Clinicopathological Features and Treatment Challenges in Triple Negative Breast Cancer Patients: A Retrospective Cohort Study
Amira ELWAN1, Aziza E. ABDELRAHMAN2, Ahmed A. ALNAGAR3, Mohamed I ABDELHAMID4, Nashwa NAWAR1
1Department of Clinical Oncology and Nuclear Medicine, Zagazig University, Faculty of Medicine, ZAGAZIG, EGYPT
2Department of Pathology, Zagazig University, Faculty of Medicine, ZAGAZIG, EGYPT
3Department of Medical Oncology, Zagazig University, Faculty of Medicine, ZAGAZIG, EGYPT
4Department of General Surgery, Zagazig University, Faculty of Medicine, ZAGAZIG, EGYPT
Keywords: Triple negative breast cancer, Androgen receptor, Capecitabine, Bicalutamide
As the genetic and molecular profiles of triple negative breast carcinoma (TNBC) are elucidated, multiple therapeutic targets have
been produced. TNBC with less than 1% androgen receptor (AR) expression may respond to enzalutamide with greater response association in
higher levels. A metronomic dose of capecitabine and docetaxel are effective developed drugs for angiogenic process inhibition. We aimed to
demonstrate the treatment outcome of triple-negative breast cancer patients in correlation to their clinicopathological features.
Materials and Methods: A retrospective cohort study of 80 TNBC patients was conducted. The patients underwent proper observation with the
reporting of their treatment and follow-up data. Patients with a metastatic disease, neoadjuvant chemotherapy, follow-up drop or data shortage
were excluded from the survival analysis.
Results: The study results revealed a significant association between negative androgen expression and younger age ≤35 years, premenopausal
status, higher grade, extracapsular extension, lymphovascular invasion, Ki 67, and CA15-3 (p=0.003, 0.02, <0.001, 0.001, 0.027, 0.005, 0.009
respectively). The three-year overall survival (OS) in patients who received bicalutamide was better than those patients who received capecitabine
or docetaxel but of no significance (p=0.46). The three-year disease free survival (DFS) was significantly better in the bicalutamide arm versus
the other two groups (p=0.012).
Conclusions: We concluded that extended adjuvant antiandrogen such as bicalutamide and metronomic capecitabine are well tolerated with
accepted compliance and affordability compared to docetaxel and are warranted for problem-solving and better DFS and OS in some TNBC
Triple-negative breast cancer (TNBC) that represents 12-
17% of all breast cancers (BC) is defined by less than 1%
of the estrogen receptor (ER) and progesterone receptor
expression, and normal human epidermal growth factor
receptor 2 (HER2) gene copy number and expression (1).
TNBCs have more aggressive behavior than non-TNBCs.
Patients with TNBC tend to have higher relapse rates and
probability of CNS and visceral metastases than those with
Different genomic and molecular technique applications
have revealed TNBC heterogeneity in the form of basal-like
(BL), immunomodulatory (IM), mesenchymal (M), and
luminal androgen receptor (LAR) subtypes, and each one
demonstrates a unique pattern of gene expression. Because
of the elucidated genetic and molecular profiles of TNBC, multiple therapeutic targets have been produced and
TNBCs are amenable for treatment intervention (3).
Anthracycline and taxane-based protocols of chemotherapy
were considered as the mainstay treatment of TNBC
patients (4). Treatment guidelines of early TNBC patients
did not include platinum agents, but their use is explained
in specific cases, such as those with a high risk of relapse
and in need of rapid disease control, where the use of
carboplatin was recommended for patients with known
mutant BRCA; however, a carboplatin-based combination
is one of the available protocols for adjuvant treatment
Androgen receptors include 3 domains consisting of
amino-terminal domain, DNA binding domain, and a
carboxyl-terminal domain that functionally act with each
other. The first one is the largest and responsible for the activation of function domain AF1 that includes the tau
1 and tau 2 transcription activating units essential for
androgen receptor activity. The amino-terminal domain
contains a polyglutamine (CAG) sequence with various
repetition numbers (6). Rebbeck et al. have discovered the
relationship between patients carrying at least one AR allele
with more than 28 CAG repeats and a significant risk of
breast cancer (7).
