Drugs 2010; 70 (17): 2247-2258

REVIEW ARTICLE 0012-6667/10/0017-2247/$55.55/0

ª 2010 Adis Data Information BV. All rights reserved.

Triple-Negative Breast Cancer

Epidemiology and Management Options
Shaheenah Dawood
Department of Medical Oncology, Dubai Hospital, Dubai Health Authority, Dubai, United Arab Emirates

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2247
1. Defining Triple-Negative Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2248
1.1 The BRCA Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2249
2. Epidemiology and Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2249
3. Radiological Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2250
4. Management Options. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2250
4.1 Targeted Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2253
5. Prognosis and Patterns of Recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2254
6. Brain Metastases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2255
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2255

Abstract The triple receptor-negative breast cancer (TNBC) subtype is character-

ized by the lack of expression of both hormone receptors as well as lack of
over-expression and/or lack of gene amplification of human epidermal
growth factor receptor 2 (HER2). Approximately 10–15% of breast carci-
nomas are known to be of the TNBC subtype, which constitutes approxi-
mately 80% of all ‘basal-like tumours’. Risk factors for TNBC include young
age at breast cancer diagnosis, young age at menarche, high parity, lack of
breast feeding, high body mass index and African American ethnicity. The
majority of BRCA1 tumours are TNBC. TNBC has a worse prognosis and
tends to relapse early compared with other subtypes of breast cancer. Con-
versely, it displays increased chemosensitivity compared with other breast
tumour subtypes. Several agents are currently being investigated as potential
therapeutic agents for the treatment of women with TNBC including agents
targeted against EGFR, anti-angiogenic agents, multityrosine kinase in-
hibitors and poly (ADP-ribose) polymerase (PARP) inhibitors. This review
focuses on the epidemiology of TNBC, its pathological features, natural
history and recurrence patterns as well as current and future management
options.

In 2010 in the US it is estimated that 207 090 to this disease.[1] Despite these figures, the mor-
women will be diagnosed with breast cancer, with tality associated with breast cancer has reduced
an estimated 39 840 associated deaths attributed over the last 2 decades[2] and this decline has
2248
principally been attributed to both a multidis-
ciplinary approach to the management of breast
cancer and a deeper understanding of its biology
leading to individualized treatment. Edith Perez’s
statement at the International Breast Cancer Con-
gress in 2010 that ‘‘the one size fits all approach is
over in the setting of breast cancer’’ certainly
summarizes the change in the way we approach
the treatment of women with breast cancer in the
21st century. As oncologists, our understanding
of the biology of breast cancer has evolved with
the acknowledgement that breast cancer is a hetero-
geneous disease with distinct biological subtypes.[3]
Each subtype is known to have a unique response
to treatment and is associated with differing prog-
nostic outcomes.
Through gene expression profiling, several intri-
nsic breast tumour subtypes have been identified,
including the luminal subtypes that are charac-
terized by the expression of hormone receptor-
related genes, the human epidermal growth factor
receptor 2 (HER2) and ‘basal-like’ subtypes. In
terms of prognosis before the introduction of the
monoclonal antibody trastuzumab (directed to-
wards the HER2 receptor) into the treatment
paradigm of women with HER2-positive breast
cancer, luminal subtypes typically had superior
prognostic outcomes compared with the HER2
and basal-like subtypes.[4,5] These subtypes not
only have differing prognostic outcomes but re-
cent evidence also indicates that they have dif-
ferent patterns of recurrence as well.
At the patient bedside, the use of hormone
receptor and HER2 receptor status has been used
to stratify breast tumours into subtypes akin to
those identified by gene expression profiling tech-
niques.[6,7] Recent studies have identified the triple
receptor-negative breast cancer (TNBC) subtype,
characterized by the lack of expression of both
hormone receptors as well lack of overexpression
and/or lack of gene amplification of HER2, to be
associated with the worst prognostic outcome.[8]
Approximately 10–15% of breast carcinomas are
known to be of the TNBC subtype, which consti-
tutes approximately 80% of all ‘basal-like tumours’.
Due to the lack of expression of commonly mea-
sured receptors present in other breast tumour
subtypes, targeted agents specifically for TNBC
ª 2010 Adis Data Information BV. All rights reserved.
Dawood
are not yet available; this is in contrast to other
subtypes of breast cancer. This review focuses on
TNBC, reviewing its epidemiology, pathologi-
cal features, natural history and recurrence pat-
terns as well as current and future management
options.
