Original Article

Triple Negative Breast Cancer Characteristics Based on Basal-like and

Non-Basal-like Subtypes
Fifi Akwarini,1 Trinugroho Heri Fadjari,2 Bethy Suryawathy Hernowo3
1
Department of Internal Medicine, Santosa Hospital Bandung Central
2
Division of Medical Oncology Hematology, Department of Internal Medicine, Faculty of Medicine, Universitas
Padjadjaran-Dr. Hasan Sadikin General Hospital, Bandung
2
Department of Pathology Anatomy, Faculty of Medicine, Universitas Padjadjaran-Dr. Hasan Sadikin Hospital,
Bandung

Abstract Objective: To observe triple negative breast cancer (TNBC) characteristics in

three hospitals located in Bandung based on basal-like (BL) and non-basal-
like (NBL) subtypes.

Methods: This was a cross-sectional study which used descriptive categorical
data from medical records and paraffin blocks of TNBC patients treated in Dr.
Hasan Sadikin General Hospital, Bandung; Borromeus Hospital; and Santosa
Hospital Bandung Central in the period of January 1, 2012–December 31,
2016. The subjects of the study were 57 TNBC patients. The data collected in
the study based on medical records were age, tumor size, histopathological
images, severity, and immunohistochemical data. The paraffin blocks of the
patients based on the completed medicals records were investigated through
examinations of immunohistochemichal cytokeratin (CK) 5/6 expressions
and epidermal growth factor receptor (EGFR).

Results: Prevalence of TNBC were 82.5% of basal-like subjects and 17.5%
of non-basal-like subjects. Among the TNBC subjects, median age of each
subtype was 50 years of basal-like subtype and 45 years of non-basal-like
subtype. Both subtypes were mostly found in the subjects who aged >40 years.
Higher histopathological grade was discovered in both subtypes. The therapy
mostly carried out to the subjects was adjuvant chemotherapy. Majority of
basal-like subtype subjects were still alive and had longer survival rate and
lower incidences of deaths when compared to the non-basal-like subtype.

Received: Conclusions: In TNBC, the basal-like subjects showed greater median age,
February 6, 2019 lower severity stage, and longer survival rate than the non-basal-like subjects.
There was no histopathology grade between both subtypes.
Revised:
Keywords:
March 15, 2019 Basal-like and non-basal-like subtypes, breast cancer,
characteristics, triple negative
Accepted:
2019
March 21, pISSN: 2302-1381; eISSN: 2338-4506; http://doi.org/10.15850/ijihs.v7n1.1570
IJIHS. 2019;7(1):26–33

Introduction number of mortalities of 27/100.000 or 18%

deaths. However, a study stated that in male
Breast cancer (BC) is considered as one of population there may be 1% of them.1 Breast
many cancers mostly found in Indonesian cancer is characteristically a heterogenous
people. Incidences of females with BC in disease consisting of numerous subtypes with
Indonesia were approximately 12/100,000 distinctive disease history. It represents large
females while in United States 92/100,000 spectrum based on clinical, pathological, and
females suffering from BC leading to a large mulecular images and has various prognostic
Correspondence: and therapy implications. Recently, central
Fifi Akwarini, Department of Internal Medicine, focus related to BC is based on molecular
Santosa Hospital Bandung Central clasification.2
Jl. Kebonjati No.38, Bandung, Indonesia
e-mail: [email protected]

26 International Journal of Integrated Health Sciences. 2019;7(1):26–33

Fifi Akwarini, Trinugroho Heri Fadjari, et al.