Androgen receptor (AR) is expressed in 12-55% of TNBC
cases (8-10). Some variation in expression frequency
between studies is due to the different use of anti-AR
antibodies or an assay cutoff difference (1% versus 10%).
BC with less than 1% AR expression may respond to
enzalutamide and may be associated with greater response
in higher levels of AR expression (8). In AR-positive TNBC
subtype patients, bicalutamide is well tolerated and could
be proposed as an alternative to cytotoxic chemotherapy in
such patients with better OS and DFS outcomes (11).
In comparison to hormone receptor-positive breast cancer,
capecitabine has shown differential activity in TNBC in
limited reported data (12). The proposal of metronomic
chemotherapy is defined by the close and the regular
intervals of chronic administration of low doses of cytotoxic
drugs with no prolonged drug-free interruptions, in favor
of lower toxicity and risk of drug-resistant tumor cell
emergence in comparison to conventional administration
(13). TNBC is considered a highly proliferative tumor with
more enhanced angiogenesis that supports rapid growth and
early metastasis, and tends to have high levels of vascular
endothelial growth factor (VEGF). The metronomic dose
of capecitabine is effective in TNBC as it leads to inhibition
of the angiogenic process (14).
Docetaxel therapy has a significant role in both neoadjuvant
and adjuvant management of triple negative breast cancer
patients (15). Metronomic administration of docetaxel has
achieved survival gains (16).
Compared to non-TNBC cases, TNBC cases are
characterized by higher levels of VEGF and the blockade of
angiogenesis will therefore lead to improving the outcomes
in such patients. This was investigated in adjuvant phase III
trials that evaluated the addition of one year of metronomic
cyclophosphamide, methotrexate CM maintenance therapy
(International Breast Cancer Study Group-22-00), as
well as bevacizumab for one year proposed as standard
chemotherapy (BEATRICE Study) (17). In this study, we
aimed to demonstrate the outcome of triple-negative breast
cancer patients treated with various strategies in correlation
to their clinicopathological features.
Eighty TNBC patients were conducted to general surgery,
pathology, clinical oncology, and medical oncology
departments as a multidisciplinary team in a retrospective
cohort study from January 2016 to January 2020. The patient
data were collected from the patient’s records with approval
by the local ethics committee (Approval no: 6394-15-09-
2020, Date: 15.09.2020). Focusing on the patient’s clinical
outcome post adjuvant treatment period as extending
treatment. Patients with metastatic disease, neoadjuvant
chemotherapy proposal, follow-up drop, and data shortage
were excluded from the survival analysis. Included
patients underwent proper observation with reporting
of their treatment and follow-up data, besides the proper
history and physical examinations. Full lab, chest x-ray,
pelvic abdominal ultrasonography, mammography, breast
ultrasound, CT chest, abdomen, and pelvis with contrast,
CT brain or MRI with contrast were requested. A bone scan
was requested according to the clinical conditions such as
bone pain in the early stage and was performed in all local
advanced and metastatic cases. Some patients underwent a
PET scan. At the general surgery department, the patients
underwent either a true-cut or excisional biopsy, breast
conservation, or modified radical mastectomy. Eighty
patients were proposed adjuvant chemotherapy and 71
patients out of 80 received adjuvant radiotherapy.
The staining was carried out using the polymer Envision
detection system the Dako EnVision™ kit (Dako,
Copenhagen, Denmark). Tissue sections (3–5 μm) were
deparaffinized in xylene and rehydrated in graded alcohol.
To block endogenous peroxidase, slides were incubated
for 10 min in 3% hydrogen peroxide. Dako target antigen
retrieval solution (pH 6.0) was applied for 20 min.
