examines the relative expression of thousands of genes in a single sample simultaneously, led to the discovery of distinct molecular subtypes
within breast cancer.20 These molecular subtypes have phenotypic diversity with regard to multiple clinical outcomes,
including response to treatment, disease-free survival, and
overall survival. Multiple datasets have confirmed these molecular breast cancer subtypes, which include (1) at least 2
luminal subtypes (luminal A and B) that comprise most ERpositive breast cancer and are characterized by a high expression of HR-related genes; (2) the basal-like subtype, which
is characterized by a high expression of a unique basal
signature that includes genes common to the breast myoepithelium, high expression of proliferation genes, and low expression of the ER signature and HER2 signatures; and (3) the
HER2-enriched subtype, which is typified by high expression
of HER2-related and proliferation genes and low expression
of HR-related genes.21-23 Another subtype, the normal breast
subtype, has expression patterns similar to nonmalignant tissue and may be a sampling artifact.
Survival analysis performed using the data from the 49
patients with locally advanced disease determined that there
was a significant difference in overall survival among the
molecular subtypes.21 The basal-like and HER2-enriched
subtypes showed the poorest prognosis with both shorter
time to progression and overall survival. Patients belonging
to the luminal A subtype had a considerably better prognosis
compared with all groups, and the luminal B subtype had an
intermediate outcome. The luminal subtypes are the most
heterogeneous with regard to biology and outcomes.20-23 Luminal A tumors have variable proliferation gene expression
and also have highly variable prognostic signatures.24 Luminal B tumors, although still expressing the HR-related gene
signature, do so at a lower level, have variable expression of

206
the HER2 signature, and are generally more proliferative than
the luminal A subtype. In multiple datasets, patients with
luminal B tumors have worse outcome compared with luminal A tumors, despite both usually being ER-positive.
Because of the technical limitations of performing microarray expression analysis on formalin fixed, paraffin-embedded
tissue, the use of the ER, HER2, and cytokeratin immunohistochemical (IHC) markers has been used as a surrogate to the
molecular subtypes. The marker combinations that best
matched the molecular profiles segregated the tumors into 4
groups: (1) ER and/or PR, HER2 for luminal A subtype;
(2) ER and/or PR, HER2 for luminal B subtype (although this is known to misclassify a significant proportion);
(3) ER, PR, HER2, cytokeratin 5/6, and/or EGFR
for basal-like subtype; and (4) ER, PR, and HER2 for
the HER2-enriched subtype.25,26 Of course, the major limitation to this simplification is that the prognostic power of the
subtypes is based on a complex gene expression signature
and that these molecular profiles are only associated with
these protein markers and not synonymous. In fact, the molecular profiles have been found to have a more robust predictive value compared with the surrogate markers.27 However,
the correlation between the molecular subtypes and these
marker combinations is reasonable, and their proxy use has
allowed for the analysis of large datasets and the discovery of
important aspects of the biology of these tumor subtypes. In
the future, it is likely that RT-PCR based approaches, such as
the recently developed PAM50 assay, which can measure a
set of 50 intrinsic genes from formalin-fixed, paraffin-embedded tissue, will permit additional molecular subtyping in
archival specimens.28
A large population-based study using the IHC surrogate
markers for molecular subtype examined the association of
molecular subtype with clinical characteristics and found
that the luminal A, luminal B, basal-like, and HER2-enriched
subtypes differed significantly by age, race, menopausal status, lymph node involvement, histology group, tumor grade,
and mitotic index.25 The most striking distinction was the
overrepresentation of basal-like tumors in premenopausal
black women (39% in premenopausal black women v 14% in
postmenopausal black women and 16% in nonblack women
of all ages, P .001). Subsequent studies have confirmed
that basal-like tumors are more frequent in younger patients
and blacks.29,30 In addition patients with basal-like tumors
tended to have aggressive features including high nuclear
grade, high mitotic index, and unfavorable histology (metaplastic, anaplastic, or undifferentiated high-grade carcinomas). Paradoxically, this subtype was not associated with
higher regional lymph node involvement. More recent analyses have provided supporting evidence for the decreased
prevalence of lymph node metastasis in basal-like tumors and
have shown a disconnect between tumor size and positive
lymph nodes in this subtype.31,32 This finding suggests a difference in mechanisms of metastasis between luminal and
basal tumors and highlights that these breast cancer molecular subtypes are distinct biological entities.

K.E. Huber, L.A. Carey, and D.E. Wazer

How Biology May

Affect Treatment Outcome
A multidisciplinary approach to the treatment of LABC with
a combination of systemic therapy, surgery, and radiation has
resulted in improved survival. Before the routine use of chemotherapy, 5-year survival was approximately 25% in patients with locally advanced disease.33 Combined modality
treatment now yields 5-year rates of survival in operable stage
IIIA patients and inoperable stage IIIB patients of 80% and
45%, respectively.33 However, patients who present with
stage III disease with identical clinical predictors of prognosis
continue to have quite variable outcomes such that many
patients develop rapid disease progression despite contemporary multimodal management. The discovery that there are
distinct molecularly defined subtypes of breast cancer has
given insight into the heterogeneous outcome in patients
with LABC and has prompted continued efforts in identifying
predictors of both response to treatment and survival based
on the tumors molecular profile.
The frequent use of preoperative chemotherapy as part
of the management of LABC has provided a unique opportunity to investigate the molecular mechanisms of tumor response to therapy. A number of studies have explored the
effect of molecular subtype on both response to treatment
and survival in patients with LABC.12,34-41 Although subtype
was identified by using various methodologies, these investigations have consistently shown that the rate of pathologic
complete response (pCR) differs considerably among the molecular subtypes (Table 1). The luminal A subtype had a very
low rate of pCR in patients treated with a variety of preoperative chemotherapy regimens. In contrast, there was a high
rate of pCR seen with the basal-like and HER2-enriched subtypes. The luminal B subtype was associated with an intermediate rate of response. Interestingly, 2 studies included the
normal breast subtype in their analysis and found that none
of the patients who were in this subset achieved a pCR; however, this finding is limited by the small sample size (collective n 16).34,35
At first glance, the inferior survival of patients with
basal-like and HER2-enriched tumors appears to stand in
contrast with the high rate of pCR observed in these patients
because achieving pCR has been shown to be associated with
improved overall survival.42,43 However, patients who have
pCR have superior survival regardless of their subtype.36,38,44 The unfavorable outcomes observed in the basallike and HER2-enriched subtypes were caused by a higher
frequency of relapse or death in those who did not achieve a
pCR with preoperative chemotherapy.36,44 Interestingly,
prior work has shown that a lower expression of HR-related
genes and a higher expression of proliferation-related genes,
similar to those that define the basal-like subtype, are associated with a higher pCR rate.45 Therefore, increased proliferation may be a double-edged sword, where rapidly dividing cells leads to increased response to chemotherapy but
also may increase their capacity for recurrence and metastasis.

Breast cancer molecular subtypes

207

Table 1 Effect of Breast Cancer Molecular Subtype on Rate of pCR to Preoperative Chemotherapy
Preoperative
Regimen

Luminal
A (%)

Luminal
B (%)

Basal
Like (%)

HER2
Enriched (%)

References

TAC
TAC
TAC
ABC, TAC
ABC, TBC, or TAC
ABC
T, A, or TAC
TAC Tr

82
50
107
68
1,731
21
100
127

6
9
0
13
6
27
3
5

ND
ND
15
25
15
ND
33
ND

45
10
27
57
22
80
39
58

45
46
36
62
29
20
36
40

.026
.024
.01
<.0001
<.0001
.08
<.01
<.001

34
35
36
37*
38*
12
39*
40*

Abbreviations: TBC, taxane-based chemotherapy; ABC, anthracycline based chemotherapy; TAC, taxane and anthracycline combination
chemotherapy; T, taxane single therapy; A, anthracycline single therapy; Tr, trastuzamab; ND, not determined.
*Immunohistochemistry measuring ER, PR, and HER2 expression were used as surrogates for molecular subtype classification.
Data from patients with IBC.

The impact of molecular subtype on the response to postmastectomy radiation was recently investigated using data
from 1,000 patients enrolled in the large Danish postmastectomy radiation trials DBCG82 b and c.46 These patients had
clinical features associated with an increased risk of local
recurrence and had been randomized to either receive or not
receive postmastectomy radiation. High-risk features included large primary tumors (5 cm), positive lymph nodes,
or invasion of the primary tumor to the adjacent skin or
pectoral fascia. The IHC surrogate markers were used for
molecular subtype classification. In this study, basal-like
(HR/HER2) and HER2-enriched (HR/HER2) subtypes showed a lower reduction in local recurrence from
postmastectomy radiation compared with the luminal subtypes (Table 2). This finding may suggest radioresistance in
the poor prognosis subtypes in contrast to the relative radiosensitivity of luminal subtypes. An alternative explanation for
the increased rate of local recurrence could be related to
the intrinsic aggressiveness of the surviving cells from basal-like and HER2-enriched tumors. However, this is disputed by the finding that the de novo probability for local
recurrence among the patients not receiving postmastectomy radiation was fairly similar among the IHC-based
molecular subtypes (Table 2).46
Evidence supporting the effect of molecular subtype on
local recurrence is seen in the Harvard analysis of 793 women
treated with breast-conservation surgery followed by radiation.47 They showed a significant increase in 5-year local
recurrence as the first event in the basal-like (HR/HER2)
and HER2-enriched (HR/HER2) subgroups (7.1% and

8.4%, respectively) compared with the luminal A (HR/

HER2) and luminal B (HR/HER2) subgroups (0.8%
and 1.5%, respectively). However, the difference in local recurrence could in part be caused by differences in systemic
treatment in these subgroups. When the patients with HR
tumors were given hormonal therapy, none of the HER2
patients in this study received trastuzumab, and there is no
currently targeted treatment available for basal-like tumors.
Prior reports have not detected an increase in ipsilateral breast
recurrence for basal-like, triple receptor-negative breast cancer treated with breast conservation and whole-breast irradiation.7,48 However, a few distinctions can be made between
these reports and the Harvard study. First, the overall rate of
local recurrence was much higher in the earlier studies (13%
for Dent et al,7 17% for Haffty et al48 v 1.8% Nguyen et al47).
Second, the earlier studies used IHC alone for HER2 classification, whereas the latter study required HER2 gene amplification in tumors with intermediate HER2 expression to
qualify as HER2, likely resulting in a reduced rate of misclassification. In addition, the earlier studies compared triple-negative tumors to all others, opposed to determining the
recurrence rate in each of the 4 subtypes. The inclusion of
HER2 tumors in the other subset could have diminished
the difference between the molecular subtypes. Despite the
differences in the findings on local recurrence among these
reports, all showed an increase in the rate of distant metastasis and decreased overall survival of the patients with basallike tumors.
Interestingly, the patterns of metastatic disease seem to
vary among the molecular subtypes.49-52 The luminal A pa-

Table 2 15-Year Overall Survival and Locoregional Recurrence as a Function of Breast Cancer Molecular Subtype and Radiation
15 Years OS
Luminal A (n 628)
Luminal B (n 96)
Basal like (n 152)
HER2 enriched (n 120)

15 Years LRR

RT (%)

No RT (%)

RT (%)

No RT (%)

44
38
39
17

33
15
32
28

.009
.07
.4
.14

3
3
15
21

32
48
32
33

<.001
<.005
.001
.2

Abbreviations: RT, radiotherapy; OS, overall survival; LRR, locoregional recurrence.

Data from Kyndi et al.46

208
tients who develop metastatic disease have a significantly
higher portion of bone relapse in contrast to those with the
basal-like subtype who have a predominance of visceral sites
of metastases. These findings again support that these subtypes are distinct biological variants of breast cancer that
predispose these patients to a particular outcome. HER2overexpressing tumors have been found to have a predilection for metastasis to the brain52 as have basal-like (or triplenegative) tumors.50 The comparison of HER2-overexpressing
breast cancer patients to HER2-negative patients showed a
4.5-fold increase in the incidence of developing brain metastasis (P .0001). It is possible that this effect is caused by the
lack of penetration of trastuzumab through the blood brain
barrier. Alternatively, this pattern of recurrence may be caused
by a biological distinct phenotype that leads to homing and
penetration of the central nervous system, as is suggested by
the studies noting other site-specific tropisms. Interestingly,
this study also showed a protective effect of ER-positive tumors for brain metastasis, suggesting that the ER-positive
subset of tumors lack the biological property that promotes
this process. These observations merit further investigation
for the monitoring of central nervous system metastasis in
patients with the HER2-enriched or basal-like subtypes and
perhaps the development of treatments that can cross the
blood brain barrier.

How Biology May

Affect Locoregional
Treatment Decisions
Data from the Danish Breast Cancer Cooperative Group showing that patients with basal-like and HER2-enriched subtype
tumors had an appreciably lower benefit from postmastectomy radiation suggests that information regarding molecular subtype may one day assist in the assessment as to
whether a patient should receive postmastectomy radiation.46 The survival benefit from postmastectomy radiation
observed in this randomized study was limited to the luminal
A subtype (HR .78, P .009). The patients with luminal B
subtype had a trend toward improved survival associated
with radiation, but this did not reach statistical significance
(HR .65, P .07). The basal-like subtype displayed an
inferior local control benefit compared with the luminal subtypes, and there was no detectable survival benefit from radiation (HR .85, P .4). Of note, there was a trend toward
a survival deficit with radiation therapy in the HER2-enriched subgroup (HR 1.35, P .14). Definitive conclusions as to the relative effect of radiation therapy in this context are limited by the retrospective nature of the study. In
addition, because of the natural distribution of the molecular
subtypes, there were fewer patients with luminal B, basallike, and HER2-enriched tumors for analysis (luminal A 63%,
luminal B-10%, basal-like 15%, and HER2 enriched 12%),
making it less likely that a survival difference would have
been detected in the less common subtypes. However, these
data call into question whether standard delivery of PMRT is
sufficient for locoregional control in LABC patients with

K.E. Huber, L.A. Carey, and D.E. Wazer

basal-like or HER2-enriched tumors and argues for the investigation of strategies for improved local control in these
patients (eg, dose escalation or radiosensitization).
The finding that HR-negative/HER2 tumors may have a
diminished benefit from postmastectomy radiation may indicate a relative radioresistance of this subtype. Preclinical
data support the hypothesis of HER2 overexpression relating
to radioresistance; however, clinical data to support this observation are limited.53,54 A retrospective analysis of 108 patients treated with neoadjuvant chemotherapy, mastectomy,
and postmastectomy radiation did not reveal an excess of
local failure in patients with HER2 disease.55 In addition, in
the molecular subtype analysis of the Danish postmastectomy radiation trials, HER2 status alone did not predict for
either local recurrence probability or the relative benefit of
radiation.46 It was the combination of HR negativity and
HER2 overexpression that was associated with a lack of benefit from radiation in this study. The probability of local
recurrence after postmastectomy radiation in patients with
the HER2-enriched molecular subtype merits further investigation. In addition, HER2-targeted therapy with trastuzumab, which has become a standard therapy for HER2
patients, may alter the sensitivity of this molecular subtype to
radiation resulting in improved local control.
The frequent use of neoadjuvant chemotherapy has led to
an increase in the number of women with locally advanced
disease who are candidates for breast conservation. Therefore, the effect of molecular subtype on local recurrence in
patients who choose to have breast conservation may be of
particular importance in this high-risk subgroup. The findings by Nguyen et al47 showed that the basal-like and HERenriched subtypes are associated with significantly higher
rates of local recurrence in the intact breast after partial mastectomy and whole-breast irradiation. Patients with locally
advanced disease made up a very small proportion of the
cohort (approximately 6%) in this study. Likewise, the rates
of local recurrence were quite low, with the high-risk basal
and HER2 subtype local recurrence rates under 10% at 5
years. However, the incidence of local recurrence in patients
with the basal-like and HER2-enriched subtype with LABC
who have breast conservation and whether molecular subtype alters the rate of in-breast recurrence in these patients
are yet to be determined.

Future Directions
Advances in the use of cytotoxic chemotherapy have played a
substantive role in the improved outcome seen in patients
with LABC. In addition, hormonal therapy and HER2-targeted agents have become key components to adjuvant therapy in patients with tumors expressing these markers. However, the lack of targeted therapy for the basal-like subtype
has clearly defined the need for the development of novel
agents directed against the aberrant biology of this subtype.
These tumors have a robust response to anthracycline- and
taxane-based chemotherapies but are subsequently associated with an unacceptable rate of relapse, high incidence of
distant metastasis, and poor overall survival. Gene analysis

Breast cancer molecular subtypes

has identified several abnormal processes within basal-like
tumors that may serve as therapeutic targets including abnormal DNA repair, increased proliferation, loss of PTEN, and
EGFR and c-KIT overexpression. The clinical data for the
effectiveness of these target-specific therapies are still limited,
but advances in the understanding of the heterogeneous biology of breast cancer are giving clear direction for future
research.

References
1. Fisher ER, Redmond CK, Liu H, et al: Correlation of estrogen receptor
and pathologic characteristics of invasive breast cancer. Cancer 45:349353, 1980
2. Jemal A, Thun MJ, Ries LA, et al: Annual report to the nation on the
status of cancer, 1975-2005, featuring trends in lung cancer, tobacco
use, and tobacco control. J Natl Cancer Inst 100:1672-1694, 2008
3. Jemal A, Ward E, Thun MJ: Recent trends in breast cancer incidence
rates by age and tumor characteristics among US women. Breast Cancer
Res 9:R28, 2007
4. Burrell HC, Sibbering DM, Wilson AR, et al: Screening interval breast
cancers: Mammographic features and prognosis factors. Radiology 199:
811-817, 1996
5. Groenendijk RP, Bult P, Tewarie L, et al: Screen-detected breast cancers
have a lower mitotic activity index. Br J Cancer 82:381-384, 2000
6. Porter PL, El-Bastawissi AY, Mandelson MT, et al: Breast tumor characteristics as predictors of mammographic detection: Comparison of
interval- and screen-detected cancers. J Natl Cancer Inst 91:20202028, 1999
7. Dent R, Trudeau M, Pritchard KI, et al: Triple-negative breast cancer:
Clinical features and patterns of recurrence. Clin Cancer Res 13:44294434, 2007
8. Sihto H, Lundin J, Lehtimaki T, et al: Molecular subtypes of breast
cancers detected in mammography screening and outside of screening.
Clin Cancer Res 14:4103-4110, 2008
9. Chang S, Parker SL, Pham T, et al: Inflammatory breast carcinoma incidence
and survival: The surveillance, epidemiology, and end results program of the
National Cancer Institute, 1975-1992. Cancer 82:2366-2372, 1998
10. Gurin M, Gabillot M, Mathieu MC, et al: Structure and expression of
c-erbB-2 and EGF receptor genes in inflammatory and non-inflammatory
breast cancer: Prognostic significance. Int J Cancer 43:201-208, 1989
11. Kleer CG, Zhang Y, Pan Q, et al: WISP3 and RhoC guanosine triphosphatase cooperate in the development of inflammatory breast cancer.
Breast Cancer Res 6:R110-R115, 2004
12. Bertucci F, Finetti P, Rougemont J, et al: Gene expression profiling
identifies molecular subtypes of inflammatory breast cancer. Cancer
Res 65:2170-2178, 2005
13. Van Laere SJ, Van den Eynden GG, Van der Auwera I, et al: Identification of cell-of-origin breast tumor subtypes in inflammatory breast
cancer by gene expression profiling. Breast Cancer Res Treat 95:243255, 2006
14. Greene F, Page D, Fleming I: AJCC cancer staging manual. New York,
NY, Springer-Verlag, 2002
15. Elston CW, Ellis IO: Pathological prognostic factors in breast cancer. I.
The value of histological grade in breast cancer: Experience from a large
study with long-term follow-up. Histopathology 19:403-410, 1991
16. Fisher B, Redmond C, Brown A, et al: Influence of tumor estrogen and
progesterone receptor levels on the response to tamoxifen and chemotherapy in primary breast cancer. J Clin Oncol 1:227-241, 1983
17. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the Her-2/neu oncogene. Science 235:177-182, 1987
18. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab
after adjuvant chemotherapy in HER2-positive breast cancer. N Engl
J Med 353:1659-1672, 2005
19. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant
chemotherapy for operable HER2-positive breast cancer. N Engl J Med
353:1673-1684, 2005

209
20. Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human
breast tumours. Nature 406:747-752, 2000
21. Srlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of
breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001
22. Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breast
tumor subtypes in independent gene expression datasets. Proc Natl
Acad Sci U S A 100:8418-8423, 2003
23. Sotiriou C, Neo SY, McShane LM, et al: Breast cancer classification and
prognosis based on gene expression profiles from a population-based
study. Proc Natl Acad Sci U S A 100:10393-10398, 2003
24. Fan C, Oh DS, Wessels L, et al: Concordance among gene-expressionbased predictors for breast cancer. N Engl J Med 355:560-569, 2006
25. Carey LA, Perou CM, Livasy CA, et al: Race, breast cancer subtypes, and
survival in the Carolina breast cancer study. J Am Med Assoc 295:24922502, 2006
26. Nielsen TO, Hsu FD, Jensen K, et al: Immunohistochemical and clinical
characterization of the basal-like subtype of invasive breast carcinoma.
Clin Cancer Res 10:5367-5374, 2004
27. Srlie T: Molecular portraits of breast cancer: Tumor subtypes as distinct disease entities. Eur J Cancer 40:2667-2675, 2004
28. Parker J, Mullins M, Cheang MCU, et al: A supervised risk predictor of
breast cancer based on intrinsic subtypes. J Clin Oncol 27:1160-1167,
2009
29. Bauer KR, Brown M, Cress RD, et al: Descriptive analysis of estrogen
receptor (ER)-negative, progesterone receptor (PR)-negative, and
HER2-negative invasive breast cancer, the so-called triple-negative
phenotype: A population-based study from the California cancer registry. Cancer 109:1721-1728, 2007
30. Millikan RC, Newman B, Tse CK, et al: Epidemiology of basal-like
breast cancer. Breast Cancer Res Treat 109:123-139, 2008
31. Crabb SJ, Cheang MC, Leung S, et al: Basal breast cancer molecular
subtype predicts for lower incidence of axillary lymph node metastases
in primary breast cancer. Clin Breast Cancer 8:249-256, 2008
32. Foulkes WD, Grainge MJ, Rakha EA, et al: Tumor size is an unreliable
predictor of prognosis in basal-like breast cancers and does not correlate closely with lymph node status. Breast Cancer Res Treat July 4,
2008 [Epub ahead of print]
33. Halperin EC, Perez CA, Brady LW: Perez and Bradys Principles and Practice of Radiation Oncology. Conshohocken, PA, Wolters Kluwer, 2007
34. Rouzier R, Perou CM, Symmans WF, et al: Breast cancer molecular
subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678-5685, 2005
35. Rody A, Karn T, Solbach C, et al: The erbB2 cluster of the intrinsic
gene set predicts tumor response of breast cancer patients receiving
neoadjuvant chemotherapy with docetaxel, doxorubicin and cyclophosphamide within the GEPARTRIO trial. Breast 16:235-240, 2007
36. Carey LA, Dees EC, Sawyer L, et al: The triple negative paradox: Primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer
Res 13:2329-2334, 2007
37. Goldstein NS, Decker D, Severson D, et al: Molecular classification
system identifies invasive breast carcinoma patients who are most likely
and those who are least likely to achieve a complete pathologic response after neoadjuvant chemotherapy. Cancer 110:1687-1696, 2007
38. Guarneri V, Broglio K, Kau SW, et al: Prognostic value of pathologic
complete response after primary chemotherapy in relation to hormone
receptor status and other factors. J Clin Oncol 24:1037-1044, 2006
39. Fernndez-Morales LA, Segu MA, Andreu X, et al: Analysis of the pathologic response to primary chemotherapy in patients with locally advanced
breast cancer grouped according to estrogen receptor, progesterone receptor, and HER2 status. Clin Breast Cancer 7:559-564, 2007
40. Snchez-Muoz A, Garca-Tapiador AM, Martnez-Ortega E, et al: Tumour molecular subtyping according to hormone receptors and HER2
status defines different pathological complete response to neoadjuvant
chemotherapy in patients with locally advanced breast cancer. Clin
Trans Oncol 10:646-653, 2008
41. Colleoni M, Viale G, Zahrieh D, et al: Expression of ER, PGR, HER1,
HER2, and response: A study of preoperative chemotherapy. Ann Oncol 19:465-472, 2008

210
42. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol
16:2672-2685, 1998
43. Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breast cancer
patients with complete pathologic primary tumor and axillary lymph node
response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol
17:460-469, 1999
44. Liedtke C, Mazouni C, Hess KR, et al: Response to neoadjuvant therapy
and long-term survival in patients with triple-negative breast cancer.
J Clin Oncol 26:1275-1281, 2008
45. Gianni L, Zambetti M, Clark K, et al: Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in
women with locally advanced breast cancer. J Clin Oncol 23:72657277, 2005
46. Kyndi M, Srensen FB, Knudsen H, et al: Estrogen receptor, progesterone receptor, Her-2, and response to postmastectomy radiotherapy in
high-risk breast cancer: The Danish Breast Cancer Cooperative Group.
J Clin Oncol 26:1419-1426, 2008
47. Nguyen PL, Taghian AG, Katz MS, et al: Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and Her-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 26:2373-2378, 2008
48. Haffty BG, Yang Q, Reiss M, et al: Locoregional relapse and distant
metastasis in conservatively managed triple negative early-stage breast
cancer. J Clin Oncol 24:5652-5657, 2006

K.E. Huber, L.A. Carey, and D.E. Wazer

49. Dent R, Hanna WM, Trudeau M, et al: Pattern of metastatic spread in
triple-negative breast cancer. Breast Cancer Res Treat, 115:423-428,
2009
50. Lin NU, Claus E, Sohl J, et al: Sites of distant recurrence and clinical
outcomes in patients with metastatic triple-negative breast cancer: High
incidence of central nervous system metastases. Cancer 113:26382645, 2008
51. Smid M, Wang Y, Zhang Y, et al: Subtypes of breast cancer show
preferential site of relapse. Cancer Res 68:3108-3114, 2008
52. Gabos Z, Sinha R, Hanson J, et al: Prognostic significance of human
epidermal growth factor receptor positivity for the development of
brain metastasis after newly diagnosed breast cancer. J Clin Oncol
24:5658-5663, 2006
53. Liang K, Lu Y, Jin W, et al: Sensitization of breast cancer cells to
radiation by trastuzumab. Mol Cancer Ther 2:1113-1120, 2003
54. Pietras RJ, Poen JC, Gallardo D, et al: Monoclonal antibody to Her-2/
neureceptor modulates repair of radiation-induced DNA damage and
enhances radiosensitivity of human breast cancer cells overexpressing
this oncogene. Cancer Res 59:1347-1355, 1999
55. Buchholz TA, Huang EH, Berry D, et al: HER2/neu-positive disease
does not increase risk of locoregional recurrence for patients treated with neoadjuvant doxorubicin-based chemotherapy, mastectomy, and radiotherapy. Int J Radiat Oncol Biol Phys 59:13371342, 2004

Workup and Staging of

Locally Advanced Breast Cancer
Gary J. Whitman, MD,* and Eric A. Strom, MD
This article reviews current approaches for workup and staging in patients with locally
advanced breast cancer (LABC). Careful clinical examination and detailed imaging are
discussed to accurately classify the extent of local, regional, and distant disease. Most
patients with LABC receive neoadjuvant chemotherapy as initial treatment, and, in such
patients, it is critical to accurately delineate the initial extent of disease because the initial
clinical stage affects subsequent local-regional treatment decisions. Emphasis is placed on
sonography, which is used extensively at the University of Texas M. D. Anderson Cancer
Center for regional lymph node staging. Other modalities discussed in this article include
mammography, magnetic resonance imaging, positron emission tomography (PET), and
PET/computed tomography (CT). Conventional imaging (chest radiography, bone scan, and
abdominal CT scans) techniques used in the evaluation of possible metastatic disease are
discussed. In addition, the role of sentinel lymph node mapping in LABC patients is
reviewed.
Semin Radiat Oncol 19:211-221 2009 Elsevier Inc. All rights reserved.

espite recent advances in screening mammography, locally advanced breast cancer (LABC) remains a challenging clinical problem. LABC, which includes all patients
with stage III disease, constitutes approximately 20% of
newly diagnosed breast cancers. LABC encompasses advanced primary tumors (T3 and T4); advanced lymph node
disease, including fixed axillary lymph nodes and/or involvement of the ipsilateral supraclavicular, infraclavicular, or internal mammary lymph nodes (N2 and N3); and the uncommon inflammatory breast carcinoma (IBC) variant.1,2
Women with LABC require careful, comprehensive workup
and staging evaluations to accurately depict the extent of
disease. Furthermore, workup and staging should be performed in a detailed manner before the initiation of multimodal treatment. Most patients with LABC are treated with neoadjuvant chemotherapy, which changes the pathologic
extent of disease in most patients. For such patients, the
initial extent of disease, defined by clinical examination and
imaging studies, is a critical determinant of subsequent localregional therapeutic decisions. Therefore, it is imperative that
*Division of Diagnostic Imaging, The University of Texas M. D. Anderson
Cancer Center, Houston, TX.
Division of Radiation Oncology, The University of Texas M. D. Anderson
Cancer Center, Houston, TX.
Address reprint requests to Gary J. Whitman, MD, Division of Diagnostic
Imaging, The University of Texas M. D. Anderson Cancer Center,
Unit 1350, PO Box 301439, Houston, TX 77230-1439. E-mail:
gwhitman@di.mdacc.tmc.edu

1053-4296/09/$-see front matter 2009 Elsevier Inc. All rights reserved.

doi:10.1016/j.semradonc.2009.05.006

all patients with LABC undergo appropriate staging studies

and have an assignment of a clinical TNM stage before the
start of treatment. In addition, prognosis depends on tumor
size, lymph node involvement, and the presence or absence
of an inflammatory component at the time of initial presentation.
In this article, initial staging recommendations are reviewed for evaluation of the breast, the regional lymph nodes,
and distant sites, including the roles of mammography,
sonography, magnetic resonance imaging (MRI), positron
emission tomography (PET), and PET/computed tomography (CT). Accurate clinical staging is reviewed along with
multidisciplinary assessment and treatment planning. In addition, placement of marker clips in the tumor bed before
initiating systemic therapy is discussed.

Clinical Examination
The prognoses for women with LABC depend on tumor size,
the extent of regional lymph node involvement, and the presence or absence of inflammatory signs.1 Clinical examination
by experienced practitioners can be helpful in estimating
tumor size and confirming or excluding inflammatory features such as diffuse erythema, peau dorange, warmth, tenderness, breast enlargement, and diffuse induration.3,4 Also,
clinical examination can identify markedly enlarged axillary
and supraclavicular lymph nodes. Smaller lymph nodes and
lymph nodes in the infraclavicular and the internal mammary
211

212
regions are usually identified with imaging, especially on
sonography.
A multidisciplinary approach is suggested in women with
LABC because optimal therapy involves multiple modalities.5
LABC patients are usually treated with neoadjuvant chemotherapy followed by surgery and radiation therapy.6 Multidisciplinary involvement may be helpful in selecting certain
subsets of LABC patients. For example, several clinicians in a
multidisciplinary setting may select women with large tumors or with limited skin involvement who may be eligible
for breast conservation therapy after initial chemotherapy.7
Clinical experience and limited outcome data suggest that
even with a good response to neoadjuvant chemotherapy,
breast conservation is contraindicated in patients with IBC.6

Mammography
Mammography is usually the first imaging test performed
after clinical examination. Mammography is used to estimate
tumor size, and mammography is more accurate in women
with fatty mammary parenchyma compared with those with
dense breast tissue.8 Mammography is the best test for identifying microcalcifications, which may be within or adjacent
to the known malignancy. Adjacent suspicious microcalcifications may represent associated ductal carcinoma in situ
(DCIS). In addition, mammography can identify multifocal
and multicentric disease.
Careful mammographic evaluation of known or suspected
malignancies is important, especially when characterizing
calcifications and evaluating mass margins. Attention should
be paid to the entire breast, including the axillary region
(where enlarged lymph nodes may be identified) and the
periareolar region (as tumors may spread through the duct
network to the region of the nipple). Magnification views
should be performed for evaluating calcifications and the
margins of masses. Spot compression views are used when
the breast imager is trying to determine if a finding is a real
mass or caused by superimposition of normal structures.
Although mammography images most of the breast tissue,
the posterior breast tissue (adjacent to the chest wall) may not
be included, depending on the patients body habitus and the
mammography technologists skills. Also, in general, mammography covers only a portion of the inferior axillary region. The other local nodal basins (the infraclavicular, the
supraclavicular, and the internal mammary basins) are not
included on mammography. Thus, to accurately stage patients with known or suspected LABC, additional imaging is
needed. At the University of Texas M. D. Anderson Cancer
Center (UTMDACC), all LABC patients are evaluated with
sonography. MRI and PET/CT can also play important roles
in staging LABC patients.

Ultrasound
Ultrasound is commonly used throughout the United States
for further assessment of breast abnormalities identified on
mammography. At UTMDACC, ultrasound also serves as the
major locoregional staging examination in patients with

G.J. Whitman and E.A. Strom

LABC. When ultrasound is combined with ultrasoundguided fine-needle aspiration (FNA), sonography is highly
specific.9 Sonography can identify additional lesions in the
ipsilateral breast and the contralateral breast and identify
abnormal lymph nodes in the axillary, infraclavicular, supraclavicular, and internal mammary regions.
Nearly all LABC patients at UTMDACC undergo sonography before initial treatment to provide a full staging evaluation. If supplemental staging evaluation with sonography or
MRI was not performed before excision, then a staging evaluation should be performed after initial excision and before
initiating radiation therapy. Although patients with multifocal malignancy often qualify for breast conservation therapy,
in general, documented multicentric disease is usually a contraindication for breast conservation. Berg and Gilbreath10
showed that whole breast ultrasound complements mammography in the preoperative evaluation of women with
breast cancer. Their study used sonography to evaluate the
ipsilateral breast of 40 women with known malignancy or a
high suspicion for cancer. Ultrasound identified 45 (94%) of
48 invasive tumor foci and 16 foci of DCIS. Mammography
identified 39 (81%) of 48 invasive tumor foci and 14 foci of
DCIS. Nine (14%) of 64 malignant foci were seen only on
ultrasound.10
Moon et al11 evaluated the ipsilateral and the contralateral
breasts in 201 women with recently diagnosed breast cancer
or with a suspicion of breast cancer. In the ipsilateral breasts,
ultrasound showed 194 (97%) of 201 invasive cancer foci
and 52 (75%) of 69 DCIS foci. Mammography and clinical
examination showed 173 (86%) invasive cancer foci and 56
(81%) DCIS foci. In the contralateral breasts, ultrasound
showed 11 (92%) of 12 invasive cancer foci and 4 (57%) of 7
DCIS foci compared with 6 (50%) invasive cancer foci and 5
(71%) DCIS foci identified by mammography and clinical
examination. Ultrasound showed mammographically and
clinically occult multifocal or multicentric cancers in 28 patients (14%) and contralateral cancers in 8 patients (4%). In
the study, sonography resulted in a change in therapy in 32
patients (16%).11
Ultrasound also plays an important role in evaluating the
regional (axillary, infraclavicular, supraclavicular, and internal mammary) lymph nodes and in guiding percutaneous
lymph node biopsies. The likelihood of axillary metastases is
related to the primary breast tumor size, and the relationship
is almost linear. A breast tumor measuring less than 2 cm has
approximately a 30% risk of axillary metastasis, and a tumor
measuring 5 cm has a 70% risk.12
Although ultrasound evaluation of the axillary lymph
nodes (Fig. 1) is being performed more commonly, careful
sonographic evaluation of the infraclavicular (Fig. 2), supraclavicular, and internal mammary lymph nodes is very important in accurate staging of women with LABC.13-15 Sonographic staging of the regional lymph node basins should be
performed before the initiation of neoadjuvant chemotherapy. Klauber-Demore et al16 showed that postchemotherapy
sonography was poor at identifying axillary lymph node metastases. On postchemotherapy axillary lymph node ultra-

Locally advanced breast cancer

213

Figure 1 A 42-year-old woman presented to her doctor after noting a palpable abnormality in the upper outer right
breast. Clinical examination revealed a suspicious, large right breast mass involving the skin. A palpable lymph node
was noted in the right axillary region. (A) Right breast laterally exaggerated craniocaudal mammogram shows a large,
lobular mass (long arrow) with associated skin thickening (arrowhead) and enlarged axillary lymph nodes (short
arrow). (B) The right breast lateromedial mammogram shows the large mass (long arrow) and suspicious axillary lymph
nodes (short arrow). (C) The right breast longitudinal extended-field-of-view sonogram shows the suspicious, lobular
mass (large arrow) extending to the skin (small arrow). An ultrasound-guided core biopsy was performed, revealing
poorly differentiated invasive ductal carcinoma (estrogen receptor negative, progesterone receptor negative, and HER2
neu overexpression negative). (D) Longitudinal right axillary ultrasound shows an enlarged, oval, hypoechoic lymph
node (arrow). Ultrasound-guided FNA showed metastatic disease.

sound, the positive predictive value was 83%, and the negative predictive value was 52% in a series of 53 patients.16
Current ultrasound technology used in daily clinical practice is not capable of identifying micrometastatic disease.
Macrometastatic disease may be identified on ultrasound as
cortical thickening, hilar displacement, hilar compression,
and loss of the normal echogenic hilum.14 Metastatic lymph
nodes tend to be rounder than benign lymph nodes.17 Yang et
al18 evaluated 145 axillary lymph nodes in 135 women with
breast cancer and found that the mean longitudinal-transverse axis ratio was significantly lower in malignant (1.8)
than in benign (2.6) lymph nodes. Also, indistinct margins
are suggestive of metastatic involvement.19 In general, on
ultrasound, more superficially located lymph nodes are identified more often and characterized more accurately than
deeper lymph nodes.