1. Defining Triple-Negative Breast Cancer
It is important to note that although often
used interchangeably, the terms ‘basal-like’ breast
cancer and TNBC are not the same entity. TNBC
refers to the breast cancer phenotype where the
estrogen and progesterone receptor are negative,
as assessed by immunohistochemistry (IHC), and
there is a lack of overexpression of HER2, as
assessed by IHC, or the absence of its gene am-
plification, as assessed by fluorescence in situ hy-
bridization technique.[9] In contrast, ‘basal-like’
tumours refer to a molecular phenotype that has
been characterized by an intrinsic gene set identi-
fied by messenger RNA (mRNA) gene expression
profiling.[3] Many of the genes identified among
‘basal-like’ tumours are genes commonly identified
in the basal or myoepithelial cells of the normal
breast and include genes of the structural elements
of the basal epithelial cells (e.g. cytokeratin [CK] 5,
CK17, P-cadherin and vimentin) as well as genes
for the interaction of basal cells with the extra-
cellular matrix (e.g. fascin, laminin).[3,5]
Several studies have identified that TNBC
subtypes do generally cluster within a ‘basal-like’
subgroup with a concordance rate of approxi-
mately 70–80%.[6,7,10,11] Although a lot of overlap
exists between TNBC and the ‘basal-like’ sub-
group, there is also evidence of discordance be-
tween the two (30%). Studies have shown that
when ‘basal-like’ tumours, as defined by gene ex-
pression profiling using an intrinsic gene list, are
subjected to IHC analysis for estrogen, proges-
terone and HER2 receptor status evaluation,
approximately 15% of these tumours will be po-
sitive for one these receptors.[12,13] Conversely,
not all TNBC appears to be part of the ‘basal-
like’ cluster, with evidence from microarray ex-
pression profiling suggesting that TNBC also
encompasses tumours with the normal breast
cancer phenotype.[14,15]
Drugs 2010; 70 (17)
Epidemiology and Management of Triple-Negative Breast Cancer
The early work of Perou and colleagues[3]
suggested that the ‘basal-like’ tumours could be
better characterized by IHC by including staining
for CK5/6. Nielsen and colleagues[6] further re-
fined this work by introducing the IHC definition
of ‘basal-like’ tumours as being those that are
negative for estrogen, progesterone and HER2
receptors and positive for CK5/6 and/or epi-
dermal growth factor receptor (EGFR) [referred
to as the ‘five marker method’]. Using this defi-
nition, the authors identified 17 of 21 (81%)
‘basal-like’ tumours (as identified by microarray
analysis). In a recent study, Cheang and collea-
gues[16] compared the traditional three marker
method that defines TNBC with the five marker
method in a large population-based cohort of
more than 3000 patients. The authors reported
that 17% of tumours were classified as basal
based on the three marker method and 9% were
basal based on the five marker method. More-
over, the authors were also able to demonstrate a
significant difference in prognostic outcomes be-
tween the two groups. To identify better IHC
surrogates of ‘basal-like’ breast cancers, several
other markers have also been investigated, in-
cluding c-kit, P-cadherin, vimentin and platelet-
derived growth factor receptor (PDGFR).[17]
However, none of these markers alone or in
combination have proved to be 100% specific and
sensitive for the IHC identification of ‘basal-like’
breast cancers.
1.1 The BRCA Association
The majority of BRCA1-associated tumours
share many phenotypic features with TNBC,[18]
and gene expression profiling studies have pro-
vided evidence for a tendency of these tumours to
cluster with the ‘basal-like’ subtype.[5] Approxi-
mately 80–90% of the BRCA1-associated tu-
mours are negative for the estrogen receptor, less
than 5% overexpress HER2, and a large propor-
tion stain for basal-like cytokeratins (CK5,
CK14, CK18), P-cadherin and EGFR.[19,20] Col-
lins and colleagues[21] recently reported on a co-
hort of 126 patients with TNBC. The authors
reported that the prevalence of BRCA1 mutation
in the whole cohort was 15% and that this in-
ª 2010 Adis Data Information BV. All rights reserved.
2249
creased to 23% when the analysis was restricted
to patients younger than 50 years of age. In
combination, this evidence indicates that women
younger than 50 years of age presenting with
TNBC tumours should be considered for BRCA1
screening.
