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A Review of Triple-Negative Breast Cancer
Article in Cancer control: journal of the Moffitt Cancer Center · July 2010
DOI: 10.1177/107327481001700305 · Source: PubMed
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So-called “triple-negative” breast cancer presents
many challenges to successful management.
Nick Patten. Last Light (detail). Oil on canvas, 44" × 56".
A Review of Triple-Negative Breast Cancer
Roohi Ismail-Khan, MD, and Marilyn M. Bui, MD, PhD
Background: An estimated 1 million cases of breast cancer are diagnosed annually worldwide. Of these, more
than 170,000 are described as triple-negative. Triple-negative breast cancer (TNBC) is defined by the lack of
protein expression of estrogen receptor (ER) and progesterone receptor (PR) and the absence of HER2 protein
overexpression. TNBC is a subtype of breast cancer that overlaps with the “basal-like” breast cancer. TNBC has
significant clinical implications.
Methods: The epidemiology, diagnosis, clinical course, prognosis, and pathology of this subtype of breast cancer
are reviewed. The authors compare the “triple-negative” and “basal-like” definitions of breast cancer. A discussion
of both standard and experimental treatments for TNBC is included.
Results: The poor prognosis of high-grade TNBC relates to poor disease-free interval in the adjuvant setting,
shortened progression-free survival in the metastatic setting, and the lack of targeted therapy. However, not all
TNBCs are associated with a poor prognosis.
Conclusions: Although chemotherapy is the main current treatment of this subtype of breast cancer, new
agents such as PARP inhibitors, which show promise in the treatment of TNBC, are currently in clinical trials.
Introduction
Breast cancer is the most common cancer among
women in the United States, the second most common
cause of cancer death, and the main cause of death in
women ages 45 to 55 years. In 2009, approximately
192,370 American women were diagnosed with breast
cancer, and an estimated 40,170 women died of the disease.1 Triple-negative breast cancer (TNBC) accounts
for approximately 15% of breast cancers.2 Although
recently in the limelight and frequently discussed,TNBC
is not a new type of breast cancer. In fact, the term has
recently been coined to describe a subtype of breast
cancer that lacks expression of the estrogen receptor
(ER) and progesterone receptor (PR) and does not overexpress human epidermal growth factor 2 receptor
(HER2) protein. TNBC is an important area of research
for both researchers and clinicians alike because (1)
TNBC is a poor prognostic factor for disease-free and
overall survival, (2) no effective specific targeted therapy
is readily available for TNBC, (3) there is a clustering of
TNBC cases in premenopausal women and in women of
African descent, and (4) the overlap of BRCA1-associated
breast cancers with the TNBC phenotype is significant.
From the Comprehensive Breast and Experimental Therapeutics
Programs (RI-K, MMB), and the Departments of Women’s Oncology
(RI-K, MMB), Sarcoma (MMB), and Anatomic Pathology (MMB) at
the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Submitted September 30, 2009; accepted March 5, 2010.
Address correspondence to Roohi Ismail-Khan, MD, Comprehensive
Breast Program, Moffitt Cancer Center, 12902 Magnolia Drive,
Tampa, FL 33612. E-mail: Roohi.Ismail-Khan@moffitt.org
No significant relationship exists between the authors and the companies/organizations whose products or services may be referenced in this article.