Ultrasound allows the capability for guidance of biopsies.

At UTMDACC, nearly all lymph node biopsies are performed
with FNA. Once the aspirate is obtained, cytology technologists prepare the slides in the ultrasound procedure room,
and cytologists assess the adequacy of the aspirate and render
preliminary interpretations before the patient is discharged
from the breast imaging suite.20
Krishnamurthy et al21 evaluated 103 women with breast
cancer and compared the findings on axillary lymph node
FNA with the histologic findings in the entire axilla after axillary
lymph node dissection. Ultrasound-guided FNA identified all
the cases with 3 or more metastatic lymph nodes and 93% of the
cases with a metastatic deposit measuring more than 0.5 mm.
The sensitivity of ultrasound-guided FNA was 86.4%, and the
specificity was 100%. The diagnostic accuracy of ultrasoundguided FNA was 79%, the positive predictive value was 100%,

214
and the negative predictive value was 67%. In most of the cases
with false-negative results (8 of 12 cases, 66%), the size of the
metastatic deposits ranged from 0.1 to 0.5 cm.21
If expert cytology support is not available, then ultrasound-guided core biopsy of suspicious lymph nodes is via-

G.J. Whitman and E.A. Strom

ble. Short-throw (1-cm) core biopsy needles are helpful especially when the lymph nodes are situated close to vessels,
nerves, implants, and chest wall structures. Topal and colleagues performed ultrasound-guided core needle biopsies
on suspicious axillary lymph nodes in 39 women with breast

Locally advanced breast cancer

cancer. In the study by Topal et al,22 ultrasound-guided axillary lymph node core biopsy resulted in a sensitivity of 90%,
a specificity of 100%, and an accuracy of 92%.
Sonography plays a crucial role for treatment planning.
Because the breast cancer staging system is based on the
assessment of the tumor (T), the regional lymph nodes (N),
and metastatic (M) disease, nodal assessment must be performed before assigning an accurate T, N, M stage. These
considerations are particularly critical when considering preoperative chemotherapy for patients with LABC in whom
prechemotherapy surgical data will not be obtained.23
Regarding accurate T, N, M staging, clinical examination is
notoriously inaccurate. On most mammograms, only a portion of the inferior axilla is included routinely. The infraclavicular, supraclavicular, and internal mammary regions are
not included on mammography. Most breast MRI protocols
include only the inferior axillary region, and coverage of the
infraclavicular region is variable. Although the internal mammary region is covered with routine breast MRI, additional
imaging would be needed to cover the entire axillary and
infraclavicular regions and the supraclavicular region. CT
and PET of the chest usually cover the axillary, infraclavicular, supraclavicular, and internal mammary basins. However,
identification of abnormal lymph nodes tends to be based on
size (1 cm being abnormal) on a CT scan24 and standard
uptake values on PET.25,26 Sonography, by contrast, may
identify subclinical disease involving the regional lymph
nodes. On ultrasound, morphology suspicious for metastatic
disease (cortical expansion or displacement of the echogenic
hilum) may be identified before lymph node enlargement.
Metastatic disease may then be confirmed with ultrasoundguided biopsy. Thus, the extent of nodal disease may be
mapped with sonography before the initiation of treatment.
When chemotherapy is the first therapeutic step in the
treatment of a patient with LABC, pretreatment imaging is
mandatory, including sonographic evaluation of the regional
lymph node basins. Preoperative chemotherapy is designed
to shrink the primary tumor and possibly facilitate breast
conservation therapy, to treat subclinical distant micrometastases, and to provide a platform for in vivo assessment of
systemic therapies.6 After the initiation of chemotherapy, periodic follow-up imaging, usually with ultrasound, is helpful
in showing that the chemotherapy is efficacious and in deter-

215
mining the operability of the primary breast tumor.4 Response to treatment in the lymph nodes is thought to have
prognostic significance.27 Shanta et al28 studied 1,117 consecutively treated LABC patients and showed that the best
prognosis was in the women who were tumor- and nodenegative postoperatively. In that study, nodal downstaging
halved the risk of disease recurrence and death, irrespective
of the status of the tumor bed. Patients with no response or
progression on therapy in the primary tumor or in the regional lymph nodes may be switched to an alternative chemotherapy regimen or offered investigational therapy.29
Local treatment planning is enhanced by the detailed regional nodal information provided by sonographic assessment. For example, when patients present with disease in the
sonographic infraclavicular region or the anatomic level II to
III axillary region and the interpectoral space, radiation therapy can address these findings.30 Most surgeons do not perform full, level I to III axillary dissections, and the interpectoral space is rarely entered. The information regarding nodal
disease sites can be used by the radiation oncologist for targeting specific sites for boosting. Likewise, disease identified
in the internal mammary and/or the supraclavicular regions,
which is rarely resected, can be addressed by appropriate
radiation therapy planning.
Altinyollar et al30 used sonography to examine the axillary
and the infraclavicular regions in 100 consecutive breast cancer patients. They identified axillary lymph nodes in 77 patients, and, in 52 of these patients, metastatic-appearing
lymph nodes were seen on ultrasound. In 49 of these 52
patients, the presence of lymph node metastases was established by histopathology. In 13 cases, sonography showed no
evidence of axillary lymph node metastases, but histopathologic examination showed metastatic deposits. Thirty-five
patients had negative sonographic evaluations of the axillary
region, and no metastatic deposits were seen on histopathologic examination. In the evaluation of the axillary region for
the presence of metastatic disease, sonography had a specificity of 92.1%, a sensitivity of 79%, a positive predictive
value of 94.2%, a negative predictive value of 72.9%, and an
overall accuracy of 84%.
In the study by Altinyollar et al,30 sonography showed
findings suspicious for infraclavicular lymph node metastases in 20 patients. In 19 of these patients, infraclavicular

Figure 2 A 75-year-old woman presented for routine, annual mammography after left breast excision 10 years earlier,
which showed a benign sclerosing lesion with focal atypical ductal hyperplasia. The clinical examination revealed no
suspicious findings in either breast or in the right or the left regional nodal basins. (A) The lateromedial mammogram
of the right breast shows an irregular mass (arrow). (B) Longitudinal ultrasound in the right breast 10 oclock region
shows a hypoechoic, taller-than-wide mass (arrow) corresponding to the mammographic abnormality. (C) An ultrasound-guided core biopsy (white arrow) was performed on the right breast 10 oclock mass (black arrow). Pathology
revealed high-grade, poorly differentiated invasive ductal carcinoma (estrogen receptor negative, progesterone receptor
negative, and HER2 neu overexpression negative) with an associated lymphoplasmacytic infiltrate. After the core
biopsy, a clip marker was placed in the known malignancy with sonographic guidance. (D) The lateromedial right
breast mammogram obtained after the marker placement shows the clip marker within the known malignancy (arrow).
(E) Transverse sonography of the medial right infraclavicular region reveals a hypoechoic, oval lymph node (arrow). (F)
An ultrasound-guided FNA (long arrow) of the hypoechoic medial right infraclavicular lymph node (short arrow) was
performed, revealing evidence of metastatic disease.

G.J. Whitman and E.A. Strom

216

Figure 3 A 45-year-old woman presented to her doctor with left breast thickening and redness involving the skin of the
lower left breast. The clinical examination revealed a 9-cm mass in the left breast, fixed to the chest wall, with associated
nipple inversion, and raised erythematous plaques in the 5-6 oclock position. A mobile lymph node was palpated in
the left axillary region. (A) The left craniocaudal mammogram reveals a large, central mass (arrow), with associated
nipple inversion. (B) The left lateromedial mammogram shows the mass (large arrow) along with enlarged axillary
lymph nodes (small arrow) and nipple inversion. (C) The sagittal dynamic contrast-enhanced left breast MRI shows the
large mass along with chest wall invasion (large arrow), nipple inversion (star), and skin involvement (arrowhead). (D)
The longitudinal extended-field-of-view ultrasound shows the large hypoechoic mass, chest wall involvement (large
arrow), and skin involvement (small arrow). Ultrasound-guided core biopsy demonstrated low-grade invasive lobular
carcinoma (estrogen receptor positive, progesterone receptor positive, and HER2 neu overexpression negative). (E)
Longitudinal left axillary sonography shows an enlarged lymph node (arrow) with a prominent cortex. (F) An ultrasound-guided left axillary FNA (long arrow) was performed on the hypoechoic lymph node (short arrow), revealing
evidence of metastatic carcinoma. (G) An ultrasound-guided FNA (thick arrow) was performed on a hypoechoic medial
left infraclavicular lymph node (thin arrow), showing evidence of metastatic carcinoma.

lymph node metastases were verified on histopathologic examination. Sonography showed no suspicious infraclavicular
lymph nodes in 21 patients, but all 21 of these patients had
infraclavicular lymph node metastases on histopathologic
examination. In 59 patients, infraclavicular sonography
showed no suspicious lymph nodes, and histopathology
showed no evidence of metastatic disease. Regarding sonographic evaluation of the infraclavicular region for the presence of metastases, the specificity was 98.3%, the sensitivity
was 47.5%, the positive predictive value was 95%, the nega-

tive predictive value was 73.7%, and the overall accuracy was
78%.30
Iyengar et al31 performed a retrospective analysis on 1,200
stage III patients treated with radiation therapy at UTMDACC
from 1996 to 2006. Of the 1,200 patients, 865 patients had
undergone sonography, which included assessment of the
regional nodal basins, at the time of their initial evaluation. In
this study, 325 out of 865 (37%) women had initial disease
beyond the breast and the low axillary region. Ninety percent
(293/325) of these patients had pathologic evaluation of

Locally advanced breast cancer

217

Figure 3 (Continued)

lymph nodes after ultrasound-guided biopsy. Compared

with clinical examination, mammography, and targeted
breast ultrasound, sonography of the regional lymph nodes
revealed previously undocumented infraclavicular disease in
32% of patients (275/865), supraclavicular disease in 16% of
patients (140/865), and internal mammary disease in 11% of
patients (98/865). Seventy-two percent of the patients with
extra-axillary regional lymph node involvement had T3 (94/
325) or T4 (141/325) primary malignancies, and 28% of
these patients had T1 or T2 primary tumors (90/325).31
In the study by Iyengar et al,31 in the most common scenario, sonographic staging changed the N stage from N1 to
N3. In patients initially presenting with T1 or T2 tumors,
there was a shift from N1 disease to N3 disease in 22% of
patients and a shift from N2 to N3 disease in 22% of patients.
For patients presenting with T3 tumors, sonography resulted
in a shift in 13% of the patients from N1 to N3 disease, and
7% of patients converted from N2 disease to N3 disease. In
patients initially presenting with T4 tumors, 13% of patients
were converted by sonography from N1 to N3 disease (Fig.
3), and 11% were converted by sonography from N2 to N3
disease. In this study, all the LABC patients with N3 disease
(37%) would have been understaged if sonography of the
regional lymph node basins was not performed. All the patients with extra-axillary regional lymph node involvement
received a radiation boost to the involved areas. Therefore, at
least 37% of the LABC patients had their radiation therapy
plans altered by the information provided by sonography in
the study by Iyengar et al.31

Sonography has also been used before the initiation of

radiation therapy to localize and measure the depth of the
lumpectomy cavity and the internal mammary lymph nodes
and to measure the chest wall thickness. Helyer et al32 used
sonography to determine the depth of the tumor bed in a
series of 53 early-stage postoperative breast cancer patients.
In 60% of the patients, sonography resulted in a change in the
electron energy compared with the clinically assessed measurements. After sonography, the energy was as likely to be
increased as decreased in the study by Helyer et al.32
Rabinovitch et al33 showed that ultrasound underestimated the dimensions of the lumpectomy cavity and concluded that sonography should not be used to guide the
design of boost fields. In general, CT-based treatment planning has superseded sonographic assessment of the chest
wall thickness and sonographic assessment of the excision
site and the internal mammary lymph node basins. A recent
study by Coles et al34 showed that 3-dimensional ultrasound
was superior to standard 2-dimensional sonography. In addition, the 3-dimensional ultrasound data could be coregistered with the planning CT data to help design appropriate
radiation fields.34
Clip markers may be placed in the primary tumor with
sonographic guidance.35 In some patients with LABC who
respond to neoadjuvant chemotherapy, the placement of clip
markers in the tumor bed may facilitate breast conservation
surgery rather than mastectomy. In some patients, the response to neoadjuvant chemotherapy is so good that there is
no evidence of residual tumor on clinical examination or on

218

G.J. Whitman and E.A. Strom

imaging studies.36 The placement of clip markers should be

considered at the time of the initial ultrasound-guided breast
biopsy. If clip markers were not placed at the time of the
initial biopsy, then clip markers should be placed in the
tumor if it shows significant shrinkage (a decrease in diameter of 50% or greater), becomes 1 cm or less in greatest
length, or is no longer palpable. Oh et al37 retrospectively
studied 410 patients who received doxorubicin-based neoadjuvant chemotherapy and underwent breast conservation
therapy and showed that the placement of clip markers was
associated with better local control independent of stage and
other clinicopathologic findings. Oh et al concluded that the
placement of clip markers should be an integral part of the
multidisciplinary approach in patients undergoing neoadjuvant chemotherapy.
Sonography may be performed in the breast imaging area
or in the operating room at the time of breast conservation
surgery to aid in localization of the primary tumor mass or
previously placed clip markers.38,39 A localizing needle may
be placed with sonographic guidance. Alternatively, sonography may be used to guide skin marking directly over the
abnormality. These techniques may obviate the need for
mammographically-guided needle localization.40 In addition, sonography can be used in the breast imaging area or in
the operating room to localize lymph nodes before excision.

MRI has been shown to be an accurate modality for assessing the extent of residual disease after preoperative chemotherapy. Kim et al44 used MRI to evaluate breast tumor size in
50 women before and after neoadjuvant chemotherapy with
doxorubicin and docetaxel. Kim et al found that the measurements on MRI agreed with the pathologically determined
tumor size in 36 patients (72%) and disagreed in 14 patients
(28%), overestimating the tumor size in 13 patients (26%)
and underestimating the tumor size in 1 woman (2%).44
Julius et al45 studied 34 LABC patients and noted that MRI
was able to accurately identify those patients suitable for
breast conservation therapy after neoadjuvant chemotherapy.
To be useful as a regional nodal staging examination, MRI
should cover the entire nodal basins. Most clinical breast MRI
protocols include the internal mammary and the infraclavicular regions, cover a portion of the axillary region, and exclude the supraclavicular region. Thus, the development of
protocols to adequately image all the regional nodal regions
and the breasts in a short scan time should be encouraged. In
addition, no firmly established criteria for metastatic lymph
node morphology on MRI have been established. MRI with
ultra-small superparamagnetic iron oxide agents has shown
great promise with a sensitivity ranging between 82% and
100% and a specificity ranging between 80% and 100% in
the assessment of axillary lymph node metastases.46-48

MRI

Sentinel Lymph Node Evaluation

Compared with mammography and sonography, MRI has

the highest sensitivity for detecting invasive breast cancer,
with sensitivities reported between 94% and 99%.8 MRI has
been able to show additional ipsilateral disease in the breast
in 7% to 37% of cases.8 Also, MRI is particularly useful for
showing chest wall involvement.41 Berg et al42 analyzed the
mammography, sonography, and MRI results in 111 consecutive patients with known or suspected breast cancer. Combined clinical examination, mammography, and MRI were
more sensitive than any 1 individual test or combination of
tests.42 After combined clinical examination, mammography,
and ultrasound, MRI showed additional tumor foci in 12 of
96 (12%) breasts and led to the overestimation of disease in 6
(6%) breasts.42 Contralateral breast cancer was shown by
mammography in 6 of 111 (5%) women and with sonography and MRI in an additional 3 (3%) women.42 In the study
by Berg et al, 1 contralateral breast cancer was shown only on
clinical examination.
Lehman et al43 evaluated the contralateral breast in 969
women with recently diagnosed breast cancer in the American College of Radiology Imaging Network 6667 Trial. In all
969 women, no abnormalities were noted in the contralateral
breast on clinical examination or mammography. MRI identified clinically and mammographically occult breast cancer
in the contralateral breast in 30 of 969 (3.1%) women. Of the
30 tumors identified with MRI, 18 were invasive malignancies and 12 were DCIS. The sensitivity of MRI in evaluating
the contralateral breast was 91%, the specificity was 88%,
and the negative predictive value was 99%.43

The role of sentinel lymph node evaluation in LABC patients

being treated with neoadjuvant chemotherapy is evolving.
Current data suggest that sentinel lymph node evaluation is
not accurate for IBC patients, and these patients should undergo axillary lymph node dissection. At many centers, sentinel lymph node evaluation is performed in LABC patients
before the initiation of neoadjuvant chemotherapy. This approach is based on the hypothesis that all involved axillary
lymph nodes may not respond to chemotherapy in an identical manner.12 Thus, an axillary lymph node with a metastatic deposit at the time of the original breast cancer diagnosis may be treated with chemotherapy and rendered
pathologically free of disease. If that same axillary lymph
node was designated as the sentinel lymph node, the sentinel
lymph node biopsy would show no evidence of tumor. However that sentinel lymph node may not be representative of
the entire axillary region because higher echelon axillary
lymph nodes may not have responded to neoadjuvant chemotherapy as well as the sentinel lymph node and still contain metastatic desposits.12 The false-negative rate for sentinel
lymph node biopsy performed after treatment with neoadjuvant chemotherapy has been reported to range between 0%
and 33%.49 The higher false-negative rates were noted in
series with larger (greater than 3.5 cm) tumors.49
If a sentinel lymph node biopsy is performed before the
start of neoadjuvant chemotherapy and the sentinel lymph
node biopsy shows metastatic disease, completion axillary
lymph node dissection will be performed at the time of definitive breast surgery. If the sentinel lymph node biopsy

Locally advanced breast cancer

shows no pathologic evidence of metastatic disease, then
completion axillary lymph node dissection is not required.49

Systemic Staging
In women presenting with LABC, systemic staging is performed to rule out distant metastatic disease.6 Staging is usually performed with chest radiography, a bone scan, and an
abdominal CTscan.50 An abnormality in one of the first-line
examinations will usually lead to a second tier study. For
example, an abnormality on a chest radiograph would be
further evaluated with a chest CT scan. Al-Husaini et al51
performed initial staging evaluations on 144 patients with
LABC and identified 15 patients (10.4%) with overt metastatic disease. Additional imaging investigations revealed another 4 patients with metastatic disease, resulting in prevalent metastases in 13.2% of the patients.51
Al-Husaini et al51 noted that because of the high rate of
systemic relapse in LABC patients, current conventional
baseline staging evaluations likely underestimate the extent
of disease. Thus, an unremarkable conventional baseline
staging evaluation may be falsely reassuring. Accurate staging
in LABC patients is crucial, and further research is needed to
define the role and the sequence of newer imaging techniques, such as MRI and PET.51

PET
18F-fluorodeoxyglucose

(FDG) PET has been evaluated as a

tool for assessing the axillary lymph nodes in breast cancer
patients with mixed results. An added value for PET is that it
can show disease in the supraclavicular and the internal
mammary nodal basins. In addition, PET allows for staging of
the entire body with high sensitivity. PET can be used to
evaluate the visceral organs (such as the liver and the lung)
and the bones. PET tends to detect more osteolytic bone
lesions than bone scans, whereas bone scans are sometimes
more sensitive than PET for identifying osteoblastic lesions.50
Mahner et al52 used PET to stage 69 patients with recently
diagnosed breast cancer and 50 patients with a previous history of breast cancer. PET was superior to conventional imaging (chest radiography, sonography of the abdomen and
the axilla, bone scintigraphy as well as skeletal radiography,
and contrast-enhanced CT scans as clinically indicated) for
the detection of distant metastases. PET detected distant metastatic disease with a sensitivity of 87% and a specificity of
83%. Combined conventional imaging yielded a sensitivity of
43% and a specificity of 98%, and contrast-enhanced CT
scans revealed a sensitivity of 83% and a specificity of 85%.52
Van der Hoeven et al53 evaluated 48 LABC patients with
whole body PET after conventional imaging (chest radiography, bone scan, and liver ultrasound or CT) failed to show
distant metastases. Fourteen of the 48 patients showed abnormal FDG uptake, and metastases were suspected in 12
cases. Further workup revealed 4 sites consistent with metastatic disease. The authors concluded that PET can be helpful
in distinguishing stage III disease from stage IV disease. In
addition, the authors emphasized that abnormal PET find-

219
ings require confirmatory imaging and/or biopsy because
there were 8 cases with false-positive FDG uptake on PET.53
Mahner et al52 used PET to evaluate the axillary region with
a sensitivity of 86% and a specificity of 97% (52). Wahl et al54
analyzed the PET scans of 360 women with recently diagnosed breast cancer. In that study, the PET scans were interpreted by 3 experienced readers in a blinded fashion. Wahl et
al concluded that PET may fail to detect axillary lymph node
metastases if there is a small number of lymph nodes and/or
if the lymph nodes are small (less than 3-5 mm).54 By contrast, PET is highly predictive for nodal involvement when
multiple intense regions of uptake are present.52
Bellon et al55 retrospectively reviewed the PET scans of 28
consecutive patients before neoadjuvant chemotherapy for
suspected LABC. Clearly, abnormal FDG uptake was noted
in the internal mammary lymph nodes in 7 patients (25%).
Prospective conventional imaging failed to identify metastases involving the internal mammary lymph nodes in any
patient. FDG uptake in the internal mammary lymph nodes
was associated with a large primary tumor size and with
inflammatory disease. FDG uptake in the internal mammary
lymph nodes predicted treatment failure by a pattern consistent with spread from internal mammary lymph node metastases.55
Baslaim et al56 used PET to evaluate 7 patients with IBC.
PET showed axillary lymph node involvement in 6 of 7 patients (85%) and skeletal metastatic disease in 1 patient
(14%). These findings were not identified on conventional
imaging. By contrast, PET may fail to detect small (less than 1
cm) masses, and, in 2 out of 7 patients with proven IBC, there
were false-negative PET studies.56
Recently, integrated PET/CT scanners have been developed, allowing PET and CT images to be obtained in close
temporal proximity without the need to reposition the patient. PET/CT studies offer whole body, dual-modality imaging in a single examination. Tatsumi et al57 evaluated 75
patients with known breast cancer and determined that
PET/CT increased the readers diagnostic confidence compared with PET alone in 60% of cases with increased FDG
uptake. In addition, in the study, PET/CT scans showed significantly better accuracy than CT alone. Therefore, Tatsumi
et al recommended PET/CT scans rather than PET alone or
CT scan alone in the evaluation of patients with known breast
cancer.
Carkaci et al58 used PET/CT scans in the initial staging
evaluation of 41 women with IBC. PET/CT scans showed
hypermetabolic uptake in the skin in all 41 patients, in the
affected breast in 40 patients (98%), in the ipsilateral axillary
lymph nodes in 37 patients (90%), and in the ipsilateral
subpectoral lymph nodes in 18 patients (44%). PET/CT scans
showed distant metastases in 20 patients (49%). In 7 (35%)
of the 20 patients with metastatic disease, the metastases
were not identified on conventional imaging before the
PET/CT examination. PET/CT scans identified metastatic disease involving the bone; the liver; the contralateral axilla; the
lung; the chest wall; the pelvis; and lymph nodes in the
subpectoral, supraclavicular, internal mammary, mediastinal, and abdominal regions.58

220
PET and PET/CT scans are useful in assessing the response
of the primary breast tumor, the regional lymph nodes, and
distant metastases to neoadjuvant chemotherapy.59 PET and
PET/CT scans can be used to differentiate responders from
nonreponders early in the course of therapy.56 A decline in
primary tumor FDG uptake by 50% or more is predictive of
a good response to neoadjuvant chemotherapy, whereas a
more modest decline in FDG uptake is characteristic of a lack
of response to treatment.59 Schelling et al60 showed that the
histopathologic response of breast cancer to chemotherapy
could be predicted by PET after the first and the second
courses of chemotherapy with an accuracy of 88% and 91%,
respectively.

Conclusions
In patients with LABC, accurate workup and staging evaluations are extremely important in facilitating appropriate multidisciplinary treatment. Careful clinical evaluation should be
followed with mammography. Thereafter, sonography is particularly helpful in showing multifocal and/or multicentric
disease and regional lymph node involvement. Ultrasoundguided biopsy can be performed to document the presence of
additional tumor foci in the breast and regional lymph node
metastases. MRI plays a role in some cases, and it is especially
useful in showing multifocal and multicentric disease and
chest wall involvement in the ipsilateral breast as well as
disease in the contralateral breast.
Conventional imaging used to evaluate for distant metastatic disease includes chest radiography, bone scan, and abdominal CT. PET and PET/CT scans have been shown to be
useful in identifying distant metastatic disease not identified
on conventional imaging. In the future, with developments in
radiopharmaceuticals and imaging detectors, it is likely that
PET/CT will play a greater role in regional lymph node staging. At the current time, because PET and PET/CT scans are
unable to identify microscopic metastatic deposits, PET and
PET/CT scans should not be used instead of axillary lymph
node biopsy or sentinel lymph node biopsy in patients with
LABC. If sentinel lymph node biopsy is being considered in a
LABC patient, it is suggested that sentinel lymph node biopsy
be performed before the initiation of neoadjuvant chemotherapy.

Acknowledgments
We thank Barbara Almarez Mahinda for assistance in manuscript preparation.

References
1. Giordano SH: Update on locally advanced breast cancer. Oncologist
8:521-530, 2003
2. Franceschini G, Terribile D, Magno S, et al: Update in the treatment of
locally advanced breast cancer: A multidisciplinary approach. Eur Rev
Med Pharmacol Sci 11:283-289, 2007
3. Cristofanilli M, Valero V, Buzdar AU, et al: Inflammatory breast cancer
(IBC) and patterns of recurrence: Understanding the biology of a
unique disease. Cancer 110:1436-1444, 2007

G.J. Whitman and E.A. Strom

4. Prati R, Minami CA, Gornbein JA, et al: Accuracy of clinical evaluation
of locally advanced breast cancer in patients receiving neoadjuvant
chemotherapy. Cancer 115:1194-1202, 2009
5. Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN: Overview
of resistance to systemic therapy in patients with breast cancer. Adv Exp
Med Biol 608:1-22, 2007
6. Chia S, Swain SM, Byrd DR, et al: Locally advanced and inflammatory
breast cancer. J Clin Oncol 26:786-790, 2008
7. Shen J, Valero V, Buchholz TA, et al: Effective local control and longterm survival in patients with T4 locally advanced breast cancer treated
with breast conservation therapy. Ann Surg Oncol 11:854-860, 2004
8. Londero V, Bazzocchi M, del Frate C, et al: Locally advanced breast
cancer: Comparison of mammography, sonography and MR imaging in
evaluation of residual disease in women receiving neoadjuvant chemotherapy. Eur Radiol 14:1371-1379, 2004
9. Bonnema J, van Geel AN, van Ooijen B, et al: Ultrasound-guided aspiration biopsy for detection of nonpalpable axillary node metastases in
breast cancer patients: New diagnostic method. World J Surg 21:270274, 1997
10. Berg WA, Gilbreath PL: Multicentric and multifocal cancer: Wholebreast US in preoperative evaluation. Radiology 214:59-66, 2000
11. Moon WK, Noh DY, Im JG: Multifocal, multicentric, and contralateral
breast cancers: Bilateral whole-breast US in the preoperative evaluation
of patients. Radiology 224:569-576, 2002
12. Pendas S, Jakub J, Giuliano R, et al: The role of sentinel lymph node
biopsy in patients with ductal carcinoma in situ or with locally advanced breast cancer receiving neoadjuvant chemotherapy. Cancer
Control 11:231-235, 2004
13. Bedrosian I, Bedi D, Kuerer HM, et al: Impact of clinicopathological
factors on sensitivity of axillary ultrasonography in the detection of
axillary nodal metastases in patients with breast cancer. Ann Surg Oncol 10:1025-1030, 2003
14. Khan A, Sabel MS, Nees A, et al: Comprehensive axillary evaluation in
neoadjuvant chemotherapy patients with ultrasonography and sentinel
lymph node biopsy. Ann Surg Oncol 12:697-704, 2005
15. Podkrajsek M, Music MM, Kadivec M, et al: Role of ultrasound in the
preoperative staging of patients with breast cancer. Eur Radiol 15:
1044-1050, 2005
16. Klauber-Demore N, Kuzmiak C, Rager EL, et al: High-resolution axillary ultrasound is a poor prognostic test for determining pathologic
lymph node status in patients undergoing neoadjuvant chemotherapy
for locally advanced breast cancer. Am J Surg 188:386-389, 2004
17. Whitman GJ, Sheppard DG, Phelps MJ, et al: Breast cancer staging.
Semin Roentgenol 41:91-104, 2006
18. Yang WT, Chang J, Metreweli C: Patients with breast cancer: Differences in color Doppler flow and gray-scale US features of benign and
malignant axillary lymph nodes. Radiology 215:568-573, 2000
19. Feu J, Tresserra F, Fabregas R, et al: Metastatic breast carcinoma in
axillary lymph nodes: In vitro US detection. Radiology 205:831-835,
1997
20. Amaral BB, Meurer L, Whitman GJ, et al: Lymph node status in the
breast cancer patient: Sampling techniques and prognostic significance. Semin Roentgenol 42:253-264, 2007
21. Krishnamurthy S, Sneige N, Bedi DG, et al: Role of ultrasound-guided
fine-needle aspiration of indeterminate and suspicious axillary lymph
nodes in the initial staging of breast carcinoma. Cancer 95:982-988,
2002
22. Topal U, Punar S, Tasdelen I, et al: Role of ultrasound-guided core
needle biopsy of axillary lymph nodes in the initial staging of breast
carcinoma. Eur J Radiol 56:382-385, 2005
23. Greene FL, Page DL, Fleming ID, et al (eds): AJCC Cancer Staging
Manual (ed 6). New York, NY, Springer, 2002, pp 223-240
24. March DE, Wechsler RJ, Kurtz AB, et al: CT-pathologic correlation of
axillary lymph nodes in breast carcinoma. J Comput Assist Tomogr
15:440-444, 1991
25. Chung A, Liou D, Karlan S, et al: Preoperative FDG-PET for axillary
metastases in patients with breast cancer. Arch Surg 141:783-789,
2006

Locally advanced breast cancer

26. Gil-Rendo A, Martinez-Requeira F, Zornoza G, et al: Association between [18F]fluorodeoxyglucose uptake and prognostic parameters in
breast cancer. Br J Surg 96:166-170, 2009
27. McIntosh SA, Ogston KN, Payne S, et al: Local recurrence in patients
with large and locally advanced breast cancer treated with primary
chemotherapy. Am J Surg 185:525-531, 2003
28. Shanta V, Swaminathan R, Rama R, et al: Retrospective analysis of
locally advanced noninflammatory breast cancer from Chennai, South
India, 1990-99. Int J Radiat Oncol Biol Phys 70:51-58, 2008
29. Beenken SW, Urist MM, Zhang Y, et al: Axillary lymph node status, but
not tumor size, predicts locoregional recurrence and overall survival
after mastectomy for breast cancer. Ann Surg 237:732-739, 2003
30. Altinyollar H, Dingil G, Berberoglu U: Detection of infraclavicular
lymph node metastases using ultrasonography in breast cancer. J Surg
Oncol 92:299-303, 2005
31. Iyengar P, Strom EA, Zhang Y-J, et al: Locally advanced breast cancer
frequently involves the extra-axillary regional nodes: Incidence and
treatment impact. Cancer Res 69:257s, 2009 (suppl, abstr)
32. Helyer SJ, Moskovic E, Ashley S, et al: A study testing the routine use of
ultrasound measurements when selecting the electron energy for breast
boost radiotherapy. Clin Oncol (R Coll Radiol) 11:164-168, 1999
33. Rabinovitch R, Finlayson C, Pan Z, et al: Radiographic evaluation of
surgical clips is better than ultrasound for defining the lumpectomy
cavity in breast boost treatment planning: A prospective clinical study.
Int J Radiat Oncol Biol Phys 47:313-317, 2000
34. Coles C, Cash CJ, Treece GM, et al: High definition three-dimensional
ultrasound to localise the tumour bed: A breast radiotherapy planning
study. Radiother Oncol 84:233-241, 2007
35. Phillips SW, Gabriel H, Comstock CE, et al: Sonographically guided
metallic clip placement after core needle biopsy of the breast. AJR Am J
Roentgenol 175:1353-1355, 2000
36. Braeuning MP, Burke ET, Pisano ED: Embolization coils as tumor
markers for mammography in patients undergoing neoadjuvant chemotherapy for carcinoma of the breast. AJR Am J Roentgenol 174:251252, 2000
37. Oh JL, Nguyen G, Whitman GJ, et al: Placement of radiopaque clips for
tumor localization in patients undergoing neoadjuvant chemotherapy
and breast conservation therapy. Cancer 110:2420-2427, 2007
38. Gittleman MA: Single-step ultrasound localization of breast lesions and
lumpectomy procedure. Am J Surg 186:386-390, 2003
39. Bennett IC, Greenslade J, Chiam H: Intraoperative ultrasound-guided
excision of nonpalpable breast lesions. World J Surg 29:369-374, 2005
40. Paramo JC, Landeros M, McPhee MD, et al: Intraoperative ultrasoundguided excision of nonpalpable breast lesions. Breast J 5:389-394, 1999
41. Morris EA: Breast cancer staging with MRI. Radiol Clin North Am
40:443-466, 2002
42. Berg WA, Gutierrez L, NessAiver MS, et al: Diagnostic accuracy of
mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. Radiology 233:830-849, 2004
43. Lehman CD, Gatsonis C, Kuhl CK, et al: MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer.
N Engl J Med 356:1295-1303, 2007
44. Kim HJ, Im YH, Han BK, et al: Accuracy of MRI for estimating residual
tumor size after neoadjuvant chemotherapy in locally advanced breast

221

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.
60.

cancer: Relation to response patterns on MRI. Acta Oncol 46:9961003, 2007

Julius T, Kemp SE, Kneeshaw PJ, et al: MRI and conservative treatment
of locally advanced breast cancer. Eur J Surg Oncol 31:1129-1134,
2005
Michel SC, Keller TM, Frohlich JM, et al: Preoperative breast cancer
staging: MR imaging of the axilla with ultrasmall superparamagnetic
iron oxide enhancement. Radiology 225:527-536, 2002
Stadnik TW, Everaert H, Makkat S, et al: Breast imaging. Preoperative
breast cancer staging: Comparison of USPIO-enhanced MR imaging
and 18F-fluorodeoxyglucose (FDC) positron emission tomography
(PET) imaging for axillary lymph node stagingInitial findings. Eur
Radiol 16:2153-2160, 2006
Memarsadeghi M, Riedl CC, Kaneider A, et al: Axillary lymph node
metastases in patients with breast carcinomas: Assessment with nonenhanced versus USPIO-enhanced MR imaging. Radiology 241:367-377,
2006
Cox CE, Cox JM, White LB, et al: Sentinel node biopsy before neoadjuvant chemotherapy for determining axillary status and treatment
prognosis in locally advanced breast cancer. Ann Surg Oncol 13:483490, 2006
Bombardieri E, Gianni L: The choice of the correct imaging modality in
breast cancer management. Eur J Nucl Med Mol Imaging 31:S179S186, 2004 (suppl 1)
Al-Husaini H, Amir E, Fitzgerald B, et al: Prevalence of overt metastases
in locally advanced breast cancer. Clin Oncol (R Coll Radiol) 20:340344, 2008
Mahner S, Schirrmacher S, Brenner W, et al: Comparison between
positron emission tomography using 2-[fluorine-18]fluoro-2-deoxy-Dglucose, conventional imaging and computed tomography for staging
of breast cancer. Ann Oncol 19:1249-1254, 2008
van der Hoeven JJM, Krak NC, Hoekstra OS, et al: 18F-2-fluoro-2deoxy-D-glucose positron emission tomography in staging of locally
advanced breast cancer. J Clin Oncol 22:1253-1259, 2004
Wahl RL, Siegel BA, Coleman RE, et al: Prospective multicenter study of
axillary nodal staging by positron emission tomography in breast cancer: A report of the staging Breast Cancer with PET Study Group. J Clin
Oncol 22:277-285, 2004
Bellon JR, Livingston RB, Eubank WB, et al: Evaluation of the internal
mammary lymph nodes by FDG-PET in locally advanced breast cancer
(LABC). Am J Clin Oncol 27:407-410, 2004
Baslaim MM, Bakheet SM, Bakheet R, et al: 18-Fluorodeoxyglucosepositron emission tomography in inflammatory breast cancer. World
J Surg 27:1099-1104, 2003
Tatsumi M, Cohade C, Mourtzikos KA, et al: Initial experience with
FDG-PET/CT in the evaluation of breast cancer. Eur J Nucl Med Mol
Imaging 33:254-262, 2006
Carkaci S, Macapinlac HA, Cristofanilli M, et al: Retrospective study of
18F-FDG PET/CT in the diagnosis of inflammatory breast cancer: Preliminary data. J Nucl Med 50:231-238, 2009
Rosen EL, Eubank WB, Mankoff DA: FDG PET, PET/CT and breast
cancer imaging. Radiographics 27:S215-S229, 2007 (suppl 1)
Schelling M, Avril N, Nahrig J, et al: Positron emission tomography
using [18F]fluorodeoxyglucose for monitoring primary chemotherapy
in breast cancer. J Clin Oncol 18:1689-1695, 2000

Neoadjuvant Chemotherapy for

Locally Advanced Breast Cancer
Jennifer Specht, MD, and Julie R. Gralow, MD
Preoperative systemic therapy is the standard of care in locally advanced breast cancer.
In this setting, the intent of preoperative systemic therapy is to expand surgical options
and to improve survival. Locally advanced and inflammatory breast cancer have different biological features, but they share the use of preoperative (primary, neoadjuvant)
systemic therapy as the initial treatment of choice. The management of these patients
necessitates involvement of a multidisciplinary team from the onset and during therapy.
The eradication of invasive cancer from the breast and axillary lymph nodes, pathologic
complete response, is a predictor of outcome associated with improved disease-free
and overall survival. However, conventional chemotherapy regimens result in pathologic complete response in only a minority of patients. The management of patients with
residual invasive disease after preoperative therapy is a common clinical problem for
which additional research is necessary. The differential expression of genes and
pathways in locally advanced and inflammatory breast cancer allows for the exploitation
of targeted therapy, and early trials have shown exciting target and tumor effects. Much
work remains, and future trials combining targeted and conventional therapies based on
molecular subtypes and/or specific targets are needed if we hope to improve survival
for patients with locally advanced breast cancer.
Semin Radiat Oncol 19:222-228 2009 Published by Elsevier Inc.
KEYWORDS breast cancer, locally advanced, inflammatory breast cancer, preoperative therapy, neoadjuvant therapy

ocally advanced breast cancers (LABCs) have historically

been defined as those that are inoperable on presentation, usually with the involvement of regional lymph nodes
and possibly the skin and/or chest wall and having a poor
survival with locoregional therapies alone.1-3 In these cancers, the use of preoperative systemic therapy has been
shown to induce tumor response and improve the local control rates after subsequent surgery and radiation therapy. The
goals of preoperative systemic therapy in LABCs include early
eradication of subclinical distant micrometastases, downstaging of the primary tumor to allow for operability (including
breast-conserving surgery in some cases), in vivo assessment of
response to specific systemic therapies, and ultimately prolonging survival and improving quality of life. The magnitude of

survival benefit of preoperative systemic therapy is unclear,

however, because of relatively few comparative clinical trials
specifically in LABC patients. Randomized trials in stage III
breast cancer that first used local therapy followed by adjuvant systemic therapy v not have shown a survival advantage
for combined modality therapy.4-6 In primary operable breast
cancer, a series of randomized trials of neoadjuvant v adjuvant chemotherapy showed equivalent outcomes.7-9 Given
that there appear to be no major disadvantages in giving
preoperative systemic therapy in operable breast cancer and
because there are multiple possible advantages to giving neoadjuvant therapy in more advanced stages as outlined earlier,
preoperative systemic therapy is the initial treatment of
choice for patients presenting with LABC.

