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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.

L ocally advanced breast cancer (LABC) is a diverse disease


that includes a wide range of clinical presentations, in-
cluding advanced primary tumors or extensive regional
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
nodal involvement without systemic metastasis. An elderly a postponement in the detection of a breast tumor until it
woman whose breast cancer has become inoperable after becomes symptomatic, which increases the likelihood that it
years of neglect as well as a young woman with rapidly grow- will be locally advanced at the time of diagnosis. The wide-
ing, aggressive breast cancer that developed between her an- spread use of screening mammography resulted in an initial
nual screening mammograms would both be described as rise in breast cancer incidence with a proportional decrease
having locally advanced disease. However, even though they in the amount of LABC diagnosed, although the number of
both represent LABC, these 2 scenarios show divergent bio- LABC cases remained fairly constant. Recent trends in breast
logical processes. The elderly woman in the first scenario may cancer in the United States have shown a decline in overall
have a biologically indolent tumor that is characterized by breast cancer incidence starting in the year 2000; however,
responsiveness to hormonal treatment, high estrogen recep- the rate of patients with larger tumors at the time of diagnosis
tor (ER) expression, low grade, and a low proliferative index.1 has not shown the same effect.2,3 These observations might
In contrast, the young woman who presented with locally suggest that there is a biologically distinct subset of tumors
advanced disease within the interval of time between annual that either have a rapid growth rate allowing them to become
screening is more likely to have an ER-negative, high-grade large tumors in the interval between screening mammogra-
tumor with a high proliferative index. Despite the fact that phy or have radiographic characteristics that limit earlier de-
they both present with locally advanced disease, the biology tection.4-6 In addition, hormone receptor (HR)-negative
of their breast cancer will confer strikingly dissimilar prog- breast cancer is disproportionately overrepresented in inter-
val tumors diagnosed outside of screening, highlighting that
tumor biology may limit the impact of screening in some
*Department of Radiation Oncology, Tufts University School of Medicine subtypes.7,8
and Tufts Medical Center, Boston, MA.
Rhode Island Hospital, Brown University School of Medicine, Providence, Inflammatory breast cancer (IBC) is an aggressive subset of
RI. LABC that is clinically defined by its rapid onset of symptoms
Department of Medicine, Division of Hematology/Oncology, Lineberger including breast edema, erythema, warmth, and induration.
Comprehensive Cancer Center, University of North Carolina, Chapel Patients with IBC have a worse clinical outcome compared to
Hill, NC.
Address reprint requests to Kathryn E. Huber, MD, PhD, Department of
stage-matched noninflammatory LABC.9 Biological charac-
Radiation Oncology, Tufts Medical Center, 800 Washington Street, Box teristics of IBC include high nuclear grade, lower ER expres-
359, Boston, MA 02111. E-mail: khuber@tuftsmedicalcenter.org sion, and higher expression of markers associated with ag-

204 1053-4296/09/$-see front matter 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.semradonc.2009.05.004
Breast cancer molecular subtypes 205

gressive pathology, such as p53, HER2 epidermal growth sion within breast cancer: those that were ER-positive and
factor receptor, and RhoC GTPase.10,11 Although considered respond to antiestrogens and those that are ER-negative and
a form of LABC, IBC appears to have distinct biology, with are refractory to hormonal manipulation.16 This crucial bio-
marked dysregulation of growth pathways, cellular adhesion, logical distinction is mirrored in noninflammatory LABC;
and interaction molecules. However, IBCs are still quite het- neglected disease is more likely to be ER-positive, whereas
erogeneous and can be distinguished by the same molecular the more aggressive forms of LABC are more likely to be
subtypes that have been defined in non-IBC.12,13 A detailed ER-negative. Another biologically distinct subset of breast
description of IBC is comprehensively covered in another cancer was discovered by novel work investigating the am-
review in this issue of Seminars in Radiation Oncology. plification of the HER2/neu oncogene in breast cancer.17 The
The advent of genomic technology has allowed for molec- analysis of 189 primary breast tumors showed that the am-
ular analysis of breast cancers, showing that the molecular plification of the HER2/neu oncogene occurred in 25% to
profiles of the tumors from the 2 patients discussed previ- 30% of the specimens and that this genomic alteration pre-
ously are likely to be quite different from one another. The dicted poor clinical outcome, even after adjustment for other
tumors molecular fingerprint may have within it informa- prognostic variables. Similar to the earlier breakthrough in-
tion regarding prognosis and response to therapy that will vestigations of HRs in breast cancer, this finding led to the
help us better treat LABC. The goal of this review was to development of targeted therapy and has had a significant
discuss LABC from the standpoint of molecular subtyping, impact on the outcome of women with HER2 overexpressing
with regard to its diversity in prognosis and response to ther- tumors.18,19
apy.