Molecular classification of breast cancer hospitals due to the expensive costs. Pratt et
can be distinguished into several groups based al.8 suggested that a study on TNBC can be
on gene expression images by using modest conducted by classifying the subjects based on
technology of microarray deoxyribonucleic basal-like tumor versus non-basal-like tumor.
acid (DNA). From gene expression images, BC Neilsen et al.6 proposed immunohistochemical
is classified into 5 subtypes: luminal A, luminal examination can be used to substitute GEP
B, triple negative or basal-like, normal like, examination in order to identify BC of basal-like
and excessive human epidermal growth factor subtype which has the same definition as cDNA
receptor 2 (HER2).3 microarray examinations such as ER- HER-2-
The molecular subtypes are commonly and CK 5/6 or EGFR+. Immunohistochemical
associated with survival rate: luminal A examination can illustrate sensitivity (76%)
tumor has favourable prognosis and normal- and specifity (100%) in identifying BC of basal-
like tumor has moderate prognosis. Luminal like subtype such as fenotype basal obtained
B, HER2 positive, and basal-like tumors are through GEP examination.
commonly associated with shorter relapse- The TNBC of basal-like subtype has the same
free survival (RFS) and overall survival morphological characteristics as the higher
(OS). The molecular subtypes can predict histopathology grade. The majority incidences
therapy response; HER2 positive and basal- found in TNBC of basal-like subtype were
like tumors show greater complete response commonly associated with disease history,
(CR) after neoadjuvant chemotherapy when locoregional disease development, and more
compared to luminal and normal-like tumors.4 agressive metastasis in the first 5 year. This
Triple negative is also known as breast condition can cause shorter survival rate and
cancer subtypes with estrogen receptor (ER) higher mortalities.
negative, progresteron receptor (PR) negative, A previous study revealed that TNBC of
and lower HER2. The triple negative breast basal-like subtype becomes an independent
cancer (TNBC) has represented 15–12% of marker so that BC can have worse prognosis
newly BC incidences. It has epidemiological, as commonly found in cancer with or without
hispathological, and clinical image which lymph node metastasis. Tumor with basal-like
are different from other BC subtypes.5 It fenotipe is a worse predictor for the patients
also shows characteristics of more agressive such as histopathology grade 3, tumor without
clinical behavior, particular metastasis images, lymph node metastasis, and the patients
and worse prognosis. The focus is on the TNBC with severe metastasis. The Basal-like tumor
is due to the limitations of the therapy. Until determines that metastasis can occur in the
today, the only therapy for TNBC patients is brain and lung but metastasis rarely occurs in
systemic chemotherapy.6 the bone or liver.7
In many incidences the TNBC is categorized There is another finding of various biological
as basal-like BC. On the contrary, several terms from TNBC which is applicable to spread
studies revealed that TNBC and basal-like BC knowledge regarding to effective systemical
are biologically different tumors. There were therapy, provide newly medication including
many TNBC incidences which could not be immune checkpoint inhibitor, poly (ADP
identified as basal-like (nearly 80%) and there ribose) polymerase (PARP) inhibitor, cytotoxic
were basal-like tumors which could not be therapy including platinum chemoherapy
determined as TNBC.7 A previous study in 2013 medication, phosphatidylinositol-3 kinase
stated that TNBC is a wide subject with various pathway inhibitors, and androgen receptor
categories so that additional subclassifications (AR) inhibitor.10 Therefore, this study aimed
is then required.8 to investigate TNBC characteristics based on
Gene expression profile (GEP) examination basal-like and nonbasal-like subtypes in three
divides TNBC into seven molecular subtypes hospitals in Bandung.
i.e. basal-like 1, basal-like 2, mesenchymal
(M), mesenchymal stem cell like (MSL),
immunomodulatory (IM), luminal androgen Methods
receptor (AR)-like (LAR), and unknown
classification (UNC).9 The classification based Target population in this study was TNBC
on these subtypes can cause distinctive patients but the population included was
response during the therapy perceived by carcinoma TNBC patients who had been treated
each patient.10 The gene expression profile in the three hospitals in Bandung, West Java,
examination becomes a non-practical medical Indonesia such as Dr. Hasan Sadikin General
tool which is regularly conducted in the Hospital, Bandung, Borromeus Hospital, and

International Journal of Integrated Health Sciences. 2019;7(1):26–33 27

 Triple Negative Breast Cancer Characteristics Based on Basal-like and Non-Basal-like Subtypes

Santosa Hospital Bandung Central, Indonesia microscope by magnifications of 400 times.