2. Epidemiology and Risk Factors
TNBC constitutes approximately 10–20% of
all newly diagnosed breast cancer.[16,22-25] There
have been no epidemiological studies specifically
designed to examine the risk factors associated
with specific molecular subtypes of breast cancer.
However, several retrospective studies of large
population-based cohorts have attempted to an-
swer this question (table I). The mean age at
diagnosis for women with TNBC tends to be
younger than those with non-TNBC tumours.
Anderson and colleagues[27] reported that the in-
cidence rates for breast tumours with poor prog-
nostic features (hormone receptor negative, tu-
mour size >2 cm, lymph node positive and high
grade) was higher than for breast tumours with
Table I. Risk factors and biological features of triple receptor-
negative breast cancer
Risk factors
Age at diagnosis <50 years[25]
African American ethnicity[22,26]
High body mass index[23]
Young age at menarche[23]
High parity[23]
Young age at time of first birth[23]
Lack of breast feeding[23]
Biological features
Negative expression for ER/PR by IHC[9]
Lack of over expression or gene amplification for HER2[9]
High Ki67[6]
p53 mutations[6,9]
Positive expression for cytokeratins and/or EGFR (when basal-like)
by IHC[6]
May have positive expression for vimentin, P-cadherin, PDGFR,
IGF-1R and c-kit by IHC[17]
EGFR = epidermal growth factor receptor; ER = estrogen receptor;
HER2 = human epidermal growth factor receptor 2; IGF-1R = insulin-
like growth factor-1 receptor; IHC = immunohistochemistry; PDGFR =
platelet-derived growth factor receptor; PR = progesterone receptor.
Drugs 2010; 70 (17)
2250
good prognostic features (hormone receptor pos-
itive, tumour size <2 cm, lymph node negative,
low grade) until the ages of 30–44 years. The au-
thors also reported that the incidence rates of
breast tumours with good prognostic features
were higher than those of poor prognostic fea-
tures after the age of 50 years. Drawing on data
derived from the California Cancer Registry,
Bauer and colleagues[25] reported that compared
with women with non-TNBC, the odds of a wo-
man with TNBC being under the age of 40 years
was 1.53.
Race is another important risk factor for
TNBC.[22,25,26] Carey and colleagues[22] evaluated
the population-based distribution and clinical as-
sociations of breast tumour subtypes of approxi-
mately 500 women with invasive breast cancer
within the Carolina Breast Cancer Study. The
authors reported that women with ‘basal-like’
tumours (defined as hormone receptor negative,
HER2 negative, CK5/6 positive and/or HER1
positive) were more likely to be African American
and premenopausal. The authors noted that 39%,
14% and 16% of women who were premenopau-
sal African American, postmenopausal African
American and non-African American, respect-
ively, had ‘basal-like’ tumours (p < 0.001).
Other potential risk factors have also been
identified for TNBC. Millikan and colleagues[23]
conducted a population-based case control study
that involved approximately 1400 women with
invasive breast cancer derived from the Carolina
Breast Cancer Study group. The authors noted
that compared with women with luminal A tu-
mours, those with ‘basal-like’ tumours were more
likely to have increased parity and younger age at
full-term pregnancy. The prevalence of ‘basal-
like’ tumours was highest among premenopausal
African American women. Furthermore, they no-
ted that, unlike women with luminal A tumours,
‘basal-like’ tumours were more likely in women
with younger age at menarche, who breast fed for
shorter durations and had a higher body mass
index. An elevated waist : hip ratio was associated
with an increased risk of ‘basal-like’ tumours re-
gardless of menopausal status, while it was as-
sociated with an increased risk of luminal A
tumours among postmenopausal women.
ª 2010 Adis Data Information BV. All rights reserved.
Dawood
3. Radiological Features
Dent and colleagues[28] reported on a cohort of
approximately 1600 women with invasive breast
cancer treated at the Henrietta Banting Breast
Centre (Toronto, ON, Canada). The authors made
the important observation that among the screen-
ed group of women over the age of 50 years, those
with TNBC were less likely to be detected by
either mammography or ultrasound than women
with non-TNBC (19.6% vs 36.0%; p = 0.0008). In
a nested case-control study, Collett and collea-
gues[29] observed that breast cancers with a basal
epithelia phenotype had a higher odds of pre-
senting between regular mammograms (as inter-
val cancers) than non-basal breast cancers (odds
ratio 2.3; p = 0.04).