Heterogeneity of Breast Cancer Molecular


Breast cancer is a heterogeneous collection of diseases with Subtypes of Breast Cancer
various histologically defined subsets, clinical presentations, Gene expression profiling, which examines the relative ex-
responses to treatment, and outcomes. Several clinical and pression of thousands of genes in a single sample simulta-
histologic factors have prognostic value, such as the presence neously, led to the discovery of distinct molecular subtypes
and extent of lymph node metastasis, age at diagnosis, tumor within breast cancer.20 These molecular subtypes have phe-
grade and histology, and size of the primary tumor. The ear- notypic diversity with regard to multiple clinical outcomes,
liest observations of the heterogeneity of breast tumors led to the including response to treatment, disease-free survival, and
histopathologic classification of these tumors based on their overall survival. Multiple datasets have confirmed these mo-
morphologic features. Currently, 15 distinct histopathologic
lecular breast cancer subtypes, which include (1) at least 2
forms of breast cancer are recognized by the American Joint
luminal subtypes (luminal A and B) that comprise most ER-
Committee on Cancer.14 A few of these subsets are associated
positive breast cancer and are characterized by a high expres-
generally with favorable (pure tubular or medullary) or un-
sion of HR-related genes; (2) the basal-like subtype, which
favorable (metaplastic or undifferentiated) prognoses; how-
is characterized by a high expression of a unique basal
ever, most of the histologic forms have considerable variation
signature that includes genes common to the breast myoepi-
in their behavior. In addition, the development of LABC does
thelium, high expression of proliferation genes, and low ex-
not correlate with a particular histologic subtype and most
LABCs, like most non-LABC primary breast cancers, are in- pression of the ER signature and HER2 signatures; and (3) the
vasive ductal and/or lobular cancers. Further characteriza- HER2-enriched subtype, which is typified by high expression
tion of microscopic cellular heterogeneity in breast cancer, of HER2-related and proliferation genes and low expression
such as nuclear pleomorphism, tubule formation, and mi- of HR-related genes.21-23 Another subtype, the normal breast
totic index, has led to widely used tumor grading systems subtype, has expression patterns similar to nonmalignant tis-
that show a strong correlation with prognosis.15 However, sue and may be a sampling artifact.