in the period of January 1 2012–December 31 The values were categorized into 5 levels: 0
2016. The study used cross-sectional method (negative); 1 (<25% if the tumor cells were in
with descriptive categorical design. Samples brown color); 2 (25–<50% if the tumor cells
were the population which met the inclusion were brown color); 3 (50–75% if the tumor
criteria. cells were brown color); 4 (>75% if the tumor
The inclusion criteria in the study were cells were brown color).
BC patients who histopathologically and Both values obtained were distributions of
immunohistochemical diagnosed suffering intensity and positivity. Then, the intensity had
from TNBC carcinoma; slices of paraffin blocks been timed to positivity due to discover the
with routine stain of Hematoxylin-eosin, ER-, final value which was regarded as histoscore
PR-, dan HER-2- which could be examined; (HS). This value was determined based on
tissue of block paraffin could be evaluated immunoreactive scoring system (IRS) by
through HE stain or immunohistochemical Remmele W. and Stegner H. E. Negative
CK 5/6 and EGFR; the data in the medical immunoexpression would be negative if
records of TNBC patients consisted of age, the histoscore was <4 (0–3) and it would be
severity, tumore grading, chemotherapy types, positive if the histoscore was >4 (4–12) .11
and chemotherapy response; tissue handling
was performed based on the standard by Histoscore= = i x d
using neutral buffer formalin. Exclusion
criteria were the patients who had given There are associations between cancers
chemotherapy before histopathological and with the treatments and examinations. The
immunohistochemical examinations while TNBC of basal-like can be diagnosed via
TNBC treatments. immunochemical examination of CK 5/6 (+)
The TNBC patients in the study were and EGFR (+), or CK 5/6 (-) and EGFR (+), or
treated which were based on histopathological CK 5/6 (+) and EGFR (-). The TNBC non-basal-
examinations from breast biopsy via like can be examined by using examinations of
immunohistochemical examinations ER(-), immunochemical CK 5/6 (-) and EGFR (-).
PR(-), HER2(-). The immunohistochemical Neoadjuvant is a chemotherapy which is
examinations determined that the ER or PR given before surgery.12 Adjuvant chemotherapy
would be negative if the result was <1% while is commonly carried out after surgery. While
the HER-2 would be negative if the result palliative chemotherapy is given to BC which
was <+1. The immunoexpressions of CK 5/6 has been metastased.12
and EGFR were presented in percentage as Neoadjuvant chemotherapy response are
the cell which expressed CK 5/6 and EGFR determined as clinical response based on
from the total tumor cells in representative response evaluation criteria in solid tumors
areas. The CK 5/6 and EGFR assessments (RECIST) with revision version of 1.1 year
were calculated by using histoscore obtained 2009. The patients may have response if the
through immunohistochemical examinations condition meets complete response (CR)
consisting of two positive values of qualitative criteria and partial response (PR) but the
calculations and distribution positive response does not meet the criteria if the
values in several quantitative calculations. conditions represent progressive disease (PD)
Nevertheless, this study could be considered and stable disease (SD).13
as a semiquantitative study. Response of adjuvant chemotherapy in
The positive values of CK 5/6 and EGFR this study was not asssessed based on RECIST
were obtained from the brown color of BC because BC mass had been resected. Palliative
cytoplasm cells observed by using light chemotherapy response was diagnosed by
microscope which can be classified into 4 using clinical response based on RECIST. The
levels: 0 (negative) represented color intensity patients could have response if the condition
was the same as negative control which is not in met the CR, PR, and SD while no response was
brown color; 1 (low positive) was light brown discovered if the condition met the criteria of
color; 2 (moderate positive) was brown color; PD.13
3 (strong positive) was dark color which was The data in this study were collected
the same color intensity as positive control. by discovering paraffin blocks, recording
The positive values of tumor cells are pathology anatomy, numbers and medica
quantitative values in the form of percentage of records’ numbers from the biopsy specimens
brown color intensity distribution per field of of the TNBC patients at the Department of
view based on the examinations by using light Pathology Anatomy, Dr. Hasan Sadikin General

28 International Journal of Integrated Health Sciences. 2019;7(1):26–33

Fifi Akwarini, Trinugroho Heri Fadjari, et al.