Several retrospective studies have looked at
the radiological features of TNBCs. Features in-
clude the presence of a smooth circumscribed mass,
generally a lack of calcifications and/or spicu-
lated margins on a mammogram, and a lack of an
echogenic halo on ultrasound.[30-32] Uematsu and
colleagues[33] retrospectively looked at the MRI
features of TNBC. The authors noted that features
significantly associated with TNBC included the
presence of a mass lesion with smooth margins,
rim enhancement, persistent enhancement pat-
tern and very high intratumoural signal intensity
on T2-weighted MRI. Using fluorodeoxy glucose
(FDG) positron emission tomography (FDG-PET),
TNBCs have demonstrated higher FDG uptake
than other breast tumour subtypes, a feature in
keeping with their aggressive biology.[34]
4. Management Options
The multidisciplinary management of women
with breast cancer has had a positive impact on
survival outcomes, indicating the importance of
the various components of treatment including
surgery, chemotherapy and radiation therapy
where indicated. TNBCs are no exception to this
rule. In the EBCTCG (Early Breast Cancer Trial-
ists’ Collaborative Group), an individual patient
data meta-analysis of patients with estrogen-poor
breast cancer revealed that the administration of
a non-taxane-containing adjuvant chemotherapy
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Epidemiology and Management of Triple-Negative Breast Cancer
among patients with either node-negative or
-positive disease resulted in a 10-year breast cancer-
specific mortality reduction of approximately
6–8%.[35] Approximately half of the patients in
the study received an anthracycline-based regi-
men. Furthermore, the recent 15-year update of
the meta-analysis by the EBCTCG group showed
specifically that 6 months of adjuvant anthra-
cyline-based combination therapy among women
with estrogen-poor breast cancer improved breast
cancer-specific cancer mortality from 31.1% to
22.3% among women younger than 50 years and
from 38.8% to 20.8% for those women aged
50–69 years.[36] Although data on HER2 status
were not available at the time of the analysis, it
appears reasonable to assume these results can be
extrapolated to women with TNBCs.
The addition of taxanes to the adjuvant treatment
of women with early-stage lymph node-positive
breast cancer has also become the standard of care.
Henderson and colleagues[37] reported on the
initial results of the CALGB (Cancer and Leu-
kemia Group B) 9344 study that prospectively
tested the benefit of the sequential addition of
four cycles of paclitaxel following four cycles of
doxorubicin and cyclophosphamide. The authors
reported that the addition of sequential paclitaxel
resulted in a significant reduction in the risk of
recurrence of 17% and reduced risk of death by
18%. Hayes and colleagues[38] conducted a retro-
spective study on a subgroup of approximately
1300 women within the CALGB 9344 study to
specifically try to answer the question of whether
the addition of sequential paclitaxel was equally
beneficial across molecular subtypes of breast
cancer. The authors reported that the patients
who derived the most benefit from the sequential
addition of paclitaxel were the subgroup of pa-
tients whose tumours over-expressed HER2 and
those patients whose tumours were negative for
both HER2 and estrogen receptor (a group most
likely to represent those with TNBCs). These re-
sults have further been confirmed by a number of
other studies.[39-44]
Using data derived from the BCIRG (Breast
Cancer International Research Group) 001 study,
a prospective randomized study that compared
six cycles of adjuvant chemotherapy with doc-
ª 2010 Adis Data Information BV. All rights reserved.
2251
etaxel, doxorubicin and cyclophosphamide (TAC)
with six cycles of fluorouracil, doxorubicin and
cyclophosphamide (FAC) among women with
node-positive breast cancer, Hugh and collea-
gues[39] reported that the 3-year disease-free sur-
vival rate among women with TNBCs was 73.5%
following administration of TAC compared with
60% among those receiving FAC (hazard ratio
[HR] 0.50; p = 0.05). Jacquemier and collea-
gues[40] conducted a retrospective study to look at
the impact of molecular subtypes of breast cancer
on the therapeutic efficacy of adding a taxane to
adjuvant treatment. The study used data derived
from the prospective PACS 01 trial that ran-
domized women with node-positive breast cancer
to receive either six cycles of adjuvant FEC100
(fluorouracil + epirubicin + cyclophosphamide) or
three cycles of FEC100 followed by three cycles
of docetaxel. The authors reported that, although
patients with ‘basal-like’ tumours had worse pro-
gnosis, the addition of taxanes positively impacted
their survival outcomes. They further observed
that compared with women with luminal tumours,
those with ‘basal-like tumours’ benefited more
from the addition of docetaxel to their adjuvant
regimen (HR 0.65; p = 0.009). All of the evidence
points to the fact that the addition of taxanes to
the adjuvant treatment of women with TNBCs
improves survival outcomes significantly com-
pared with non-taxane-containing anthracyline
regimens.