Afterwards, the slides were incubated for 60 min with the
primary anti-ER antibody (clone D07, DAKO), anti-PR
antibody (PR 636, Dako at 1:50 dilution); Polyclonal HER2
antibody in the Herceptin kit (HercepTest, DAKO); Ki67
antibody (clone MIB-1, 1:50 dilution; Dako); and Anti-
Androgen receptor antibody [EPR1535 (2)] (ab133273).
The reaction was visualized by incubating the sections with
diaminobenzidine (DAB) for 15 min after which Mayer’s
hematoxylin was used
Interpretation of Immunohistochemical Staining
For ER and PR expression, moderate to strong nuclear
staining in ≥ 1% of the tumor cells was considered positive.
Her2/neu was considered positive if at least 10% of tumor
cells exhibited 3+ cell membrane staining. The cut-off point for Ki67 expression was 14%. AR expression was semiquantitatively
scored using an H-score like the method
described by Niemeier et al. An immunohistochemical
score >10 was considered as a positive result (18).
We analyzed the extended adjuvant treatment after initially
proposed protocols of chemotherapy ± radiotherapy, which
was reported in patient files and records. Hence, patients
were followed in 3 groups: the first received bicalutamide
(anti-androgen) in AR positive in 50 mg, with or without
meals once daily for 2 years, and group 2 who had negative
AR and received capecitabine 650 mg/ m2 BID for one year,
and group 3 patients who had unknown AR status and
received docetaxel in a protocol of 15mg/ m2 in weekly for
4 weeks to be escalated to 20 mg/m2 once per week with
accepted lab consideration for 6 months.
Continuous variables were expressed as the mean ± SD
and median (range), and the categorical variables were
expressed as a number (percentage). The percentages of
categorical variables were compared using Pearson’s Chisquare
test or Fisher’s exact test when appropriate. The
trend of change in the distribution of relative frequencies
between ordinal data was compared using the Chi-square
test for trend. Overall Survival (OS) was calculated as the
time from diagnosis to death or the most recent followup
contact (censored). Disease-Free Survival (DFS) was
calculated as the time from the date of surgery to the date of
relapse or the most recent follow-up contact when patient
was known to be relapse-free. Stratification of OS and DFS
was done according to intention to treat (ITT). These timeto-
event distributions were estimated using the method of
Kaplan-Meier plot and compared using a two-sided exact
log-rank test. All tests were two-sided. A p-value <0.05 was
considered significant. All statistics were performed using
SPSS 22.0 for windows (IBM Inc., Chicago, IL, USA).
The mean age at presentation was 42.60 ±12.05 years.
Most of the cases were grade III (56.3%) and 82.5 %
showed lymph node metastasis. IDC of no special type
was the most common histopathological type (65%). As
regards the pathologic stage, 55% of the cases were T1
with lymphovascular invasion in 55% of the cases. The
clinicopathological data of the cases enrolled in this study
were summarized in (Table I).
Click Here to Zoom
|Table I: Clinicopathological features, treatment, and outcome of triple-negative breast cancer patients.
The Relation Between Clinicopathological Features and
Androgen Receptor IHC Staining
Positive androgen expression was noted in 26.3% of the
studied cases (Figure 1A-C). Negative Androgen expression
revealed strong association with younger age ≤35 years, premenopausal
status, higher grade, extracapscular extension,
lympho-vascular emboli, Ki 67 and CA15-3 with p values
(0.003, 0.02, <0.001, 0.001, 0.027, 0.005, 0.009 respectively)
(Table II). Regarding to the toxicity of bicalutamide and
capecitabine was shown in (Table II).
Click Here to Zoom
|Figure 1: A) A case of TNBC grade 1 showing positive androgen expression (IHC; x400). B) A case of TNBC grade 2 showing positive
androgen expression (IHC; x400). C) A case of TNBC grade 3 showing positive androgen expression (IHC; x400).