Hospital, Bandung; Borromeus Hospital; and Table 1 Basic Characteristics of the

Santosa Hospital Bandung Central. Afterwards, Subjects Based on Triple Negative
the data of medical records were synchronized Breast Cancer between Basal-like
based on the data stored at the three hospitals. and Non-basal- like Subtypes
If the paraffin blocks were available and still in
proper condition, the paraffin blocks would be Basal-like Non-basal-like
Variables
observed relating to the immunohistochemical n=47 n=10
expressions of CK 5/6 and EGFR at the
laboratory of the Department of Pathology Age (yrs.)
Anatomy, Dr. Hasan Sadikin General Hospital, Mean (SD) 50 ± 11 45 ± 13
Bandung. Range 30 – 75 23 – 68
Age group (yrs.)
Results <40 10 (21.3) 3 (30.0)
This study was initiated to investigate the >40 37 (78.7) 7 (70.0)
TNBC characteristics based on basal-like and Tumor size (cm)
non-basal-like subtypes during March 2017 ≤2 10 (21.3) 2 (20.0)
to November 2017. Population in the study
was TNBC patients who were treated in Dr. 2.1–5 23 (48.9) 2 (20.0)
Hasan Sadikin General Hospital, Bandung; >5 14 (29.8) 6 (60.0)
Borromeus Hospital; and Santosa Hospital
Bandung Central in the period of January to Tumor necrosis
December 2016. Existed 14 (29.8) 3 (30.0)
Among the samples, only 57 samples were
None 30 (63.9) 6 (60.0)
included in the study as the subjects. The study
could be regarded as the first study which No data 3 (6.3) 1 (10.0)
divided TNBC into basal-like and non-basal- Lymphocyte
like in Bandung, Indonesia. infiltration
Among the subjects, fourty seven subjects
had TNBC through CK5/6 and EGFR (basal- Existed 24 (51.1) 2 (20.0)
like subtype) examinations while 10 subjects None 20 (42.6) 7 (70.0)
were observed by using expressions of No data 3(6.3) 1 (10.0)
immunohistochemical CK 5/6 negative and
EGFR negative (nonbasal-like subtype) (Table Lymphovascular
1). invasion
Adjuvant chemotherapy were mostly Existed 26 (55.3) 7 (70.0)
given to the subjects in the study (32 out of
57 subjects). The adjuvant chemotherapy None 21 (44.7) 3(30.0)
commonly given to the subjects combination Histopathology
of were doxorubicin and cyclophosphamide grade
(Table 2). Grade 1 2 (4.3) 0 (0.0)
Neoadjuvant chemotherapy was given to
4 TNBC of basal-like subtype subjects. The Grade 2 18 (38.3) 3 (30.0)
results revealed that the response showed Grade 3 23 (48.9) 5 (50.0)
partial response (PaR), the tumor shrinked
>30% after neoadjuvant chemotherapy. No data 4 (8.5) 2(20.0)
Additionally, all the subjects were given Lymp node
neoadjuvant chemotherapy with surgery and metastasis
adjuvant chemotherapy. None 18 (38.3) 5 (50.0)
Neoadjuvant chemotherapy was also given
to a subject with non-basal-like with PaR then 1–3 15 (31.9) 0 (0.0)
the subject was given surgery and adjuvant ≥4 11 (23.4) 5 (50.0)
chemotherapy. After six months, metastasis
No data 3(6.4) 0(0.0)
occurred in the lung and brain and the subject
died one month later. Tumor stage
I 4(8.5) 1 (10.0)

International Journal of Integrated Health Sciences. 2019;7(1):26–33 29

 Triple Negative Breast Cancer Characteristics Based on Basal-like and Non-Basal-like Subtypes

II 21 (44.7) 3 (30.0) Without 21 (44.7) 1 (10.0)