Recently, the scheduling of taxanes has been
investigated and found to be an important fac-
tor with regards to its impact on survival out-
comes. Sparano and colleagues[45] reported on
a prospective study of more than 4000 women
who received four cycles of doxorubicin and
cyclophosphamide followed by either weekly or
3-weekly paclitaxel or docetaxel. The authors
reported that compared with women receiving
3-weekly paclitaxel, the odds ratio for disease-free
survival was 1.27 (p = 0.006), 1.23 (p = 0.02) and 1.09
(p = 0.29) among women receiving weekly pacli-
taxel, 3-weekly docetaxel and weekly docetaxel,
respectively, with an odds ratio above 1 favouring
the group of women receiving the experimen-
tal treatment. The improvement in survival out-
comes among women receiving weekly paclitaxel
Drugs 2010; 70 (17)
2252
was irrespective of the hormonal status of their
tumours.
A number of studies have made the interesting
observation that when women with TNBCs are
subjected to preoperative chemotherapy a greater
response to treatment is observed than in women
with other subtypes of breast cancer.[46,47] This is
an especially important observation because evi-
dence indicates that attaining a pathological com-
plete response (pCR) to preoperative chemotherapy
serves not only as an in vivo assessment of in vivo
chemosensitivity but also as a surrogate marker of
long-term outcome.[48] Carey and colleagues[46]
reported on a cohort of more than 100 women
with breast cancer receiving preoperative anthra-
cycline-based chemotherapy looking at the asso-
ciation of response to chemotherapy and survival
outcomes stratified by breast tumour subtypes.
The authors reported a higher clinical response
rate of 85% and 70% among women with ‘basal-
like’ and HER2-positive tumours than the 47%
observed among women with luminal breast tu-
mours. A pCR of 36%, 27% and 7% was observed
among women with HER2-positive, ‘basal-like’
and luminal tumours, respectively. The authors
noted that despite the high clinical and pCR rates
among women with ‘basal-like’ and HER2-posi-
tive tumours, they remained the group with the
poorest survival outcomes. Liedtke and collea-
gues[47] reported on a cohort of more than 1000
women with stage I–III breast cancer treated at the
MD Anderson Cancer Center (Houston, TX, USA)
with a variety of anthracyline-/taxane-based pre-
operative regimens. The authors noted a higher
pCR among women with TNBCs than in those
with hormone receptor-positive disease (22% vs
11%; HR 1.53; p = 0.034). Despite the high pCR
rates, on the whole women with TNBCs had
decreased 3-year progression-free (63% vs 76%)
and overall survival (74% vs 89%) when com-
pared with women with non-TNBC tumours. An
interesting observation made was that if a pCR
was achieved, survival outcomes were similar
among women with TNBC and non-TNBC tu-
mours (p = 0.24).
Recent data have also shown that the addition
of ixabepilone, a microtubule stabilizing agent,
in the preoperative setting resulted in 26% pCR
ª 2010 Adis Data Information BV. All rights reserved.
Dawood
among women with TNBC.[49] This will be fur-
ther evaluated in the PACS08 trial, which will
randomize patients to either FEC100 followed by
ixabepilone or FEC100 followed by docetaxel.