Epidemiology
An estimated 1 million cases of breast cancer are diagnosed annually worldwide.3 Of these, approximately
170,000 are of the triple-negative (ER–/PR–/HER2–) phenotype.3 Of these TNBC cases, about 75% are “basal-like.”4
The prevalence of TNBC is highest in premenopausal
African American women; a recent report notes that
39% of all African American premenopausal women
diagnosed with breast cancer are diagnosed with
July 2010, Vol. 17, No. 3
Cancer Control 173
TNBC.5 The prevalence of TNBC in this same age group
in non–African American women is much less, at
approximately 15%. These ethnic or menopausal differences are not seen in either the ER+/HER2+ breast
cancer subgroup or the ER+/HER2– subgroup.5
Multiple other studies and abstracts have confirmed
that TNBC occurs in a higher percentage of African American women. Of these TNBC cases, about 75% are also of
the basal-type molecular classification. As presented initially in 2006 at the San Antonio Breast Cancer Symposium in a study of racial differences in the prevalence of
triple-negative invasive breast tumors, researchers found
that the incidence of triple-negative disease among
African American women was more than twice that
among white women. They also reported that 47% of
tumors in African American women were “triple-negative” compared with 22% in white women. After adjusting for age and stage at diagnosis, African American
women were almost 3-fold more likely than white
women to have triple-negative tumors.2
These disparities in incidence among different racial
groups leads us to question whether genes or mutations
predispose women, particularly premenopausal African
American women, to TNBC. Studies have shown that
breast cancers in women with germ-line BRCA1 mutations are more likely to be triple-negative and high-grade.6
Gene expression studies have confirmed this phenomenon and also that BRCA1-associated breast cancer appears
to cluster in the basal-like subtype.7
Pathologic and Molecular Features
Although the terms basal-like breast cancer and TNBC
are often used interchangeably, they are not synonymous. TNBC refers to the immunophenotype of the
breast cancer that is immunologically negative to ER,
PR, and HER2. These immunological studies are done
on formalin-fixed and paraffin-embedded tumor sections. Basal-like breast cancer refers to the molecular
phenotype of the tumor that has been defined by cDNA
microarrays. Of these TNBCs, about 75% of them are of
the basal-like type.
Perou et al8 were the first to describe the various
molecular subtypes or molecular profiles of breast cancers. They described four subtypes based on cDNA
microarrays, including a basal-like subtype of breast
cancer, and noted that most TNBCs clustered in the
basal-like subtype.8 Since then, multiple studies of gene
expression profiling have advanced the understanding
of the molecular diagnosis of breast cancer, thus providing the background for oncologists to use the triplenegative phenotype to describe the basal-like molecular subtype.7,9-11
The luminal subtypes of breast cancers express
high amounts of luminal cytokeratins and express genetic markers of luminal epithelial cells and normal breast
cells.12,13 In contrast, basal-like breast cancers tend to
express cytokeratins associated with basal types of cancers, as they arise from the outer basal layer.
Basal-like breast cancers are typically high-grade
and poorly differentiated when examined morphologically. While the TNBC phenotype is defined by immunohistochemistry, no established diagnostic criteria have
been identified for basal-like breast cancer on a morphological basis. In general, basal-like breast carcinomas
are morphologically consistent with a high nuclear grade,
high mitotic count, and necrosis (Fig 1), such as a grade 3
invasive ductal carcinoma, not otherwise specified (Fig 1).
Some have the histomorphology of medullary carcinoma
or metaplastic carcinoma. It has also been reported that
almost 82% of basal-like breast cancers express p53 compared with 13% in the luminal A subgroup.10
A subset of TNBC and basal-like breast cancer that is
of low histological grade includes secretory, adenoid
cystic, acinic cell, and apocrine breast carcinoma. Useful
immunohistochemical markers for characterizing basallike carcinomas are CK5 (Fig 2), CK6, CK14, CK8/CK18,
p63, P-cadherin, vimentin, epidermal growth factor receptor 1 (EGFR1 [or HER1]), c-kit, and other growth factors
such as insulin-like growth factor receptor (IGFR).4,13,14
Not all basal-like carcinomas are HER2–. A study
found that 23% of basal-like tumors, which are defined
by gene expression study, were HER2+.15 Therefore,
Fig 1. — This high-grade breast cancer (invasive ductal carcinoma, not otherwise specified, grade 3) is an example of a triple-negative breast cancer, basallike carcinoma (hematoxylin-eosin, ×400).
Fig 2. — This tumor shows CK5 positivity, which is typical for a basal-like
cancer (immunohistochemical CK5 stain, ×400). The insert is a CK5 stain of
a normal control slide highlighting the basal cells (hematoxylin-eosin, ×200).
174 Cancer Control
July 2010, Vol. 17, No. 3
HER2 immunoreactivity should not be used to rule out
a basal-like carcinoma.