Department of Medicine, Medical Oncology, University of Washington

School of Medicine, Seattle, WA.
Dr Specht was supported by Pfizer grant IIR #GA9000S1 (CC IRB #6488)
and NCCN grant (CC IRB #6489).
Address reprint requests to Julie R. Gralow, MD, Seattle Cancer Care
Alliance, 825 Eastlake Avenue East, G3-630, Seattle, WA 98109.
E-mail: pink@u.washington.edu

Optimal
Chemotherapy Regimens

222

1053-4296/09/$-see front matter 2009 Published by Elsevier Inc.

doi:10.1016/j.semradonc.2009.05.001

In early studies of chemotherapy in LABC, anthracyclinebased regimens resulted in improved survival rates (up to
25% at 10 years) compared with historical experience with

Neoadjuvant chemotherapy
local therapy alone.10-15 More recent trials have focused on
the addition of newer agents (particularly taxanes) and alternative schedules, such as dose-dense chemotherapy. A phase
III trial involving large (3 cm) primary and LABCs showed
superiority for the sequential addition of 4 cycles of docetaxel
after 4 cycles of a neoadjuvant anthracycline-based regimen
(cyclophosphamide, vincristine, doxorubicin, and prednisone [CVAP]) when compared with 8 cycles of the anthracycline regimen alone in the preoperative setting.16 Other
trials have looked at combinations of anthracycline and taxanes given concurrently and in sequence.17,18 In a trial of
preoperative chemotherapy specifically in LABC/inflammatory breast cancer (IBC), dose intensification of an anthracycline regimen was not superior to a standard anthracycline
regimen, although interpretation of these results is difficult
because in addition to the chemotherapy interval timing
there were many other dissimilarities in drug administration
between the 2 arms.19
A newer approach to chemotherapy sequencing that has
shown promise in LABC is metronomic or continuous dose
scheduling. Strickly speaking, metronomic chemotherapy
refers to subtherapeutic, low doses of chemotherapy given on
a frequent or continuous schedule without dose interruption.
In vitro, metronomic dosing appears to exert antiangiogenic
effects. In breast cancer clinical therapy, metronomic or
continuous chemotherapy refers to the administration of
higher, cytotoxic doses of chemotherapy at shorter treatment intervals, often weekly for intravenous drugs, such
as doxorubicin, and daily for oral cyclophosphamide.
Most recently, the preliminary results of a large trial of
LABC/IBC patients randomized to conventional anthracycline and cyclophosphamide (doxorubicin, 60 mg/m2, and
cyclophosphamide, 600 mg/m2 both every 3 weeks) v metronomic dosing doxorubicin, 24 mg/m2 weekly, and cyclophosphamide, 60 mg/m2 daily) with growth factor support (both arms followed by standard weekly paclitaxel)
showed an improved pathologic complete response (pCR)
rate (19% v 31%, respectively; OR 2.11, P .020) with
the metronomic schedule.20 The pCR improvement was
most pronounced in the IBC cohort (12% v 32%). Mature
results of the trial are awaited. Further studies with other
conventional chemotherapeutic combinations or schedules are ongoing, but future significant gains will likely be
achieved with targeted agents in combination with conventional chemotherapeutic agents as preoperative therapy.
It is highly unlikely that a single preoperative chemotherapy regimen will be optimal for all types of patients and
cancers. Identifying which tumors are most likely to respond
to specific agents and regimens could significantly improve
preoperative treatment outcomes. In general, patients receiving preoperative chemotherapy should receive treatment regimens that reflect state-of-the-art adjuvant chemotherapy
regimens. Outside of a clinical trial, there is no current rationale for using different chemotherapy approaches in the preoperative setting than would be used in the postoperative
setting.

223

Initial Chemotherapy
Response As A Guide
to Subsequent Treatment
A unique aspect of preoperative therapy is the opportunity
to monitor tumor response and potentially to tailor treatment based on response. Changes on physical examination and breast imaging have shown a moderate correlation with the ultimate pathologic assessment of residual
disease. Although it is clear that early clinical response is
associated with higher rates of pCR and better long-term
outcome, trials have not shown a consistent improvement
in outcome with a midcourse chemotherapy switch based
on presence or lack of response. In the GeparTrio trial,21,22
patients received 2 cycles of preoperative docetaxel, doxorubicin, and cyclophosphamide (TAC). Patients with clinically nonresponding disease (defined as a failure to decrease in size by at least 50% by ultrasound), representing
about 30% of patients on the study, were randomized to
receive 4 more cycles of TAC v 4 cycles of vinorelbine and
capecitabine before surgery. The pCR rate in the nonresponders was low (5.3% and 6% for TAC and vinorelbine
and capecitabine, respectively) and was not improved by
switching to the non cross-resistant chemotherapy regimen. In another trial, investigators in Aberdeen used an
early assessment of clinical response to ask if prolonging
the duration of the initial treatment would be beneficial in
those patients whose tumors were responding to this therapy.23 All patients received 4 cycles of preoperative CVAP.
Based on the assessment of clinical response, patients with
stable or progressive disease after 4 cycles were switched
to docetaxel for 4 cycles. pCR in this group was 2%, suggesting that tumors not responding to one chemotherapy regimen
are unlikely to show dramatic response to another regimen.
Patients who had a complete or partial clinical response in this
study to the first 4 cycles of CVAP were randomized to 4 more
cycles of CVAP v a switch to 4 cycles of docetaxel. The pCR was
twice as high in the group that switched to docetaxel (31% v
16%). Both disease-free (DFS) and overall survival (OS) were
significantly superior for responders randomized to the CVAP/
docetaxel arm compared with those who continued with CVAP.
Although both the GeparTrio and Aberdeen studies involved a randomization to continue treatment or switch to
a new regimen, they differ in terms of the randomized
patient populations (sensitive v resistant disease) and with
regard to the timing of randomization (4 v 2 cycles). Nevertheless, both studies suggest that a treatment plan
should be devised at the outset and should not be altered
based on early response, unless there is clear evidence of
disease progression. Deviating from the planned course of
therapy in clinical nonresponders has not been shown to
increase either clinical or pCR rates or improve survival.
Patients with outright disease progression during preoperative systemic treatment should be switched to an alternate regimen, offered local therapy, or considered candidates for investigational approaches, particularly if their
disease is unresectable. To date, we have been unable to

224
exploit the potential for improved outcome based on
changing chemotherapy based on the response to specific
drugs given in the preoperative setting.

The Role of Additional

Chemotherapy in Patients
With Residual Disease at
The Time of Definitive Surgery
After preoperative chemotherapy, patients should receive definitive breast surgery and, when indicated, radiation therapy. In addition, patients should receive appropriate endocrine therapy and human epidermal growth factor receptor-2
(HER-2)targeted therapy, according to the biological features of their tumor. To date, no trial has shown that additional chemotherapy given to patients with residual disease
after a modern preoperative chemotherapy (generally anthracycline and taxane based) improves outcome. In an M. D.
Anderson trial of adjuvant chemotherapy after preoperative
anthracycline-based chemotherapy, 106 patients with 1
cm of residual disease were randomized to continue the regimen they received preoperatively (CVAP) or received vinblastine, methotrexate with calcium leukovorin rescue, and
5-fluorouracil postoperatively.24 Although there was no statistical difference between the arms, there was a trend favoring the vinblastine, methotrexate with calcium leukovorin
rescue, and 5-fluorouracil arm with respect to DFS (P .16).
Given the limited size of the trial, no definitive conclusions
can be drawn from this experience. Moreover, the trial was
conducted before the time when taxanes were generally included in the treatment plan. Although there is no evidence
that more chemotherapy will be of value, it is also fully recognized that this clinical situation is one that arises frequently
in clinical practice because most patients treated with preoperative therapy do not achieve a pCR. Outside of a clinical
trial, the use of additional chemotherapy after a standard
course of treatment should be discouraged. Within the context of a clinical trial, a variety of approaches could be tested,
including the use of non cross-resistant chemotherapy, angiogenesis inhibitors, high-dose bisphosphonates, vaccines,
and a variety of other biological therapies.
Phase III trials proposed to address the management of
patients with residual disease after neoadjuvant chemotherapy include National Surgical Adjuvant Breast and Bowel
Project B45, which will randomize patients with residual invasive disease to receive sunitinib (an oral multitargeted receptor tyrosine kinase inhibitor of vascular endothelial
growth factor (VEGF)-1, -2, -3; platelet-derived growth factor receptor, kit, and FMS-like tyrosine kinase 3) v placebo.
The use of additional chemotherapy is not specified in this
trial. In the Southwest Oncology Group (SWOG), a phase III
trial is planned for breast cancer patients with residual HER2negative invasive disease to be randomized to receive additional non cross-resistant chemotherapy and/or a biological agent or no further therapy postoperatively. Results of
these studies will provide much-needed data on how to improve outcomes in both locally advanced and early-stage pa-

J. Specht and J.R. Gralow

tients who do not achieve a complete response to preoperative therapy.

Preoperative Endocrine Therapy

There is a smaller body of evidence regarding preoperative
endocrine approaches. Although not widely used in the
United States, preoperative endocrine therapy is a treatment
option for women with endocrine-sensitive tumors, usually
defined as expressing the estrogen receptor (ER) and/or progesterone receptor. Studies have established the safety of this
strategy for limited durations, typically not exceeding 6
months, before definitive local therapy. When endocrine
therapy is given preoperatively, clinical responses are frequently observed and the proportion of patients who can
undergo breast conservation can be increased.25-28 Despite
the clinical activity of preoperative endocrine therapy, pCR is
rare, occurring in less than 5% of cases. Trials of 3 to 4
months of preoperative tamoxifen v aromatase inhibitors
showed statistically significant improvements in breast-conservation rates in the aromatase inhibitor arms.25-27 Either a
decline in the Ki-67 percent after exposure to preoperative
endocrine therapy or the absolute Ki-67 percent after 2
weeks of therapy appear to be predictors of long-term outcome.29 In a trial of preoperative letrozole v tamoxifen, patients with high ER expression had similar favorable responses to the 2 endocrine agents, whereas patients with
intermediate ER expression had a higher response rate to
letrozole.30 Patients with low ER expression had minimal
in-breast response to either agent. At this time, the optimal
duration of preoperative endocrine therapy is uncertain and
will depend on the goals of the treatment for the individual
patient. A longer duration of preoperative endocrine therapy
appears to be associated with higher response rates. In 63
patients treated with extended durations of preoperative
letrozole, tumor volume continued to decrease for up to 12 to
24 months.31 Outside of a clinical trial, preoperative endocrine therapy appears to be a reasonable approach for postmenopausal patients who are not thought to be candidates
for preoperative chemotherapy either because of comorbidity
or tumor biology.
In general, preoperative endocrine therapy should not be
viewed as a substitute for surgery. A study in operable breast
cancer patients over the age of 70 comparing tamoxifen alone
v surgery plus tamoxifen showed a significantly higher locoregional relapse rate with tamoxifen alone (23% v 8%) and
a worse overall and breast cancer mortality (HR 1.68) for
the tamoxifen-alone group.32,33

Targeted Biological
Therapies for HER-2
Overexpressing Breast Cancer
In tumors with overexpressed or amplified HER-2, numerous phase II studies have shown that adding trastuzumab to
preoperative chemotherapy achieves high pCR rates. The
M. D. Anderson group conducted a small, randomized phase

Neoadjuvant chemotherapy
II preoperative trial of paclitaxel and fluorouracil, epirubicin,
and cyclophosphamide chemotherapy with or without trastuzumab in HER-2 overexpressing breast cancer.34 The pCR
rate was 25% in the chemotherapy-only arm v 67% in the
chemotherapy-trastuzumab arm. This magnitude of increase
in pCR in the trastuzumab arm was similar to the magnitude
of improvement in DFS seen in the adjuvant trastuzumab
trials. Similar results have been reported by Gianni et al in a
trial that randomized patients with locally advanced, HER2positive breast cancer to chemotherapy alone or chemotherapy plus trastuzumab.35 The primary endpoint of this
phase III trial was event-free survival. At a median follow-up
of 3 years, the hazard ratio for event-free survival was 0.56
(P .006) for patients with HER-2positive disease receiving chemotherapy plus trastuzumab. In patients with HER2positive disease receiving trastuzumab, pCR was observed
in 43% v 23% in those treated with chemotherapy only. In
this study, as in the M. D. Anderson trial, trastuzumab was
administered concurrently with an anthracycline-based
chemotherapy regimen. Caution must be advised regarding the concomitant use of trastuzumab with anthracyclines. If used, protocol evaluated doses and schedules
should be given. The safety of concurrent v sequential
administration of trastuzumab with epirubicin is under
evaluation in the American College of Surgeons Uncology
Group Z1041 trial.
A number of other HER-2targeted agents are in development. Lapatinib, an oral tyrosine kinase inhibitor of
epidermal growth factor receptor and HER-2, received
Food and Drug Administration approval based on results
of a randomized phase III trial comparing capecitabine
alone with capecitabine with lapatinib in patients with
advanced HER-2positive breast cancer who had progressed on an anthracycline, a taxane, and trastuzumab.36
Also, in the advanced-disease setting, a phase II trial of
lapatinib in refractory/relapsed IBC (of which most patients had previously received trastuzumab) reported a
clinical response rate of 50% on skin lesions and a 28%
response rate by response evaluation criteria in solid tumors criteria was observed.37 In the neoadjuvant setting,
lapatinib monotherapy followed by lapatinib and weekly
paclitaxel in patients with newly diagnosed IBC resulted in
a clinical response rate of 77% (including a 30% response
rate to only 2 weeks of lapatinib monotherapy) and a pCR
of 17% in patients with HER-2positive IBC.38 The optimal preoperative therapy strategy for HER-2 overexpressing tumors is under evaluation in a number of ongoing trials. Trastuzmab v lapatinib or the combination with
chemotherapy is being evaluated in the neo-adjuvant lapatinib and/or trastuzumab treatment optimization Grupo Espaol
de Investigacin del cncer de Mama 2006-14, and Cancer and
Leukemia Group B 40601 trials. The role of new agents with
activity against HER-2 overexpressing tumors, such as neratinib (HKI-272) and trastuzumab-DM1 (HER-2 antibodydrug conjugate), are eagerly awaited as the armamentarium
against this tumor type expands.

225

Antiangiogenic
Therapy in LABC
Because of the overexpression of particular genes and proteins, the aggressive nature of LABC, and the ability to measure treatment response in vivo, clinical trials of neoadjuvant-targeted agents either alone or in combination with
chemotherapeutic agents are particularly attractive. Bevacizumab is a humanized monoclonal antibody to VEGF-A that
garnered Food and Drug Administration approval for the
treatment of advanced breast cancer in combination with
paclitaxel based on a significant improvement in DFS from
5.9 to 11.8 months (HR 0.60, P .001).39 The experience
with bevacizumab in the neoadjuvant setting is fairly limited
to date.
A small, phase II pilot trial of bevacizumab in combination
with doxorubicin and docetaxel as preoperative therapy in
LABC/IBC yielded a clinical response rate of 67% (with a 5%
pCR rate).40 Importantly, this trial showed a marked decrease
in tumor VEGF receptor activation and an increase in tumor
cell apoptosis after treatment with the bevacizumab alone.
These correlative studies suggest that by blocking VEGF, bevacizumab inhibits the activation of VEGFR2 and induces
tumor apoptosis. Greil et al41 have reported on the combination of bevacizumab, docetaxel, and capecitabine as preoperative therapy in HER-2negative breast cancer.41 In this
phase II trial, pCR was observed in 22% of patients, with all
the pCRs occurring in patients with hormone receptornegative disease. There were no surgical complications, congestive heart failure, hypertension, or wound-healing disorders
observed with the preoperative use of bevacizumab. The
safety and efficacy of neoadjuvant bevacizumab or placebo
followed by TAC in patients with stage II and III breast cancer
was reported by Hurvitz et al.42 In this trial, patients were
randomized to 1 of 4 arms with low-dose bevacizumab, 7.5
mg/kg; a standard dose of bevacizumab, 15 mg/kg; or placebo all given as an initial run-in followed by bevacizumab or
placebo with TAC chemotherapy for 6 cycles and then followed by bevacizumab or placebo in the adjuvant setting.
Preliminary data on the first 50 evaluable patients included a
pCR rate of 20%, which was not significantly different across
the treatment arms with and without bevacizumab. Woundhealing complications were observed more often in patients
receiving neoadjuvant bevacizumab (21% v 12%, P .699).
Based on the pilot experiences described earlier, the efficacy of antiangiogenic therapy in the metastatic setting, and
the substantial unmet need for more efficacious systemic
therapy options, bevacizumab and other targeted agents are
being evaluated in neoadjuvant clinical trials for women with
LABC and high-risk operable breast cancer. In an ambitious,
randomized, phase III trial, National Surgical Adjuvant
Breast and Bowel Project B40 will evaluate 3 neoadjuvant
chemotherapy regimens each with or without bevacizumab
for patients with operable, HER-2negative breast cancer.
The primary endpoint of this trial is pCR with secondary
endpoints to evaluate efficacy of the addition of bevacizumab, safety, and evaluation of DFS.

J. Specht and J.R. Gralow

226
In the North American Breast Cancer InterGroup, an alternative strategy combining sunitinib with nabpaclitaxel followed by doxorubicin and cyclophosphamide chemotherapy
will be led by the SWOG for patients presenting with LABC
and IBC (SWOG S0800). Sunitinib is one of several, oral,
small-molecule tyrosine inhibitors with promising antitumor
and antiangiogenic activities through the inhibition of platelet-derived growth factor receptor, VEGF receptors (VEGF-1,
-2, and -3), kit, and FMS-like tyrosine kinase 3. Investigators
at the University of Washington and Arizona Cancer Center
are evaluating the safety and efficacy of sunitinib in combination with weekly paclitaxel followed by metronomic
weekly doxorubicin and daily oral cyclophosphamide as preoperative therapy for patients with LABC and IBC in a phase
II pilot trial that is ongoing.

Predictive Factors for

Response and Prognosis
of Attaining A pCR
There is a clear correlation between tumor response in the
breast and lymph nodes and both DFS and OS. pCR and
other pathologic measures may be useful as surrogate endpoints in evaluating and understanding new therapies. pCR
has emerged as the most commonly used surrogate endpoint
for gauging the efficacy of preoperative therapy for several
reasons. First, the attainment of pCR is associated with a
favorable prognosis; such patients have a far lower risk of
subsequent recurrence than do patients with residual invasive tumor at the time of surgery and also appear to have
improved OS.8,10,43-49 Second, although there are variations
in the criteria and reporting for pathologic response, the measurement of pCR has been more uniform and less subject to
difficulties in interpretations. Nonetheless, the definition of
pCR has varied across clinical trials and throughout the literature.50
There is a general agreement that the preferred definition
of pCR is the absence of residual invasive cancer within both
the breast and axillary lymph nodes. The presence or absence
of residual ductal carcinoma in situ after preoperative therapy does not impact long-term DFS or OS.51 The presence of
any amount of nodal disease after preoperative therapy predicts for a poorer prognosis and should be included as residual disease in defining pCR.52-56
Not all patients who achieve a pCR remain free of recurrence, and not all patients who do not achieve a pCR develop
recurrent disease. pCR after chemotherapy is probably most
predictive with respect to relapse and death for ER-negative,
HER-2negative tumors.57,58 Even in this setting, however,
pathologic response cannot be used as an endpoint to define
new standards of care. It is widely believed that pCR is not a
sufficiently robust endpoint, and other surrogate endpoints
and pathologic grading systems are under evaluation.59,60
Ultimately, the most significant benefit of systemic therapy
rests in its impact on OS. In the adjuvant setting, DFS is often
used as a surrogate for OS because systemic recurrences frequently lead to breast cancer deaths, and there is a high

correlation between DFS and OS. In the preoperative setting,

pCR has emerged as an important prognostic factor. Patients
achieving a pCR have a significantly lower risk of recurrence
than patients with residual invasive tumor. Factors associated
with a higher likelihood of pCR include tumor size, histology
(ductal lobular), tumor intrinsic subtype (basal-like or
HER-2 enriched luminal), hormone receptor status (ER
negative ER positive), and grade (high low). Of these
factors, negative hormone receptor status appears to be the
most predictive for response to preoperative therapy and
pCR.49,61-65
More recently, gene expression profiling by microarray has
revealed greater complexity in breast tumors and defined
intrinsic subtypes of breast cancer incuding luminal A, luminal B, HER-2 enriched, basal like, and normal like.66,67
Multiple studies have shown important interactions between
intrinsic subtype and prognosis.66,68 These intrinsic subtypes
reveal the limitations of classic histologic prognostic factors,
such as tumor grade, ER, and HER-2 by immunohistochemistry in that all the intrinsic subtypes are present in cohorts of
patients with ER-positive or ER-negative tumors.69 A recent
publication by Parker et al69 reports on the development of
risk of relapse predictor based on a 50-gene set (PAM50
assay) that classifies breast tumors by intrinsic subtypes. This
PAM50 assay was used to develop a risk of relapse model that
generates a score that was also highly predictive of response
to neoadjuvant anthracycline and taxane chemotherapy. The
development of this and other molecular profiling models70
represent exciting advances that may allow one to further
personalize preoperative systemic therapy for specific tumor types in the future.

Conclusions
In LABC, the use of preoperative systemic therapy has been
shown to induce tumor response, to improve surgical options because of the tumor response to therapy, to facilitate
local control through subsequent surgery and radiation therapy, and to improve survival. Preoperative systemic therapy
is established as the standard of care for patients with LABC.
Preoperative therapy should be administered as part of a
multimodality treatment program. When patients are given
preoperative systemic therapy, the preferred therapeutic regimens are the same as those established as safe and active in
the adjuvant setting. A variety of clinical, imaging, and pathologic measurements are available to gauge tumor response to
treatment. At present, there are no data to suggest that systemic treatment should be tailored in one direction or another based on the initial tumor response or the lack thereof
(except in the setting of frank disease progression while on
treatment) or the extent of residual disease.
The preoperative setting provides a unique opportunity to
study the impact of systemic therapies on breast cancer biology. Using pCR and other pathologic measures as surrogate
endpoints, it is hoped that promising therapies can undergo
preliminary evaluation and then be definitely studied in
larger, adjuvant trials. The preoperative setting can thus serve
as a testing ground, and preoperative trials are likely to be-

Neoadjuvant chemotherapy
come more prevalent over the next decade. Research in the
preoperative setting has the potential to facilitate drug development and lead to more rapid improvements in the care of
women with breast cancer.

227

20.

References
1. Davila E, Vogel CL: Management of locally advanced breast cancer
(stage III): A review. Int Adv Surg Oncol 7:297-327, 1984
2. Zucali R, Uslenghi C, Kenda R, et al: Natural history and survival of
inoperable breast cancer treated with radiotherapy and radiotherapy
followed by radical mastectomy. Cancer 37:1422-1431, 1976
3. Hortobagyi GN: Comprehensive management of locally advanced
breast cancer. Cancer 66:1387-1391, 1990
4. Caceres B, Zaharia M, Lingan M, et al: Combined therapy of stage III
adenocarcinoma of the breast. Proc Am Assoc Cancer Res 21:199, 1980
5. Knight WA, Rivkin SE, Glucksberg H, et al: Adjuvant therapy of breast
cancer. The Southwest Oncology Group experience. Breast Cancer Res
Treat 3:27-33, 1983
6. Buzdar AU, Kau SW, Smith TL, et al: Ten year results of FAC adjuvant
chemotherapy trial in breast cancer. Am J Clin Oncol 12:123-128,
1989
7. Wolmark N, Wang J, Mamounas E, et al: Preoperative chemotherapy in
patients with operable breast cancer: Nine-year results from national
surgical adjuvant breast and bowel project B18. J Natl Cancer Inst
Monogr 30:96-102, 2001
8. Rastogi P, Anderson SJ, Bear HD, et al: Preoperative chemotherapy:
Updates of national surgical adjuvant breast and bowel project protocols B18 and B27. J Clin Oncol 26:778-785, 2008
9. Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant systemic treatment in breast cancer: A meta-analysis. J Natl Cancer Inst
97:188-194, 2005
10. Hortobagyi GN, Ames FC, Buzdar AU, et al: Management of stage III
primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer 62:2507-2516, 1988
11. Valagussa P, Zambetti M, Bonadonna G, et al: Prognostic factors in
locally advanced noninflammatory breast cancer. Long-term results
following primary chemotherapy. Breast Cancer Res Treat 15:137-147,
1990
12. Ragaz J, Olivotto IA, Spinelli JJ, et al: Locoregional radiation therapy in
patients with high-risk breast cancer receiving adjuvant chemotherapy:
20-year results of the British Columbia randomized trial. J Natl Cancer
Inst 97:116-126, 2005
13. Jacquillat C, Baillet F, Weil M, et al: Results of a conservative treatment
combining induction (neoadjuvant) and consolidation chemotherapy,
hormonotherapy and external and interstitial irradiation in 98 patients
with locally advanced breast cancer (IIIA-IIIB). Cancer 61:1977-1982,
1988
14. Serrou B, Sancho-Garnier H, Cappelaere P, et al: Results of a randomized trial of prophylactic chemotherapy in T3-4 breast cancer patients
previously treated by radiotherapy. Recent Results Cancer Res 68:105108, 1978
15. Bonadonna G, Valagussa P, Brambilla C, et al: Primary chemotherapy in
operable breast cancer: Eight year experience of the Milan Cancer Institute. J Clin Oncol 16:93-100, 1998
16. Hutcheon AW, Heys SD, Sarkar TK, et al: Neoadjuvant docetaxel in
locally advanced breast cancer. Breast Cancer Res Treat 79:S19-S24,
2003 (suppl 1)
17. Evans TRJ, Yellowlees A, Foster E, et al: phase III randomized trial of
doxorubicin and docetaxel versus doxorubicin and cyclophosphamide
as primary medical therapy in women with breast cancer: An AngloCeltic Cooperative Oncology Group study. J Clin Oncol 23:29882995, 2005
18. Untch M, Konecny G, Ditsch N: Dose dense sequential epiribucinpaclitaxel as preoperative treatment of breast cancer: Results of a randomized AGO study. Proc Am Soc Clin Oncol 21:a133, 2002
19. Therasse P, Mauriac L, Welnicka-Jaskiewicz M, et al: Final results of a
randomized phase III trial comparing cyclophosphamide, epirubicin
and fluorouracil with dose intensified epirubicin and cyclophospha-

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.
32.

33.

34.

35.

36.

mide filgrastim as neoadjuvant treatment in locally advanced breast

cancer: An EORTC-NCIC-SAKK multicenter study. J Clin Oncol
21:843-850, 2003
Ellis GK, Green SJ, Russell CA, et al: SWOG 0012, a randomized phase
III comparison of standard doxorubicin and cyclophosphamide followed by weekly paclitaxel versus weekly doxorubicin and daily oral
cyclophosphamide plus G-CSF followed by weekly paclitaxel as neoadjuvant therapy for inflammatory and locally advanced breast cancer.
Proc Am Soc Clin Oncol 24:LBA537, 2006
Von Minckwitz G, Kmmel S, Vogel P, et al: Neoadjuvant vinorelbinecapecitabine versus docetaxel-doxorubicin-cyclophosphamide in early
non-responsive breast cancer: phase III randomized GeparoTrio trial.
J Natl Cancer Inst 100:542-551, 2008
Von Minckwitz G, Kmmel S, Vogel P, et al: Intensified neoadjuvant
chemotherapy in early-responding breast cancer: Phase III randomized
GeparoTrio study. J Natl Cancer Inst 100:552-562, 2008
Smith IC, Heys SD, Hutcheon AW, et al: Neoadjuvant chemotherapy in
breast cancer: Enhanced response with docetaxel. J Clin Oncol 20:
1456-1466, 2002
Thomas E, Holmes FA, Smith TL, et al: The use of alternate, non-crossresistant adjuvant chemotherapy on the basis of pathologic response to
neoadjuvant doxorubicin-based regimen in women with operable
breast cancer: Long-term results from a prospective randomized trial.
J Clin Oncol 22:2294-2302, 2004
Eiermann W, Paepke S, Appfelstaedt J, et al: Preoperative treatment of
postmenopausal breast cancer patients with letrozole: A randomized
double-blind multicenter study. Ann Oncol 12:1527-1532, 2001
Smith IE, Dowsett M, Ebbs SR, et al: Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: The immediate preoperative anastrozole, tamoxifen, or combined with tamoxifen (IMPACT) multicenter double-blind randomized
trial. J Clin Oncol 23:5108-5116, 2005
Cataliotti L, Buzdar AU, Noguchi S, et al: Comparison of anastrozole
versus tamoxifen as preoperative therapy in postmenopausal women
with hormone receptor-positive breast cancer: The pre-operative
Arimidex compared to tamoxifen (PROACT) trial. Cancer 106:20952103, 2006
Semiglazov VF, Amiglozov V, Ivanov V, et al: The relative efficacy of
neoadjuvant endocrine therapy versus chemotherapy in postmenopausal women with ER-positive breast cancer. Proc Am Soc Clin Oncol
23:a591, 2004
Dowsett M, Smith IE, Ebbs SR, et al: Prognostic value of Ki67 expression after short-term pre-surgical endocrine therapy for primary breast
cancer. J Natl Cancer Inst 99:167-170, 2007
Ellis MJ, Coop A, Singh B, et al: Letrozole is more effective neoadjuvant
endocrine therapy than tamoxifen for ErbB-1-and/or ErbB-2-positive,
estrogen receptor-positive primary breast cancer: Evidence from a
Phase III Randomized Trial. J Clin Oncol 19:3808-3816, 2001
Macaskill EJ, Dixon JM: Neoadjuvant use of endocrine therapy in breast
cancer. Breast J 13:243-250, 2007
Bates T, Riley DL, Houghton J, et al: Breast cancer in elderly women: A
cancer research campaign trial comparing treatment with tamoxifen
and optimal surgery with tamoxifen alone. The Elderly Breast Cancer
Working Party. Br J Surg 78:591-594, 1991
Fennessy M, Bates T, MacRae K, et al: Late follow-up of a randomized
trial of surgery plus tamoxifen versus tamoxifen alone in women aged
over 70 years with operable breast cancer. Br J Surg 91:699-704, 2004
Buzdar AU, Valero V, Ibrahim NK, et al: Neoadjuvant therapy with
paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal
growth factor receptor 2-positive operable breast cancer: An update of
the initial randomized study population and data of additional patients
treated with the same regimen. Clin Cancer Res 13:228-233, 2007
Gianni L, Eiermann W, Semiglazov V, et al: Neoadjuvant trastuzmab in
patients with Her-2 positive locally advanced breast cancer: Primary
efficacy analysis of the NOAH trial. Presented at the 31st Annual San
Antonio Breast Cancer Symposium. San Antonio, TX, December 10-14,
2008
Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for

J. Specht and J.R. Gralow

228

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.
51.

52.

HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743,

2006
Spector NL, Blackwell K, Hurley J, et al: EGF103009, a phase II trial of
lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): Clinical activity and biologic predictors of
response: Presented at the ASCO Annual Meeting, Atlanta, GA, June
2-6 2006. J Clin Oncol 24:502, 2006 (suppl)
Cristofanilli M, Boussen H, Ben Ayed F: A phase II combination study
of lapatinib (TYKERB) and paclitaxel as neoadjuvant therapy in patients
with newly diagnosed inflammatory breast cancer. IBC. Presented at
29th Annual San Antonio Breast Cancer Symposium. San Antonio, TX,
December 14-17, 2006
Miller K, Wang M, Gralow J, et al: Paclitaxel plus bevacizumab versus
paclitaxel alone for metastatic breast cancer. N Engl J Med 357:26662676, 2007
Wedam SB, Low JA, Yang SX, et al: Antiangiogenic and antitumor
effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 24:769-777, 2006
Greil R, Moik M, Reitsamer R, et al: Neoadjuvant bevacizumab, docetaxel and capecitabine combination therapy for HER2/neu-negative
invasive breast cancer: Efficacy and safety in a phase II pilot study. Eur
J Surg Oncol 2009 July 13; [epub ahead of press]
Hurvitz SA, Bosserman LD, Leland-Jones B, et al: A multicenter, double-blind randomized phase II trial of neoadjuvant treatment with single-agent bevacizumab or placebo, followed by docetaxel, doxorubicin,
and cyclophosphamide (TAC), with or without bevacizumab, in patients with stage II or stage III breast cancer: Presented at ASCO Annual
Meeting. Chicago, IL, May 30-June 3, 2008
Feldman LD, Hortobagyi GN, Buzdar AU, et al: Pathological assessment of response to induction chemotherapy in breast cancer. Cancer
Res 46:2578-2581, 1986
Sataloff DM, Mason BA, Prestipino AJ, et al: Pathologic response to
induction chemotherapy in locally advanced carcinoma of the breast: A
determination of outcome. J Am Coll Surg 180:297-304, 1995
Honkoop AH, Pinedo HM, de Jong JS, et al: Effects of chemotherapy on
pathologic and biologic characteristics of locally advanced breast cancer. Am J Clin Pathol 107:211-218, 1997
Honkoop AH, van Diest PJ, de Jong JS, et al: Prognostic role of clinical,
pathological and biological characteristics in patients with locally advanced breast cancer. Br J Cancer 77:621-626, 1998
Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on outcome of women with operable breast cancer. J Clin Oncol
16:93-100, 1998
Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breast
cancer patients with complete pathologic primary tumor and axillary
lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460-469, 1999
Guarneri V, Broglio K, Kau S, et al: Prognostic value of pathologic
complete response after primary chemotherapy in relation to hormone
receptor status and other factors. J Clin Oncol 24:1037-1044, 2006
Buzdar AU: Preoperative chemotherapy treatment of breast cancer: A
review. Cancer 110:2394-2407, 2007
Mazouni C, Peintinger F, Wan-Kau S, et al: Residual ductal carcinoma
in situ in patients with complete eradication of invasive breast cancer
after neoadjuvant chemotherapy does not adversely affect patient outcome. J Clin Oncol 25:2650-2655, 2007
Kuerer HM, Newman LA, Buzdar AU, et al: Residual metastatic axillary
nodes following neoadjuvant chemotherapy predict disease-free sur-

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.
67.

68.

69.

70.

vival in patients with locally advanced breast cancer. Am J Surg

176:502-509, 1998
Machiavelli MR, Romero AO, Prez JE, et al: Prognostic significance of
pathological response of primary tumor and metastatic axillary lymph
nodes after neoadjuvant chemotherapy for locally advanced breast carcinoma. Cancer J Sci 4:125-131, 1998
Gajdos C, Tartter PI, Estabrook A, et al: Relationship of clinical and
pathologic response to neoadjuvant chemotherapy and outcome of
locally advanced breast cancer. J Surg Oncol 80:4-11, 2002
McCready DR, Hortobagyi GN, Kau SW, et al: The prognostic significance of lymph node metastasis after preoperative chemotherapy for
advanced breast cancer. Arch Surg 124:21-25, 1989
Bonadonna G, Valagussa P, Brambilla C, et al: Primary chemotherapy in
operable breast cancer: Eight-year experience at the Milan Cancer Institute. J Clin Oncol 16:93-100, 1998
Carey LA, Dees EC, Sawyer L, et al: The triple negative paradox: Primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer
Res 13:2329-2334, 2007
Liedtke C, Mazouni C, Hess KR, et al: Response to neoadjuvant therapy
and long-term survival in patients with triple negative breast cancer.
J Clin Oncol 26:1275-1281, 2008
Ogston KN, Miller ID, Payne S, et al: A new histological grading system
to assess response of breast cancers to primary chemotherapy: Prognostic significance and survival. Breast 12:320-327, 2003
Symmans WF, Peintinger F, Hatzis C, et al: Measurement of residual
breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 28:4414-4422, 2007
Bear HD, Anderson S, Smith RE, et al: Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National surgical adjuvant breast
and bowel project protocols B27. J Clin Oncol 24:2019-2027, 2006
Colleoni M, Viale G, Zahrieh D, et al: Chemotherapy is more effective in
patients with breast cancer not expressing steroid hormone receptors: A
study of preoperative treatment. Clin Cancer Res 10:6622-6628, 2004
Fisher ER, Wang J, Bryant J, et al: Pathobiology of preoperative chemotherapy findings from the national surgical adjuvant breast and bowel
project (NSABP) protocols B18. Cancer 95:681-695, 2002
Faneyte IF, Schrama JG, Peterse JL, et al: Breast cancer response to
neoadjuvant chemotherapy: Predictive markers and relation to outcome. Br J Cancer 88:406-412, 2003
Mittendorf EA, Tucker SL, Meric-Bernstam A: Relationship between
extent of estrogen receptor (ER) expression and pathologic complete
response and pathologic complete response rates after administration
of neoadjuvant chemotherapy: Presented at the ASCO Breast Cancer
Symposium. Washington, DC, September 5-7, 2008
Perou CM, Srlie T, Eisen MB, et al: Molecular portraits of human
breast tumors. Nature 406:747-752, 2000
Srlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of
breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001
Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breast
tumor subtypes in independent gene expression sets. Proc Natl Acad
Sci U S A 100:8418-8423, 2003
Parker JS, Mullins M, Cheang MCU, et al: Supervised risk predictor of
breast cancer based on intrinsic subtypes. J Clin Oncol 27:1160-1167,
2009
Gianni L, Zambetti M, Clark K, et al: Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in
women with locally advanced breast cancer. J Clin Oncol 23:72657277, 2005

Breast Conservation Therapy for

Patients With Locally Advanced Breast Cancer
Mohamed A. Alm El-Din, MD,*, and Alphonse G. Taghian, MD, PhD*
Neoadjuvant chemotherapy achieves high response rates in patients with breast cancer
and has been used to reduce tumor size and allow for breast conservation in individuals
who initially required mastectomy. The goals of this approach are to achieve optimal
locoregional control together with acceptable cosmesis. In the setting of locally advanced
disease, breast preservation appears to be feasible for appropriately selected patients
whose tumors show adequate downstaging in response to induction chemotherapy. Nevertheless, further prospective randomized trials are warranted to better evaluate the results
of this approach as compared with mastectomy.
Semin Radiat Oncol 19:229-235 2009 Elsevier Inc. All rights reserved.
KEYWORDS breast cancer, locally advanced, breast conservation

astectomy followed by postmastectomy radiation has

been the standard of treatment for patients with locally
advanced breast cancer (LABC) in that a breast-conserving
approach for patients with larger primary tumors may not
have been technically feasible, may not have been as effective,
and may have resulted in significant cosmetic deformity.
However, since the introduction of neoadjuvant chemotherapy (NACT), a large number of patients with locally advanced primary disease have enjoyed a conservative approach. This review addresses some of the issues and
concerns related to the use of this approach.

Success
Rates of Breast
Conservation After NACT
A number of studies and clinical trials have shown that breast
conservation after NACT is possible for selected patients who
otherwise would require mastectomy. A study from M. D.
Anderson Cancer Center was one of the early reports that
investigated the feasibility of breast conservation after induction chemotherapy in patients with locally advanced dis-

*Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Department of Radiation Oncology, Tanta University Hospitals, Tanta Faculty of Medicine, Tanta, Egypt.
Address reprint requests to Alphonse G. Taghian, MD, PhD, Department of
Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street
Cox Building 302, Boston, MA 02114. E-mail: ataghian@partners.org.

1053-4296/09/$-see front matter 2009 Elsevier Inc. All rights reserved.

doi:10.1016/j.semradonc.2009.05.005

ease.1 Mastectomy specimens from 143 patients with stage

IIB and III breast cancer (77% stage IIIA or IIIB) were retrospectively analyzed after NACT. A complete response was
observed in 16%, whereas 86% were considered as partial
responders. The authors were able to define strict selection
criteria for breast conservation on the basis of the pathologic
assessment of mastectomy specimens. These criteria included complete resolution of skin edema, residual tumor
size of less than 5 cm, no evidence of multicentric lesions,
and the absence of extensive intramammary lymphatic invasion or extensive microcalcifications. The authors found that
23% of this study cohort would have been eligible for conservative surgery rather than modified radical mastectomy on
the basis of these criteria.
Two randomized prospective trials, the National Surgical
Adjuvant Breast and Bowel Project (NSABP) B18 trial and
European organization of research and treatment of cancer
(EORTC) 10902 trial, which compared preoperative versus
postoperative chemotherapy, have showed that a higher percentage of patients among preoperative chemotherapy arms
underwent breast-conserving surgery.2-4 Among the B18
trial, there was an overall increase in lumpectomies by 12% in
the preoperative chemotherapy group. The improvement in
lumpectomy rate was more pronounced, with 7-fold increase, in patients with tumors 5 cm. In the 10902 trial, 57
patients (23%), among the preoperative chemotherapy
group, underwent breast-conserving surgery and not the
planned mastectomy.
Other smaller studies have also indicated that breast conservation is feasible after NACT. In a study involving 97
229

M.A. Alm El-Din and A.G. Taghian

230
Table 1 Local Recurrence Rate for Breast-Conserving Surgery After NACT
Study
al10

McIntoch, et
Chen, et al12
Shen, et al11
Clark, et al8
Hunt, et al9
NSABP B184
Asoglu, et al13
Mauriac, et al14

Population

Stage

Number of BCS

LRR (%)

Median Follow-up (mo)

173*
340
33
34
93
1531
28
272

T2 > 4 cm, T3, T4 or N2

I-III
IIIB and IIIC
T3/T4, N0-2
IIA-IV
T1-3, N0-1
IIB-IIIB
T2 > 3 cm/T3, N0-1

44
340
33
15
86
503
28
40

2
5
6
6.6
9.7
10.7
14
22.5

62
60
60
30
55
114
60
124

Abbreviations: BCS, breast-conserving surgery; LRR, locoregional recurrence rate; NSABP, National Surgical Adjuvant Breast and Bowel
Project.
*Data available for 166.
Supraclavicular metastases only.
The number of lumpectomies among patients who had preoperative chemotherapy.
The rate of ipsilateral breast tumor recurrence.

patients with LABC, the addition of docetaxel to CVAP (cyclophosphamide, vincristine, doxorubicin, and prednisone)
as opposed to further CVAP as induction chemotherapy resulted in higher complete clinical and pathologic response,
and this translated into a higher breast conservation rate
(67% v 48%).5 In another study on a small cohort of patients
with LABC (n 29) who received NACT, Lebowitz et al6
found that 59% underwent breast conservation, whereas
only 13% were considered eligible for this type of surgery at
presentation. In the NSABP B27 trial, 2,411 patients with
operable breast cancer were randomized to anthracyclines
with or without taxanes.7 Although the pathologic complete
response was doubled (26.1% v 13.7%), there was no significant improvement with regard to the rate of the breast conservation rate (61.6% v 63.7%) or the overall survival.
Several studies have documented acceptable rates of local
recurrence in patients with breast cancer undergoing breast
conservation after NACT (Table 1).4,8-12 However, when interpreting such data, it is important to consider that some of
these studies included both patients with early stage and
those with locally advanced disease. In the NSABP B18, there
was no significant difference in the rates of ipsilateral breast
tumor recurrence (IBTR) between women treated with
lumpectomy in the setting of preoperative versus postoperative chemotherapy. However, the rate of IBTR among patients who underwent breast conservation after their tumors
had been downstaged by NACT was significantly higher
compared with that encountered among those who were initially candidates for breast conservation (15.9% v 9.9%, P
.04).4 It is important to note that the selection of type of
surgery was not randomized in the B18 study, which might
affect the accuracy of the results. Asoglu et al13 reported
slightly higher locoregional recurrence (LRR) rate in a group
of patients with LABC who were treated by induction chemotherapy followed by surgery. Most of this study cohort
(75%) was stage III (Table 1). Mauriac et al14 also reported a
higher rate of isolated local recurrence among breast cancer
patients with operable tumors larger than 3 cm who were
treated by initial chemotherapy (Table 1).
Buchholz et al15 suggested that higher rates of local recurrence among patients undergoing breast conservation after

NACT could be explained by the small volume of resection

that might not be appropriate for a large tumor that has
responded to induction chemotherapy. Several prospective clinical trials have addressed the issue of survival in
patients with early stage or LABC receiving preoperative
chemotherapy versus those receiving postoperative chemotherapy.2,4,14,16-20 These trials have confirmed overall
survival equivalence for the two approaches further emphasizing the safety of the NACT. Based on these results together
with the advantage of improving tumor resectability, induction chemotherapy followed by surgery and radiation has
become the preferred approach for patients with bulky, locally advanced disease at the time of diagnosis. Furthermore,
Kuerer et al21 and Schwartz et al17 reported better disease-free
and overall survival in patients with LABC undergoing breast
conservation after NAC. However, when the responders were
stratified with regard to age, there was no difference in survival between the mastectomy arm and the breast conversation arm. In addition, the studies with better survival in patients with LABC undergoing breast conservation after
induction chemotherapy as compared with those undergoing
mastectomy might represent selection bias because the breast
conservation group likely includes patients who achieve a good
response to chemotherapy.

Concerns Over This

Approach/Volume of Resection
As shown in several pathologic studies, the pattern of response to induction chemotherapy is not uniform but rather
heterogeneous, with some cases leaving clusters of viable
tumor cells at a distance from the central residual tumor
site.3,22 This might explain the discrepancy between the clinical and the pathologic response to induction chemotherapy
that was reported in several studies.3,21,23-25
In a retrospective study by Clouth et al,26 101 patients
with LABC underwent NACT. Twenty-five patients (25%)
achieved a complete clinical and radiologic response and
were subjected to multiple core biopsies centrally and at all
four quadrants. Pathologic examination revealed pathologic

Breast conservation therapy

complete response in 16 patients, and they received adjuvant
radiotherapy with no further surgery. Most of the patients
(8/9) who had residual disease underwent mastectomy indicating the existence of tumor in more than one quadrant
despite achieving complete clinical and radiologic response
after NACT. In another study of 226 patients with tumors 3
cm (87% had tumors between 3 and 5 cm) receiving NACT
followed by surgery, the histopathology showed multifocality in the primary tumor in 37 patients (16.3%) and complete
pathologic response was seen in only 8 patients (3.5%).22
Therefore, the assessment of tumor response to induction
chemotherapy with the elimination of patients with multifocal disease is crucial when offering breast conservation in
patients with LABC undergoing NACT.

Appropriate Selection Criteria

Several institutions have reported their experience regarding
the role of breast conservation following induction chemotherapy for LABC, nevertheless the fraction of patients offered breast conservation varies tremendously due to variability of methods utilized as well as the inconsistence of
selection criteria.
The eligibility criteria for breast conservation after induction chemotherapy in LABC are similar to those applied in
early-stage breast cancer. Presence of multicentric disease,
extensive micro-calcification, extensive skin changes, and
lymphatic permeation are generally considered as contraindications for breast conservation in those patients.27 Mathew
et al28 suggested that breast conservation should be performed for selected group of patients with LABC particularly
those who achieve pathological complete response after
NACT. Nevertheless, patients who respond partially with a
significant downstaging of the tumor size, as long as lumpectomy is technically feasible, could also be candidates for conservative surgery after NACT.
In the study from M. D. Anderson Cancer Center, 110 of
143 patients were not considered as good candidates for
breast conservation after induction chemotherapy.1 Among
those patients, 55 (50%) had tumor in other quadrants. The
factors most commonly associated with multiple quadrant
involvement were persistent skin edema, residual tumor size
larger than 4 cm, extensive intramammary lymphatic invasion and mammographic evidence of multicentric disease.
The patient desire for breast preservation is an important
issue and should be also considered.
Magnetic resonance imaging (MRI) may also play an important role in better identification of patients who would be
good candidates for breast conservation following NACT.
Multiple studies have addressed the benefit of MRI in patients
with known breast cancer reporting that approximately 9%
will be found to have multicentric disease that was not detected by conventional imaging.29-33 Evaluation of disease
response to chemotherapy is another potential role of breast
MRI in the setting of preoperative chemotherapy. Several
studies have suggested a greater agreement between MRI and
extent of residual disease as compared to that achieved with
physical examination or conventional imaging.34-38 Yet, the

231
role of breast MRI to evaluate the feasibility of breast conservation after NACT has to be defined. Concerns regarding the
sensitivity, the availability and the cost of MRI should be also
considered. Positron emission tomography scans, as predictors of pathological response, have been also tried but the
data remain immature and require further validation.39

Importance of
Prechemotherapy Clip Placement
Localization of the tumor within the breast following NACT
appears to be challenging particularly in the subset of patients who achieve a complete clinical or radiological response. In a study by Edeiken et al,40 implantation of metallic
markers guided by ultrasound has shown to be optimal in
localization of the tumor bed in case complete response occurs following NACT. In 23 patients (47%), the metallic
markers were the only remaining marker for the tumor bed
following NACT. The authors added that the metallic markers showed no evidence of migration as comparisons were
made on mammograms after implantation and shortly before
surgery. The position of the markers was also confirmed on
histopathological examination by proximity to fibrosis or
scar tissue related to post-chemotherapy changes.
In a recent study from M. D. Anderson Cancer Center, the
omission of radio-opaque clip placement in patients undergoing preoperative chemotherapy was associated with increased incidence of local recurrence.41 The 5-year rate of
local control was 98.6% in patients who had radio-opaque
clips placed versus 91.7% in patients who did not have tumor
marker clips placed (P .02). The authors recommended
placement of radio-opaque clips in the tumor bed before or
during NACT to facilitate accurate tumor bed localization
and to reduce the risk of breast tumor recurrence. However,
clip placement may not be required for lesions associated
with microcalcifications as they have an inherent target for
subsequent localization. Skin tattooing has been shown to be
effective in identification of the tumor bed as suggested by
Veronesi et al.22 Nevertheless, localization by metallic markers has been more popular among surgeons particularly with
the advent of recent imaging modalities.

Radiotherapy After
Breast Conservation in LABC
As in early breast cancer, postoperative radiotherapy is an
integral part in the management of patients with LABC undergoing breast conservation. The technique of irradiation is
generally the same; however, existing data are limited regarding whether comprehensive irradiation is absolutely necessary to achieve optimal locoregional control in patients
whose tumors achieve substantial degree of downstaging in
response to chemotherapy.
The results of surgical pathology have been traditionally
used to estimate the odds of locoregional recurrence following surgery in breast cancer patients and hence identifying
those who would benefit from nodal irradiation. However,

232
this could not be applied for patients undergoing preoperative chemotherapy with an expected response rate up to 80%.
The investigators at M. D. Anderson Cancer Center suggest
that, in the preoperative chemotherapy setting, both the initial clinical stage and the final pathologic extent of the disease
independently predict the risk of a locoregional recurrence.42
After NACT and mastectomy, comprehensive radiation
was found to benefit both local control and survival for patients presenting with clinical T3 tumors or stage lll-IV (ipsilateral supraclavicular nodal) disease and for patients with
four or more positive nodes.43 The 5-year locoregional recurrence rate in 12 patients with stage III disease who achieved
a pathologic complete remission, remained high when radiation was not used (33.3% 15.7%).44 Therefore, for selected patients undergoing breast conservation after NACT,
irradiation of the supraclavicular and may be the upper internal mammary nodes might be considered in conjunction
with breast radiotherapy regardless the response to systemic
treatment. Mauriac et al14 highlighted the role of surgery for
axillary control as they reported higher nodal relapse in patients undergoing preoperative chemotherapy who were
treated exclusively by nodal irradiation as compared to those
who had axillary dissection (10 v 1, respectively).
The data from NSABP B-18 & B-27 and M. D. Anderson
Cancer Center suggest that patients with clinical stage II disease who have negative lymph nodes after induction chemotherapy have an 8-year risk of LRR after mastectomy that is
less than 10%.45,46 Given that local or regional radiotherapy
was not given in the above mentioned studies, the rate of LRR
does not appear to justify nodal irradiation in this subset of
patients. The power of such conclusions is limited and needs
further confirmation in prospective randomized trials especially all patients from the above mentioned studies underwent axillary dissections (with or without sentinel lymph
node surgery).
Another challenge in the setting of postoperative radiotherapy in patients with LABC undergoing NACT is the boost
volume. The question is whether or not the pre-chemotherapy volume should be irradiated particularly in patients
whose tumors show significant or complete response to induction chemotherapy. Although the issue of irradiating the
pre- or post-chemotherapy is still controversial, the majority
of institutions consider the pre-chemotherapy size. However,
the cosmetic results of irradiating such large volume, in some
cases, need to be addressed because a large portion of the
breast will be included in the treatment portals.

Predictors of
Locoregional Failure
The investigators at M. D. Anderson Cancer Center reported
the results of NACT and breast conversation in 340 women,
of whom 130 (38%) were stage III.12 At a median follow-up
period of 60 months, the 5-year actuarial rates of IBTR-free
and LRR-free survival were 95% and 91%, respectively. Rates
of IBTR and LRR were correlated with clinical N2 or N3
disease, pathologic residual tumor larger than 2 cm, a multi-

M.A. Alm El-Din and A.G. Taghian

focal pattern of residual disease, and lymphovascular invasion. The presence of any one of these factors was associated
with 5-year actuarial IBTR-free and LRR-free survival rates of
87% to 91% and 77% to 84%, respectively. Nevertheless, the
authors concluded that breast conservation is an acceptable
modality of treatment after induction chemotherapy for patients with stage III disease.
The previously mentioned four parameters were incorporated into a classification system that can be used in clinical
decision-making and to counsel patients treated with this
multimodality approach.47 The M. D. Anderson Prognostic
Index (MDAPI) was developed by assigning scores of 0 (favorable) or 1 (unfavorable) for each of these four variables
and using the total to give an overall MDAPI score of 0-4.
Using the MDAPI score, patients who undergo breast conservation after NACT can be stratified into a low, intermediate,
or high-risk group for IBTR and LRR. Patients with a score of
3 to 4, LRR was 60% after breast conservation and was
0% with mastectomy.48 The authors suggested that according to MDAPI score, patients at higher risk of recurrence may
benefit from alternative locoregional treatment strategies.
Asoglu et al13 suggested that negative surgical margins following breast conservation in patients undergoing NACT
could be more important than clinical and histological parameters in terms of prediction of local recurrence rate.

Predictors of
Disease-Free and Overall Survival
The NSABP B-18 trial confirmed the association between the
category of clinical response to induction chemotherapy and
survival in operable breast cancer.4 Of the 682 patients, 247
(36%) had complete clinical response and 88 (13%) had
complete pathological response. At 9 years of follow-up, the
rates of disease-free survival was 64% in patients with complete clinical response compared to 46% in non-responders
(stable disease and progressive disease; P 0.0008). The
overall survival was similarly better (75% v 65%, P 0.005).
In this study, histological response was found to be better
predictor of outcome. At 9 years, the disease-free survival in
patients who achieved complete pathological response was
75% compared to 58% for incomplete responders (P
0.0005). For overall survival the rates were 85% and 73%
(P .00008).
In a randomized controlled trial including patients with
LABC, Heys et al5 reported significant increase in disease-free
survival at 3 years in those with better clinical and pathological response (90% v 77%, P 0.03). Another study of 200
patients with LABC, 17.6% had complete clinical response
and 12.2% had complete pathological response.49 Patients
with complete clinical response had better recurrence-free
and overall survival as compared to those with partial response (79% and 85%, v 40% and 52%, respectively; P
0.0001). The recurrence-free and overall survival were also
significantly better for patients with complete pathological
response (85% for both) as compared to those with incomplete response (52% and 59%, respectively; P 0.0001). In

Breast conservation therapy

the prospective study by Kuerer et al21 that included 372
patients with LABC receiving NACT, the 5-year disease-free
and overall survival of the patients who achieved complete
pathological response (87% and 89%, respectively) was
significantly better than that of patients who did not respond completely to chemotherapy (58% and 64%, respectively; P 0.01).
The residual disease in the axilla following NACT has been
reported to be a poor prognostic factor for the outcome.22,50,51 Rouzier et al50 reported an interesting finding on
multivariate analysis of the data of 152 patients with T1 to T3
tumors with cytologically proven metastasis in the axilla. The
authors found that conversion of positive to negative nodes
(occurred in 23%) was a strong predictor of survival (P
0.01) where complete pathological response in the breast was
a marker of pathological axillary conversion following chemotherapy rather than a predictor of survival by itself.

Is Breast Surgery Necessary?

The choice of local treatment modality after NACT has been
always an area of major controversy particularly in patients
with complete clinical response. After NACT, surgery and
radiotherapy have been tried solely or in combination in the
context of multidisciplinary approach. Touboul et al52
treated 147 patients with tumors more than 3 cm with four
cycles of chemotherapy. Ninety-five patients were eligible for
breast conservation (48; complete response and 47; residual
disease). Patients with complete response received only radiotherapy boost where those with residual disease underwent wide excision and received two more cycles of chemotherapy followed by radiotherapy. The 5-year overall survival
in the patients who underwent wide excision and radiotherapy was 81% as compared to 65% in the radiotherapy alone
group. For those who underwent mastectomy, the 5-year
survival was 76%. Another French study reported extremely
high rate of locoregional recurrence (34%) in a group of
breast cancer patients who were treated by initial chemotherapy followed by breast and nodal irradiation with no surgery.14
The results of two meta-analyses stressed on the potential
role of surgery in breast cancer patients receiving NACT. The
first meta-analysis evaluated the results of nine randomized
studies, including a total of 3946 patients with breast cancer.53 Among the included studies, the tumor size ranged
from T0 to T4b where the nodal status ranged from N0 to N2.
Primary outcomes were death, disease progression, distant
disease failure, and locoregional disease recurrence. The authors reported no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy
arms associated with death (risk ratio [RR] 1.00; 95%
confidence interval [CI], 0.90 to 1.12), disease progression
(RR 0.99; 95% CI, 0.91 to 1.07), or distant disease failure
(RR 0.94; 95% CI, 0.83 to 1.06). However, the risk of
locoregional disease recurrences (RR 1.22; 95% CI, 1.04 to
1.43) was significantly higher in neoadjuvant therapy compared with adjuvant therapy, particularly in trials where
more patients in the neoadjuvant arm received radiation

233
therapy without surgery (RR 1.53; 95% CI, 1.11 to 2.10).
The authors recommended avoiding the use of radiotherapy
without any surgical treatment, even in the presence of an
apparently good clinical response to NACT.
More recently, the rates of breast conservation as well as
the rates of local recurrence were examined in those receiving
NACT compared to those receiving adjuvant chemotherapy
in meta-analysis of 11 studies including over 5000 patients
with operable breast cancer.54 Despite the significantly decreased rates of mastectomy among the neoadjuvant group,
the local recurrence rates were significantly higher among the
same group. In the three studies, which account for more
than one third of the patients, radiotherapy was the only
modality of local treatment as surgery was not done after
complete response. After exclusion of the results of these
studies, there was no significant difference between the two
groups with regard to local recurrence (Hazard Ratio 1.12;
95% CI, 0.92-1.37).
Resection is also essential for documenting chemotherapy
response and achieving locoregional control.55 Surgery,
therefore, remains the mainstay in management of patients
with LABC receiving NACT as clinical assessment could be
deceiving.

Review of Data
In summary, breast conservation after NACT appears to be
feasible in patients with LABC because it offers an acceptable
rate of disease control. The proper selection of patients who
are candidates for this modality is crucial because it will affect
the treatment outcome in terms of locoregional control rate,
disease-free survival, and overall survival. Pre-chemotherapy
clip placement is an integral part if breast conservation is to
be considered after NACT, especially for those patients who
might achieve complete clinical and radiologic responses.
Frozen section and histopathological examination at the time
of breast-conserving surgery could be important because the
findings from the pathology might reveal a high probability
of multicentricity, which would preclude the use of a conservative approach.

References
1. Singletary SE, McNeese MD, Hortobagyi GN: Feasibility of breast-conservation surgery after induction chemotherapy for locally advanced
breast carcinoma. Cancer 69:2849-2852, 1992
2. Fisher B, Brown A, Mamounas E, et al: Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project
B-18. J Clin Oncol 15:2483-2493, 1997
3. van der Hage JA, van de Velde CJ, Julien JP, et al: Preoperative chemotherapy in primary operable breast cancer: results from the European
Organization for Research and Treatment of Cancer trial 10902. J Clin
Oncol 19:4224-4237, 2001
4. Wolmark N, Wang J, Mamounas E, et al: Preoperative chemotherapy in
patients with operable breast cancer: Nine-year results from National
Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst
Monogr 30:96-102, 2001
5. Heys SD, Hutcheon AW, Sarkar TK, et al: Neoadjuvant docetaxel in
breast cancer: 3-year survival results from the Aberdeen trial. Clin
Breast Cancer 3:S69-S74, 2002 (suppl 2)

M.A. Alm El-Din and A.G. Taghian

234
6. Lebowitz PF, Eng-Wong J, Swain SM, et al: A phase II trial of neoadjuvant docetaxel and capecitabine for locally advanced breast cancer. Clin
Cancer Res 10:6764-6769, 2004
7. Bear HD, Anderson S, Smith RE, et al: Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast
and Bowel Project Protocol B-27. J Clin Oncol 24:2019-2027, 2006
8. Clark J, Rosenman J, Cance W, et al: Extending the indications for
breast-conserving treatment to patients with locally advanced breast
cancer. Int J Radiat Oncol Biol Phys 42:345-350, 1998
9. Hunt KK, Singletary SE, Smith TL: Conservation surgery and radiation:
the M.D. Anderson experience, in Bland KI, Copeland EM III (eds): The
Breast (ed 2). Philadelphia, PA, Saunders, 1998, p 1179
10. McIntosh SA, Ogston KN, Payne S, et al: Local recurrence in patients
with large and locally advanced breast cancer treated with primary
chemotherapy. Am J Surg 185:525-531, 2003
11. Shen J, Valero V, Buchholz TA, et al: Effective local control and longterm survival in patients with T4 locally advanced breast cancer treated
with breast conservation therapy. Ann Surg Oncol 11:854-860, 2004
12. Chen AM, Meric-Bernstam F, Hunt KK, et al: Breast conservation after
neoadjuvant chemotherapy: the MD Anderson cancer center experience. J Clin Oncol 22:2303-2312, 2004
13. Asoglu O, Muslumanoglu M, Igci A, et al: Breast conserving surgery
after primary chemotherapy in locally advanced breast cancer. Acta
Chir Belg 105:62-68, 2005
14. Mauriac L, MacGrogan G, Avril A, et al: Neoadjuvant chemotherapy for
operable breast carcinoma larger than 3 cm: a unicentre randomized
trial with a 124-month median follow-up. Institut Bergonie Bordeaux
Groupe Sein (IBBGS). Ann Oncol 10:47-52, 1999
15. Buchholz TA, Lehman CD, Harris JR, et al: Statement of the science
concerning locoregional treatments after preoperative chemotherapy
for breast cancer: A National Cancer Institute conference. J Clin Oncol
26:791-797, 2008
16. Mauriac L, Durand M, Avril A, et al: Effects of primary chemotherapy in
conservative treatment of breast cancer patients with operable tumors
larger than 3 cm. Results of a randomized trial in a single centre. Ann
Oncol 2:347-354, 1991
17. Schwartz GF, Birchansky CA, Komarnicky LT, et al: Induction chemotherapy followed by breast conservation for locally advanced carcinoma of the breast. Cancer 73:362-369, 1994
18. Schwartz GF, Lange AK, Topham AK: Breast conservation following
induction chemotherapy for locally advanced carcinoma of the breast
(stages IIB and III). A surgical perspective. Surg Oncol Clin N Am
4:657-669, 1995
19. Powles TJ, Hickish TF, Makris A, et al: Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary
breast cancer. J Clin Oncol 13:547-552, 1995
20. Makris A, Powles TJ, Ashley SE, et al: A reduction in the requirements
for mastectomy in a randomized trial of neoadjuvant chemoendocrine
therapy in primary breast cancer. Ann Oncol 9:1179-1184, 1998
21. Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breast
cancer patients with complete pathologic primary tumor and axillary
lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460-469, 1999
22. Veronesi U, Bonadonna G, Zurrida S, et al: Conservation surgery after
primary chemotherapy in large carcinomas of the breast. Ann Surg
222:612-618, 1995
23. Bonadonna G, Valagussa P, Brambilla C, et al: Primary chemotherapy in
operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 16:93-100, 1998
24. Gardin G, Rosso R, Campora E, et al: Locally advanced non-metastatic
breast cancer: analysis of prognostic factors in 125 patients homogeneously treated with a combined modality approach. Eur J Cancer
31A:1428-1433, 1995
25. von Minckwitz G, Costa SD, Eiermann W, et al: Maximized reduction
of primary breast tumor size using preoperative chemotherapy with
doxorubicin and docetaxel. J Clin Oncol 17:1999-2005, 1999
26. Clouth B, Chandrasekharan S, Inwang R, et al: The surgical management of patients who achieve a complete pathological response after

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

primary chemotherapy for locally advanced breast cancer. Eur J Surg

Oncol 33:961-966, 2007
Rustogi A, Budrukkar A, Dinshaw K, et al: Management of locally
advanced breast cancer: evolution and current practice. J Cancer Res
Ther 1:21-30, 2005
Mathew J, Asgeirsson KS, Cheung KL, et al: Neoadjuvant chemotherapy for locally advanced breast cancer: a review of the literature and
future directions. Eur J Surg Oncol 35:113-122, 2009
Harms SE, Flamig DP, Hesley KL, et al: MR imaging of the breast with
rotating delivery of excitation off resonance: clinical experience with
pathologic correlation. Radiology 187:493-501, 1993
Fischer U, Kopka L, Grabbe E: Breast carcinoma: effect of preoperative
contrast-enhanced MR imaging on the therapeutic approach. Radiology 213:881-888, 1999
Mumtaz H, Hall-Craggs MA, Davidson T: Staging of symptomatic primary breast cancer with MR imaging. AJR Am J Roentgenol 169:417424, 1997
Liberman L, Morris EA, Dershaw DD, et al: MR imaging of the ipsilateral breast in women with percutaneously proven breast cancer. AJR
Am J Roentgenol 180:901-910, 2003
Schelfout K, Van Goethem M, Kersschot E, et al: Contrast-enhanced
MR imaging of breast lesions and effect on treatment. Eur J Surg Oncol
30:501-507, 2004
Balu-Maestro C, Chapellier C, Bleuse A, et al: Imaging in evaluation of
response to neoadjuvant breast cancer treatment benefits of MRI. Breast
Cancer Res Treat 72:145-152, 2002
Rosen EL, Blackwell KL, Baker JA, et al: Accuracy of MRI in the detection of residual breast cancer after neoadjuvant chemotherapy. AJR
Am J Roentgenol 181:1275-1282, 2003
Weatherall PT, Evans GF, Metzger GJ, et al: MRI vs. histologic measurement of breast cancer following chemotherapy: comparison with
x-ray mammography and palpation. J Magn Reson Imaging 13:868-75,
2001
Yeh E, Slanetz P, Kopans DB, et al: Prospective comparison of mammography, sonography, and MRI in patients undergoing neoadjuvant
chemotherapy for palpable breast cancer. AJR Am J Roentgenol 184:
868-877, 2005
Partridge SC, Gibbs JE, Lu Y, et al: Accuracy of MR imaging for revealing residual breast cancer in patients who have undergone neoadjuvant
chemotherapy. AJR Am J Roentgenol 179:1193-1199, 2002
Kim SJ, Kim SK, Lee ES, et al: Predictive value of [18F]FDG PET for
pathological response of breast cancer to neo-adjuvant chemotherapy.
Ann Oncol 15:1352-1357, 2004
Edeiken BS, Fornage BD, Bedi DG, et al: US-guided implantation of
metallic markers for permanent localization of the tumor bed in patients with breast cancer who undergo preoperative chemotherapy.
Radiology 213:895-900, 1999
Oh JL, Nguyen G, Whitman GJ, et al: Placement of radiopaque clips for
tumor localization in patients undergoing neoadjuvant chemotherapy
and breast conservation therapy. Cancer 110:2420-2427, 2007
Buchholz TA, Tucker SL, Masullo L, et al: Predictors of local-regional
recurrence after neoadjuvant chemotherapy and mastectomy without
radiation. J Clin Oncol 20:17-23, 2002
Huang EH, Tucker SL, Strom EA, et al: Postmastectomy radiation improves local-regional control and survival for selected patients with
locally advanced breast cancer treated with neoadjuvant chemotherapy
and mastectomy. J Clin Oncol 22:4691-4699, 2004
McGuire SE, Gonzalez-Angulo AM, Huang EH, et al: Postmastectomy
radiation improves the outcome of patients with locally advanced
breast cancer who achieve a pathologic complete response to neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys 68:1004-1009, 2007
Garg AK, Strom EA, McNeese MD, et al: T3 disease at presentation or
pathologic involvement of four or more lymph nodes predict for locoregional recurrence in stage II breast cancer treated with neoadjuvant
chemotherapy and mastectomy without radiotherapy. Int J Radiat Oncol Biol Phys 59:138-145, 2004
Mamounas T: Sentinel node biopsy after neoadjuvant chemotherapy:
The pros. Presented at Preoperative Therapy in Invasive Breast Cancer:

Breast conservation therapy

47.
48.