Evidence from preclinical and clinical studies
indicate that tumours with dysfunctional BRCA1
that harbours dysfunctional DNA repair mech-
anisms have an increased sensitivity to platinum
agents such as carboplatin and cisplatin.[50,51]
With the known close association between TNBC
and BRCA1 mutations, several studies have in-
vestigated these agents in this breast tumour
subtype[52-60] (table II). In a small preoperative
North Central Cancer Treatment Group study
(N0338) of dose-dense docetaxel and carboplatin
among patients with locally advanced breast
cancer, the authors were able to demonstrate a
pCR rate of 43% among women with TNBC.[55]
In a prospective study of ten patients with BRCA1-
positive breast cancer, Byrski and colleagues[56]
demonstrated a pCR rate of 90% with four cycles
of single-agent preoperative cisplatin (adminis-
tered at a dose of 75 mg/m2 every 3 weeks). In a
larger retrospective study, Byrski and colleagues[57]
studied a cohort of 102 women with BRCA1-
positive breast cancer who had been treated with
preoperative chemotherapy. The investigators
demonstrated a pCR of 7%, 8%, 22% and 83%
among women who had received preoperative
cyclophosphamide, methotrexate and fluoroura-
cil (CMF), doxorubicin and docetaxel (AT), FAC
or doxorubicin and cyclophosphamide (AC), and
single-agent cisplatin, respectively. In a more recent
prospective study of 28 women with stage II and
III TNBC, Silver and colleagues[58] demonstrated
a pCR of 22% when four cycles of single-agent
cisplatin was given as preoperative chemothera-
py. The investigators demonstrated that factors
that were significantly associated with a good cis-
platin response included young age, low BRCA1
mRNA expression, BRCA1 promotor methyla-
tion, p53 mutation and a gene expression signature
of E2F3 activation. Although the data described
are certainly provocative, it is important to note
that the data regarding the use of platinums
among women with TNBC are limited by several
factors including small numbers of patients in the
prospective studies thus far and the fact that there
Drugs 2010; 70 (17)
Epidemiology and Management of Triple-Negative Breast Cancer 2253

Table II. Selected studies of platinum agents and biological agents among women with triple-negative breast cancer (TNBC)
Study Setting No. of patients Chemotherapy Response (%) Survival
with TNBC
Platinum-containing regimens
Byrski et al.[57] Preoperative 102 CMF vs AT vs FAC vs cisplatin pCR 7% vs 8% vs
22% vs 83%
Silver et al.[58] Preoperative 28 Cisplatin pCR 22%
Torrisi et al.[59] Preoperative 30 Epirubicin-cisplatin-fluorouracil pCR 40%
followed by paclitaxel
Leone et al.[60] Preoperative 125 TC with or without AC pCR with AC 40%
pCR without AC 29%
Biological agents
O’Shaughnessy First-line 103 Irinotecan-carboplatin – cetuximab RR 49% vs 30%
et al.[53] metastatic
Carey et al.[61] Previously treated 102 Carboplatin + cetuximab ORR 18% OS 12 months
metastatic CBR 27%
Miller et al.[62] First-line 722 Paclitaxel – bevacizumab PFS 8.8 vs
metastatic (TNBC = 233) 4.6 months
O’Shaughnessy First-line 116 Gemcitabine-carboplatin – iniparib ORR 62% vs 21% PFS 6.9 vs
et al.[63] metastatic (BSI-201) 3.3 months
OS 9.2 vs
5.7 months
Tutt et al.[64] Previously treated 27 Olaparib ORR 41% PFS 5.7
metastatic months
AC = doxorubicin and cyclophosphamide; AT = doxorubicin and docetaxel; CBR = clinical benefit rate; CMF = cyclophosphamide, methotrex-
ate and fluorouracil; FAC = fluorouracil, doxorubicin and cyclophosphamide; ORR = overall response rate; OS = overall survival;
pCR = pathological complete response; PFS = progression-free survival; RR = response rate; TC = docetaxel and carboplatin.

are no prospective comparisons between platinum-
based regimens and the standard anthracyline-/
taxane-based regimens. As such, with the data
available thus far, outside the confines of a clin-
ical trial, platinum agents cannot be recommended
for routine incorporation into either preoperative
or adjuvant-based regimens. The ongoing CALGB
40603 trial is currently testing the benefit of ad-
ding preoperative carboplatin to taxane therapy
among women with stage II and III TNBC.[65]
Similarly, the TBCRC 009 study is currently in-
vestigating single-agent platinum (carboplatin or
cisplatin) among women with metastatic TNBC,
with a specific focus on determining the bio-
markers for predicting platinum sensitivity.[66]
4.1 Targeted Agents
The introduction of several targeted agents
such as the monoclonal antibody trastuzumab
directed against the HER2 receptor and the endo-
crine agents directed against estrogen and proges-
terone receptors has revolutionized the manage-
ment of women with HER2-positive and hormone
receptor-positive breast cancers, respectively. The
lack of these receptors in TNBCs means these
agents are not viable options for this subtype of
breast cancer. Several other targeted agents have
been investigated among women with TNBCs,
including agents targeted against EGFR, anti-
angiogenic agents, multityrosine kinase inhibi-
tors and poly (ADP-ribose) polymerase (PARP)
inhibitors.