although LABC can be associated with high grade, this asso- Survival analysis performed using the data from the 49
ciation is not consistent. The limitations in the prognostic patients with locally advanced disease determined that there
value of these clinical and microscopic variables have driven was a significant difference in overall survival among the
the exploration of the molecular diversity of this disease with molecular subtypes.21 The basal-like and HER2-enriched
the anticipation that it will help identify patients with poor subtypes showed the poorest prognosis with both shorter
prognosis and lead to the development of novel treatments time to progression and overall survival. Patients belonging
that will target the specific aberrant biology of their cancer. to the luminal A subtype had a considerably better prognosis
The first molecular distinction made in breast cancer was compared with all groups, and the luminal B subtype had an
from the work in the 1960s and 1970s that identified and intermediate outcome. The luminal subtypes are the most
characterized estrogen and progesterone receptor expression heterogeneous with regard to biology and outcomes.20-23 Lu-
on breast cancer cells. This discovery quickly led to the de- minal A tumors have variable proliferation gene expression
velopment of antiestrogen therapies. Responsiveness of the and also have highly variable prognostic signatures.24 Lumi-
tumor to hormonal therapy correlated directly with receptor nal B tumors, although still expressing the HR-related gene
expression and identified an important biological subdivi- signature, do so at a lower level, have variable expression of
206 K.E. Huber, L.A. Carey, and D.E. Wazer

the HER2 signature, and are generally more proliferative than How Biology May
the luminal A subtype. In multiple datasets, patients with
luminal B tumors have worse outcome compared with lumi-
Affect Treatment Outcome
nal A tumors, despite both usually being ER-positive. A multidisciplinary approach to the treatment of LABC with
Because of the technical limitations of performing microar- a combination of systemic therapy, surgery, and radiation has
ray expression analysis on formalin fixed, paraffin-embedded resulted in improved survival. Before the routine use of che-
tissue, the use of the ER, HER2, and cytokeratin immunohis- motherapy, 5-year survival was approximately 25% in pa-
tochemical (IHC) markers has been used as a surrogate to the tients with locally advanced disease.33 Combined modality
molecular subtypes. The marker combinations that best treatment now yields 5-year rates of survival in operable stage
matched the molecular profiles segregated the tumors into 4 IIIA patients and inoperable stage IIIB patients of 80% and
groups: (1) ER and/or PR, HER2 for luminal A subtype; 45%, respectively.33 However, patients who present with
(2) ER and/or PR, HER2 for luminal B subtype (al- stage III disease with identical clinical predictors of prognosis
though this is known to misclassify a significant proportion); continue to have quite variable outcomes such that many
(3) ER, PR, HER2, cytokeratin 5/6, and/or EGFR patients develop rapid disease progression despite contem-
for basal-like subtype; and (4) ER, PR, and HER2 for porary multimodal management. The discovery that there are
the HER2-enriched subtype.25,26 Of course, the major limita- distinct molecularly defined subtypes of breast cancer has
tion to this simplification is that the prognostic power of the given insight into the heterogeneous outcome in patients
subtypes is based on a complex gene expression signature with LABC and has prompted continued efforts in identifying
and that these molecular profiles are only associated with predictors of both response to treatment and survival based
these protein markers and not synonymous. In fact, the mo- on the tumors molecular profile.
lecular profiles have been found to have a more robust pre- The frequent use of preoperative chemotherapy as part
dictive value compared with the surrogate markers.27 However, of the management of LABC has provided a unique opportu-
the correlation between the molecular subtypes and these nity to investigate the molecular mechanisms of tumor re-
marker combinations is reasonable, and their proxy use has sponse to therapy. A number of studies have explored the
allowed for the analysis of large datasets and the discovery of effect of molecular subtype on both response to treatment
and survival in patients with LABC.12,34-41 Although subtype
important aspects of the biology of these tumor subtypes. In
was identified by using various methodologies, these inves-
the future, it is likely that RT-PCR based approaches, such as