49.

50.

Reviewing the State of the Science and Exploring New Research

Directions. National Cancer Institute, March 26, 2007, Bethesda, MD
Chen AM, Meric-Bernstam F, Hunt KK, et al: Breast conservation after
neoadjuvant chemotherapy. Cancer 103:689-695, 2005
Huang EH, Strom EA, Perkins GH, et al: Comparison of risk of localregional recurrence after mastectomy or breast conservation therapy for
patients treated with neoadjuvant chemotherapy and radiation stratified according to a prognostic index score. Int J Radiat Oncol Biol Phys
66:352-357, 2006
Thomas E, Holmes FA, Smith TL, et al: The use of alternate, non-crossresistant adjuvant chemotherapy on the basis of pathologic response to
a neoadjuvant doxorubicin-based regimen in women with operable
breast cancer: long-term results from a prospective randomized trial.
J Clin Oncol 22:2294-2302, 2004
Rouzier R, Extra JM, Klijanienko J, et al: Incidence and prognostic significance of complete axillary downstaging after primary chemotherapy in
breast cancer patients with T1 to T3 tumors and cytologically proven
axillary metastatic lymph nodes. J Clin Oncol 20:1304-1310, 2002

235
51. Kuerer HM, Newman LA, Buzdar AU, et al: Residual metastatic axillary
lymph nodes following neoadjuvant chemotherapy predict disease-free
survival in patients with locally advanced breast cancer. Am J Surg
176:502-509, 1998
52. Touboul E, Lefranc JP, Blondon J, et al: Primary chemotherapy and
preoperative irradiation for patients with stage II larger than 3 cm or
locally advanced non-inflammatory breast cancer. Radiother Oncol 42:
219-229, 1997
53. Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant systemic treatment in breast cancer: A meta-analysis. J Natl Cancer Inst
97:188-194, 2005
54. Mieog JS, van der Hage JA, van de Velde CJ: Preoperative chemotherapy for women with operable breast cancer. Cochrane Database Syst
Rev CD005002, 2007
55. Hortobagyi GN, Ames FC, Buzdar AU, et al: Management of stage III
primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer 62:2507-2516, 1988

Postmastectomy Radiation Therapy for

Patients With Locally Advanced Breast Cancer
Reshma Jagsi, MD, DPhil, and Lori Pierce, MD
Radiation therapy is an integral component of the multimodal treatment of locally advanced
breast cancer. Even after mastectomy and systemic therapy, occult residual disease in the
chest wall and/or regional lymph nodes may serve as the source of morbid locoregional
recurrence as well as the source of distant seeding or reseeding of metastases. Thus,
postmastectomy radiation therapy offers substantial benefits in appropriately selected
patients. This review article summarizes the data from randomized trials revealing a
significant benefit from postmastectomy radiation therapy in patients with locally advanced
disease as well as results from other relevant studies. It concludes with a summary of
consensus guideline recommendations in this important area.
Semin Radiat Oncol 19:236-243 2009 Elsevier Inc. All rights reserved.

or patients with pathologic stage III breast cancer either

historically defined1 or as defined in the current 6th edition of the American Joint Committee on Cancers Cancer
Staging Manual,2 radiation therapy is an integral component
of multimodal treatment. Even after mastectomy and systemic therapy, occult disease may remain in the chest wall
and/or regional lymph nodes. This residual disease may serve
not only as a source of potentially morbid locoregional recurrence but also as an important reservoir from which distant
metastases may be seeded or reseeded after the initial elimination of distant disease by sophisticated modern systemic
therapies. Interest in postmastectomy radiation therapy
(PMRT) stems from the concept that when an isolated locoregional reservoir of tumor cells remains after surgery and systemic therapy, if radiation therapy is able to eliminate this
reservoir, PMRT may contribute both to the improvement of
local control and also to the reduction of breast cancer-related mortality.
In 2005, the Oxford Early Breast Cancer Trialists Collaborative Group published a landmark update of their comprehensive meta-analysis, considering data from 8,505 women
with lymph node-positive disease treated with mastectomy
and axillary clearance and enrolled on randomized trials of
PMRT. In this update, which included patients enrolled on
trials initiated through 1995, the 5-year local recurrence risk
was reduced with radiotherapy from 22.8% to 5.8%, with
15-year breast cancer mortality risks of 54.7% v 60.1% (re-

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.

Address reprint requests to Reshma Jagsi, MD, DPhil, Department of Radiation Oncology, UHB2C490, SPC 5010, 1500 East Medical Center
Drive, Ann Arbor, MI 48109-5010. E-mail: rjagsi@med.umich.edu

236

1053-4296/09/$-see front matter 2009 Elsevier Inc. All rights reserved.

doi:10.1016/j.semradonc.2009.05.009

duction 5.4%, 2P .0002) and an overall mortality reduction of 4.4% (64.2% v 59.8%, 2P .0009).3 Figure 1 shows
these findings. Thus, there has now been documented not
only substantial improvement in local control but also a clear
overall survival (OS) advantage because of the use of PMRT in
node-positive patients.
These findings provide a strong rationale for the use of
radiation therapy in the management of patients with locally
advanced breast cancer. In this article, we first review the
evidence gathered from the randomized trials of PMRT regarding the relative reduction in risk of locoregional recurrence afforded by radiotherapy and associated effects on
survival, including a detailed discussion of the issues of appropriate patient selection that continue to generate debate in
the field. We then turn to the particular complexities introduced into the decision-making process when neoadjuvant
chemotherapy has been used. Finally, we conclude by presenting a summary of the consensus statements issued by
various professional societies and organizations to guide
practice in this area.

Evidence From
Randomized Trials
PMRT has been a subject of considerable study over the past
several decades. Multiple randomized trials have consistently
revealed a substantial reduction in the risk of locoregional
recurrence of breast cancer with the use of PMRT.4-6
However, most early studies failed to show an improvement in OS, and meta-analyses suggested that the benefits of
PMRT in cancer control were offset by treatment-related tox-

Postmastectomy radiation therapy

237

Figure 1 Early Breast Cancer Trialists Collaboratve Group meta-analysis results regarding effects of PMRT in nodepositive patients. (Reprinted with permission.3)

icity, especially cardiotoxicity.7 Outdated radiation techniques, such as anterior hockey stick photon fields, led
large volumes of the heart to receive high doses of radiation in
many older studies. Therefore, the salutary effect of PMRT
upon OS was not convincingly established until large studies
utilizing modern techniques of radiotherapy matured.
The Eastern Cooperative Oncology Group conducted a
trial from 1982 to 1987 focusing exclusively on patients with
operable locally advanced disease as defined by 1978 American Joint Committee on Cancer staging treated with both
mastectomy and systemic therapy.8 It included patients with
pathologic T4 lesions excluding T4d disease, T3 lesions with
positive nodes, N2 disease (defined as metastases to ipsilateral lymph nodes fixed to one another or to other structures),
or earlier stage lesions fixed to underlying muscle. Patients
underwent modified or standard radical mastectomy with
grossly tumor-free margins and had examination of at least
8 axillary nodes. Patients went on to receive 6 courses of
cyclophosphamide, doxorubicin, fluorouracil, tamoxifen,
and fluoxymesterone (CAFTH) systemic therapy and were
then randomized to PMRT or observation. By focusing on a
group at high risk of locoregional recurrence, all of whom
received systemic therapy in the hopes of addressing any
distant micrometastatic disease that existed on presentation,
and by using relatively modern techniques and doses of radiotherapy, this study attempted to address many of the concerns of critics of the previous trials. Unfortunately, high
rates of noncompliance with treatment assignment and insufficient numbers of patients analyzed with relatively short follow-up to allow detection of a modest survival difference
ultimately limited the impact of the study.9 The analysis of
outcomes in the 312 randomized patients, after a median
follow-up of 9 years, revealed a significant and substantial
reduction in locoregional recurrence as a component of initial failure in patients who were assigned to radiotherapy
PMRT (15% v 24%). However, PMRT had no detectable im-

pact on overall time to relapse or survival in this series of

locally advanced breast cancer patients.
In contrast, randomized trials from Denmark and British
Columbia, initially published in 1997, did finally show a
significant survival benefit from PMRT. The British Columbia
trial randomized 318 premenopausal patients with pathologically positive lymph nodes, status post modified radical mastectomy with axillary lymph node dissection, to CMF chemotherapy alone or chemotherapy and PMRT to the chest wall
and regional lymph nodes.10 In this study, PMRT both reduced locoregional failure (from 28% to 10%) and improved
OS (20-year OS improved from 37% to 47%, P .03). The
Danish 82b trial randomized 1,708 premenopausal women
with high-risk breast cancer (defined as involvement of the
axillary nodes, tumor size 5 cm, or invasion of the skin or
pectoral fascia), status post total mastectomy and axillary
dissection, to CMF chemotherapy and PMRT to the chest
wall and regional lymph nodes v CMF chemotherapy alone.11
In this study, PMRT also led to both a reduction in locoregional failure (from 32% to 9%) and an improvement in OS
(10-year OS improved from 45% to 54%, P .001). The Danish 82c trial randomized 1,375 postmenopausal high-risk breast
cancer patients younger than 70 years of age, status post total
mastectomy and axillary dissection, to radiation therapy plus
tamoxifen v tamoxifen alone.12 Again, PMRT reduced locoregional recurrence (from 35% to 8%) and improved OS (10-year
OS improved from 36% to 45%, P .03). Of note, in each of
these 3 trials, PMRT benefited not only patients with 4 or more
axillary nodes involved but also those with 1 to 3 nodes positive.
Together, these studies have been extremely influential in shifting opinion in favor of PMRT, at least for patients at high risk of
locoregional recurrence, such as those presenting with locally
advanced disease by current staging.
These studies met with certain criticisms, however. These
included concerns about the adequacy of the surgery performed. The median number of lymph nodes removed in the

R. Jagsi and L. Pierce

238
Danish study was only 7, lower than that expected from a
standard level I/II axillary dissection, prompting the concern
that inadequate regional surgery may have led to the underestimation of the true extent of axillary disease in these patients and possibly also contributed to an increased incidence
of locoregional failures. Because locoregional recurrence
rates after mastectomy (and without PMRT) in retrospective
American series of patients with 1 to 3 positive lymph nodes
have been lower (13% in large series from Eastern Cooperative Oncology Group13 and the National Surgical Adjuvant
Breast and Bowel Project (NSABP)14) than those observed in
the Danish and British Columbia studies, some have questioned the role of PMRT for American patients with only 1 to
3 lymph nodes involved. Indeed, consensus panels convened
in this country around the turn of the millennium concluded
that the evidence to support PMRT was only strong enough to
sustain a recommendation for patients with 4 or more lymph
nodes involved as well as a suggestion for treatment for patients with T3, node-positive disease.15 For patients with 1 to
3 lymph nodes involved, these panels concluded there was
insufficient evidence to make suggestions or recommendations for the routine use of PMRT, and practice in the United

States became divided between radiation oncologists who

routinely treat and those who routinely observe this subgroup of patients.16 Unfortunately, the Intergroups randomized study designed to assess the role of PMRT in American
patients with 1 to 3 positive lymph nodes failed to accrue and
closed in 2003.
More recently, however, increasing evidence has accumulated in support of a role for PMRT even among patients with
1 to 3 lymph nodes involved. The Danish studies were
pooled and reanalyzed to include only the 1152 node-positive patients with 8 or more lymph nodes removed. A survival
benefit of the same absolute magnitude (9%) was observed in
patients with 1 to 3 lymph nodes involved as among patients
with 4 or more lymph nodes involved, even though the locoregional recurrence rates were lower among the former
group (Fig. 2).17 This led the authors to note that the survival
benefit of PMRT is likely related to the ability of systemic
therapy to eliminate any existing metastatic deposits at the
time of diagnosis; therefore, PMRT may be particularly important in the subgroup of patients with less extensive nodal
involvement in whom the burden of distant disease at diagnosis is likely to be less substantial (and potentially more

Figure 2 Findings from the subset analysis of the Danish postmastectomy trials. (Reprinted with permission.17)

Postmastectomy radiation therapy

amenable to elimination by systemic therapies) or absent.
Further compelling findings have emerged from the Oxford
Early Breast Cancer Trialists Collaborative Groups metaanalysis, as discussed earlier.
Although the participants in the Danish and Canadian trials were primarily patients with node-positive disease, patients with large or advanced primaries and node-negative
disease were included in the Danish trials and may also benefit from PMRT. Patients with node-negative disease who
have large or otherwise locally advanced primary tumors,
although uncommon, have traditionally been considered at
high risk for locoregional recurrence after mastectomy in the
absence of radiation therapy.18,19 Moreover, in the Danish
trials, not only the node-positive patients but also patients
with node-negative high risk disease (ie, tumor size greater
than 5 cm and/or invasion to skin or pectoral fascia) appeared
to benefit from radiotherapy. More specifically, among the
135 node-negative patients in the 82b randomized trial, locoregional recurrence was 3% among patients treated with
chemotherapy and radiation and 17% in those treated with
chemotherapy alone; 10-year disease-free survival was 74%
in patients treated with radiation and chemotherapy and
62% in those treated with chemotherapy alone, and 10-year
OSs were 82% and 70%, respectively.11 In the 82c randomized trial, among the 132 node-negative patients included,
local recurrence as first recurrence occurred in 6% of the
patients treated with radiation and tamoxifen and 23% in
those treated with tamoxifen alone; 10-year disease-free survival was 43% in patients treated with radiation and tamoxifen and 40% in those treated with tamoxifen alone, and
10-year OS was 56% and 55%, respectively.12 Given these
findings, we continue to advocate the routine use of PMRT in
women with large or locally advanced primary tumors and
node-negative disease.
We should note, however, that the use of radiotherapy in
patients with small, node-negative T3 lesions warrants discussion. Recent studies have suggested that rates of locoregional recurrence may be lower than expected among patients with node-negative, borderline T3 (stage II) disease. A
recent retrospective study of 70 patients treated at 3 institutions by mastectomy and systemic therapy (but no PMRT) for
T2-3, N0 disease (with mean tumor size of 6 cm) revealed a
5-year locoregional recurrence rate of only 7.6%.20 Another
recent study examined the long-term outcomes of 313 stage
II node-negative patients with tumors greater than or equal to
5 cm (with a median tumor size of 5.5 cm) who underwent
mastectomy but not PMRT in 5 NSABP trials.21 The investigators found that the overall 10-year cumulative incidence of
isolated locoregional failure was 7.1%, and the incidence of
locoregional failure with or without distant failure in this
population was 10.0%. They were unable to identify any
statistically significant prognostic factors for locoregional
failure. With such low incidences of locoregional failure over
an extended follow-up period, the authors recommended
that patients with T2-3 primaries and negative axillae not
undergo PMRT. It is important to note, however, that these
were small, retrospective series, and the median size of the
tumors in these studies was on the smaller end of the spec-

239
trum for T3 tumors so that relatively fewer tumors of extremely large size were included. Patients with T3N0 tumors
still warrant consultation with a radiation oncologist who
may discuss these data with the patient as well as the prospective data showing benefit after the use of PMRT in patients with large or advanced primary tumors and node-negative disease. Furthermore, in light of evidence from several
other retrospective studies of node-negative patients that included patients with smaller primary tumors,22-24 it may be
prudent to consider a number of other potential prognostic
features, including patient age, tumor size, margin status,
presence of lymphovascular invasion, use of systemic therapy, and nuclear grade, when determining whether to use
PMRT in patients with node-negative disease without clearly
advanced primary tumors for whom the risk of locoregional
failure appears to be less substantial. Further prospective
studies are ongoing and necessary to quantify the potential
benefits of PMRT in this group.25
Ultimately, all patients with locally advanced breast cancer
merit consultation with radiation oncology because there is
strong consensus regarding the need for treatment in patients
with stage III disease. Patients with stage II disease should be
counseled regarding their estimated risks of locoregional recurrence in the absence of radiotherapy, the estimated benefit in terms of locoregional control expected from radiotherapy, and the estimated impact on OS associated with this
treatment so that they may determine whether they wish to
receive treatment.

Patients Treated With

Neoadjuvant Chemotherapy
Because none of the patients enrolled on the randomized
trials of PMRT just discussed were treated with neoadjuvant
systemic therapy, appropriate patient selection for PMRT after neoadjuvant therapy is more complicated than when
pathologic staging has been unaffected by disease response to
systemic agents. In the absence of prospective trials, decisions regarding the role of PMRT in patients treated with
neoadjuvant chemotherapy have largely been guided by retrospective analyses.
Investigators at the M. D. Anderson Cancer Center have
conducted a series of retrospective studies seeking to illuminate these issues. Their data suggest that both the initial
clinical stage and final pathologic extent of disease are independently predictive of the risk of locoregional failure in the
setting of neoadjuvant chemotherapy and that radiation therapy is effective at reducing this risk. For example, in one
analysis, they compared the outcomes of 542 patients treated
with neoadjuvant chemotherapy, mastectomy, and PMRT
with the outcomes of a control group of 134 patients not
treated with PMRT. At 10 years, local-regional recurrence
rates were significantly lower for irradiated patients at 11%
compared with 22%.26 The small subset of patients who presented with clinical stage III disease who subsequently
achieved a complete pathologic response to systemic therapy
also had a significantly reduced locoregional recurrence rate

240
compared with patients not treated with PMRT. At 10 years,
these patients had a 3% rate of locoregional recurrence (1
event among 35 patients) v 33% (3 events among 11 patients)
in nonirradiated patients. Postmastectomy radiation also improved cause-specific survival in patients with stage IIIB disease, clinical T4 tumors, and greater than 4 positive lymph
nodes. The authors suggested that PMRT should be considered for patients in all of these subsets, regardless of their
response to preoperative systemic chemotherapy.
A follow-up retrospective review of the same series of 542
patients was published in 2005 examining the risk factors
associated with locoregional recurrence after PMRT.27 The
authors remarked on the importance of disease staging both
before and after neoadjuvant chemotherapy because several
risk factors were associated with either the pretreatment or
posttreatment extent of disease. For the patients who were
treated with PMRT after neoadjuvant chemotherapy and
mastectomy, supraclavicular nodal involvement on presentation was associated with a higher risk of locoregional recurrence after treatment. On postneoadjuvant chemotherapy assessment, evidence of skin or nipple involvement and
extracapsular invasion were also strongly correlated with
LRR. The lack of tamoxifen use postoperatively was also associated with increased LRR, but, because of the preponderance of patients with ER-negative disease with increased LRR,
it was believed to be of little clinical significance. Of note,
ER-receptor negative disease was the strongest predictor of
LRR in this group. Patients with 1 or none of these factors had
a 4% 10-year LRR rate, but this rate jumped to 28% with the
presence of 3 or more risk factors.
The NSABP trials of neoadjuvant chemotherapy, in which
PMRT was not administered, also offer an opportunity to
determine which patients face substantial risks of locoregional failure in the absence of PMRT. In the B18 study,
among patients undergoing mastectomy, multivariate analysis of risk factors for locoregional recurrence were similar in
both the pre- and postoperative chemotherapy arms with
respect to age less than 50 years (related to the use of tamoxifen only in women 50 years of age) and pathologically
positive axillary nodes. Breast tumor response was also significantly associated with local control in patients receiving
neoadjuvant chemotherapy.28 A pooled analysis of the B18
and B27 trials, conducted by Mamounas,29 reveals an 8-year
risk of locoregional recurrence of 15% for 447 patients with
residual positive lymph nodes on pathologic evaluation after
neoadjuvant chemotherapy (Fig. 3).
In 2008, a multidisciplinary expert panel organized by the
National Cancer Institute published a statement of the science concerning locoregional treatments after preoperative
chemotherapy for breast cancer.30 That statement concludes
that PMRT should be considered for patients presenting with
clinical stage III disease or with histologically positive lymph
nodes after preoperative chemotherapy. It further concludes
that there is a need for prospective trials to evaluate the benefits of PMRT in patients with clinical stage II disease who
have negative lymph nodes after preoperative chemotherapy.
In any case, given the complexities of assessing risks based on
prechemotherapy clinical data and postchemotherapy pa-

R. Jagsi and L. Pierce

Figure 3 Eight-year cumulative incidence of locoregional failure

among patients treated with mastectomy and without radiotherapy
on NSABP neoadjuvant chemotherapy studies B18 and B27 (E.
Mamounas, unpublished data).

thology in patients treated with neoadjuvant chemotherapy,

treatment in a multidisciplinary context with radiation oncology consultation before any treatment commences would
be especially prudent in these cases.

Consensus Guidelines
The complexities of the data described earlier motivated several professional societies to develop practice guidelines regarding the use of PMRT. The American Society of Clinical
Oncology (ASCO) Health Services Research Committee commissioned a multidisciplinary panel of breast cancer experts
for an in-depth review of worldwide data on locoregional
failure from breast cancer and the ability of PMRT to reduce
risk of locoregional as well as distant relapse.31 When evidence-based data were inadequate, the expert panel was
charged with using their expert opinion to assess the utility of
PMRT. The panels systematic, graded review of all published
evidence regarding PMRT was assembled into a clinical practice guideline as summarized in Table 1.
Of note, the language used to express the guidelines has
very specific implications. Recommendation refers to
guidelines based on level I or level II data. Level I data are
derived from meta-analyses of multiple well-designed, controlled studies or from highly powered, randomized trials.
Level II data are based on at least 1 well-designed experimental trial and low-powered randomized trials. Suggestion
refers to guidelines based on data from levels III, IV, or V.
Data in these levels are weaker so these guidelines are based
in some part on consensus from the ASCO panel. Insufficient evidence denotes a lack of either evidence or panel
consensus regarding the population in question.
The ASCO PMRT practice guideline includes recommendations for the routine use of PMRT in cases of highest-risk
breast cancer, as defined by disease with at least 4 metastatic
lymph nodes. PMRT was suggested for cases of operable stage
III disease. The panel concluded that data regarding net ben-

Postmastectomy radiation therapy

241

Table 1 2001 ASCO Practice Guidelines for the Use of PMRT

1. Patients with 4 or more positive
axillary nodes
2. Patients with 1 to 3 positive axillary
nodes
3. Patients with T3N1 or Stage III
tumors
4. Patients undergoing preoperative
systemic therapy
5.
6.
7.
8.

9.

10.
11.

12.

13.
14.

15.

PMRT is recommended for patients with 4 or more positive axillary lymph

nodes.
There is insufficient evidence to make recommendations regarding patients with
T1/T2 tumors and 1 to 3 positive axillary nodes.
PMRT is suggested for patients with T3 tumors with positive axillary nodes and
patients with operable stage III tumors.
There is insufficient evidence to make recommendations whether patients
initially treated with preoperative systemic therapy should be given PMRT
after surgery.
Modification of these guidelines for
There is insufficient evidence for modifying the above guidelines based on other
special patient subgroups
tumor-related, patient-related, or treatment-related factors.
Chest wall irradiation
In patients given PMRT, the panel suggests that adequately treating the chest
wall is mandatory.
Details of chest wall irradiation
There is insufficient evidence for the panel to recommend aspects of chest wall
irradiation, such as total dose, fraction size, bolus use, and scar boosts.
Axillary nodal irradiation
The panel suggests that full axillary radiotherapy not be given routinely to
patients undergoing complete or level I/level II axillary dissection. There is
insufficient evidence to suggest whether some patient subgroups may benefit
from axillary irradiation.
Supraclavicular nodal irradiation for
The incidence of clinical supraclavicular failure is sufficiently great in patients
patients with 4 or more positive
with four or more positive axillary nodes that the panel suggests
axillary nodes
supraclavicular field radiation in all such patients.
Supraclavicular irradiation for patients There is insufficient evidence to state whether supraclavicular radiation should
with 1-3 positive axillary nodes
or should not be used in patients with one to three positive axillary nodes.
Internal mammary nodal irradiation
There is insufficient evidence to make recommendations on whether deliberate
internal mammary nodal irradiation should or should not be used in any
patient subgroup.
Sequencing of PMRT and systemic
There is insufficient evidence to recommend the optimal sequencing of
therapy
chemotherapy, tamoxifen, and PMRT. The panel does suggest, given the
available evidence regarding toxicities, that doxorubicin not be administered
concurrently with PMRT.
Integration of PMRT and
There is insufficient evidence to make recommendations with regard to the
reconstructive surgery
integration of PMRT and reconstructive surgery.
Long-term toxicities
The potential long-term risks of PMRT include lymphedema, brachial plexopathy,
radiation pneumonitis, rib fractures, cardiac toxicity, and radiation-induced
second neoplasms. There is sufficient evidence for the panel to suggest that,
in general, the risk of serious toxicity of PMRT (when performed using modern
techniques) is low enough that such considerations should not limit its use
when otherwise indicated. However, follow-up in patients treated with current
radiotherapy techniques is insufficient to rule out the possibility of very late
cardiac toxicity.
Toxicity consideration for special
There is insufficient evidence to make recommendations that PMRT should not
patient subgroups
be used for some subgroups of patients because of increased rates of toxicity
(such as radiation carcinogenesis) compared with the rest of the population.

efits of PMRT in cases of T1 to 2 tumors and 1 to 3 metastatic

nodes were insufficient to make suggestions or recommendations for its routine use. Similarly, the panel assessed the
available evidence on using patient factors (such as age or
menopausal status) and primary tumor features (such as lymphovascular invasion) and concluded that there was insufficient evidence to make recommendations or suggestions for
modifying the guidelines based on these factors. Most of the
panel favored the routine use of PMRT in breast cancer cases
receiving neoadjuvant chemotherapy because patients with
relatively more advanced clinical stages of disease constitute
the population most likely to be referred for this treatment
sequence. However, the panel acknowledged the paucity of
clinical trial data to address this issue and concluded that no

definitive recommendation could be offered for this patient

population. Furthermore, neoadjuvant chemotherapy is used
increasingly for patients with T2 tumors as a strategy for improving lumpectomy eligibility, and this treatment sequence
is no longer restricted to cases of locally advanced disease.
Additional evidence from retrospective analyses conducted
after the time of the ASCO panel was considered by the
National Cancer Institutes consensus panel on neoadjuvant
therapy, as described earlier, and its recommendations
should be considered in addition to those of the ASCO panel
for this subset of patients.
Similar guidelines have been developed by the American
Society for Therapeutic Radiology and Oncology,32 the
American College of Radiology,33 and the Canadian Commit-

242
tee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer.34 Of note, all expert panels recommended the use of PMRT in patients with 4 or more positive
axillary nodes. They also all acknowledged the lesser clarity
surrounding patients with 1 to 3 positive axillary nodes. Of
note, the ASTRO experts stated, The data regarding patient
selection for survival advantage are less clear, but the most
recent evidence suggests that the greatest survival benefit is
seen in node-positive patients with low tumor burdens (i.e.,
fewer positive nodes or smaller tumors). Radiation therapy in
these patients for survival benefit is worthy of consideration,
pending more definitive data . . . . Consultation with a radiation oncologist should occur in node-positive patients
treated with mastectomy to help patients assess the risks and
benefits of PMRT. The ACR recommendations echo this
statement. Since the time of these reports, additional published analyses have shown benefit from PMRT in patients
with 1 to 3 positive nodes. Thus, discussion of the pros and
cons of PMRT is warranted in these patients.
As clinical studies continue to mature, the oncology community continues to debate the potential value of PMRT for
categories of intermediate-risk breast cancer in which data
were insufficient to warrant definitive recommendations by
expert panels. However, there is a strong consensus regarding the role of PMRT in patients with truly locally advanced
disease. Indeed, a survey of radiation oncologists found that
the vast majority (98%) reported that they would offer
radiation to at least the chest wall in patients with 4 or more
involved lymph nodes, although there was less consensus in
the cases of T3N0 disease (in which 88.3% would offer PMRT
to the chest wall) and even less so for cases in which 1 to 3
lymph nodes were involved (with 85.2% offering PMRT to at
least the chest wall if extracapsular extension was noted and
61.7% offering it if it were absent).16 Thus, all patients with
locally advanced breast cancer merit referral to radiation oncology, and PMRT is considered an integral component of
their multimodal management.

References
1. American Joint Committee on Cancer: AJCC: Cancer staging Manuals
(eds 1-5). Chicago, IL, AJCC
2. American Joint Committee on Cancer: AJCC: Cancer Staging Manual
and Handbook (ed 6). Chicago, IL, AJCC, 2002
3. Clarke M, Collins R, Darby S, et al: Early Breast Cancer Trialists Collaborative Group: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year
survival: An overview of the randomised trials. Lancet 366:2087-2106,
2005
4. McArdle CS, Crawford D, Dykes EH, et al: Adjuvant radiotherapy and
chemotherapy in breast cancer. Br J Surg 73:264-266, 1986
5. Griem KL, Henderson IC, Gelman R, et al: The 5-year results of a
randomized trial of adjuvant radiation therapy after chemotherapy in
breast cancer patients treated with mastectomy. J Clin Oncol 5:15461555, 1987
6. Velez-Garcia E, Carpenter JT, Moore M, et al: Postsurgical adjuvant
chemotherapy with or without radiotherapy in women with breast
cancer and positive axillary nodes: A South-Eastern Cancer Study
Group (SEG) trial. Eur J Cancer 28A:1833-1837, 1992
7. Cuzick J, Stewart H, Rutqvist L, et al: Cause-specific mortality in longterm survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 12:447-453, 1994

R. Jagsi and L. Pierce

8. Olson JE, Neuberg D, Pandya KJ, et al: The role of radiotherapy in the
management of operable locally advanced breast carcinoma: Results of
a randomized trial by the Eastern Cooperative Oncology Group. Cancer
79:1138-1149, 1997
9. Fowble B: Postmastectomy radiation: A modest benefit prevails for high
risk patients. Cancer 79:1061-1066, 1997
10. Ragaz J, Olivotto IA, Spinelli JJ, et al: Locoregional radiation therapy in
patients with high-risk breast cancer receiving adjuvant chemotherapy:
20-year results of the British Columbia randomized trial. J Natl Cancer
Inst 97:116-126, 2005
11. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive
adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b
Trial. N Engl J Med 337:949-955, 1997
12. Overgaard M, Jensen MB, Overgaard J, et al: Postoperative radiotherapy
in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 353:1641-1648, 1999
13. Recht A, Gray R, Davidson NE, et al: Locoregional failure 10 years after
mastectomy and adjuvant chemotherapy with or without tamoxifen
without irradiation: Experience of the Eastern Cooperative Oncology
Group. J Clin Oncol 17:1689-1700, 1999
14. Taghian A, Jeong JH, Mamounas E, et al: Patterns of locoregional failure
in patients with operable breast cancer treated by mastectomy and
adjuvant chemotherapy with or without tamoxifen and without radiotherapy: Results from five national surgical adjuvant breast and bowel
project randomized clinical trials. J Clin Oncol 22:4247-4254, 2004
15. Recht A, Edge SB, Solin LJ, et al: Postmastectomy radiotherapy: Clinical
practice guidelines of the American Society of Clinical Oncology. J Clin
Oncol 19:1539-1569, 2001
16. Ceilley E, Jagsi R, Goldberg S, et al: Radiotherapy for invasive breast
cancer in North America and Europe: Results of a survey. Int J Radiat
Oncol Biol Phys 61:365-373, 2005
17. Overgaard M, Nielsen HM, Overgaard J: Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as
recommended by international consensus reports? A subgroup analysis
of the DBCG 82 b & c randomized trials. Radiother Oncol 82:247-253,
2007
18. Mignano JE, Gage I, Piantadosi S, et al: Local recurrence after mastectomy in patient with T3N0 breast carcinoma treated without postoperative irradiation. Breast Cancer Res Treat 41:255, 1996 (abst)
19. Helinto M, Blomqvist C, Heikkila P, et al: Post-mastectomy radiotherapy in pT3N0M0 breast cancer: Is it needed? Radiother Oncol 52:213217, 1999
20. Floyd SR, Buchholz TA, Haffty BG, et al: Low local recurrence rate
without postmastectomy radiation in node-negative breast cancer patients with tumors 5 cm and larger. Int J Radiat Oncol Biol Phys 66:
358-364, 2006
21. Taghian AG, Jeong JH, Mamounas EP, et al: Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm
or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: Results from five national surgical adjuvant
breast and bowel project randomized clinical trials. J Clin Oncol 24:39273932, 2006
22. Wallgren A, Bonetti M, Gelber RD, et al: Risk factors for locoregional
recurrence among breast cancer patients: Results from International
Breast Cancer Study Group Trials I through VII. J Clin Oncol 21:12051213, 2003
23. Jagsi R, Raad RA, Goldberg S, et al: Locoregional recurrence rates and
prognostic factors for failure in node-negative patients treated with
mastectomy: Implications for postmastectomy radiation. Int J Radiat
Oncol Biol Phys 62:1035-1039, 2005
24. Truong PT, Lesperance M, Culhaci A, et al: Patient subsets with T1-T2,
node-negative breast cancer at high locoregional recurrence risk after
mastectomy. Int J Radiat Oncol Biol Phys 62:175-182, 2005
25. Medical Research Council: SUPREMO trial. Available at: http://www.
supremo-trial.com/index.html. Accessed January 13, 2009
26. Huang EH, Tucker SL, Strom EA, et al: Postmastectomy radiation improves local-regional control and survival for selected patients with

Postmastectomy radiation therapy

27.

28.

29.

30.

locally advanced breast cancer treated with neoadjuvant chemotherapy

and mastectomy. J Clin Oncol 22:4691-4699, 2004
Huang EH, Tucker SL, Strom EA, et al: Predictors of locoregional recurrence in patients with locally advanced breast cancer treated with
neoadjuvant chemotherapy, mastectomy, and radiotherapy. Int J Radiat Oncol Biol Phys 62:351-357, 2005
Mamounas EP, Wang J, Bryant J, et al: Patterns of loco-regional failure
in patients receiving neoadjuvant chemotherapy: Results from NSABP
B18. Breast Cancer Res Treat 82:S17, 2003 (abstr 35)
Mamounas E: Sentinel node biopsy after neoadjuvant chemotherapy: The pros: Presented at Preoperative Therapy in Invasive Breast
Cancer: Reviewing the State of the Science and Exploring New Research Directions. National Cancer Institute. Bethesda, MD, March
26, 2007
Buchholz TA, Lehman CD, Harris JR, et al: Statement of the science

243

31.

32.

33.