assessment
III 18 (38.3) 4(40.0)
IV 4 (8.5) 2 (20.0)
Palliative chemotherapy was given to 3
Histopathology
types TNBC subjects. Among the 2 subjects with
basal-like, 1 subject who was given palliative
Invasive ductal chemotherapy had lung metastasis and
carcinoma showed response after SD chemotherapy.
mammae (IDCM) Palliative chemotherapy was carried out to a
/ invasive 38 (80.9) 8(80.0) TNBC of non-basal-like subject with liver and
carcinoma
mammae non bone metastases and showed response after
specified type SD chemotherapy.
More than a half of TNBC of basal-like
Metaplastic subtype subjects were still alive, 20% of non-
carcinoma 3 (6.4) 0 (0.0) basal-like subtype subjects were alive, and
mammae
30% of the subjects died. However, a half of
Invasive lobular TNBC of non-basal-like subtype subjects until
carcinoma October 2017 relating to their status were still
mammae 3 (6.4) 0 (0.0) unknown (Table 3). Mean alive of the TNBC
(ILCM)/ ILCM of basal-like subtype subjects had 7 months
plemorphic type more of prolonged life when compared to the
Mucoid non-basal-like subtype.
carcinoma 0 (0.0) 1 (10.0)
mammae
Secretory Discussion
carcinoma 1 (2.1) 0 (0.0)
mammae Prevalences of TNBC of basal-like subtype in
Mixed IDCM+ this study were 82.5% (47 out of 57 subjects)
1 (2.1) 0 (0.0) while prevalences of TNBC non-basal-like
medulary
subtype were 17.5% (10 out of 57 subjects).
Mixed IDCM+ The results were in accordance with a previous
mucoid study included GEP examination reported
0 (0.0) 1 (10.0)
carcinoma
mammae that 70–80% TNBC subjects were basal-like
subtype and 20–30% subjects were non-
Mixed IDCM + basal-like subtype.9 The GEP examination in
1 (2.1) 0 (0.0)
Paget Disease BC can distinguish intrinsic subtype which has
Type of significant prognostic and predicative value
chemotherapy but it is uneasily performed in daily clinical
Neoadjuvant 4 (8.5) 1 (10.0) examination. The immunohistochemical is
affordable for daily clinical examinations
Adjuvant 29 (63.8) 3 (40.0) due to identify protein expression as a
Palliative 2 (8.5) 1 (10.0) marker of TNBC of basal-like gene. The
immunohistochemical examination is suitable
No to detect TNBC of basal-like (cytokeratin
5 (6.4) 0 (0.0)
chemotherapy CK5/6 and or EGFR positive, ER negative, and
No data 7 (12.8) 5 (40.0) HER2 negative) which has 76% sensitivity
Ki-67 and 100% specifity.4 The TNBC of basal-like
subtype has different molecular lesion (p53
<20% 17 (36.2) 8 (80.0) stabilization and more indication of mitosis)
≥20% 21 (44.7) 0 (0.0) and is associated with lower level of survival
rate when compared to the non-basal-like
Without subtype.4,9
9 (19.1) 2 (20.0)
assessment
Mean age of TNBC of basal-like subtype
P53 in this study was 50 years (ranged 30–75)
Negative 12 (25.5) 5 (50.0) which lower than the non-basal-like subtype
(45 years ranged 23–68). A study by Fadare
Positive 14 (29.8) 4 (40.0) and Tavassoli revealed that mean age of basal-

30 International Journal of Integrated Health Sciences. 2019;7(1):26–33

Fifi Akwarini, Trinugroho Heri Fadjari, et al.

Table 2 Characteristic of Chemotherapy Response of Triple Negative Breast Cancer of

Basal-like and Non-basal- like Subtypes Based on Chemotherapy Types
Basal-like Non-basal-like
Chemotherapy Types Responses n=36 n=5

Neoadjuvant Response (CR, PaR) 4 1

No respon (SD, PD) 0 0
Cannot be assessed 0 0
Adjuvant
Cannot be assessed 30 3
Palliative Response (CR, PaR, SD 1 1
No Response (PD) 1 0
Cannot be assessed 0 0