tigations have consistently shown that the rate of pathologic
the recently developed PAM50 assay, which can measure a
complete response (pCR) differs considerably among the mo-
set of 50 intrinsic genes from formalin-fixed, paraffin-embed-
lecular subtypes (Table 1). The luminal A subtype had a very
ded tissue, will permit additional molecular subtyping in
low rate of pCR in patients treated with a variety of preoper-
archival specimens.28
ative chemotherapy regimens. In contrast, there was a high
A large population-based study using the IHC surrogate
rate of pCR seen with the basal-like and HER2-enriched sub-
markers for molecular subtype examined the association of
types. The luminal B subtype was associated with an inter-
molecular subtype with clinical characteristics and found
mediate rate of response. Interestingly, 2 studies included the
that the luminal A, luminal B, basal-like, and HER2-enriched normal breast subtype in their analysis and found that none
subtypes differed significantly by age, race, menopausal sta- of the patients who were in this subset achieved a pCR; how-
tus, lymph node involvement, histology group, tumor grade, ever, this finding is limited by the small sample size (collec-
and mitotic index.25 The most striking distinction was the tive n 16).34,35
overrepresentation of basal-like tumors in premenopausal At first glance, the inferior survival of patients with
black women (39% in premenopausal black women v 14% in basal-like and HER2-enriched tumors appears to stand in
postmenopausal black women and 16% in nonblack women contrast with the high rate of pCR observed in these patients
of all ages, P .001). Subsequent studies have confirmed because achieving pCR has been shown to be associated with
that basal-like tumors are more frequent in younger patients improved overall survival.42,43 However, patients who have
and blacks.29,30 In addition patients with basal-like tumors pCR have superior survival regardless of their sub-
tended to have aggressive features including high nuclear type.36,38,44 The unfavorable outcomes observed in the basal-
grade, high mitotic index, and unfavorable histology (meta- like and HER2-enriched subtypes were caused by a higher
plastic, anaplastic, or undifferentiated high-grade carcino- frequency of relapse or death in those who did not achieve a
mas). Paradoxically, this subtype was not associated with pCR with preoperative chemotherapy.36,44 Interestingly,
higher regional lymph node involvement. More recent anal- prior work has shown that a lower expression of HR-related
yses have provided supporting evidence for the decreased genes and a higher expression of proliferation-related genes,
prevalence of lymph node metastasis in basal-like tumors and similar to those that define the basal-like subtype, are asso-
have shown a disconnect between tumor size and positive ciated with a higher pCR rate.45 Therefore, increased prolif-
lymph nodes in this subtype.31,32 This finding suggests a dif- eration may be a double-edged sword, where rapidly divid-
ference in mechanisms of metastasis between luminal and ing cells leads to increased response to chemotherapy but
basal tumors and highlights that these breast cancer molec- also may increase their capacity for recurrence and metasta-
ular subtypes are distinct biological entities. sis.
Breast cancer molecular subtypes 207

Table 1 Effect of Breast Cancer Molecular Subtype on Rate of pCR to Preoperative Chemotherapy
Preoperative Luminal Luminal Basal HER2
Regimen N A (%) B (%) Like (%) Enriched (%) P References
TAC 82 6 ND 45 45 .026 34
TAC 50 9 ND 10 46 .024 35
TAC 107 0 15 27 36 .01 36
ABC, TAC 68 13 25 57 62 <.0001 37*
ABC, TBC, or TAC 1,731 6 15 22 29 <.0001 38*
ABC 21 27 ND 80 20 .08 12
T, A, or TAC 100 3 33 39 36 <.01 39*
TAC Tr 127 5 ND 58 40 <.001 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 post- 8.4%, respectively) compared with the luminal A (HR/
mastectomy radiation was recently investigated using data HER2) and luminal B (HR/HER2) subgroups (0.8%
from 1,000 patients enrolled in the large Danish postmastec- and 1.5%, respectively). However, the difference in local re-
tomy radiation trials DBCG82 b and c.46 These patients had currence could in part be caused by differences in systemic
clinical features associated with an increased risk of local treatment in these subgroups. When the patients with HR
recurrence and had been randomized to either receive or not tumors were given hormonal therapy, none of the HER2
receive postmastectomy radiation. High-risk features in- patients in this study received trastuzumab, and there is no
cluded large primary tumors (5 cm), positive lymph nodes, currently targeted treatment available for basal-like tumors.