It is important to realize that TNBC and basal-like
breast cancer are not all of high histological grade. For
the above-mentioned low-grade tumors, the clinical management strategies outlined in this article are not applicable. Therefore, oncologists need to be aware of this
when using triple-negative to define a potentially aggressive group of breast cancers. Although the majority of
TNBCs are basal-like and the majority of basal-like breast
cancers are triple-negative, there is approximately a 25%
discordance between the two descriptive subgroups.4
However, for the remainder of this article, the TNBC phenotype is used to represent this molecular subtype.
Clinical Course and Prognosis
TNBCs are biologically aggressive; although some reports
suggest that they respond to chemotherapy better than
other types of breast cancer, prognosis remains poor.16
This is due to two factors: shortened disease-free interval
in the adjuvant and neoadjuvant setting and a more
aggressive clinical course in the metastatic setting.
Triple-negative tumors have a good initial response
to chemotherapy, particularly anthracycline and taxanebased therapy. Although these tumors are initially sensitive to standard neoadjuvant chemotherapy, they continue to exhibit a short disease-free survival.17 Recently
published neoadjuvant studies have clarified the fact that
patients who have a good pathologic outcome from
surgery also have a good clinical response. However,
within the group of patients who have residual disease
after completing neoadjuvant chemotherapy, a worse
prognosis is seen in the triple-negative subgroup.18
Carey et al18 examined the relationship of neoadjuvant chemotherapy response to clinical outcome
among three breast cancer subtypes. They used immunohistochemical profiles to represent molecular
subtypes of breast cancer. The three groups compared
were the HER2+/hormone receptor-negative (HER2
overexpressed) subtype, the hormone receptor-negative and HER2– (basal-like) subtype, and the hormone
receptor-positive (luminal) subtype. They followed a
prospectively maintained data set of patients with
breast cancer treated with neoadjuvant anthracyclinebased chemotherapy — doxorubicin plus cyclophosphamide (AC). They then analyzed each subtype for
clinical and pathologic response to neoadjuvant
chemotherapy and examined the relationship of this
response to distant disease-free and overall survival.
After neoadjuvant AC, 75% received subsequent
chemotherapy, and all patients who were hormone
receptor-positive received endocrine therapy.
The chemotherapy regimen and the pretreatment
stage did not differ by subtype. The clinical response to
AC neoadjuvant therapy was higher in the HER2+/ER–
(70%) and basal-like (85%) subtypes than in the luminal
subtype (47%; P < .0001). Pathologic complete response
occurred in 36% in the HER2+/ER– group, 27% in the
basal-like group, and 7% in the luminal subtype (P =
July 2010, Vol. 17, No. 3
.01). Of interest, despite displaying initial chemosensitivity, patients with the basal-like and HER2+/ER– subtypes had worse distant disease-free survival (P = .04)
and overall survival (P = .02) than those with the luminal subtype. This worse outcome among the basal-like
and HER+/ER– subtypes was due to higher relapse
among those patients with residual disease after completing neoadjuvant chemotherapy (P = .003).
In another study, TNBC was associated with
increased risk for visceral metastases (P = .0005), lower
risk for bone recurrence (P = .027), and shorter postrecurrence survival (P < .0001).19 If pathologic complete response (pCR) was achieved, patients with TNBC
and non-TNBC had similar survival (P = .24). In contrast, patients with residual disease had worse overall
survival if they had TNBC compared with non-TNBC
(P < .0001). This study concluded that patients with
TNBC have increased pCR rates compared with those
without TNBC and that those with a pCR have excellent survival. However, patients with residual disease
after neoadjuvant chemotherapy have significantly
worse survival if they have TNBC compared with those
without TNBC, particularly in the first 3 years.
Even in early-stage TNBC, early relapse is common.