Click Here to Zoom
|Table II: Relationship between clinicopathological features and androgen receptor IHC staining.
Bicalutamide was well tolerated as 17 (81%) patients out of
21 patients had shown no toxicity, only 2 patients showed
grade (G) 2 hot flushes, one patient showed weight change
in the form of increase in weight, only one patient suffered
from G1 drowsness. 14 /27 patients (58.3%) had shown no
toxicity of capecitabine proposal, 5( 20.8%) patients were
presented by G2 diarrhea, 3 patients (12.5%) presented by G1
hand pain, redness and swelling, only 2(8.3%) patients were
presented by G2 nausia and vomiting. Regards docetaxel,
more toxicity was observed only 7 (25.9%) who had no
toxicity. Hematological toxicity was observed in 20 patients
(74%), all are G1,2 except 2 patients showed G4 anemia, 8
(29.6%) patients were observed with G 1,2 pleural effusion and 6 (22.2%) patients exhibited G1, 2 hepatotoxicity. All
previous manifestations were well controlled by medical
treatment and proper observations (Table III , IV).
The mean 3 years DFS was 35.3 months in patients who
received bicalutamide, 33.16 months in patients received
capecitabine, while in the docetaxel arm was 28.2 months with significance P=0.001, better DFS was in the favor of
bicalutamide administration. 3 years overall survival (OS)
in patients who received bicalutamide better than those
received capecitabine or docetaxcel but of no significance
P=0.46 (Table V and Figure 2).
Click Here to Zoom
|Table V: Comparison between anti-androgen arm, capecitabine arm, and docetaxel arm regarding survival outcome.
Click Here to Zoom
|Figure 2: Kaplan Meier plot of the studied arms, Left panel: Disease-free survival (A), Right panel: Overall survival (B).
In the current study, we investigated the clinic-pathological
criteria of triple-negative breast cancer patients who were
conducted at our institutes at a specific period with high
lighting on the proposed treatment such as antiandrogen
(bicalutamide), capecitabine and docetaxel as an extended
In this study we found that negative androgen expression
had shown strong associations with younger age (≤35
years), premenopausal status, higher grade, extracapsular
extension, lymphovascular invasion, Ki 67, and CA15-
3, this was agreed with Farag et al. who studied the
prevalence of androgen receptor expression in 90 patients
of TNBC and the criteria of their clinic-pathology with no
treatment proposal and revealed that AR negative patients
was significantly associated with higher grade, higher
stage, lymph node metastasis, distant metastasis, vascular,
perineural invasion and high CA15-3 (19).
In our study 71/80, patients received adjuvant radiotherapy
post adjuvant chemotherapy protocols such as AC-Taxens,
carboplatin-Taxens, and EC-Taxens. Pal et al. confirmed the
efficacy of combination treatment for TNBC patients (20).
These findings were focused on evidence-based treatment recommendations (12,21,22). Furthermore, Chen et al.
reported that radiotherapy post-mastectomy was associated
with more prognosis improvement (23).
We agreed with Zakaria et al. who reported in their study
with inclusion of 77 TNBC patient that the median age was
35.6 with a range of (19-63) and 21∕ 77 patients (27.2%)
were AR positive. AR expression was associated with high
grade, high KI 67, positive nodal status and CA15-3. Along
with her study, nobody died in AR positive patients, these
patients received bicalutamide 50 mg once daily over 2
years as treatment duration with better 2 and 3 year OS
which were 85% and 78% with p values of <0.001, 0.0005
respectively; bicalutamide was well-tolerated toxicity, no
grade 3 and 4 adverse events in TNBC AR positive patients
as well as 6 (28.57%) out of 21 patients presented in the form
of 3 patients presented with nausea, two patients presented
with breast fullness, tenderness, and hot flushes and only
one patient who was presented by weight gain but with
better OS and DFS outcome (11). In our study we found
that bicalutamide was well tolerated as 17 (81%) patients
out of 21 patients had shown no toxicity, only 2 patients
showed G2 hot flushes, one patient showed weight change
in the form of an increase in weight, and only one patient
suffered from G1 drowsiness. These were all tolerated with
more affordability. The mean 3-year DFS was 35.3 months in
patients who received bicalutamide as extended treatment
and better OS.