or invasion of the primary tumor to the adjacent skin or Prior reports have not detected an increase in ipsilateral breast
pectoral fascia. The IHC surrogate markers were used for recurrence for basal-like, triple receptor-negative breast can-
molecular subtype classification. In this study, basal-like cer treated with breast conservation and whole-breast irradi-
(HR/HER2) and HER2-enriched (HR/HER2) sub- ation.7,48 However, a few distinctions can be made between
types showed a lower reduction in local recurrence from these reports and the Harvard study. First, the overall rate of
postmastectomy radiation compared with the luminal sub- local recurrence was much higher in the earlier studies (13%
types (Table 2). This finding may suggest radioresistance in for Dent et al,7 17% for Haffty et al48 v 1.8% Nguyen et al47).
the poor prognosis subtypes in contrast to the relative radio- Second, the earlier studies used IHC alone for HER2 classifi-
sensitivity of luminal subtypes. An alternative explanation for cation, whereas the latter study required HER2 gene ampli-
the increased rate of local recurrence could be related to fication in tumors with intermediate HER2 expression to
the intrinsic aggressiveness of the surviving cells from bas- qualify as HER2, likely resulting in a reduced rate of mis-
al-like and HER2-enriched tumors. However, this is dis- classification. In addition, the earlier studies compared tri-
puted by the finding that the de novo probability for local ple-negative tumors to all others, opposed to determining the
recurrence among the patients not receiving postmastec- recurrence rate in each of the 4 subtypes. The inclusion of
tomy radiation was fairly similar among the IHC-based HER2 tumors in the other subset could have diminished
molecular subtypes (Table 2).46 the difference between the molecular subtypes. Despite the
Evidence supporting the effect of molecular subtype on differences in the findings on local recurrence among these
local recurrence is seen in the Harvard analysis of 793 women reports, all showed an increase in the rate of distant metasta-
treated with breast-conservation surgery followed by radia- sis and decreased overall survival of the patients with basal-
tion.47 They showed a significant increase in 5-year local like tumors.
recurrence as the first event in the basal-like (HR/HER2) Interestingly, the patterns of metastatic disease seem to
and HER2-enriched (HR/HER2) subgroups (7.1% and 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 15 Years LRR
RT (%) No RT (%) P RT (%) No RT (%) P
Luminal A (n 628) 44 33 .009 3 32 <.001
Luminal B (n 96) 38 15 .07 3 48 <.005
Basal like (n 152) 39 32 .4 15 32 .001
HER2 enriched (n 120) 17 28 .14 21 33 .2
Abbreviations: RT, radiotherapy; OS, overall survival; LRR, locoregional recurrence.
Data from Kyndi et al.46
208 K.E. Huber, L.A. Carey, and D.E. Wazer

tients who develop metastatic disease have a significantly basal-like or HER2-enriched tumors and argues for the in-
higher portion of bone relapse in contrast to those with the vestigation of strategies for improved local control in these
basal-like subtype who have a predominance of visceral sites patients (eg, dose escalation or radiosensitization).
of metastases. These findings again support that these sub- The finding that HR-negative/HER2 tumors may have a
types are distinct biological variants of breast cancer that diminished benefit from postmastectomy radiation may in-
predispose these patients to a particular outcome. HER2- dicate a relative radioresistance of this subtype. Preclinical
overexpressing tumors have been found to have a predilec- data support the hypothesis of HER2 overexpression relating
tion for metastasis to the brain52 as have basal-like (or triple- to radioresistance; however, clinical data to support this ob-
negative) tumors.50 The comparison of HER2-overexpressing servation are limited.53,54 A retrospective analysis of 108 pa-
breast cancer patients to HER2-negative patients showed a tients treated with neoadjuvant chemotherapy, mastectomy,
4.5-fold increase in the incidence of developing brain metas- and postmastectomy radiation did not reveal an excess of
tasis (P .0001). It is possible that this effect is caused by the local failure in patients with HER2 disease.55 In addition, in
lack of penetration of trastuzumab through the blood brain the molecular subtype analysis of the Danish postmastec-
barrier. Alternatively, this pattern of recurrence may be caused tomy radiation trials, HER2 status alone did not predict for
by a biological distinct phenotype that leads to homing and either local recurrence probability or the relative benefit of
penetration of the central nervous system, as is suggested by radiation.46 It was the combination of HR negativity and
the studies noting other site-specific tropisms. Interestingly, HER2 overexpression that was associated with a lack of ben-
this study also showed a protective effect of ER-positive tu- efit from radiation in this study. The probability of local
mors for brain metastasis, suggesting that the ER-positive recurrence after postmastectomy radiation in patients with
subset of tumors lack the biological property that promotes the HER2-enriched molecular subtype merits further inves-
this process. These observations merit further investigation tigation. In addition, HER2-targeted therapy with trastu-
for the monitoring of central nervous system metastasis in zumab, which has become a standard therapy for HER2
patients with the HER2-enriched or basal-like subtypes and patients, may alter the sensitivity of this molecular subtype to
perhaps the development of treatments that can cross the radiation resulting in improved local control.