34.

concerning locoregional treatments after preoperative chemotherapy

for breast cancer: A National Cancer Institute conference. J Clin Oncol
26:791-797, 2008
Recht A, Edge SB, Solin LJ, et al: Postmastectomy radiotherapy: Clinical
practice guidelines of the American Society of Clinical Oncology. J Clin
Oncol 19:1539-1569, 2001
Harris JR, Halpin-Murphy P, McNeese M, et al: Consensus statement
on postmastectomy radiation therapy. Int J Radiat Oncol Biol Phys
44:989-990, 1999
Taylor ME, Haffty BG, Shank BM, et al: Postmastectomy radiotherapy;
American College of Radiology, ACR: Appropriateness criteria. Radiology 215:1153-1170, 2000 (suppl)
Truong PT, Olivotto NA, Whelan TJ, et al: Clinical practice guidelines
for the care and treatment of breast cancer. 16. Locoregional postmastectomy radiotherapy. CMAJ 170:1263-1273, 2004

Radiation Techniques and

Toxicities for Locally Advanced Breast Cancer
Meena S. Moran, MD,* and Bruce G. Haffty, MD,
Radiation therapy is used in the management of locally advanced breast cancer in the
postmastectomy or neoadjuvant chemotherapy and breast-conservation setting to improve
local-regional control and survival. Using modern-day technology, the therapeutic ratio has
increased and the potential morbidity has decreased. This article reviews the technical
aspects of radiation therapy for locally advanced breast cancer with emphasis on 3-dimensional radiotherapy techniques and discusses potential toxicities and how to reduce them.
Semin Radiat Oncol 19:244-255 2009 Elsevier Inc. All rights reserved.

adiation therapy is an integral component in the multidisciplinary management of locally advanced breast cancer (LABC). In the postmastectomy setting, radiation has
been used for decades to reduce the risk of local-regional
recurrence; with modern-day techniques, postmastectomy
radiation (PMRT) for advanced-disease stages has been
shown to improve overall survival. More recently, for selected patients with LABC wishing to conserve their breast,
neoadjuvant chemotherapy is being used in an attempt to
shrink the tumor/lymph nodes before breast-conservation
therapy (conservative surgery followed by radiation to the
intact breast). The techniques for radiation treatment to the
chest wall and breast have evolved significantly since their
initial use in the 1940s. Using computed tomography (CT)
simulators, modern-day linear accelerators, computerized
treatment planning modalities, and on-board imaging techniques, the therapeutic ratio for radiation therapy in LABC
has markedly improved, whereas the potential for side effects
has diminished significantly.
In this article, the traditional tangential and more conformal radiation techniques for chest wall radiation for LABC
are reviewed. We discuss the delineation of target volumes,
doses, complications of radiation, and methods to maximize
locoregional control and minimize toxicity in the postmastectomy setting. In addition, technical aspects of radiation

*Department of Therapeutic Radiology, Yale University School of Medicine,

New Haven, CT.
Department of Radiation Oncology, UMDNJ-Robert Wood Johnson School
of Medicine, New Brunswick, NJ.
The Cancer Institute of New Jersey, New Brunswick, NJ.
Address reprint requests to Meena S. Moran, MD, Yale University School of
Medicine, 333 Cedar Street, PO Box 208040, New Haven, CT 065208040. E-mail: meena.moran@yale.edu

244

1053-4296/09/$-see front matter 2009 Elsevier Inc. All rights reserved.

doi:10.1016/j.semradonc.2009.05.007

therapy after neoadjuvant systemic therapy and breast-conserving surgery for LABC are discussed.

Target Volumes
Although it is routinely accepted that the entire chest wall
and mastectomy scar be included for PMRT, there is no consensus among physicians who treat LABC as to which nodal
basins to routinely include. Although most patients receiving
PMRT have lymph node-positive disease and therefore the
ipsilateral supraclavicular (SC) fossa is generally included in
the treatment volume, significant controversy exists as to
when to include the dissected axilla and internal mammary
(IM) nodes in the radiation treatment volumes. Despite the
use of comprehensive radiation to include all lymph nodes
at risk in the 3 most recent and important randomized studies of PMRT,1-3 the inclusion of all lymph node basins is not
uniformly used in this country for several reasons. First, there
is often an added technical difficulty in treatment planning/
delivery when attempting to include all nodal regions at risk.
Second, the increase in the target volumes comes with the
potential for adding toxicity. Furthermore, the additional
benefit of nodal radiation to chest wall radiation alone has yet
to be shown in a randomized, prospective fashion. Because of
variations in the philosophies, the target volumes to be irradiated for LABC are commonly generated based on the treating physicians opinion regarding these issues and the clinical/pathologic characteristics of each individual case and
often are influenced by the institutional policies of the treating facility. Patterns of care with respect to regional nodal
irradiation are widely variable as reflected in a worldwide
survey of radiation oncologists published by Taghian et al.4
Furthermore, the American College of Radiology ACR appropriateness criteria panel for PMRT did not reach uniform

Radiation techniques and toxicities

consensus on the treatment of IM nodes or full axillary radiation in the postmastectomy setting.5
The issue of whether or not to intentionally include the IM
nodes in all LABC cases continues to be debated and remains
controversial. The issue is currently being investigated in 2
prospective, randomized studies conducted by the European
Organization for Research Treatment of Cancer (protocol
22,922/10,925) and National Cancer Institute of Canada.
From a technical standpoint, treatment of the IM nodes is
often challenging; inclusion of IM nodes in deep tangential
fields often results in excessive radiation to the lung and heart
(particularly for left sided tumors) and other techniques,
such as the use of a matched medial electron field to more
lateral tangent fields can result in a cold triangle in an area
at risk for recurrence.
At our institutions, the SC fossa and axillary apex (level III)
are routinely included for all patients receiving PMRT for
lymph node-positive diseases, whereas the decisions regarding radiation to the IM nodes and dissected level I/II axilla are
made on a case-by-case basis. Because most patients with
LABC will have undergone a level I/II axillary nodal dissection (AND), and risk of axillary relapse in these patients is
low,6 we only intentionally include the level I/II axilla after a
nodal dissection in the following circumstances: (1) the number of lymph nodes removed was inadequate/incomplete, (2)
there is evidence of gross residual disease, (3) there is extensive extracapsular extension on pathology report suggestive
of a high residual tumor burden, or (4) an incomplete AND
or an axillary sampling was performed. For IM nodes, the
decision is individualized based on the risk of IM involvement and whether treatment would result in an excessive
amount of heart/lung based on the patients anatomy. At
some centers, comprehensive radiation is routinely delivered to all the regional nodes when PMRT is indicated, regardless of the potential technical difficulty of encompassing
all these regions. As shown in the first patterns-of-care study
of PMRT, there remains no consensus regarding regional
nodal radiation throughout the United States.7 Seventy-eight
percent of the patients who received PMRT had regional
nodal radiation. When RT to the nodes was delivered, SC
nodes were included in 98%, IM nodes in 23%, and a supplemental axillary field in 46%.7 Until results of the randomized trials become available, variability and individualized
treatment will continue to be based on the treating physicians preferences, normal tissue tolerance considerations,
and patients risk factors.

Tangential Chest
Wall Radiation Techniques
The first step in radiation therapy treatment planning is patient immobilization. Immobilization is necessary to reproduce the patients position daily, avoid radiation to normal
tissue structures and ensure treatment of targeted regions.
There are many commercially available devices for immobilization; most commonly, a breast board or a customized
foam mold are used. During immobilization, the patients

245
ipsilateral arm is abducted 90 to 120 and the shoulder is
externally rotated so the arm is out of the way of the radiation
beams. Because the sternum in most patients slopes superiorly,
which can potentially make adequate coverage of the chest wall
with the tangential beams technically difficult, the patient
should be positioned so the sternum is parallel to the table, if
possible. Once immobilized, the specific setup parameters for
immobilization are recorded for the patient to maximize the
daily reproducibility. Tentative field borders can then be placed
using radiopaque catheters on the skin for better radiographic
visualization of the field borders during the treatment planning
process.
The use of a CT simulator and virtual simulation is preferable for treatment planning purposes in that they permit
3-dimensional visualization of targets and normal tissues. A
fluoroscopic simulator can be used to set up the treatment for
the chest wall and regional nodes if CT technology is not
available. In either case, the chest wall field borders should be
clinically determined and tentatively delineated by the radiation oncologist. The chest wall field is generally defined
superiorly by the inferior portion of the clavicular head, laterally at the midaxillary line, medially to the midsternum,
and inferiorly to 2 cm below the previous location of the
inframammary fold (using the contralateral inframammary
fold as a reference, if present). The anterior field edge should
clear air by 2 to 3 cm over the chest wall, and the posterior
edge should include from 1 to 3 cm of the lung, as measured
by the perpendicular distance of the posterior edge of the
tangential field edge to the posterior portion of the anterior
chest at the center of the field.8 The entire chest wall, the
mastectomy scar, and all drainage scars, if possible, should be
encompassed in the radiation field.
The posterior edges of the medial and lateral tangential
beams are aligned so that there is no divergence into the lung
and heart. We typically do not use a collimator angle, and
blocking of the heart and lung are often achieved using multileaf collimation to shape the posterior edge of the tangent
beams. If blocks are placed, it is important to clinically recheck the fields with blocks in place to ensure that the entire
chest wall, mastectomy flap, and all scars are covered.
An alternative to tangential photon radiation is the use of
en face electrons to treat the chest wall. This technique has
been used in many centers throughout the world with comparable outcomes and toxicity to tangential photon beams.9
There can be issues related to homogeneity dependent on the
chest wall contour, patient anatomy, and difficulty in matching the electron fields to the IM and SC fields. Kirova et al10
recently reported on a modified electron technique that
showed improved homogeneity and conformality over their
standard electron technique.
Regardless of the technique used, it is important to avoid
high doses of radiation to the heart when considering different treatment techniques for left-sided lesions. In a comparison of heart doses using various postmastectomy chest wall
techniques, Pierce et al noted that the volume of heart receiving 30 Gy was least using partially wide tangent fields (described later) and as expected, greatest when using cobalt
techniques.11

246
The dose delivered to the chest wall is typically 50 Gy in
2-Gy fractions using 6-MV photons with a 0.5- to 1.0-cm
bolus placed on the entire chest wall field every other day or
for the first 20 Gy during the treatment (Fig. 1). It is important to recognize that even in patients with a reconstructed
breast, the use of bolus is recommended to ensure that the
skin and immediate subcutaneous target tissues receive an
adequate dose of radiation. The use of a boost to the mastectomy scar is variable. As reported in the American College of
Radiology Appropriateness Criteria, there are no clear data to
support or discourage the use of a boost to the mastectomy
scar, and its use remains highly individualized.5 When used,
it is typically delivered via en face electrons to a generous area
around the mastectomy scar to 60 Gy. If a patient has a
positive margin, a higher boost dose is often used (64-66 Gy).

Technique of SC Fossa and

Axillary Treatment
An oblique anterior-posterior SC field can be matched to the
chest wall fields to target the SC fossa and axillary apex. The
superior clinical border of this field is typically placed at the
level of the cricoid cartilage, inferior border abutting the superior edge of the tangential fields, medial border on the
pedicles of the vertebral bodies, and lateral border extending
to the coracoid process (Fig. 2). If the dissected axilla is to be
included, the lateral border of the SC field is extended to the
lateral aspect of the humeral head. The SC field gantry is
angled 10 to 20.
The geometric edges of the inferior border of the SC and
superior border of the tangential fields must be aligned so
that there is no divergence of the 3 beams, which would cause
hotspots and overdosing in the regions of overlap. Various
techniques have been described to match these fields, all of
which are effective in producing a uniform dose across the
match line. At our institutions, we generally use a single
isocentric technique that half beam blocks the inferior aspect
of the SC field and then the superior aspect of the tangential
fields (using the independent collimator jaws) so the beam

Figure 1 A patient receiving postmastectomy chest wall radiation

immobilized on a breast board with bolus covering the entire chest
wall field. (Color version of figure is available online.)

M.S. Moran and B.G. Haffty

Figure 2 The supraclavicular/axillary field (SAF) in yellow and the

posterior axillary boost (PAB) in red. (Color version of figure is
available online.)

edges are perfectly aligned.12 This technique requires that the

clinical borders be tentatively determined and the isocenter
location be determined along the match line of the SC and
tangent fields in the superior to inferior, anterior to posterior,
and medial to lateral axis either during fluoroscopic or CT
(virtual) simulation (Fig. 3). During treatment, the 3 fields
are treated in succession without movement of the isocenter.
Although blocks can be used (ie, to block the lung or heart in
the tangential fields or the spinal cord and central structures
in the SC field), no blocks are required with this technique to
achieve matching between the tangents and the SC field (Fig.
4). This technique is favored at our institutions because no
movement of the treatment table is required between fields
but has the limitation of a size of 20 20 cm for the tangent
fields because of the standard beam width of 40 cm on current linear accelerators. Another commonly utilized technique is the rod-and-chain13; this method uses tabletop
rotation, gantry and collimator angles, and corner blocks to
match the SC field to the tangents, and is not limited by the

Figure 3 A single isocentric technique to match SAF to the tangents.

The isocenter is not moved, and matching is achieved by half beam
blocking the superior and inferior portions of the treatment fields
with the independent collimator jaws. Image shows the medial and
lateral chest wall field and the anterior SAF projected on skin. (Color
version of figure is available online.).

Radiation techniques and toxicities

Figure 4 Digital reconstructions of the beams eye view of the single

isocentric technique to match SAF to the tangents. The isocenter is
depicted by the large dot. The 3 fields are treated in succession, and
matching does not require blocks or a couch shift. Normal tissue
structure blocking can be used as in the SAF above. (Color version
of figure is available online.)

20 cm tangent field size. Various other matching techniques

using different blocking methods14-18 have also been described in the literature. All the previously mentioned techniques adequately achieve the goal of preventing overlap of
the SC and tangential fields and will provide a uniform dose
at the match line.
The level of the SC match line placement has recently been
shown to be an important consideration to ensure adequate
coverage of the level III lymph nodes of the axillary apex.19
Placement of the superior tangential/SC match caudal to the
clavicular head results in statistically improved coverage of
the high axillary apex lymph nodes in comparison to patients
who have match lines that are more superior.
The SC field has traditionally been treated using 6-MV
photons, delivering 46 to 50 Gy to a depth of approximately
3 cm. Routine radiation prescriptions have been shown to
suboptimally cover intended targets across all body mass
indexes,20 and, therefore, optimized CT-based treatment
planning should be used whenever possible to treat the SC
nodes. Using CT simulation, the depth of the SC and level III
lymph nodes can be more precisely assessed and contoured
and treatment planning can be specified to the patients anatomy (Fig. 5). For instance, in a large patient, if the depth of
the SC nodes is greater than 5 to 6 cm, the use of higherenergy photons or an anterior-posterior/posterior-anterior
field can be considered. Furthermore, if the axillary treatment is warranted, the CT simulation scan allows for the
accurate measurement of the dose to the axilla relative to the
SC nodes so that a boost to the axilla using a posterioranterior field can be added if necessary.

247
tion, we now know that the depths of the axillary and SC
nodes are similar in most patients.21 A PAB is still sometimes
indicated when the maximal depths of the SC and axillary
nodes differ significantly when a single anterior field alone is
not adequate. A standard PAB is shown in Figure 2. The dose
for the PAB is prescribed so that a point at the depth of the
axillary nodes or the midplane of the axilla receives the full
prescribed dose. With modern CT-based treatment planning
and a broad range of external beam shaping and modulating
techniques available, contouring the target nodal volumes at
risk and the use of field arrangements that optimally cover
the target are recommended over empiric prescriptions to the
axilla.

IM Node Treatment
When the IM nodes are to be included with chest wall radiation, visualization of the IM vessels on CT simulation will
allow one to determine if these nodes can be encompassed in
the tangential fields without excessive radiation to the lung
(and heart). To achieve this, it is helpful to contour the easily
visualized IM artery and vein in the first 3 costal interspaces.
Although the precise position should be determined by a CT
scan when available, traditional IM portals have been 5 to 6
cm in width, extending from midline medially, just below the
clavicular head superiorly to include the first 3 intercostal
spaces, with the inferior border at the fourth interspace. This
separate IM field can be treated with electrons alone or a
combination of low-energy photons and electrons, with a
minimum of 50% of the dose being delivered by electrons to
minimize the dose to underlying heart and lung tissue. A
popular technique is to tilt the gantry angle of the electron
field 5 to 15 less than the medial tangent, minimizing the
cold triangle just below the skin match of the 2 fields as
shown in Figure 6.
A common technique to treat the IM nodes is the use of
partially wide tangential fields.11 When using this technique,

Posterior Axillary Boost

Historically, before the CT-simulation era, a posterior axillary
boost (PAB) was routinely used at some institutions to account for the assumed difference in depth of the level I/II
axillary lymph nodes from the depth of the level III axilla and
SC nodes. The posterior PAB photon beam supplemented the
anterior supraclavicular/axillary field (SAF) to boost the axilla
to therapeutic doses. With the widespread use of CT simula-

Figure 5 Typical dosimetry for a SC field. Isodose lines start at 105%,

then 100%, 98%, 95%, and 90%. CT simulation should be used to
assess the depth of the nodes at risk. (Color version of figure is
available online.)

248

Figure 6 A tangential chest wall field with a separate IM electron

field. The location of IM chain nodes is outlined in red. Electron
field is angled 5% less than tangential field, minimizing cold triangle
at the match. (Color version of figure is available online.)

blocking is used on the deep edge of the tangent fields to

allow deeper coverage of the IM nodes in the upper 3 intercostal spaces, while providing more blocking of the lung
and/or heart in the inferior portion of the field as shown in
Figure 7. This technique avoids the issue of matching fields
and, depending on the patients anatomy, offers an attractive
alternative to a separate IM field in selected patients. Care
must be taken to minimize overlap of dose into the contralateral breast in the superior portion of the field and ensure
complete coverage of all target tissue and the entire mastec-

M.S. Moran and B.G. Haffty

Figure 8 A tangential chest wall field with the IM nodes intentionally

included. The location of IM chain is outlined and included in the
tangential field. Note that the amount of lung for this technique is
acceptable (3 cm) in this instance, but is not achievable in many
patients. (Color version of figure is available online.)

tomy scar in the inferior portion of the field, in the region of

the block.
Occasionally, the IM nodes can be treated by what is commonly referred to as deep tangents (Fig. 8). Using this technique, the medial border of the tangential field is brought
across the midline, such that the IM nodes are included
within the tangential field. This technique, however, generally results in an excessive volume of lung and/or heart within
the tangential field, and studies have shown the dose volume
histogram for heart and lung with this technique may be
unacceptably high. Depending on the patients anatomy,
however, this technique may be acceptable in some patients.

Three-Dimensional
Conformal and IntensityModulated Radiation Therapy:
The More Conformal Techniques

Figure 7 Partially wide tangential radiation field to include IM nodes

in the first 3 intercostal spaces in the superior aspect of the tangent
field, with a block to shield the lung and/or heart in the lower
portion of the tangential field. (Color version of figure is available
online.)

The potential benefit of the newer generation of 3-dimensional CT-based treatment planning techniques is the potential to sculpt the dose to the tissue at risk and improve
homogeneity in the target volumes while theoretically
minimizing dose to surrounding normal tissue. Although
2 prospective, randomized studies of 2-dimensional versus 3-dimensional treatment techniques have shown a
benefit in acute skin reactions and long-term side effects of
fibrosis/cosmesis using the more conformal technique22,23
for the intact breast, the more conformal techniques have
not been prospectively studied for LABC in the post-mastectomy setting. Furthermore, the long-term toxicity to
normal tissue (heart, lung, brachial plexus, ribs, and so
on) using the 3-dimensional techniques have not been
reported to date.

Radiation techniques and toxicities

249

Table 1 Breast and Chest Wall Contour: Anatomic Boundaries

Cranial
Breast

Caudal

Clinical reference Clinical reference loss

second rib
of CT apparent breast
insertion

Anterior
Skin

Breast chestwalla Same

Same

Same

Chestwallb

Clinical reference loss

of CT apparent
contralateral breast

Skin

Caudal border of
the clavicle head

Posterior

Lateral

Medial

Excludes pectoralis
Clinical reference mid Sternal-rib
muscles, chestwall
axillary line typically,
junction
muscles, ribs
excludes lattismus
(Lat.) dorsi m.
Includes pectoralis
Same
Same
muscles, chestwall
muscles, ribs
Rib-pleural interface Clinical
Sternal-rib
(includes pectoralis
reference/midaxillary
junction
muscles, chestwall
line typically, excludes
muscles, ribs)
lattismus dorsi m

Reprinted with permission from White J, Tai A, Arthur D, et al: RTOG Breast Cancer Atlas for Radiation Therapy Planning: Consensus
Definitions.
aBreast chestwall CTV definitions should be utilized after appropriate lumpectomy for more locally advanced cases including those: with
clinical stage IIb/III who receive neoadjuvant chemotheraphy and lumpectomy, who have sufficient high risk disease to require postmastectomy radiation if a mastectomy had been performed.
bCTV after mastectomy, lateral border to estimate the lateral border of the previous breast. Typically extends beyond the lateral edge of the
pectoralis muscles but excludes the lattismus dorsi muscle. Should encompass the lateral and medial extent of the mastectomy scar.

Although the exact definitions of intensity-modulated radiation therapy (IMRT) versus 3-dimensional conformal radiation for breast cancer treatment have broad variability in
meaning, the vast majority of published data on breast cancer
conformal radiation techniques use multiple, static fieldwithin-field techniques with multileaf collimation and forward planning (as opposed to inverse planning). With IMRT,
the multisegment (segmental) fields make use of fixed field
shaping to create intensity-modulated fields by adding the
dose from several different-shaped beam portals (segments)
that have the same beam direction,24 with the number of
segments varying based on the different types of planning
and optimization tools used to plan each case. Although intensity-modulated treatment planning is typically inverse
planned in most tumor sites (ie, head and neck and prostate),
IMRT for breast cancer treatment planning is often done with
forward planning. Therefore, the definitions of 3-dimensional conformal versus IMRT for breast cancer radiation
treatment remain broad. Therefore, we will comprehensively
refer to the newer generation of treatment planning with
3-dimensional conformal or IMRT as the more conformal
techniques.
It is important to note that when using the more conformal
techniques for LABC, the delivery of radiation is based on
anatomic volumes from CT simulation scans; thus, all tissue
at risk must be meticulously delineated to allow the dose of
radiation to be sculpted to the target structures (ie, chest
wall regional nodes), while minimizing dose to the normal
structures (ie, heart and lung). Although these techniques
improve the homogeneity across the clinical target volume(s)
and have the potential to decrease the radiation doses to
normal, unaffected tissue, a relatively in-depth knowledge of
the anatomy and tissue at risk is critical to reproduce similar
long-term outcomes as were achieved with the older 2-dimensional techniques. A recent study conducted by the Radiation Therapy Oncology Group (RTOG) has brought to
light the variability that exists in contouring targets for breast
cancer radiation therapy and the need for consensus defini-

tions to reduce interphysician variability in delineating the

tissue at risk and normal structures for breast cancer treatment planning.25 Based on the findings of their study, the
group has created a breast cancer atlas to provide consensus
guidelines for contouring of the chest wall/breast (Table 1),
SC nodes, axilla (level I, II, II), IM nodes (Table 2), and
heart/lung volumes (Table 3). These guidelines were generated from geometric averaging of contours performed by a
panel of breast experts and should serve as a reference when
contouring the chest wall, regional nodes, and heart/lung
volumes for 3-dimensional delivery techniques.
A relatively common conformal technique generated by
forward planning is described. First, the tangential fields are
created in the standard fashion with matching to the SAF, if
indicated. Once the medial and lateral tangent fields are created with clinical and radiographic coverage of the target
structures and nondivergent posterior field edges, the dosimetry of the open fields is generated with the dose normalized
to a point at midseparation at the boundary between the
pectoralis major and chest wall tissue. The dose distribution
of the tangent fields is then examined, and the fields are
weighted to optimize the dosimetry. Then, a dose cloud of
the 115% isodose curve volume is projected in the beams eye
view of the treatment fields. A new segment is generated
using multileaf collimation onto the medial tangent field to
account for 15% of the dose. This process can then be repeated for the 110% dose cloud, the 107% dose cloud, and so
on. Generally, 4 to 6 fields are required to achieve optimization of dose homogeneity, typically 1 open medial with 1 to 2
collimated medial and 1 open lateral with 1 to 2 collimated
lateral (Fig. 9). Occasionally, higher-energy photons need to
be considered when the patient separation is large.26 Figure
10 compares isodose plans for a patient planned with traditional tangential techniques versus a more conformal radiation therapy plan.
It is important to note that using the more conformal techniques in which the beam orientation remains tangential as
described above, the homogeneity is often improved with

M.S. Moran and B.G. Haffty

Ribs and intercostal

muscles
Posterior surface
Pec. Major m.
Superior aspect of
the medial 1st rib
Internal
mammary

Axillalevel III

Axillary vessels
cross medial edge
of Pec. Minor m.
Pec. Minor m. insert
on cricoid
Axillalevel II

Reprinted with permission from White J, Tai A, Arthur D, et al: RTOG Breast Cancer Atlas for Radiation Therapy Planning: Consensus Definitions.

Medial border of Pec.

Minor m.

Toxicity of Radiation Therapy

Axillary vessels cross

lateral edge of Pec.
Minor m.
Axillary vessels cross
medial edge of Pec.
Minor m.
Cranial aspect of the 4th rib

Anterior surface of
subscapularis m.

little to no improvement in dose conformality. If multiple

beam arrangements are used, as in a noncoplanar plan or a
planar but nontangential plan, improvements in the volume
of high-dose regions may be seen with a further sculpted
dose but needs to be weighted against the expense of exposure of significantly more normal tissue to lower doses of
radiation (ie, lung, heart, soft tissue and contralateral breast).

Chestwall

Lateral border of Pec.

Minor m.
Ribs and intercostal
muscles

Plane defined by:

anterior surface of
Pec. Maj. m. and
Lat. Dorsi m.
Anterior surface Pec.
Minor m.
Axillary vessels
cross lateral edge
of Pec. Minor m.
Axillalevel I

Pectoralis (Pec.) major

muscle insert into ribs

Medial border of
Pec. Minor m.

Excludes thyroid and

trachea

Cranial: lateral edge of

SCM m.
Caudal: junction 1st
rib-clavicle
Medial border of lat.
dorsi m.
Anterior aspect of the
scalene m.
Caudal to the cricoid
cartilage
Supraclavicular

Junction of brachioceph.axillary vns./caudal edge

clavicle head

Sternocleido mastoid
(SCM) muscle (m.)

Lateral border of
Pec. Minor m.

Medial
Lateral
Posterior
Anterior
Caudal
Cranial

Table 2 Regional Nodal Contours: Anatomic Boundaries

250

The potential side effects for PMRT therapy can be separated

into acute and late toxicity categories. Acutely, a patient may
experience some fatigue and radiation dermatitis/skin reaction in the treatment portals, which generally begins in the
second to third week of treatment and in some cases results in
a transient moist desquamation of the skin. The most common potential late sequelae of radiation therapy are chronic
changes of the radiated skin and soft tissue (fibrosis, hyperpigmentation, and, rarely, telangectasias). In patients who
undergo axillary node dissection and receive adjuvant irradiation to the axilla, the risk of lymphedema significantly increases with the addition of radiation beyond the risk of AND
alone. Although modern-day techniques have significantly
reduced the risk of lung and cardiac complications, careful
3-dimensional treatment planning should be used to minimize the radiation doses to these relatively sensitive organs.
The risk of joint complications, rib fractures, and brachial
plexus complications is relatively low with current treatment
techniques.

Cardiac Toxicity
Several meta-analyses of the randomized studies of the first
generation of PMRT therapy trials suggested that the benefit
of radiation, with respect to survival, were counteracted by
cardiac mortality.27-30 Although postmastectomy, adjuvant
radiation therapy for node-positive patients appears to produce about a two thirds reduction in local recurrence and
subsequently, an approximately 10% reduction in breast
cancer mortality rates, these favorable findings were offset by
an increase in death from other causes, which appeared to be
related to vascular/coronary-associated deaths from the unintended radiation of the coronary and carotid arteries.31
When analyzed further, these findings of cardiac deaths were
significantly more apparent in the older trials from Europe,32-34 which used outdated techniques and equipment
(ie, en face chest wall photon fields, cobalt units, larger fractionation size, and orthovoltage units). Further supporting
this observation, the risk of cardiac mortality has been shown
to be significantly higher in patients with radiation for leftsided breast cancers than right-sided breast cancers.35,36 With
megavoltage units replacing the previously used orthovoltage
and cobalt-60 units and improved techniques, the doses to
the heart have been significantly reduced.37 Furthermore,
using modern-day techniques, the normal tissue complication probability for late cardiac tissue toxicity has been decreased by 30% to 50%.38-40 The risk of cardiac death after
adjuvant radiotherapy for breast cancer has also been sub-

Radiation techniques and toxicities

251

Table 3 Heart and Lung Contours: Anatomic Boundaries

Cranial
Hearta

Lungb

Caudal

Anterior

Posterior

Lateral

Medial

Inferior aspect of the left Loss of CT apparent Pericardium Excludes descending aorta, Pericardium Pericardium
pulmonary artery
heart
esophagus, and vertebral
body
Pleura
Pleura
Pleura
Pleura
Pleura
Pleura

Reprinted with permission from White J, Tail A, Arthur D, et al: RTOG Breast Cancer Atlas for Radiation Therapy Planning: Consensus
Definitions.
aHeart caudal border: the heart blends with the diaphragm and liver at its caudal end-adjusting the window/level can assist in discerning the
heart versus these other organs.
bLung volumes: the lung volume within the pleural surface excluding ribs, mediastinum, and diaphragm can be auto-contoured by most planning
systems.

stantially decreased over time.36 In that study, no difference

was noted in the incidence of mortality from ischemic heart
disease between left- and right-sided tumor in the 1980 to
1984 or 1985 to 1989 timeframe, although large difference
were found in earlier time periods. With each succeeding
year after 1979, the hazard of death from ischemic heart
disease decreased by 6%. With these reductions of cardiac
doses from the use of modern machines and techniques, the
most recent data show an overall survival advantage in patients receiving PMRT therapy.1,2,41 Furthermore, data from
the most modern postmastectomy trials suggest that combined modality treatment with mastectomy, systemic therapy, and adjuvant radiation did not result in clinically relevant cardiotoxic effects.42
Comparison of the volume of heart irradiated and the dose
received for the standard tangential versus newer, more conformal radiation techniques have been difficult to evaluate for
several reasons. The definition of the organ at risk has not
been well defined or consistent (ie, whole heart v left ventricle

Figure 9 Digital radiographs showing a field-within-field, more

conformal technique in which the (a) the optimized open lateral
tangent is treated (b) first and (c) 2 additional lateral fields using
multileaf collimation are delivered to improve homogeneity. (Color
version of figure is available online.)

v myocardium); the dosimetric data for historic techniques

have not been well reported; the clinical manifestations of
cardiac toxicity often occur with a latency period of greater
than 10 years after treatment with endpoints that are often
difficult to measure (ie, pericarditis, coronary artery disease
leading to angina, myocardial infarction, and thromboemboli), with no established surrogates for clinical toxicity (ie,
perfusion studies) other than death from cardiac causes.
There is significant controversy regarding the threshold for

Figure 10 The top image is a traditional tangential radiation isodose

plan optimized with wedging. The bottom image is a more conformal radiation isodose technique using 6 fields. Red, 100%; yellow,
105%; pink, 110% isodose lines.

M.S. Moran and B.G. Haffty

252
acceptable low and intermediate doses for the heart and what
the heart volume to be contoured should be. Based on the
new guidelines in the RTOG breast atlas,25 the entire heart
should be contoured. The cardiac doses should be measured
to generate a dose-volume histogram to allow for accurate
assessment of the dose to various portions of the heart. The
maximum heart distance (MHD) is the maximum distance
between the anterior cardiac contour and the posterior tangential views,39,40,43 which is measured on the beams eye
view on CT-simulator or traditional simulation film. The
MHD has been found to be a reliable predictor of the mean
heart dose and mean left anterior descending artery dose and
can potentially be useful in clinical practice. When the MHD
is 1 cm, the risk probability is reported to be less than
1%.39,40,44 For these reasons, the use of CT-based treatment
planning and conformal radiation techniques for chest wall
radiotherapy should be used whenever possible in an attempt
to decrease normal tissue exposure, with the goal of sparing
the heart as best as possible, without conceding to a suboptimal coverage of the planning target volume and homogeneity. Three-dimensional planning with CT-generated contours
can be more precisely customized to the individual patient
with analysis of the dose volumes for critical structures.
Several modern maneuvers for chest wall radiation have
been shown to reduce the volume of the heart irradiated.
Breath-holding techniques (using active breathing control
devices or unassisted) and respiratory gating have been
shown as effective techniques to reduce cardiac volumes45-47;
in addition, advancements in patient treatment positioning
have made a significant difference in the amount of heart
irradiated. An inclined breast board has been shown to decrease the mean cardiac dose, the maximal dose to the heart,
and the cardiac volume in the 50% isodose curve compared
with positioning patients flat.48,49 Several studies also suggest
that treatment in the prone position allow for sparing of the
heart and lung tissue.50,51
There are several treatment-related factors that have been
shown to increase cardiac toxicity including intentional treatment of the lower IM nodes, anthracycline-based systemic
therapy, and potentially trastuzamab. When the lower IM
nodes are intentionally included with chest wall radiation,
the volume of heart irradiated has been shown to increase,
particularly when an additional IM field is added.52 When
adding a separate IM field it is prudent to use a combination
of electrons and photons or electrons alone (as opposed to an
en face photon field) and to obtain a treatment plan in which
the cardiac doses are minimized. Anthracycline-based chemotherapeutic drugs are well known to be cardiotoxic; although the mechanisms of cardiac damage with the drug
versus radiotherapy differ, the potentiation of the toxicity is
thought to be additive.53 Again, in patients receiving anthracycline drugs at higher risk for cardiotoxicity, meticulous
attention is needed to minimize cardiac volumes irradiated.
Although trastuzamab is commonly delivered concomitantly
with radiation and is also known to be cardiotoxic, there is a
paucity of data on the safety of delivering these 2 treatment
modalities together. A recent study showed that trastuzamab,
when delivered weekly with radiation therapy, was an inde-

pendent prognostic factor for left ventricular ejection fraction

decrease.54 Although the median follow-up was only 16
months and additional follow-up to assess long-term toxicity
is warranted, the authors concluded that cardiac volume
sparing and careful selection of patients for IM irradiation be
considered in patients receiving trastuzamab with RT.

Lung Toxicity
The incidence of pulmonary toxicity after radiation therapy
for breast cancer varies significantly in the literature but is
typically well under 10% with modern treatment units and
techniques. Although most of the studies assessing radiationinduced pneumonitis have been performed in patients after
breast-conservation therapy and not specifically in the postmastectomy setting, the acute and long-term effects are similar in that they are primarily dependent on the volume of
lung irradiated and thus higher with the addition of SC or IM
fields. Furthermore, the use and sequencing of systemic therapy clearly impact the rate of pneumonitis, with a significantly higher risk when concurrent versus sequential radiation therapy is delivered.55
Although the ultimate endpoint of incidence of pulmonary toxicity differs significantly based on the method used
to quantify pulmonary complications, whether it be patient
symptoms assessment, chest radiographs, pulmonary function testing, perfusion studies, or CT scans, several studies
have suggested that the frequency of pulmonary toxicity can
be predicted based on the amount of lung in the tangential
fields.56-58 Although various models for predicting lung toxicity after breast radiation therapy have been proposed in the
literature, no specific model has been consistently used in
clinical practice or in the literature.
It is generally recommended that the amount of lung in the
radiation field be kept under 3.0. When this is not possible
because of anatomic limitations, the more conformal radiation techniques should be considered.