In our study, 13/27 patients (42.7%) had shown toxicity to
capecitabine proposal, 5 (20.8%) patients presented with G2 diarrhea, 3 patients (12.5%) presented with G1 hand pain,
redness and swelling, and only 2 (8.3%) patients presented
with G2 nausea and vomiting while hematological toxicity
was observed in 2 (8.3%) patients. In the docetaxel arm,
unfortunately 20 (74%) patients exhibited hematological
toxicity, and 8 (29.6%) patients complained of pleural
effusion G1,2 where the pattern of toxicity was milder than
reported by Abdelaziz et al. investigated 22 patients with
TNBC who received metronomic capecitabine as extended
treatment in non-metastatic condition, common toxicities
were in the form of 2 patients presented by G1/ G2 hand
foot syndrome and another 2 patients presented by G3/4
hand foot syndrome, 3 patients presented by G1/2 nausea
and vomiting and 2 patients presented by G3 diarrhea, on
the other hand hematological toxicity was observed in 5
patients in the form of anemia, in our study The 3 years
DFS was 79.2%, 3 years OS 83.3% that was near to what
was reported by Abdelaziz et al. as 3 years OS was 86.4%,
while 3 year DFS was 81%.22; (24) in contrary to Alagizy et
al., who studied 41 patients of TNBC and reported higher
adverse effects of extended metronomic capecitabine
after adjuvant chemotherapy such as G1 palmar– plantar
erythrodysesthesia in 13 patients (31.7%); G 1 diarrhea in
five patients (12.2%); and G1 vomiting in two patients (4.9%)
with no G3∕ 4 adverse effects. follow-up mean disease-free
survival (DFS) was 42.4 months (95% CI). overall survival
was 44.34 months (95% CI) with a lower incidence of
recurrence and distant metastasis in comparison to other
Abdelmaksoud et al. investigated the role of docetaxel in
an extended treatment of 31 patients with triple negative
breast cancer with a 3-year DFS and OS of 56.4 and 78.1,
respectively, and a tolerable toxicity profile, and encouraged
the use role of metronomic docetaxel for better survival
TNBC patients may benefit from antiandrogen treatment
as it is well tolerated with significantly lower toxicity than
that of chemotherapy, and it can be proposed with other
agent combinations (8,26-28). We agree with Locatelli et
al. who stated that low dose maintenance capecitabine was
an attractive approach with low cost, good tolerability, and
manageability, especially in high-risk disease (29).
Inhibitors of such pathways as CDK4/6, PI3K, RAS, and
MEK which command cell cycle progression, survival,
proliferation, invasiveness, and drug escape can be
optimally combined with an AR antagonist (30-32).
Our recommendation is to encourage further collaborative
studies on a larger number of studied cases to gain more accurate information in the absence of data bias with
searching for novel, easy and cheap methods and aiming for
proper treatment strategies and a proper patient selection
guidance philosophy, targeting each triple-negative
phenotype in different clinical scenarios.
In conclusion, progress in the treatment of TNBC remains
an important challenge. The proposed bicalutamide shows
better outcomes in favor of OS and toxicity with better
tolerability. On the other hand, metronomic capecitabine
is well tolerated with accepted patient compliance and
affordability compared to docetaxel and is warranted for
problem solving with better disease-free survival and overall
survival in some triple-negative breast cancer patients.
CONFLICT of INTEREST
The authors declared that there is no conflict of interest.
Concept: AE, HSM, Design: AEA, Data collection or
processing: NN, Analysis or Interpretation: AE, Literature
search: MIA, Writing: AAA, Approval: AE, AEA, NN,
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