blood brain barrier. 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. There-
How Biology May fore, the effect of molecular subtype on local recurrence in
Affect Locoregional patients who choose to have breast conservation may be of
particular importance in this high-risk subgroup. The find-
Treatment Decisions ings by Nguyen et al47 showed that the basal-like and HER-
Data from the Danish Breast Cancer Cooperative Group show- enriched subtypes are associated with significantly higher
ing that patients with basal-like and HER2-enriched subtype rates of local recurrence in the intact breast after partial mas-
tumors had an appreciably lower benefit from postmastec- tectomy and whole-breast irradiation. Patients with locally
tomy radiation suggests that information regarding molecu- advanced disease made up a very small proportion of the
lar subtype may one day assist in the assessment as to cohort (approximately 6%) in this study. Likewise, the rates
whether a patient should receive postmastectomy radia- of local recurrence were quite low, with the high-risk basal
tion.46 The survival benefit from postmastectomy radiation and HER2 subtype local recurrence rates under 10% at 5
observed in this randomized study was limited to the luminal years. However, the incidence of local recurrence in patients
A subtype (HR .78, P .009). The patients with luminal B with the basal-like and HER2-enriched subtype with LABC
subtype had a trend toward improved survival associated who have breast conservation and whether molecular sub-
with radiation, but this did not reach statistical significance type alters the rate of in-breast recurrence in these patients
(HR .65, P .07). The basal-like subtype displayed an are yet to be determined.
inferior local control benefit compared with the luminal sub-
types, and there was no detectable survival benefit from ra-
diation (HR .85, P .4). Of note, there was a trend toward
Future Directions
a survival deficit with radiation therapy in the HER2-en- Advances in the use of cytotoxic chemotherapy have played a
riched subgroup (HR 1.35, P .14). Definitive conclu- substantive role in the improved outcome seen in patients
sions as to the relative effect of radiation therapy in this con- with LABC. In addition, hormonal therapy and HER2-tar-
text are limited by the retrospective nature of the study. In geted agents have become key components to adjuvant ther-
addition, because of the natural distribution of the molecular apy in patients with tumors expressing these markers. How-
subtypes, there were fewer patients with luminal B, basal- ever, the lack of targeted therapy for the basal-like subtype
like, and HER2-enriched tumors for analysis (luminal A 63%, has clearly defined the need for the development of novel
luminal B-10%, basal-like 15%, and HER2 enriched 12%), agents directed against the aberrant biology of this subtype.
making it less likely that a survival difference would have These tumors have a robust response to anthracycline- and
been detected in the less common subtypes. However, these taxane-based chemotherapies but are subsequently associ-
data call into question whether standard delivery of PMRT is ated with an unacceptable rate of relapse, high incidence of
sufficient for locoregional control in LABC patients with distant metastasis, and poor overall survival. Gene analysis
Breast cancer molecular subtypes 209

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