Lymphedema
After treatment for LABC, upper-extremity arm edema is a
commonly experienced complication, particularly for those
patients who have undergone AND followed by radiation
therapy to the full axilla. Similar to the issues regarding lung
toxicity measurements, the frequency of lymphedema is variable depending on the definition used, whether it be patient
versus lymphedema specialists assessment and subjective severity versus quantitative measurements. The risk of
lymphedema increases with the extent of lymph nodes excised and is higher after radiotherapy is administered to the
dissected axilla versus AND alone.59,60 Other known risk factors include older age and obesity (high body mass index).
There are some data suggesting that the addition of a SC field
to tangential fields and the use of a posterior axillary boost
field may increase the risk of lymphedema in node positive
patients.61 For patients who are being managed with a full
AND and comprehensive PMRT to intentionally include the
axilla, it is recommended that conventional fractionation

Radiation techniques and toxicities

253

(1.8-2.0 Gy/d) and doses of 45 to 50 Gy be used. Sparing the

skin at the top of the shoulder allows for collateral lymphatic
drainage; therefore, whenever SC radiation is delivered, it is
recommended that a strip of skin be spared, if possible.62
Lastly, in patients for whom only high (level 3) axillary radiation is warranted, the use of surgical clips to mark the area of
dissection will help in treatment planning, so the portion of
the axilla that has been dissected can be avoided with conformal radiation techniques.

Brachial Plexopathy
Because the brachial plexus transverses through the SC field
into the axilla, it needs to be considered an organ at risk, with
the potential for significant toxicity. The effects of dose, volume, and fractionation need to be well thought through, just
as with the other organs at risk. The long-term sequela of
radiation to the brachial plexus is radiation-induced brachial
plexopathy, a clinical syndrome in which patients who have
had previous SC fossa/axillary radiation present with symptoms of arm numbness, tingling, pain, or motor weakness
months to years after treatment. When these symptoms occur, workup to rule out neoplastic infiltration of tumor recurrence is imperative. Although the incidence of brachial
plexopathy is relatively low in patients who undergo conformal treatment planning techniques and standard fractionation schemas (46-50 Gy in 1.8-2-Gy fractions), older studies
using outdated techniques have shown that the doses to the
brachial plexus can be as high as 130% of the prescribed
dose, therefore significantly increasing the risk of brachial
plexus injury.63 To ensure minimizing the risk of radiationinduced brachial plexopathy, it is important to (1) reduce
significant hotspots in the SAF, (2) avoid usage of large doses
per fraction, and (3) place the match line for the SAF below
the level of the brachial plexus whenever possible.64

Radiation After
Neoadjuvant Chemotherapy
and Breast Conservation
for LABC
The management of LABC treated with neoadjuvant therapy
and breast conservation is reviewed by Taghian et al in this
issue of Seminars in Radiation Oncology. Herein, we describe
the technical aspects appropriate for this treatment approach.
For patients with LABC in which breast preservation is attempted, it is imperative that a multidisciplinary approach is
taken upfront with involvement of the surgeon, medical oncologist, and radiation oncologist. The location of the primary tumor should be marked with radiopaque clips inserted
percutaneously before initiating chemotherapy so the tumor
bed can be readily located for surgical excision if there is a
complete clinical regression of disease. All patients should
undergo surgical excision to obtain negative margins, even
those who achieve complete clinical response. Furthermore,
all patients should receive whole-breast irradiation followed
by a radiation boost to the lumpectomy cavity.

Figure 11 The dosimetry for a patient who underwent neoadjuvant

chemotherapy, breast-conserving surgery, and axillary node dissection. The technique incorporates a electron/photon IM field with the
2 conformal field-in-field tangents and a matched SC field. Note the
added dose to the heart with the addition of the IM field. (Color
version of figure is available online.)

The simulation, treatment planning, and delivery of radiation to the intact breast do not differ significantly from that
of the chest wall radiation. Similar to PMRT, the role of adding regional nodal radiation to that of the intact breast (IM
nodes and axilla after an AND) have yet to be evaluated in a
prospective, randomized setting. Contrary to what is typically
done for early-stage breast cancer treated with breast conservation, the threshold for including the regional lymph nodes is
higher in patients with LABCs, and therefore the target volume is
often extended beyond the intact breast in these patients
(Fig. 11). There are also controversies specific to the neoadjuvant approach that warrant further investigation, for instance,
whether to irradiate the full axilla in a patient who initially had a
positive sentinel lymph node, received neoadjuvant chemotherapy, and subsequently has a negative axillary dissection or
whether to add a radiation boost in a patient who has had a
complete pathologic response with no residual disease at the
time of lumpectomy.
Again, treatment planning should be performed with CT
guidance whenever possible, and all attempts should be
made to deliver a homogeneous dose to the breast and regional nodes (if treating) and minimize the dose to the organs
at risk. If contouring for conformal treatment planning,
guidelines set forth by the RTOG are useful.25 The breast
typically receives 50 Gy in 2-Gy fractions delivered with standard tangential fields or more conformal methods as described earlier.
At our institution, a boost is typically delivered for all
patients who are treated with neoadjuvant chemotherapy
and breast-conserving surgery, regardless of pathologic response. For the boost field, the second set of clips placed at
time of lumpectomy will help to localize the tumor cavity.
Although the boost can be treated with tangential photon
fields in very large-breasted women, electrons are generally

M.S. Moran and B.G. Haffty

254
used in most cases. Often, repositioning of the patient is
required (different position than the whole-breast radiation)
in an attempt to align the skin over the clips parallel to the
treatment table so the electron field can be delivered en face.
Once the clips are visualized, a 2- to 3-cm margin is placed in
all directions to define the boost field. The energy of the
electrons should be determined by the thickness of the breast
from the skin to the chest wall in the treatment position and
prescribed to the 90% isodose line. The boost dose is typically 10 to 16 Gy in 2.0-Gy fractions.

12.

13.

14.

15.

Conclusions
Radiation therapy is an important component of the multidisciplinary management of LABC. The treatment units and
techniques have evolved significantly over the years, with a
subsequent decrease in the long-term cardiac complications
and cardiac-related deaths and improvements in overall survival. The current technology mandates an in-depth knowledge of the anatomy and treatment techniques to improve
homogeneity in the treatment field while minimizing the
dose to organs at risk. Only with optimal radiation treatment
planning and delivery can the survival benefit with adjuvant
radiation therapy for LABC continue to be achieved.

16.

17.
18.

19.

20.

References
1. Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer.
N Engl J Med 337:956-962, 1997
2. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy
in high-risk premenopausal women with breast Cancer who receive
adjuvant chemotherapy. Danish Breast Cancer Cooperative Group, p
82b Trial. N Engl J Med 337:949-955, 1997
3. Overgaard M, Jensen MB, Overgaard J, et al: Postoperative radiotherapy
in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomized trial. Lancet 353:1641-1648, 1999
4. Taghian A, Jagsi R, Makris A, et al: Results of a survey regarding irradiation of internal mammary chain in patients with breast cancer: Practice is culture driven rather than evidence based. Int J Radiat Oncol Biol
Phys 60:706-714, 2004
5. Taylor ME, Haffty BG, Shank BM, et al: Postmastectomy radiotherapy;
American College of Radiology, ACR: Appropriateness criteria. Radiology 215:1153-1170, 2000 (suppl)
6. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl
J Med 347:1233-1241, 2002
7. White J, Moughan J, Pierce LJ, et al: Status of post-mastectomy radiotherapy in the United States: A patterns of care study. Int J Radiat Oncol
Biol Phys 60:77-85, 2004
8. Bornstein BA, Cheng CW, Rhodes LM, et al: Can simulation measurements be used to predict the irradiated lung volume in the tangential
fields in patients treated for breast cancer? Int J Radiat Oncol Biol Phys
18:181-187, 1990
9. Kirova YM, Campana F, Fournier-Bidoz N, et al: Postmastectomy electron beam chest wall irradiation in women with breast cancer: A clinical
step toward conformal electron therapy. Int J Radiat Oncol Biol Phys
69:1139-1144, 2007
10. Kirova YM, Campana F, Fournier-Bidoz N, et al: Post-mastectomy electron beam chest wall irradiation in women with breast cancer: A clinical
step toward conformal electron therapy. Int J Radiat Oncol Biol Phys
69:1139-1144, 2007
11. Pierce LJ, Butler JB, Martel MK, et al: Postmastectomy radiotherapy of

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

the chest wall: Dosimetric comparison of common techniques. Int J

Radiat Oncol Biol Phys 52:1220-1230, 2002
Hartsell WF, Kelly CA, Schneider L, et al: A single isocenter three-field
breast irradiation technique using an empiric simulation and a symmetric collimator. Med Dosimetry 19:169-173, 1994
Chu JC, Solin LJ, Hwang CC, et al: A nondivergent three field matching
technique for breast irradiation. Int J Radiat Oncol Biol Phys 19:10371040, 1990
Svensson GK, Bjarngard BE, Larsen RD, et al: A modified three-dimensional technique for breast treatment. Int J Radiat Oncol Biol Phys
6:689-694, 1980
Svensson GK, Chin LM, Siddon RL, et al: Breast treatment techniques at
the Joint Center for Radiation Therapy, in Harris JR, Hellman S and
Silen W (eds): Conservative Management of Breast Cancer: New Surgical and Radiotherapeutic Techniques. Philadelphia, JB Lippincott,
1983, pp 239-255
Siddon RL, Buck BA, Harris JR, et al: Three-field technique for breast
irradiation using tangential field corner blocks. Int J Radiat Oncol Biol
Phys 9:583-588, 1983
Lebesque JV: Field matching in breast irradiation: An exact solution to
a geometrical problem. Radiother Oncol 5:47-57, 1986
Podgorsak EB, Gosselin M, Kim TH, et al: A simple isocentric technique
for irradiation of the breast, chest wall and peripheral lymphatics. Br J
Radiol 57:57-63, 1984
Garg AK, Frija EK, Sun TL, et al: Effects of variable placement of
superior tangential/supraclavicular match line on dosimetric coverage
of level III axilla/axillary apex in patients treated with breast and supraclavicular radiotherapy. Int J Radiat Oncol Biol Phys 73:370-374, 2009
Liengsawangwong R, Yu TK, Sun TL, et al: Treatment optimization
using computed tomography-delineated targets should be used for supraclavicular irradiation for breast cancer. Int J Radiat Oncol Biol Phys
69:711-715, 2007
Bentel GC, Marks LB, Hardenbergh PH, et al: Variability of the depth of
supraclavicular and axillary lymph nodes in patients with breast cancer:
Is a posterior axillary boost field necessary? Int J Radiat Oncol Biol Phys
47:755-758, 2000
Pignol JP, Olivotto I, Rakovitch E, et al: A multicenter randomized trial
of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis. J Clin Oncol 26:2085-2092, 2008
Donovan E, Bleakley N, Denholm E, et al: Randomised trial of standard
2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT)
in patients prescribed breast radiotherapy. Radiother Oncol 82:254264, 2007
Fraass BA, Kessler ML, McShan DL, et al: Optimization and clinical use
of multisegment intensity-modulated radiation therapy for high-dose
conformal therapy. Semin Radiat Oncol 9:60-77, 1999
White J, Tai A, Arthur D, et al: RTOG breast cancer atlas for radiation
therapy planning: Consensus definitions: Presented at the ASCO 2008
Breast Cancer Symposium, Washington DC, 2008
Buchholtz TA: Breast cancer, in Chao C, Apisrathanarax S, Ozyigit G
(eds): Practical Essentials of Intensity Modulated Radiation Therapy.
Philadelphia, PA, Lippincott, Williams & Wilkins, 2005, p 248
Cuzick J, Stewart H, Rutqvist L, et al: Cause-specific mortality in longterm survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 12:447-453, 1994
Early Breast Cancer Realists Collaborative Group: Effects of radiotherapy and surgery in early breast cancer: An overview of the randomized
trials. N Engl J Med 333:1444-1455, 1995
Paszat LF, Mackillop WJ, Groome PA, et al: Mortality from myocardial
infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. J Clin Oncol
16:2625-2631, 1998
Rutqvist LE, Johansson H: Mortality by laterality of the primary tumour
among 55,000 breast cancer patients from the Swedish Cancer Registry. Br J Cancer 61:866-868, 1990
EBCTCG: Favourable and unfavourable effects on long-term survival of
radiotherapy for early breast cancer: An overview of the randomised
trials. Early Breast Cancer Trialists Collaborative Group. Lancet 355:
1757-1770, 2000

Radiation techniques and toxicities

32. Host H, Brennhovd IO, Loeb M: Postoperative radiotherapy in breast
cancerLong-term results from the Oslo study. Int J Radiat Oncol Biol
Phys 12:727-732. 1986
33. Early Breast Cancer Trialists Collaborative Group: Treatment of Early
Breast Cancer: Worldwide Evidence 1985-1990 (vol 1). Oxford, Oxford University Press, 1990
34. Jones J, Ribeiro G: Mortality patterns over 34 years of breast cancer
patients in a clinical trial of post-operative radiotherapy. Clin Radiol
40:204-208, 1989
35. Haybittle JL, Brinkley D, Houghton J, et al: Postoperative radiotherapy
and late mortality: Evidence from the cancer research campaign trial for
early breast cancer. BMJ 298:1611-1614, 1989
36. Giordano SH, Kuo YF, Freeman JL, et al: Risk of cardiac death after
adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97:419-424,
2005
37. Fuller SA, Haybittle JL, Smith RE, et al: Cardiac doses in post-operative
breast irradiation. Radiother Oncol 25:19-24, 1992
38. Muren LP, Maurstad G, Hafslund R, et al: Cardiac and pulmonary doses
and complication probabilities in standard and conformal tangential
irradiation in conservative management of breast cancer. Radiother
Oncol 62:173-183, 2002
39. Hurkmans CW, Borger JH, Bos LJ, et al: Cardiac and lung complication
probabilities after breast cancer irradiation. Radiother Oncol 55:145151, 2000
40. Hurkmans CW, Cho BC, Damen E, et al: Reduction of cardiac and lung
complication probabilities after breast irradiation using conformal radiotherapy with or without intensity modulation. Radiother Oncol 62:
163-171, 2002
41. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of
differences in the extent of surgery for early breast cancer on local
recurrence and 15-year survival: An overview of the randomised trials.
Lancet 366:2087-2106, 2005
42. Hojris I, Overgaard M, Christensen JJ, et al: Morbidity and mortality of
ischemic heart disease in high-risk breast-cancer after adjuvant postmastectomy systemic treatment with or without radiotherapy: Analysis
of DBCG 82b and 82c randomized trails. Lancet 354:1425-1430, 1999
43. Taylor C, McGale P, Povall J, et al: Estimating cardiac exposure from
breast cancer radiotherapy in clinical practice. Int J Radiat Oncol Biol
Phys Octoer 73:1061-1068, 2009
44. Gagliardi G, Lax I, Rutqvist LE: Partial irradiation of the heart. Semin
Radiat Oncol 11:224-233, 2001
45. Lu HM, Cash E, Chen MH, et al: Reduction of cardiac volume in
left-breast treatment fields by respiratory maneuvers: A CT study. Int J
Radiat Oncol Biol Phys 47:895-904, 2000
46. Korreman SS, Pedersen AN, Nottrup TJ, et al: Breathing adapted radiotherapy for breast cancer: Comparison of free breathing gating with the
breath-hold technique. Radiother Oncol 76:311-318, 2005
47. Remouchamps VM, Vicini FA, Sharpe MB, et al: Significant reductions
in heart and lung doses using deep inspiration breath hold with active
breathing control and intensity modulated radiation therapy for patients treated with locoregional breast irradiation. Int J Radiat Oncol
Biol Phys 55:392-406, 2003

255
48. Canney PA, Deehan C, Glegg M, et al: Reducing cardiac dose in postoperative irradiation of breast cancer patients: The relative importance
of patient positioning and CT scan planning. Br J Radiol 72:986-993,
1999
49. Canney PA, Sanderson R, Deehan C, et al: Variation in the probability
of cardiac complications with radiation technique in early breast cancer. Br J Radiol 74:262-265, 2001
50. Formenti SC, Truong MT, Goldberg JD, et al: Prone accelerated partial
breast irradiation after breast-conserving surgery: Preliminary clinical
results and dose-volume histogram analysis. Int J Radiat Oncol Biol
Phys 60:493-504, 2004
51. Griem KL, Fetherston P, Kuznetsova M, et al: Three-dimensional photon
dosimetry: A comparison of treatment of the intact breast in the supine and
prone position. Int J Radiat Oncol Biol Phys 57:891-899, 2003
52. Gyenes G, Gagliardi G, Lax I, et al: Evaluation of irradiated heart volumes in stage I breast cancer patients treated with postoperative adjuvant radiotherapy. J Clin Oncol 15:1348-1353, 1997
53. Yahalom J, Portlock CS: Cancer: Principles and Practice of Oncology
(ed 7). Philadelphia, PA, Lippincott/Williams & Wilkins, 2005
54. Belkacemi Y, Gligorov J, Ozsahin M, et al: Concurrent trastuzamab with
adjuvant radiotherapy in HER2-positive breast cancer patients: Acute
toxicity analyses from the French multicentric study. Ann Oncol 19:
1110-1116, 2008
55. Lingos TI, Recht A, Vicini F, et al: Radiation pneumonitis in breast
cancer patients treated with conservative surgery and radiation therapy.
Int J Radiat Oncol Biol Phys 21:355-360, 1991
56. Kimsey FC, Mendenhall NP, Ewald LM, et al: Is radiation treatment
volume a predictor for acute or late effects on pulmonary function? A
prospective study of patients treated with breast-conserving surgery
and post-operative irradiation. Cancer 73:2549-2555, 1994
57. Lind P, Wennberg B, Gagliardi G, et al: Pulmonary complications following different radiotherapy techniques for breast cancer, and the
association to irradiated lung volume and dose. Br Cancer Res Treat
68:199-210, 2001
58. Krengli M, Sacco M, Loi G, et al: Pulmonary changes after radiotherapy
for conservative treatment of breast cancer: A prospective study. Int J
Radiat Oncol Biol Phys 70:1460-1467, 2008
59. Kissin MW, Querci della Rovere G, Easton D, et al: Risk of lymphedema
following treatment for breast cancer. Br J Surg 73:580-584, 1986
60. Dewar JA, Sarrazin D, Benhamou E, et al: Management of the axilla in
conservatively treated breast cancer: 592 patients treated at the institue
Gustave-Roussy. Int J Radiat Oncol Biol Phys 13:475-481, 1987
61. Hayes SB, Freedman GM, Li T, et al: Does axillary boost increase
lymphedema compared with supraclavicular radiation alone after
breast conservation? Int J Radiat Oncol Biol Phys 72:1449-1455, 2008
62. Leitch A, Meek A, Smith R, et al: Workgroup I: Treatment of the axilla
with surgery and radiation-preoperative and postoperative risk assessment. Cancer S83:2877-2879, 1998
63. Svensson H, Westling P, Larsson L-G: Radiation-induced lesions of the
brachial plexus correlated to the dose-time-fractionation schedule.
Acta Radiol Ther Phys Biol 14:228-238, 1975
64. Benson S, Dische S: Morbidity related to axillary irradiation in the
treatment of breast cancer. Acta Oncol 39:337-347, 2000

Inflammatory Breast Cancer

Wendy A. Woodward, MD, PhD,* and Massimo Cristofanilli, MD
Inflammatory breast cancer (IBC) represents the most virulent form of breast cancer,
characterized by involvement of the skin and rapid progression of the disease. Management involves careful coordination of all multidisciplinary modalities, including imaging,
systemic chemotherapy, surgery, and radiation therapy. The use of neoadjuvant chemotherapy has contributed significantly to improvement in overall survival since the first
descriptions of this entity and has made the role of locoregional therapy, including surgery
and radiation critical to continued improvements in this disease. In this article, we examine
the unique epidemiology and pathology of IBC and review the various treatment modalities
noting the significance of a multimodality approach and delineating each of the specific
components. Moreover, we briefly describe the current research in IBC that will hopefully
contribute further to improve systemic therapies.
Semin Radiat Oncol 19:256-265 2009 Published by Elsevier Inc.

he historic background of inflammatory breast cancer

(IBC), recently reviewed,1 apparently begins with Sir
Charles Bell in 1814 who observed that a purple color on the
skin over the tumor accompanied by shooting pains is a very
unpropitious beginning.2 The term inflammatory carcinoma of the breast was first used by Lee and Tannenbaum in
1924,3 noting that as the disease progresses, the skin becomes deep red or reddish-purple, and to the touch is
brawny and infiltrated. The inflamed area presents a distinct
raised periphery after the fashion of erysipelas (Fig. 1). Currently, the most widely referenced definition is that of the
American Joint Committee on Cancer,4 which states in part
that inflammatory carcinoma is a clinicopathologic entity characterized by diffuse erythema and edema (peau dorange) of the
breast, often without an underlying mass. These clinical findings
should involve the majority of the breast . . . It is important to
remember that inflammatory carcinoma is primarily a clinical
diagnosis. Involvement of the dermal lymphatics alone does
not indicate inflammatory carcinoma in the absence of clinical findings.
*Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
Department of Breast Medical Oncology, The University of Texas M. D.
Anderson Cancer Center, Houston, TX.
Supported by Komen Foundation Promise grant KGO81287, the University
of Texas Institutional Research grants K12-5611B through the University
of Texas Health Sciences Centre from the National Institute of Health,
and the University of Texas M. D. Anderson Cancer Center grant no.
R01CA138239-01; IRG.
Address reprint requests to Massimo Cristofanilli, MD, Department of Breast
Medical Oncology, Unit 1354, The University of Texas M. D. Anderson
Cancer Center, 1515 Holcombe Blvd., Houston, TX. E-mail: mcristof@
mdanderson.org

256

1053-4296/09/$-see front matter 2009 Published by Elsevier Inc.

doi:10.1016/j.semradonc.2009.05.008

An apparently useful model for the consideration of the

spectrum of disease manifestations leading to IBC was proposed by Denoix5 who used the term pousee evolutive (PEV)
or rapidly progressing breast cancer in which the most advanced form, PEV 3, as used in the Tunisian IBC studies,6 is
defined as a designation given to patients with inflammation
covering more than half the breast surface, which is clearly
compatible with the American Joint Committee on Cancer
case definition. Cases with PEV 2 in Tunisia that have inflammatory signs affecting less than half the breast did slightly
better than PEV 3 cases in the first 3 years but had virtually
identical poor survival at four years and beyond.7

Epidemiologic Features
Although there are some differences among the 4 large population-based studies,8-11 many of the features are similar.
The specific details differ considerably for several reasons.
They cover different time periods ranging from 1975 to
19819 to 1988 to 2000.8 They use different databases including the Surveillance, Epidemiology and End Results Program
for 38-10 and the North American Association of Central Cancer Registries for 1.11 Most importantly, they select different
patients with 28,9 using both clinical and pathologic criteria to
select patients and 210,11 restricting cases to those defined
pathologically as IBC. For pathologic definition, all 4 used
International Classification of Diseases for Oncology morphology code 8530/3.
Despite these differences in analysis, all reports document
that IBC has a higher incidence in black women compared
with white women and that in both groups IBC occurs at a
younger age than non-IBC breast cancer. Regarding racial/

Radiotherapy for IBC

257

Figure 1 (A) Clinical and pathologic signs of IBC. Erythema of the breast with tumor nodules extending to the opposite
breast (arrows). (B) Prominent ridging is present in the unaffected breast and represents a postoperative change after
prior mammoplasty. (C) Peau dorange encompassing most of the breast. (D) Inflammatory recurrence on the back
immediately outside the radiation field evident as hyperpigmentation of the skin (arrows). Dermal lymphatic invasion
in a patient with clinical signs of IBC.

ethnic differences, blacks had at least a 50% higher incidence

than whites, were diagnosed at an earlier age, and had a
shorter survival, as also seen in non-IBC breast cancer.
Wingo et al11 also looked at other racial-ethnic groups and
noted that Hispanic women had the youngest mean age of
onset (50.5 years) compared with 55.2 for black women and
58.1 for white women. Other findings of interest include the
suggestion that the incidence of IBC in the United States has
increased over time.8,10 These studies also confirm a poor
survival in clinically and pathologically defined cases8,9 but
have noted an improving survival in recent years with important advances in chemotherapy.8,10 The increasing incidence
in IBC contrasts markedly with non-IBC breast cancer, which
has leveled off since 2001 to 2003.12 In addition, IBC tumors
include a generally higher tumor grade and more estrogen
receptor (ER)-negative tumors than non-IBC breast cancer,
with the ER-negative disease making well more than 50% of
all cancers in IBC.8 In regard to the incidence of IBC, the use
of the clinical codes (EOD-E 70 for tumor extension and
EOD-S 998 for tumor size), which are now available in Surveillance, Epidemiology and End Results, indicate that IBC
comprises 2.5% of all incident breast cancer cases,8 which is
a higher rate than reported in the 2 studies using only pathologically diagnosed IBC.

Risk Factors
It has been reported that women with aggressive breast cancer were more likely to have had their first child at a younger
age than non-IBC patients. This was noted in the Tunisian
PEV patients; 14 of 15 premenopausal women with first
births at the age of 18 or earlier were diagnosed as PEV
positive. This finding was weakly supported by the study of
Chang et al,13 who compared 68 IBC patients with 143 nonIBC breast cancer patients and 134 patients with cancer at
other sites and found the lowest median age at first live birth
in the IBC patients, but the difference was not statistically
significant. In a comparison of 116 patients with aggressive
breast cancer as defined by tumor grade, 99 patients with
nonaggressive breast cancer, and 135 patients from our IBC
registry, both IBC patients and the non-IBC patients with
aggressive breast cancer were more likely to have a first child
before age 20 than the breast cancer patients with nonaggressive breast cancer, and the patients with aggressive breast
cancer were 3 times more likely to have their first child before
age 20 than the patients with nonaggressive breast cancer.14
A high body mass index has consistently been reported as
a risk factor in premenopausal and postmenopausal women
as well.13 Because relative weight is associated with a reduced

258
or similar risk of breast cancer in premenopausal women in
general,15 this appears to be another example of a difference
between IBC and non-IBC aggressive breast cancer versus
nonaggressive breast cancer.

Clinical Inflammatory Signs

The histologic hallmark of IBC is the presence of dermal
lymphatic invasion in which numerous dilated dermal lymphatics filled with tumor emboli that are usually retracted
away from the surrounding endothelial lining (Fig. 1).16 Dermal lymphatic invasion and the subsequent lymphatic obstruction, rather than infiltration by inflammatory cells, is
purported to be responsible for clinical inflammatory signs
and symptoms and, ultimately, for the highly metastatic potential of IBC. Likely because of sampling heterogeneity,
however, DLI is identified in fewer than 75% of IBC tumors
and is not required for the diagnosis. Importantly, although
the diagnosis of IBC versus non-IBC can be made based on
clinical signs and does not require pathologic evidence of
DLI, pathologic confirmation of breast cancer is required to
distinguish IBC from benign disease.

Adhesion Molecules
It has been proposed that the molecular basis of dermal lymphatic invasion might involve adhesion molecules, either on
tumor cells or endothelial cells, or angiogenic growth factors
and proteolytic enzymes elaborated by tumor cells that enable intravasation. E-cadherin is a calcium-dependent transmembrane glycoprotein and, as part of a membrane complex
with -catenin and -catenin, is essential in maintaining adhesion between epithelial cells.17 In most epithelial malignancies, including breast carcinoma, decreased or lost Ecadherin expression is associated with malignant progression
including high histologic grade, increased proliferation, invasion, metastasis, and poor prognosis.18-24 Using immunohistochemistry on 20 IBC and 22 stage-matched non-IBC
tumors, Kleer et al18 found that E-cadherin was preferentially
expressed in IBC tumors (100% IBC v 68% non-IBC). No
association was found between E-cadherin expression and
hormonal receptors or Her-2 status.18 Colpaert et al25 reported a strong E-cadherin expression in 33 of 35 IBC tumors. In particular, intralymphatic tumor emboli of IBC also
strongly expressed E-cadherin. These findings indicated that
E-cadherin is required for tumor emboli formation by enhancing tumor celltumor cell adhesion and maintaining the
integrity of IBC tumor emboli in the dermal lymphatics. In
addition to an intact and overexpression of E-cadherin/,
-catenin axis,26 sialyl-Lewis X/A-deficient MUC1 appears to
be another key factor that contributes to lymphovascular metastasis of IBC.27,28 MUC1 is a glycoprotein in the cell surface
mucin family and is the ligand of E-selectin (a cell adhesion
receptor) on the surface of endothelial cells. The sialyl-Lewis
X/A carbohydrate ligand-binding epitope on MUC1 facilitates the ligand-receptor interaction.27 Nonsialylated MUC1
does not bind E-selectin, resulting in epithelial cell endothelial cell aversion. Notably, the overexpression of E-cadherin

W.A. Woodward and M. Cristofanilli

and MUC1 were included as part of inflammatory signature
of IBC in a study by Charafe-Jauffret et al.29
IBC is further characterized by extensive angiolymphatic
invasion and early lymph node involvement. Using immunohistochemical staining, McCarthy et al30 found that intratumoral microvessel density in IBC was significantly higher
than in non-IBC. In a study with 35 IBC and 104 non-IBC
tumors, Colpaert et al25 observed intense angiogenesis in IBC
tumors that was manifested not only by increased vascular
density but also high endothelial cell proliferation rate. Moreover, the same study showed a significant positive correlation
between carbonic anhydrase IX, a hypoxia marker, and endothelial cell proliferation in IBC, implying that the angiogenesis is at least partly hypoxia driven.

Conventional Biomarkers
IBC more frequently shows negative ER and progesterone
receptor (PR) status than non-IBC.29,31-33 Up to 83% of IBC
tumors lack ER expression compared with other forms of
LABCs that are mostly ER positive.31,34-37 IBC has a higher
incidence of EGFR and Her-2 overexpression than nonIBC.29,38-40 Her-2 overexpression and/or amplification rate
has been reported in up to 100% of IBC tumors tested but
is generally reported within the 40% to 50% positivity
range.38-43 Also, Her-2 and C-myc proto-oncogene overexpression is mutually exclusive in IBC38 and c-myb protooncogene expression was lower in IBC than non-IBC.40 The
c-myb expression was found to be directly associated with
good prognostic factors (ie, lowest histopathologic grade,
positive ER and PR status, and pS2 gene expression)40,44 and
negatively correlated with poorer prognosis in both IBC and
non-IBC, suggesting a biological link with molecular features
of less aggressive disease. The difference of Her-2 status between IBC and non-IBC tumors has also been observed at
molecular level, with IBC tumors more frequently showing gene
amplification (by Southern blotting) and messenger RNA expression (by Northern blotting and reverse transcription polymerase chain reaction) relative to non-IBC tumors.38,39,45 These
data indicated that the newer Her-2 directed therapies are
likely to improve the outcome of the population of patients with
IBC compared with historic standards.
In many studies, p53 gene mutation and/or nuclear overexpression of mutated p53 protein was found to be associated with the advanced stage of the disease (ie, large tumor
size, high grade, and early metastasis) and poor overall survival.37,46-48 Riou et al37 showed that IBC patients with tumors
carrying a p53 gene mutation and nuclear overexpression of
the p53 protein had an 8.6-fold higher risk of death compared with patients with tumors having neither mutation nor
the protein overexpression. The prognosis was even worse
when the tumors were also ER negative.37 Data on association
between p53 status and response to primary systemic therapy are somewhat controversial.46,47,49,50

Other Biological Factors

Van Golen et al51 identified 2 genes whose expression was
concomitantly altered. With in situ hybridization, RhoC

Radiotherapy for IBC

GTPase, a breast-specific oncogene, was overexpressed in
90% of the IBC tumors compared with 38% of the stagematched non-IBC tumors, whereas WISP3 (also known as
lost in IBC) was lost in 80% of IBC tumors versus in only 21%
of non-IBC tumors. RhoC GTPase is involved in cytoskeletal
reorganization and contributes to the metastatic potential by
increasing cellular motility and invasion and inducing actin
stress fiber and focal adhesion complex formation.52 Kleer et
al53,54 showed that RhoC overexpression is associated with
high histologic grade, positive lymph nodes, and negative
hormonal receptor status. In addition, high RhoC expression
was shown to be a predictor of poor overall survival in patients with breast cancer and an independent predictor of
poor response to doxorubicin-based chemotherapy. Transcription factor nuclear factor kB (NF-kB) is an important
mediator of cell proliferation, apoptosis, and migration. Van
Laere et al55,56 reported a significant overexpression of many
NF-B target genes in the IBC tumors compared with nonIBC tumors by complementary DNA microarray, which was
confirmed by reverse transcription polymerase chain reaction. In addition, they observed a significant increase in the
amount of positively stained nuclear in IBC for 2 NF-kB
subunits (RelB and NF-kB1). The immunostaining result was
verified by NF-kB DNA-binding experiments. NF-kB target
genes were also found to be significantly elevated in ERnegative breast cancers. Their findings suggested that the
NF-kB transcription factor pathway may play an important
role in the aggressive behavior of IBC.

Survival Trends Over Time and

History of the Treatment of IBC
Before the availability of combination chemotherapy, IBC
was almost uniformly fatal. Fewer than 5% of patients treated
with surgery and/or radiotherapy survived past 5 years, and
the expected median survival time for such patients was less
than 15 months.57 Local recurrence rates with surgery and/or
radiotherapy were also high at approximately 50%,58,59 and
most patients were not surgical candidates at all. One of the
first successful efforts to improve locoregional control before
a role for surgery in this disease was made by researchers at
the University of Texas M. D. Anderson Cancer Center. IBC
was recognized to have a rapid proliferative potential, and as
such, 1 mechanism for displaying resistance to radiation was
the repopulation of tumor cells during the interval between
radiation treatments. Based on this principle,60 investigators
sought to circumvent this rapid tumor cell growth rate by
incorporating accelerated hyperfractionated radiotherapy
into the definitive treatment of these patients.61 This shortened the overall radiotherapy course from 6 to 7 weeks to a
little more than 4 weeks (51 to 54 Gy in twice-daily fractions
of 1.5 Gy followed by a boost to the highest-risk volume of 15
to 20 Gy). Although this strategy was successful in improving
locoregional control, most patients still died from distant
metastatic disease.

259

Trimodality Therapy for IBC

During the 1970s, doxorubicin-based chemotherapy was introduced into the management of this disease, and in the late
1970s neoadjuvant chemotherapy was introduced.62 High
rates of tumor response were noted. Four prospective trials
conducted at the M.D. Anderson Cancer Center that enrolled
patients with IBC between 1974 and 200163-67 compared 4
anthracycline-containing regimen in combination with locoregional therapies, all of which showed equivalent efficacy
with overall clinical response and complete clinical response
rates of 72% and 12%, respectively. Baldini et al68 reported
on a cohort of 68 patients with IBC treated on 2 prospective
randomized trials in which patients received primary systemic chemotherapy with 3 cycles of cyclophosphamide,
doxorubicin, and 5-fluorouracil or cyclophosphamide, epirubicin, and 5-fluorouracil followed by surgery, adjuvant
chemotherapy, and finally radiotherapy. In this study, 5- and
10-year disease-free survival rates were reported at 29% and
20%, respectively, and overall survival rates were reported to
be 44% and 32%, respectively. Again, both outcomes were
far superior to outcomes reported before the introduction of
anthracycline-containing primary systemic treatment. These
results in combination with those observed for other breast
cancer types established anthracycline-containing primary
systemic regimens as a standard in the combined modality
treatment of IBC.