EGFR expression is seen to be over-expressed
in approximately 60% of TNBCs.[6] This observa-
tion has led to the investigation of the monoclo-
nal antibody cetuximab that targets the EGFR.[53,61]
In a randomized phase II study, O’Shaughnessy
and colleagues[53] investigated the combination
of irinotecan and carboplatin with and without
cetuximab in a cohort of 103 women with metasta-
tic TNBC. The authors reported that the addition

ª 2010 Adis Data Information BV. All rights reserved. Drugs 2010; 70 (17)
2254
of cetuximab resulted in a higher response rate
(49% vs 30%) but was associated with a higher
incidence of grade 3 and 4 toxicity. In a second
phase II study, Carey and colleagues[61] looked at
the combination of cetuximab and carboplatin in
102 women with previously treated metastatic
TNBC. The authors reported that, although there
was an overall response and clinical benefit rate
of 18% and 27%, respectively, time to progression
was short at 2 months, with an overall survival of
12 months reported. There are currently ongoing
trials investigating the use of anti-EGFR agents
in the treatment of women with TNBC that will
shed light on their efficacy in this subtype of
breast cancer.[67]
Studies have reported increased levels of vas-
cular endothelial growth factor (VEGF) among
women with TNBC, which are associated with
decreased relapse-free survival when compared
with women with non-TNBC.[68] Thus, the use of
agents targeting VEGF for the treatment of TNBC
appears to be a reasonable strategy. The mono-
clonal antibody bevacizumab, which is targeted
against VEGF, has been prospectively investigat-
ed in a randomized clinical trial in combination
with paclitaxel versus single-agent paclitaxel in
the treatment of women with HER2-negative meta-
static breast cancer.[62] The study results indicat-
ed a significant improvement in progression-free
survival with the addition of bevacizumab, an ef-
fect that persisted among women with TNBC
(HR 0.53; 95% CI 0.4, 0.7). The BEATRICE
(Bevacizumab Adjuvant Therapy in Triple Nega-
tive Breast Cancer) trial is currently investigating
the addition of bevacizumab to adjuvant chemo-
therapy among women with TNBC. The oral multi-
targeted tyrosine kinase inhibitor sunitinib malate,
which inhibits VEGF, c-kit, PDGFR and colony-
stimulating factor-1 receptor, has also been investi-
gated in the treatment of metastatic breast cancer. A
15% response rate has been reported when it is used
as monotherapy among patients with TNBC who
were resistant to taxanes and anthracylines.[69]
PARP is a nuclear enzyme that plays a criti-
cal role in cell proliferation and DNA repair.
In the absence of PARP, single-strand DNA
breaks may degenerate into double-strand breaks
that cannot be repaired. The inhibition of PARP
ª 2010 Adis Data Information BV. All rights reserved.
Dawood
has therefore been explored in a number of phase
I and II trials.[70] In a randomized phase II trial,
the PARP inhibitor iniparib (BSI-201) was in-
vestigated in combination with gemcitabine and
carboplatin in women with TNBC.[63] The investi-
gators reported a significant improvement in the
clinical benefit rate (52% vs 12%), progression-
free survival (6.9 vs 3.3 months; HR 0.3; 95% CI
0.15, 0.59; p = 0.0003) and overall survival (9.2
vs 5.7 months; HR 0.24; 95% CI 0.09, 0.61;
p = 0.0012) in the group of patients who received
iniparib. The oral PARP inhibitor olaparib has also
been investigated in a phase II setting in women
with chemotherapy-refractory BRAC1 or BRCA2
mutated metastatic breast cancer.[64] The authors
demonstrated an overall response rate of 41% and
a median progression-free survival of 5.7 months
when used as a single agent.