like subtype subjects was 47.7–55 while mean (91%) was ductal carcinoma. Several studies
age of analyses by using GEP examination with immunohistochemical examination also
was 54.14 Another previous study stated that supported that ductal cancer is the mostly
tumor with greater basal was mostly found histological TNBC of basal-like subtype. If
in 40–50 years.2 There is still unclear finding the analyses were focused on the ER- tumor
that TNBC of basal-like subtype subjects are group, the data would show that 80% of both
younger than the non-basal-like subtype TNBC of nonbasal-like and basal-like subtypes
subjects because many related previous are considered as ductal carcinoma or
studies have different results.14 The basal-like combination of ductal carcinoma and another
subtype have significantly younger mean age hisopathology types.
when compared to non-basal-like subtype Beside invasive ductal carcinoma mammae
subjects. In contrary, Polish Breast Cancer histopathology, other histopathologies can
Study (804 subjects) and Nurses’s Health be found in basal-like subtype subjects such
Study (872 subjects) reported that there was as carcinoma metaplastic, invasive lobular
no difference age between TNBC of basal-like carcinoma mammae pleomorphic type,
and non-basal-like subtypes.14 secretory carcinoma mammae, medullary,
The TNBC of basal-like subtype was mostly dan Paget disesase. Among histopathologies,
found in subjects who were in stage II while mucoid carcinoma mammae was frequently
non-basal-like subtype was mostly found in found in non-basal-like subtype subjects. This
stage III. The stage IV of TNBC of basal-like finding is similar to a previous study which
subjects in this study had metastases in the stated that histopatologies such as medullary
lung, bone, and liver while metastases in the carcinoma or combination of ductal carcinoma
liver and bone were found in the non-basal- and medullary carcinoma represents basal-
like subjects. This finding is different from a like phenotype.
cohort study in Japan which described that
TNBC basal-like subtype had brain and lung
metastases. Another study confirmed that Table 3 Characteristics of the Last
TNBC of basal-like subtype and TNBC which Condition between Triple Negative
has relation to BRCA1 mutation which has Breast Cancer of Basal-like and
metastasis in the brain. The TNBC of basal-like Non-basal-like Subtypes
had lower metastases in the bone and liver Basal-like Non-basal-
when compared to ductal carcinoma of stage Last Condition n=47 (%) like n=10(%)
III non-basal-like subtype.14
There is no histopathology different type in Alive 25 (53.2) 2 (20.0)
both basal-like and non-basal-like subtypes in
this study is invasive ductal carcinoma. This is Dead 13 (27.7) 3 (30.0)
suitable with a study in morphological basal- Unknown 9 (19.1) 5 (50.0)
like subtype with GEP, 21 out 23 patients

International Journal of Integrated Health Sciences. 2019;7(1):26–33 31

 Triple Negative Breast Cancer Characteristics Based on Basal-like and Non-Basal-like Subtypes

The GEP examination from ductal study and those previous studies. Besides, the
carcinoma and medullary carcinoma with samples of TNBC non-basal-like subtype in this
hispathology stage III showed that 95% study were 10 out of 57 subjects. The results in
medullary carcinoma was the ductal basal-like the study cannot describe precise information
subtype group.14 In this study, chemotherapy relating to the TNBC of non-basal-like subtype
response was assessed in neoadjuvant and so that larger samples are required in order to
palliative chemotherapies. In the neoadjuvant describe the real condition.
chemotherapy group, the response was found This was a retrospective study which
in 3 basal-like subtype subjects and 1 basal- collected the data based on the medical
like subtype subject. The subjects who had records. Uncompleted data found in the
been given chemotherapies among 57 subjects medical records caused problems to obtain
were 5 subjects (neoadjuvant chemotherapy) sufficient data and information such as
and 3 subjects (palliative). Therefore, carcinoma history of the family, menarche and
this study could not clearly describe the menopause statuses. The medical records of
response between neoadjuvant and palliative inpatiens or outpatients at the Department
chemotherapies in TNBC of basal-like and of Oncology Surgery, Department of Internal
non-basal-like subtypes. Medicine, and Department of Pathology
In this study, more than 50% subjects Anatomy, of both hospital in Dr. Hasan Sadikin
(32 out of 57 subjects) were given adjuvant General Hospital, Bandung and Borromeus
chemotherapy because it is suggested for TNBC Hospital did not have integrated access so that
and HER2 + subjects in the early up to locally the data were collected manually.
advanced. The TNBC subjects negative who In summary, TNBC in the hospitals in
had been given neoadjuvant chemotherapy Bandung was classified into two subtypes,
had pathologic complete response (pCR) basal-like and non-basal-like. The prevalences
approximately 27–45% while the pCR value in of TNBC of basal-like subtypes were higher
BC with HER-2 negative and hormone receptor than another one. Mean age of TNBC basal-
positive had 10% lower of pCR. In contrary, the like was higher than non-basal-like. There was
TNBC subjects who had been given adjuvant no different type and degree of hispathology
chemotherapy did not show higher risk of pCR found in both subtypes. More severe BC was
leading to early metastasis.4 discovered in non-basal-like subtype. The
This study determined that among TNBC theraphy commonly given to the subjects of
subjects, non-basal-like subtype had worse both subtypes was adjuvant chemotherapy so
condition when compared to the basal-like that the chemotherapy response was hardly
subtype. This finding is different from the discovered in this study. Among the subjects,
previous study which stated that TNBC of deaths in this study were mostly found in
basal-like subtype has worse result than other TNBC of non-basal subtype when compared to
TNBC subtypes.10 This condition is caused by the basal-like subjects.
different race characteristics between this

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