Neoadjuvant Chemotherapy for IBC

The prognostic impact of neoadjuvant systemic therapy can
be assessed by the percentage of patients who achieve a
pathologic complete response (defined as the absence of disease in both the breast and the axilla).69 Furthermore, Hennessy et al70 evaluated the prognostic significance of attaining
a pathologic complete response in the axillary lymph nodes
in a cohort of 61 IBC patients with cytologically confirmed
axillary lymph node metastases. In this study, the 5-year
overall and disease-free survival rates were higher in the
group that attained a pathologic complete response (82.5%
and 78.6%, respectively) in the axillary lymph nodes compared with those who had evidence of residual disease
(37.1% and 25.4%, respectively). These results served to extend the prognostic significance of response to treatment in
patients with IBC.
In the subsequent years, there were efforts to investigate
novel chemotherapy regimens that would increase the rate of
pathologic complete response in patients with IBC. Therefore, several studies introduced taxanes, such as paclitaxel
and docetaxel, to anthracycline-containing primary systemic
treatment regimens. The results of a cohort of 44 patients
with IBC treated with 4 cycles of fluorouracil, adriamycin,
cyclophosphamide (FAC)-based primary systemic chemotherapy, 16 of whom crossed over to receive paclitaxel after a
less than partial response to first-line chemotherapy, were
reported by Cristofanilli et al.71 Of the 16 patients who received paclitaxel, 7 achieved a partial response and underwent mastectomies. In a subsequent follow-up retrospective
study,72 the investigators compared 178 patients with IBC

W.A. Woodward and M. Cristofanilli

260
treated with FAC alone with 62 patients with IBC who were
treated with FAC followed by paclitaxel (either every 3 weeks
or on a high-dose weekly schedule). The investigators reported significantly higher pathologic complete response
rates with the addition of paclitaxel compared with FAC
alone (25% v 10%, P .012) with a higher median overall
survival and progression-free survival rates in the group receiving paclitaxel.
Among the several molecular determinants of IBC, particularly significant is the overexpression and/or amplification
of members of the HER-1 (ErbB1) and Her-2 (erbB2) family
of receptors. Trastuzumab, a humanized monoclonal antibody-targeted against the Her-2 protein, has recently been
shown to significantly improve survival outcomes in patients
with early73,74 and advanced-stage breast cancer.75 In addition, Buzdar et al76 reported pathologic response rates as high
as 60% when trastuzumab was incorporated into an anthracycline/taxane-based primary systemic chemotherapy regimen in a cohort of women with non-IBC early-stage breast
cancer. Similar pathologic complete response rates were subsequently reported by Dawood et al77 in a cohort of patients
with locally advanced breast cancer (that included IBC) when
treated with the same regimen as used by Buzdar et al76 in
operable disease.
Several studies have reported a higher incidence of Her-2
overexpression in patients with IBC,38,41 making trastuzumab an ideal agent to incorporate into the treatment paradigm of IBC. Hurley et al78 reported on a cohort of 48
patients with Her-2positive locally advanced breast cancer
(including IBC) who were treated with 12 weeks of docetaxel, cisplatin, and trastuzumab followed by surgery, adjuvant chemotherapy, and radiation therapy. The study reported a pathologic response rate (breast and axilla) of 17%
for the entire cohort with 4-year progression-free and overall
survival rates reported as 100% for those who attained a
pathologic complete response and 83% and 76%, respectively, for those who had evidence of residual disease. Van
Pelt et al79 reported on a cohort of 22 patients (9 of whom had
IBC) who were treated with a combination of docetaxel and
trastuzumab as part of their primary systemic regimen. In this
cohort, a complete response of 40% was observed. Limentani
et al80 evaluated a primary systemic regimen that was composed of docetaxel, vinorelbine, and trastuzumab on a cohort
of 31 patients with Her-2amplified breast carcinomas (including IBC) and reported clinical and pathologic response
rates of 94% and 39%, respectively. Burstein et al81 reported
on a pilot study that evaluated a cohort of 40 women with
stage II and III breast cancer (including 6 who had IBC) who
were treated with a primary systemic regimen of trastuzumab
and paclitaxel that was followed by surgery and adjuvant
anthracycline-based chemotherapy. In this cohort, complete
clinical response and pathologic complete response rates of
30% and 18% were reported, respectively. The results of
these studies when taken in combination with the known
survival advantage observed when trastuzumab is administered to patients with early-stage breast cancer and the survival advantage attained by obtaining a pathologic complete

response suggest that trastuzumab may indeed be a vital

component in the treatment of Her-2positive IBC.
Lapatinib (Tykerb, GlaxoSmithKline, Research Triangle
Park, NC 27709) is a reversible inhibitor of the ErbB1 and
ErbB2 tyrosine kinases that has been shown in ErbB1/ErbB2dependent tumor cell lines to induce growth arrest and/or
cell apoptosis.82 Partial responses to lapatinib in women with
extensively pretreated IBC have been reported.83,84 Based on
such observations, Cristofanilli et al85 evaluated the combination of lapatinib and paclitaxel as part of the primary systemic therapy regimen in a cohort of 21 chemo-naive patients
who had Her-2 overexpressing IBC. In this study, patients
received daily lapatinib at a dose of, 1500 mg initially as
monotherapy for 14 days after which it was given in combination with weekly paclitaxel, 80 mg/m, for 12 weeks. In
addition to good tolerance to this regimen, the authors noted
a 95% clinical response rate. Because of the remarkable clinical activity observed, these results will be prospectively validated.

Surgery for IBC

An important issue in reviewing reports about treatment efficacy has to do with the criteria used in selecting patients for
surgery. Various studies that have not found a benefit from
the addition of surgery have reserved mastectomy only for
those patients who did not respond well to primary chemotherapy with or without radiation.86-88 In these cases, surgery
is performed as a debulking procedure, rather than with curative intent. These studies have had mixed results, in part
because there is residual disease in a significant percentage of
patients who are disease free by clinical examination after the
completion of chemotherapy.89,90
In contrast, multiple studies have shown that surgery is
especially important for patients who respond well to chemotherapy, with the combination of therapies giving these
patients a real chance at long-term survival. Two studies published in 1989 showed that in patients receiving primary
chemotherapy, surgery, and radiation therapy, 5-year disease-free survival was significantly higher in patients with a
complete clinical response to primary chemotherapy compared with patients showing only a partial response or no
response.62,91 More recently, Fleming et al92 reviewed treatment outcomes in 178 women with IBC treated with doxorubicin-based multimodality therapy. They found that the
addition of mastectomy to chemotherapy and radiotherapy
improved local control. Also, the addition of mastectomy
improved distant disease-free survival and overall survival
but only in patients with a clinical complete or partial response to primary chemotherapy. There was no survival or
local control benefit from the addition of mastectomy for
patients who showed no significant response to primary chemotherapy.
A primary concern in surgical planning is that the operative field needs to be wide enough to encompass all the secondary skin changes. This is true even if surgery is undertaken only as a palliative measure. If this is not possible,
additional chemotherapy may be considered. Although as

Radiotherapy for IBC

much skin as necessary should be removed, tension must be
avoided in closing the skin flaps because this would make the
site unsuitable for radiotherapy. If necessary, repair with autologous tissue flaps should be used to ensure a healthy, flat
chest wall. This will usually be a latissimus dorsi myocutaneous flap, unless extremely broad coverage is needed.
Another major concern in surgical planning is the difficulty in determining the extent of surgical resection necessary in a patient with a significant clinical response to neoadjuvant chemotherapy. Clinical response as judged by physical
examination or imaging may underestimate the extent of residual disease in more than 60% of patients.89,90 Intuitively,
the extent of residual disease will be directly related to margin
status, and outcomes in patients with IBC are strongly influenced by margin status as reported by Curcio et al.93 These
investigators performed a 25-year review of outcome data
from 90 patients with IBC. In stage IIIB patients treated with
surgery, negative margin status was associated with 3-year
overall survival, disease-free survivavl, and local control rates
of 47.4%, 37.5%, and 60.3%, respectively, compared with
0%, 16.7%, and 31.3% in patients with positive margins.

Radiation for IBC

The addition of neoadjuvant chemotherapy to the treatment
regimen made mastectomy an appropriate treatment option
for most patients and proved to be a significant therapeutic
advance in locoregional management. With the addition of
mastectomy, the dose for the twice-daily fractionation
scheme was reduced to 45 Gy delivered over 3 weeks, with a
15-Gy boost to the chest wall. An analysis of the first 61
patients with clinically diagnosed IBC who were treated at
M. D. Anderson Cancer Center using this trimodality approach was published in 1989.62 Thirty-seven patients (61%)
showed some clinical response to induction chemotherapy;
10 of them (16%) experienced clinical complete response (6
patients with confirmed pathologic complete response), and
27 of them (45%) experienced at least a 50% reduction in
clinical signs of disease. Only 24 patients (39%) had no response. Mastectomy was performed on 56 patients (92%)
after neoadjuvant chemotherapy. Among the patients treated
with mastectomy, 9 had pathologically positive margins and
underwent immediate postoperative radiation. The remaining 46 patients completed planned adjuvant chemotherapy
before beginning radiation using once-daily (n 14) or
twice-daily (n 32) radiation. As noted previously, this
study showed that the initial clinical response to chemotherapy was associated with improved 5-year actuarial diseasefree survival rates, and the initial clinical response to chemotherapy also correlated with the probability of locoregional
control. The 5-year actuarial locoregional control rates were
89% in the patients experiencing a complete response, 68%
in those with a partial response, and 33% those with no
response; the overall rate was 58%. Most local failures occurred in the irradiated volume of the chest wall and occurred more frequently among patients who did not achieve
brisk erythema or moist desquamation from the radiation. In
the 46 patients who completed treatment as initially planned

261
(excluding the 9 patients who had immediate postmastectomy radiation secondary to positive margins), no difference
in local control was noted between the 2 radiation fractionation schedules, with 3 of 14 patients (21%) treated daily and
7 of 32 patients (22%) treated twice each day failing locally.
Because the locoregional recurrence in both arms was high,
these results provided the rationale to conduct dose-escalation studies using the twice-daily fractionation schema.
The next study built on these results attempted to escalate
the dose of hyperfractionated radiation by approximately
10%.94 The twice-daily regimen was delivered in 34 fractions
over 3.5 weeks to fields encompassing the chest wall and the
supraclavicular, infraclavicular, and internal mammary lymph
nodes to a total dose of 51 Gy. Subsequently, a 15-Gy boost
was delivered to the chest wall in a dosage of 1.5 Gy twice
daily over 5 days, yielding a total dose of 66 Gy. From 1986
through 1993, 39 patients with IBC were treated postmastectomy with this fractionation schedule. During this period, 8
patients were treated preoperatively with twice-daily radiation to a dose of 51 Gy, and 7 others were treated postoperatively with a daily radiation to 60 Gy. A comparison of
patients treated before 1986 (n 61) versus those treated
after 1986 (n 54) revealed significant improvement in
locoregional control rates in the latter group with trends toward better disease-free and overall survival as well. To evaluate the effects of dose escalation, a specific comparison was
made between the 32 patients who were treated postmastectomy with twice-daily radiation to a total dose of 60 Gy and
the 39 patients treated similarly but to a total dose of 66 Gy.
There was a significant improvement in locoregional control
in the high-dose group compared with the low-dose group,
84% versus 58% and 77% versus 58% at 5 and 10 years,
respectively (P .04). A statistically significant improvement
also occurred in 5- and 10-year overall survival rates between
these 2 groups (P .03), and a trend toward improvement in
5- and 10-year disease-free survival rates was noted (P
.06). As also noted in other studies,68,92,95-97 the degree of the
initial response to chemotherapy predicted for significantly
better local control, overall survival, and disease-free survival. Patients whose disease did not respond to chemotherapy had extremely poor outcomes regardless of treatment,
with 5-year overall survival and disease-free survival rates of
9% and 3%, respectively. Late toxicity occurred in 23 patients (20%). This complication rate was similar in the patients treated before 1986 and those treated after 1986.
Studies from other institutions have also compared dose
fractionation schedules and/or dose escalation and have
come to similar conclusions.98-100 For example, Pisansky et
al100 compared once-daily radiation given preoperatively to a
dose of 50.4 Gy over 28 days in 16 patients with twice-daily
radiation given preoperatively to a dose of 44.2 Gy over 13
days in 13 patients. Patients given the twice-daily treatment
appeared less likely to fail locally than patients treated with
daily irradiation, with an 8% local recurrence risk at 5 years
and a median time to progression of 17 months in the twicedaily group versus 26% and 13 months in the once-daily
group. In addition, Liauw et al98 reported their experience
with 61 patients with IBC who were treated curatively from

W.A. Woodward and M. Cristofanilli

262
1982 through 2001. Although postmastectomy radiotherapy
was delivered using once-daily fractionation schedules, the
authors concluded that total radiation doses greater than 60
Gy resulted in better freedom from locoregional disease progression and that local control was strongly predictive of
better cause-specific survival (P .0003). However, 22% of
the patients in this study developed locally recurrent disease
as a component of failure. In an attempt to further decrease
these local recurrence rates, these authors have now adopted
the use of hyperfractionated radiotherapy for their patients
with IBC.98
The most recent update of the M. D. Anderson experience
with twice-a-day radiation reports data with increased patient numbers and more mature follow-up. This report confirmed that treatment to a chest wall cumulative dose of 66
Gy was of clinical value for patients with a poor response to
chemotherapy, patients with close or positive surgical margins, patients with 4 or more positive lymph nodes after
neoadjuvant chemotherapy, and patients under 45 years old.
Importantly, excellent locoregional control rates were achieved
with a dose of 60 Gy dose for patients without any of these
features. Stratification of patients according to these features
may be warranted in that there was a trend for increased
significant late toxicity associated with dose escalation to 66
Gy. The actuarial risk of developing a grade 3 to 4 late complication as a function of radiation dose (29% in the 66-Gy
group v 15% in the 60-Gy group, P .08). From these data,
it was concluded that hyperfractionated dose escalation
could be reserved for the patient cohorts with high-risk features as described earlier.

Ongoing IBC Research

Patients whose disease does not respond initially to chemotherapy remain a therapeutic challenge. Despite clear advantages to adjuvant chemoradiation strategies in other disease
sites, such as gynecologic, gastrointestinal, and head and
neck malignancies,101,102 this strategy has not been extensively explored in breast cancer therapy. An unpublished
review of 42 IBC patients treated preoperatively with radiation alone at UT MdACC led to a 5-year local control and
distant metastasis-free survival rate of 75% and 20%, respectively. Eight patients were alive without distant disease at
40 months. Although preliminary, the MDACC experience
using concurrent capecitibine and radiation in 55 patients
with inoperable non-IBC breast cancer was favorable, with
91% of these patients converting to operable. The clinical complete response rate was 33%; moreover, the overall pathologic
complete response rate was 20% (unpublished data, SABCS,
2007). In general, patients have tolerated this treatment well
with very few additional acute side effects, and, as such, this
may represent an alternative strategy to dose acceleration/
escalation in patients with IBC at a high risk for local failure.
Despite advances optimizing trimodality therapy for IBC,
to date, no IBC specific therapy is available clinically in part
because of the few models exist to study IBC. Two cell lines,
Sum 149 and SUM190, which can be transplanted into immunocompromised mice to generate human xenografts have

been developed and used for in vitro and in vivo studies,103

and 2 orthotopic animal models, Mary-X104 and WIBC-9,105
have been established by transplanting cells derived from
human IBC into the cleared mammary fat pads of immunocompromised mice. Clinically, most IBC tumors are ER negative31 and Her-2/neu (H2N) positive,40 but IBC can be observed in tumors of any receptor combination. Mary-X tumors
originate from a tumor negative for ER, PR, and Her-2-neu,104
whereas WIBC-9 tumors are ER, PR, H2N positive.105 Adding
to these models, we have developed a third orthotopic human
xenograft, MDA-IBC-1 (unpublished data, WAW, MC) that is
ER positive (low), PR negative, and H2Neu negative, and
which unlike Sum 149, actively secretes WISP3, an insulinlike growth factor binding protein described as an IBC tumor
suppressor gene.51,106 Although it is presumed that the failure
to identify tumor emboli in the dermal lymphatics is clinically simply a sampling error in the biopsy, this xenograft can
manifest significant skin erythema as expected in IBC with
only rare tumor emboli noted, suggesting that other factors
may mediate skin change in addition to congested lymphatic
emboli. It is hoped that expanding the array of models available to study IBC will hasten the development of targeted IBC
therapy and increase overall survival for this aggressive disease.

Acknowledgments
Dr S. Krishnamurthy for providing DLI images, The Morgan
Welch Inflammatory Breast Cancer Research Program and
Clinic, The State of Texas Grant for Rare and Aggressive
Cancers, and The American Airlines.

References
1. Anderson WF, Schairer C, Chen BE, et al: Epidemiology of inflammatory breast cancer (IBC). Breast Dis 22:9-23, 2005
2. Bell C: A System of Operative Surgery (vol 2). Hartford, CT, Hale and
Homser, 1814
3. Lee B, Tannenbaum N: Inflammatory carcinoma of the breast: A report of twenty-eight cases from the breast clinic of Memorial Hospital.
Surg Gynecol Obstet 39:580, 1924
4. Greene FL, Page DL, Fritz A, et al: Breast, in AJCC Cancer Staging
Manual. New York, NY, Springer-Verlag, 2002, pp 255-281
5. Denoix P: Treatment of malignant breast cancer, in Recent Results in
Cancer Research. Berlin, Springer-Verlag, 1970, pp 92-94
6. Mourali N, Muenz LR, Tabbane F, et al: Epidemiologic features of rapidly
progressing breast cancer in Tunisia. Cancer 46:2741-2746, 1980
7. Mourali N, Tabbane F, Muenz LR, et al: Ten-year results utilizing
chemotherapy as primary treatment in nonmetastatic, rapidly progressing breast cancer. Cancer Invest 11:363-370, 1993
8. Hance KW, Anderson WF, Devesa SS, et al: Trends in inflammatory
breast carcinoma incidence and survival: The surveillance, epidemiology, and end results program at the National Cancer Institute. J Natl
Cancer Inst 97:966-975, 2005
9. Levine PH, Steinhorn SC, Ries LG, et al: Inflammatory breast cancer:
The experience of the surveillance, epidemiology, and end results
(SEER) program. J Natl Cancer Inst 74:291-297, 1985
10. Chang S, Parker SL, Pham T, et al: Inflammatory breast carcinoma
incidence and survival: The surveillance, epidemiology, and end results program of the National Cancer Institute, 1975-1992. Cancer
82:2366-2372, 1998
11. Wingo PA, Jamison PM, Young JL, et al: Population-based statistics for
women diagnosed with inflammatory breast cancer (United States).
Cancer Causes Control 15:321-328, 2004

Radiotherapy for IBC

12. American Cancer Society: Cancer Facts and Figures. Atlanta, American Cancer Society, 2007
13. Chang S, Buzdar AU, Hursting SD: Inflammatory breast cancer and
body mass index. J Clin Oncol 16:3731-3735, 1998
14. Levine PH: Factors for the development of aggressive inflammatory
and non-inflammatory breast cancer. Breast Cancer Res Treat p S91,
2004 (suppl 1)
15. Swanson CA, Brinton LA, Taylor PR, et al: Body size and breast cancer
risk assessed in women participating in te breast Cancer Detection
Demonstration project. Am J Epidemiol 130:1133-1141, 1989
16. Bonnier P, Charpin C, Lejeune C, et al: Inflammatory carcinomas of
the breast: A clinical, pathological, or a clinical and pathological definition? Int J Cancer 62:382-385, 1995
17. Takeichi M: Cadherin cell adhesion receptors as a morphogenetic
regulator. Science 251:1451-1455, 1991
18. Kleer CG, van Golen KL, Braun T, et al: Persistent E-cadherin expression in inflammatory breast cancer. Mod Pathol 14:458-464, 2001
19. Gamallo C, Palacios J, Suarez A, et al: Correlation of E-cadherin expression with differentiation grade and histological type in breast
carcinoma. Am J Pathol 142:987-993, 1993
20. Oka H, Shiozaki H, Kobayashi K, et al: Expression of E-cadherin cell
adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res 53:1696-1701, 1993
21. Bukholm IK, Nesland JM, Karesen R, et al: E-cadherin and alpha-,
beta-, and gamma-catenin protein expression in relation to metastasis
in human breast carcinoma. J Pathol 185:262-266, 1998
22. Hunt NC, Douglas-Jones AG, Jasani B, et al: Loss of E-cadherin expression associated with lymph node metastases in small breast carcinomas. Virchows Arch 430:285-289, 1997
23. Siitonen SM, Kononen JT, Helin HJ, et al: Reduced E-cadherin expression is associated with invasiveness and unfavorable prognosis in
breast cancer. Am J Clin Pathol 105:394-402, 1996
24. Heimann R, Lan F, McBride R, et al: Separating favorable from unfavorable prognostic markers in breast cancer: The role of E-cadherin.
Cancer Res 60:298-304, 2000
25. Colpaert CG, Vermeulen PB, Benoy I, et al: Inflammatory breast cancer shows angiogenesis with high endothelial proliferation rate and
strong E-cadherin expression. Br J Cancer 88:718-725, 2003
26. Tomlinson JS, Alpaugh ML, Barsky SH: An intact overexpressed Ecadherin/alpha, beta-catenin axis characterizes the lymphovascular
emboli of inflammatory breast carcinoma. Cancer Res 61:5231-5241,
2001
27. Alpaugh ML, Tomlinson JS, Kasraeian S, et al: Cooperative role of
E-cadherin and sialyl-Lewis X/A-deficient MUC1 in the passive dissemination of tumor emboli in inflammatory breast carcinoma. Oncogene 21:3631-3643, 2002
28. Alpaugh ML, Tomlinson JS, Ye Y, et al: Relationship of sialylLewis(x/a) underexpression and E-cadherin overexpression in the
lymphovascular embolus of inflammatory breast carcinoma. Am J
Pathol 161:619-628, 2002
29. Charafe-Jauffret E, Tarpin C, Bardou VJ, et al: Immunophenotypic
analysis of inflammatory breast cancers: Identification of an inflammatory signature. J Pathol 202:265-273, 2004
30. McCarthy NJ, Yang X, Linnoila IR, et al: Microvessel density, expression of estrogen receptor alpha, MIB-1, p53, and c-erbB-2 in inflammatory breast cancer. Clin Cancer Res 8:3857-3862, 2002
31. Paradiso A, Tommasi S, Brandi M, et al: Cell kinetics and hormonal
receptor status in inflammatory breast carcinoma. Comparison with
locally advanced disease. Cancer 64:1922-1927, 1989
32. Harvey HA, Lipton A, Lawrence BV, et al: Estrogen receptor status in
inflammatory breast carcinoma. J Surg Oncol 21:42-44, 1982
33. Nguyen DM, Sam K, Tsimelzon A, et al: Molecular heterogeneity of
inflammatory breast cancer: A hyperproliferative phenotype. Clin
Cancer Res 12:5047-5054, 2006
34. Jaiyesimi IA, Buzdar AU, Hortobagyi G: Inflammatory breast cancer: A
review. J Clin Oncol 10:1014-1024, 1992
35. Van den Eynden GG, Van der Auwera I, Van Laere S, et al: Validation
of a tissue microarray to study differential protein expression in in-

263

36.

37.

38.

39.

40.

41.
42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

flammatory and non-inflammatory breast cancer. Breast Cancer Res

Treat 85:13-22, 2004
Aziz SA, Pervez S, Khan S, et al: Case control study of prognostic
markers and disease outcome in inflammatory carcinoma breast: A
unique clinical experience. Breast J 7:398-404, 2001
Riou G, Le MG, Travagli JP, et al: Poor prognosis of p53 gene mutation
and nuclear overexpression of p53 protein in inflammatory breast
carcinoma. J Natl Cancer Inst 85:1765-1767, 1993
Turpin E, Bieche I, Bertheau P, et al: Increased incidence of ERBB2
overexpression and TP53 mutation in inflammatory breast cancer.
Oncogene 21:7593-7597, 2002
Guerin M, Gabillot M, Mathieu MC, et al: Structure and expression of
c-erbB-2 and EGF receptor genes in inflammatory and non-inflammatory breast cancer: Prognostic significance. Int J Cancer 43:201-208,
1989
Guerin M, Sheng ZM, Andrieu N, et al: Strong association between
c-myb and oestrogen-receptor expression in human breast cancer.
Oncogene 5:131-135, 1990
Parton M, Dowsett M, Ashley S, et al: High incidence of Her-2 positivity in inflammatory breast cancer. Breast 13:97-103, 2004
Charpin C, Bonnier P, Khouzami A, et al: Inflammatory breast carcinoma: An immunohistochemical study using monoclonal anti-pHER2/neu, pS2, cathepsin, ER and PR. Anticancer Res 12:591-597, 1992
Sawaki M, Ito Y, Akiyama F, et al: High prevalence of Her-2/neu and
p53 overexpression in inflammatory breast cancer. Breast Cancer 13:
172-178, 2006
Foekens JA, Rio MC, Seguin P, et al: Prediction of relapse and survival
in breast cancer patients by pS2 protein status. Cancer Res 50:38323837, 1990
Prost S, Le MG, Douc-Rasy S, et al: Association of c-erbB2-gene amplification with poor prognosis in non-inflammatory breast carcinomas but not in carcinomas of the inflammatory type. Int J Cancer
58:763-768, 1994
Gonzalez-Angulo AM, Sneige N, Buzdar AU, et al: p53 expression as a
prognostic marker in inflammatory breast cancer. Clin Cancer Res
10:6215-6221, 2004
Faille A, De Cremoux P, Extra JM, et al: p53 mutations and overexpression in locally advanced breast cancers. Br J Cancer 69:11451150, 1994
Resetkova E, Gonzalez-Angulo AM, Sneige N, et al: Prognostic value
of P53, MDM-2, and MUC-1 for patients with inflammatory breast
carcinoma. Cancer 101:913-917, 2004
Aas T, Borresen AL, Geisler S, et al: Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 2:811-814, 1996
Kandioler-Eckersberger D, Ludwig C, Rudas M, et al: TP53 mutation
and p53 overexpression for prediction of response to neoadjuvant
treatment in breast cancer patients. Clin Cancer Res 6:50-56, 2000
van Golen KL, Davies S, Wu ZF, et al: A novel putative low-affinity
insulin-like growth factor-binding protein, LIBC (lost in inflammatory
breast cancer), and RhoC GTPase correlate with the inflammatory
breast cancer phenotype. Clin Cancer Res 5:2511-2519, 1999
van Golen KL, Wu ZF, Qiao XT, et al: RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially
recapitulates the inflammatory breast cancer phenotype. Cancer Res
60:5832-5838, 2000
Kleer CG, van Golen KL, Zhang Y, et al: Characterization of RhoC
expression in benign and malignant breast disease: A potential new
marker for small breast carcinomas with metastatic ability. Am J
Pathol 160:579-584, 2002
Kleer CG, Griffith KA, Sabel MS, et al: RhoC-GTPase is a novel tissue
biomarker associated with biologically aggressive carcinomas of the
breast. Breast Cancer Res Treat 93:101-110, 2005
Van Laere S, Van der Auwera I, Van den Eynden GG, et al: Distinct
molecular signature of inflammatory breast cancer by cDNA microarray analysis. Breast Cancer Res Treat 93:237-246, 2005
Van Laere SJ, Van der Auwera I, Van den Eynden GG, et al: Nuclear
factor-kappaB signature of inflammatory breast cancer by cDNA
microarray validated by quantitative real-time reverse transcrip-

W.A. Woodward and M. Cristofanilli

264

57.
58.
59.

60.

61.

62.

63.

64.

65.

66.
67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

tion-PCR, immunohistochemistry, and nuclear factor-kappaB

DNA-binding. Clin Cancer Res 12:3249-3256, 2006
Bozzetti F, Saccozzi R, Lena MD, et al: Inflammatory cancer of the
breast: Analysis of 114 cases. J Surg Oncol 18:355-361, 1981
Barker JL, Nelson AJ, Montague ED: Inflammatory carcinoma of the
breast. Radiology 121:173-176, 1976
Zucali R, Uslenghi C, Kenda R, et al: Natural history and survival of
inoperable breast cancer treated with radiotherapy and radiotherapy
followed by radical mastectomy. Cancer 37:1422-1431, 1976
Thames HD Jr, Peters LJ, Withers HR, et al: Accelerated fractionation
vs hyperfractionation: Rationales for several treatments per day. Int J
Radiat Oncol Biol Phys 9:127-138, 1983
Barker JL, Montague ED, Peters LJ: Clinical experience with irradiation of inflammatory carcinoma of the breast with and without elective
chemotherapy. Cancer 45:625-629, 1980
Thoms WW Jr, McNeese MD, Fletcher GH, et al: Multimodal treatment for inflammatory breast cancer. Int J Radiat Oncol Biol Phys
17:739-745, 1989
Ueno NT, Buzdar AU, Singletary SE, et al: Combined modality treatment of inflammatory breast carcinoma: Twenty years of experience at
M. D. Anderson center. Cancer Chemother Pharmacol 40:321-329,
1997
Blumenschein G, Montague ED, Eckles NE, et al: Sequential combined modality therapy for inflammatory breast cancer. Breast 2:1620, 1976
Koh EH, Buzdar AU, Ames FC, et al: Inflammatory carcinoma of the
breast: Results of a combined-modality approach-M. D. Anderson
Cancer Center experience. Cancer Chemother Pharmacol 27:94-100,
1990
Singletary SE, Ames FC, Buzdar AU: Management of inflammatory
breast cancer. World J Surg 18:87-92, 1994
Buzdar AU, Singeltary SE, Booser DJ, et al: Combined modality treatment of stage III and inflammatory breast cancer. M. D. Anderson
Cancer Center experience. Surg Oncol Clin North Am 4:715-734,
1995
Baldini E, Gardin G, Evangelista G, et al: Long-term results of combined-modality therapy for inflammatory breast cancer. Clin Breast
Cancer 5:358-363, 2004
Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breast
cancer patients with complete pathological primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460-469, 1999
Hennessy BT, Gonzalez-Angulo AM, Hortobagyi GN, et al: Diseasefree and overall survival after pathological complete disease remission
of cytologically proven inflammatory breast carcinoma axillary lymph
node metastases after primary systemic chemotherapy. Cancer 106:
1000-1006, 2006
Cristofanilli M, Buzdar AU, Sneige N, et al: Paclitaxel in the mulitmodality treatment for inflammatory breast carcinoma. Cancer 92:17751782, 2001
Cristofanilli M, Gonzalez-Angulo AM, Buzdar AU, et al: Paclitaxel
improves the prognosis in estrogen receptor negative inflammatory
breast cancer: The M. D. Anderson Cancer Center experience. Clin
Breast Cancer 4:415-419, 2004
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab
after adjuvant chemotherapy in HER2-positive breast cancer. N Engl
J Med 353:1659-1684, 2005
Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant
chemotherapy in HER2-positive breast cancer. N Engl J Med 353:
1673-1684, 2005
Slamon DJ, Leyland-Jones B, Shak S, et al: Human breast cancer: Use
of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpress HER2. N Engl J Med 344:783792, 2001
Buzdar AU, Ibrahim NK, Francis D, et al: Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth receptor 2-positive
operable breast cancer. J Clin Oncol 23:3676-3685, 2005

77. Dawood S, Gonzalez-Angulo AM, Peintinger F, et al: Efficacy and

safety of neoadjuvant trastuzumab combined with paclitaxel and epirubicin: A retrospective review of the M. D. Anderson experience.
Cancer 110:1195-1200, 2007
78. Hurley J, Doliny P, Reis I, et al: Docetaxel, cisplatin, and trastuzumab
as primary systemic therapy for human epidermal growth factor: Receptor 2postive locally advanced breast cancer. J Clin Oncol 24:18311838, 2006
79. Van Pelt AE, Mohsin S, Elledge RM, et al: Neoadjuvant trastuzumab
and docetaxel in breast cancer: Preliminary results. Clin Breast Cancer
4:348-353, 2003
80. Limentani SA, Brufsky AM, Erban JK, et al: phase II study of neoadjuvant docetaxel, vinorelbine, and trastuzumab followed by surgery
and adjuvant doxorubicin plus cyclophosphamide in women with
human epidermal growth factor receptor 2-overexpressing locally advanced breast cancer. J Clin Oncol 25:1232-1238, 2007
81. Burstein HJ, Harris LN, Gelman R, et al: Preoperative therapy with
trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast
cancer: A pilot study. J Clin Oncol 21:46-53, 2003
82. Xia W, Mullin RJ, Keith BR, et al: Anti-tumor activity of GW572016:
A dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2
and downstream ERK1/2 and AKT pathways. Oncogene 21:62556263, 2002
83. Ha B III, Hurwitz HI, Dees EC, et al: Phase I safety, pharmacokinetics,
and clinical activity study of lapatinib (GW572016), a reversible dual
inhibitor of epidermal growth factor receptor tyrosine kinases, in
heavily pretreated patients with metastatic carcinomas. J Clin Oncol
23:5305-5313, 2005
84. Spector NL, Blackwell K, Hurley J, et al: EGF103009, a phase II trial of
lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): Clinical activity and biologic predictors of
response. J Clin Oncol 24:502, 2006 (suppl)
85. Cristofanilli M, Boussen H, Baselga J, et al: A phase II combination
study of lapatinib and paclitaxel as a neoadjuvant therapy in patients
with newly diagnosed inflammatory breast cancer (IBC). Breast Cancer Res Treat 55:58, 2006 (abstr 1)
86. Arthur DW, Schmidt-Ullrich RK, Friedman RG, et al: Accelerated
superfractionated radiotherapy for inflammatory breast carcinoma:
Complete response predicts outcome and allows for breast conservation. Int J Radiat Oncol Biol Phys 44:289-296, 1999
87. de Boer RH, Allum WH, Ebbs SR, et al: Multimodality therapy in
inflammatory breast cancer: Is there a place for surgery? Ann Oncol
11:1147-1153, 2000
88. Swain SM, Sorace RA, Bagley CS, et al: Neoadjuvant chemotherapy in
the combined modality approach of locally advanced nonrnetastatic
breast cancer. Cancer Res 47:3889-3894, 1987
89. Hortobagyi G, Singletary SE, Strom EA: Treatment of locally advanced
and inflammatory breast cancer, in Harris JR, Lippman ME, Morrow M
(eds): Treatment of Locally Advanced and Inflammatory Breast Cancer.
Philadelphia, PA, Lippincott, Williams Sc Wis, 2000, pp 645-660
90. Vlastos G, Fomage BD, Mirza NW, et al: The correlation of axillary
ultrasonography with histologic breast cancer downstaging after induction chemotherapy. Am J Surg 179:446-452, 2000
91. Fields JN, Perez CA, Kuske RR, et al: Inflammatory carcinoma of the
breast: Treatment results on 107 patients. Int J Radiat Oncol Biol Phys
17:149-155, 1989
92. Fleming RYD, Asmar L, Buzdar AU, et al: Effectiveness of mastectomy
by response to induction chemotherapy for control in inflammatory
breast carcinoma. Ann Surg Oncol 4:452-461, 1997
93. Curcio LD, Rupp E, Williams WL, et al: Beyond palliative mastectomy
in inflammatory breast cancer-a reassessment of margin status. Ann
Surg Oncol 6:249-254, 1999
94. Liao Z, Strom EA, Buzdar AU, et al: Locoregional irradiation for inflammatory breast cancer: Effectiveness of dose escalation in decreasing recurrence. Int J Radiat Oncol Biol Phys 47:1191-1200, 2000
95. Panades M, Olivotto IA, Speers CH, et al: Evolving treatment strategies
for inflammatory breast cancer: A population-based survival analysis.
J Clin Oncol 23:1941-1950, 2005

Radiotherapy for IBC

96. Maloisel F, Dufour P, Bergerat JP, et al: Results of initial doxorubicin,
5-fluorouracil, and cyclophosphamide combination chemotherapy
for inflammatory carcinoma of the breast. Cancer 65:851-855, 1990
97. Harris EE, Schultz D, Bertsch H, et al: Ten-year outcome after combined modality therapy for inflammatory breast cancer. Int J Radiat
Oncol Biol Phys 55:1200-1208, 2003
98. Liauw SL, Benda RK, Morris CG, et al: Inflammatory breast carcinoma: Outcomes with trimodality therapy for nonmetastatic disease.
Cancer 100:920-928, 2004
99. Chu AM, Cope O, Russo R, et al: Treatment of early stage breast cancer
by limited surgery and radical irradiation. Int J Radiat Oncol Biol Phys
6:25-30, 1980
100. Pisansky TM, Schaid DJ, Loprinzi CL, et al: Inflammatory breast cancer: Integration of irradiation, surgery, and chemotherapy. Am J Clin
Oncol 15:376-387, 1992

265
101. Eifel PJ: Chemoradiotherapy in the treatment of cervical cancer. Semin Radiat Oncol 16:177-185, 2006
102. Cox JD: Chemoradiation for malignant epithelial tumors. Cancer Radiother 2:7-11, 1998
103. Ethier SP: Human breast cancer cell lines as models of growth regulation and disease progression. J Mammary Gland Biol Neoplasia
1:111-121, 1996
104. Alpaugh ML, Tomlinson JS, Shao ZM, et al: A novel human xenograft
model of inflammatory breast cancer. Cancer Res 59:5079-5084, 1999
105. Shirakawa K, Tsuda H, Heike Y, et al: Absence of endothelial cells,
central necrosis, and fibrosis are associated with aggressive inflammatory breast cancer. Cancer Res 61:445-451, 2001
106. Kleer CG, Zhang Y, Pan Q, et al: WISP3 is a novel tumor suppressor
gene of inflammatory breast cancer. Oncogene 21:3172-3180,
2002