5. Prognosis and Patterns of Recurrence
The initial studies defining different molecular
subtypes of breast cancer revealed that each
subtype was associated with a unique prognostic
outcome.[3-6] Sørlie and colleagues[4] studied 49
patients with locally advanced breast cancer and
reported that that overall survival was signif-
icantly different across subtypes of breast cancer,
with ‘basal-like’ and HER2-positive subtypes
associated with the shortest survival times. These
results have been replicated in several larger stud-
ies.[5,6,22,28,46,47,71] In a Canadian study involving
a large population by Drent and colleagues,[28]
women with TNBC had an increased risk of
death (HR 3.2; p < 0.0001) and distant recurrence
(HR 2.6; p < 0.0001) compared with women with
non-TNBC. Cheang and colleagues[16] hypothe-
sized that it is probably the proportion of women
with ‘basal-like’ tumours within the TNBC group
that drives the negative prognostic impact. Using
the five marker method to identify women with
‘basal-like’ tumours, they were able to show that
women with ‘basal-like’ TNBC had worse survi-
val outcomes than those with non-‘basal-like’
TNBC. Interestingly, despite the clear survival
disparity that exists among women with breast
cancer of different racial groups[72] and the higher
incidence of TNBC observed among African
Drugs 2010; 70 (17)
Epidemiology and Management of Triple-Negative Breast Cancer
American women,[22,25] evidence indicates that
when women of different racial groups who have
TNBC receive similar treatment and follow-up,
prognostic outcomes between the different racial
groups are similar.[73]
Several unique features regarding the recur-
rence patterns of women with TNBC have been
identified. First, the peak risk of recurrence oc-
curs during the first 3 years following treatment,
with rapid decline in the risk thereafter.[28] Sec-
ond, the risk of recurrence beyond 5 years de-
creases by 50% compared with women who have
hormone receptor-positive disease.[74] Third,
short survival time is typically observed following
a diagnosis of metastatic TNBC.[28] Fourth, evi-
dence indicates that visceral and soft tissue re-
lapses are more common than bone relapse among
women with TNBC compared with those with
hormone receptor-positive disease.[47,75]
6. Brain Metastases
The risk of developing brain metastases has
been reported to range from 10% to 16%, ap-
proaching 30% when autopsy diagnosis of brain
metastases is included.[76] Evidence indicates that
the frequency of brain metastases, ranging from
6% to 46%, may be higher among women with
TNBC than in other breast tumour subtypes.[77-79]
In a single institution study of over 3000 women,
Hietz and colleagues[78] looked at the association
of breast tumour subtype and the development of
brain metastases. The authors reported that wo-
men with TNBC had a higher risk of developing
brain metastases (10.58% vs 2.5%) and a shorter
median survival following a diagnosis of brain
metastases (4 vs 8 months) than other breast tu-
mour subtypes. Dawood and colleagues[79] report-
ed that among women with early-stage TNBC the
cumulative incidence of developing brain metas-
tases at 2 and 5 years was 5.6% and 9.6%, respec-
tively. Furthermore, the authors observed that
the median survival following a diagnosis of brain
metastases was approximately 2.9 months. The
data thus provide provocative evidence for stud-
ies to focus on the prediction of groups of wo-
men with TNBC at high risk of developing brain
metastases.
ª 2010 Adis Data Information BV. All rights reserved.
2255
7. Conclusions
TNBC represents a distinct subtype of breast
cancers that is associated with unique clinical
characteristics, risk factors, prognostic outcomes
and sensitivity to chemotherapeutic agents. How-
ever, it is important to remember that, although a
large proportion of TNBCs are ‘basal-like’, not
all TNBCs are ‘basal-like’, with the converse also
being true. It will be important for future studies
to focus on refining methods to accurately detect
‘basal-like’ tumours in the clinic setting. This will
be even more vital with the introduction of tar-
geted agents into the treatment paradigm of wo-
men with these tumours in order to allow for
proper patient selection to maximize therapeutic
benefit. Several agents are currently under in-
vestigation for the treatment of TNBC, including
anti-angiogenic agents, PARP inhibitors, as well
as DNA-damaging agents such as platinums. It is
hoped that results from studies investigating
these agents will have a positive impact on this pro-
gnostically poor subtype of breast cancer. Future
research focusing on the identification and incor-
poration of biomarkers into future clinical trials of
women with TNBC to better select patients will
also be important in achieving this goal.
Acknowledgements
No sources of funding were used to assist in the prepara-
tion of this review. The author has no conflicts of interest that
are directly relevant to the content of this review.
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Correspondence: Dr Shaheenah Dawood, Department of
Medical Oncology, Dubai Hospital, Dubai Health
Authority, PO Box 8179, Dubai, UAE.
E-mail: Shaheenah@post.harvard.edu
Drugs 2010; 70 (17)