There is a predilection for visceral metastasis, including
lung, liver and, notably, brain metastasis. Current estimates are that approximately 15% of TNBC patients
develop brain metastasis. The risk for developing brain
metastasis is higher for patients with TNBC than with
other types of breast cancer. Studies show have shown
that even in patients with cerebral metastasis, TNBC
patients have a poor prognosis, as metastasis to the
brain occurred earlier.20
According to NCCN guidelines, treatment of T1N0
breast cancer is based on both tumor size and cellular
characteristics. Oncologists tend to treat patients with
T1N0 TNBC with more aggressive chemotherapy, in
both the neoadjuvant and adjuvant setting. When examining the number of patients treated and also the type
of adjuvant chemotherapy administered, triple-negative
T1N0 patients have greater recurrence risk despite this
more aggressive therapy.21 In 2007, researchers from
the Swedish Cancer Institute from Seattle, Washington,
reported that patients with T1N0 TNBC have twice the
risk of recurrence, despite receiving more aggressive
treatment.17
In addition to having a short disease-free survival,
triple-negative breast tumors are aggressive in the
metastatic setting, significantly contributing to the
shortened overall survival.3 Progression-free survival is
estimated to be 4 months at best in TNBC for first-line
therapy, even with bevacizumab-based therapy.22
Future Directions in Research
Although TNBC is sensitive to chemotherapy, early
relapse is more likely in patients with TNBC than with
other subtypes, and visceral metastasis, including brain
metastasis, is commonly seen. Targeted agents that are
currently being investigated include EGFR, vascular
Cancer Control 175
endothelial growth factor (VEGF), poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors.
The antiangiogenic agent bevacizumab (Avastin),
a monoclonal antibody targeting VEGF, is active in many
solid tumors including breast cancer. Miller et al22 demonstrated a significant improvement in progression-free survival (11.8 vs 5.9 months, hazard radio [HR] = .60; P <
.001) when adding bevacizumab to paclitaxel chemotherapy compared with single-agent paclitaxel alone in
first-line treatment of metastatic disease. Examining the
TNBC subset of patients in this study confirmed the
same improvement (HR = .53; 95% confidence interval,
0.40–0.70).22,23 Most oncologists would strongly consider an Avastin combination for first-line therapy when
treating patients with metastatic TNBC.
The fact that the majority of BRCA1-associated breast
cancers are also triple-negative and basal-like has led
researchers to question the extent to which the BRCA1
pathway contributes to the behavior of sporadic basal-like
breast cancers. It has been shown that basal-like breast
carcinomas frequently harbor defects in DNA doublestrand break repair through homologous recombinations
such as BRCA1 dysfunction. The DNA-repair defects characteristic of BRCA1-deficient cells confer sensitivity to
poly(ADP-ribose) polymerase 1 (PARP1) inhibition.24
The PARP1 gene encodes a chromatin-associated
enzyme that modifies various nuclear proteins. This
gene is involved in the molecular events leading to cell
recovery from DNA damage. When PARP1 is inhibited,
breaks in double-strand DNA accumulate that, under
normal conditions, would be repaired via homologous
recombination. Both BRCA1 and BRCA2 are required
for the homologous recombination pathway to function properly. Therefore, cells deficient in either BRCA1
or BRCA2 are sensitive to PARP1 inhibition, resulting in
cell death and apoptosis. Intuitively, inhibition of the
PARP pathway should benefit patients with BRCA-associated malignancies.25 However, as stated above, not all
TNBC cases are associated with BRCA mutations.
Several PARP1 inhibitors are currently in clinical
development and hold promise in TNBC and basal-like
breast cancers. As presented in a plenary session in
2009,26 the results of a randomized phase II study with
BSI-201 (a PARP inhibitor) showed benefit in patients
with TNBC who had two or fewer previous lines of
chemotherapy. When BSI-201 was combined with gemcitabine and carboplatin, the clinical benefit rate
improved to 62% compared with 21% in the gemcitabine
and carboplatin alone arm (P < .0002).26 Clinical benefit rate is defined as complete response plus partial
response plus stable disease for at least 6 months. In
addition, the overall response rate was notably improved
in the BSI-201 arm at 48% compared with the control
arm at 16%. Progression-free survival was improved to
6.9 months in the BSI-201 arm vs 3.3 months in the
gemcitabine and carboplatin alone arm.26 Currently,
many initial trials on targeted therapy with PARP
inhibitors are underway to study their use in the treatment of TNBC. In addition, several new agents are being
176 Cancer Control
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investigated that may be beneficial for patients with this
subgroup of breast cancer.
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July 2010, Vol. 17, No. 3