Download Breast Cancer Outcomes as Defined by the Estrogen

World J Surg
DOI 10.1007/s00268-015-3133-2
ORIGINAL SCIENTIFIC REPORT
Breast Cancer Outcomes as Defined by the Estrogen Receptor,
Progesterone Receptor, and Human Growth Factor Receptor-2
in a Multi-ethnic Asian Country
S. Subramaniam1 • N. Bhoo-Pathy2 • N. A. Taib3 • G. H. Tan3 • M. H. See3
S. Jamaris3 • G. F. Ho4 • L. M. Looi5 • C. H. Yip3
•
Ó Société Internationale de Chirurgie 2015
Abstract
Introduction Breast cancer can be divided into four subtypes based on the expressions of estrogen receptor (ER),
progesterone receptor (PR), and human epidermal growth factor-2 (HER2). Each subtype has different clinicopathological features and outcomes.
Objective To compare the clinicopathological features and survival of ER and/or PR positive HER2 negative
(ER?PR?HER2-, ER?PR-HER2- or ER-PR?HER2-), ER and/or PR positive HER2 positive (ER?PR?HER2?, ER?PR-HER2? or ER-PR?HER2?), ER negative PR negative HER2 positive (ER-PR-HER2?), and
ER negative PR negative HER2 negative (ER-PR-HER2-) subtypes.
Methods 1957 patients with Stage 1–3 breast carcinoma diagnosed between Jan 2005 and Dec 2011 were categorized into the four subtypes. The clinicopathological features between the subtypes were compared using v2 test.
Kaplan–Meier analysis was performed to estimate 5-year overall survival. Multivariate Cox regression was used to
determine the association between subtypes and mortality adjusted for age, ethnicity, stage, pathological features, and
treatment.
Results ER-PR-HER2? and ER-PR-HER2- subtypes were associated with younger age, larger tumors, and
higher grade. There was no difference in the 5-year survival of the ER-PR-HER2? and ER-PR-HER2- subtypes
(75.1 and 74.4 %, respectively) and survival was poorer than in the ER and/or PR positive HER2 negative and ER
and/or PR positive HER2 positive subtypes (87.1 and 83.1 %, respectively). Only 9.5 % of women with HER2
positive breast cancer had access to trastuzumab.
Conclusion In a low resource setting with limited access to trastuzumab, there is no difference in survival between
the ER-PR-HER2? and ER-PR-HER2- subtypes of breast cancer.
& C. H. Yip
[email protected]
G. H. Tan
[email protected]
S. Subramaniam
[email protected]
M. H. See
[email protected]
N. Bhoo-Pathy
[email protected]
S. Jamaris
[email protected]
N. A. Taib
[email protected]
G. F. Ho
[email protected]
123
World J Surg
Introduction
Methodology
Breast cancer is a heterogeneous disease that is made up
of several distinct entities with different biological characteristics and clinical behaviors. In 2000, gene expression using DNA microarray identified 4 subtypes of breast
cancer, namely, Luminal A, Luminal B, HER2 (Human
epidermal growth factor 2) overexpressing, and Basal-like,
with differences in survival, demographics, and tumor
characteristics. [1] However because gene expression
using microarray is not used in routine clinical practice,
studies were limited to small numbers. Immunohistochemical (IHC) expression of estrogen receptor (ER)
protein, progesterone receptor (PR) protein, and human
epidermal growth factor-2 (HER2) oncoprotein is routinely available, and often used as a practical substitute
for the more expensive molecular subtyping, which are
not available for population-based or cohort studies.
While the ER?PR?HER2- tumor is a surrogate for
Luminal A breast cancer, the IHC surrogate for Luminal
B is imprecise. While some groups consider any
ER?PR?HER2? as Luminal B [2], others have added a
Luminal B HER2- group where ER is positive, HER2
negative and at least one of: Ki67 high (defined as
[14 %) and PR negative or low (defined as \20 %) [3].
Some have also used Grade 3 as a surrogate for Ki67
which is not readily available [4].
Patient population
Objectives
The objective of this study is to determine the proportions
of the 4 subtypes of breast cancer based on immunohistochemical assessment of ER, PR, and HER2 in women
presenting with breast cancer in a multiethnic Malaysian
setting, and to investigate the differences in patients’
demography, tumor characteristics, and overall survival
between the four subtypes.
L. M. Looi
[email protected]
1
National Clinical Research Centre, Kuala Lumpur Hospital,
Kuala Lumpur, Malaysia
2
Department of Social and Preventive Medicine, Julius Center
University of Malaya, University of Malaya, Kuala Lumpur,
Malaysia
3
Department of Surgery, University Malaya Medical Centre,
Kuala Lumpur, Malaysia
4
Department of Clinical Oncology, University Malaya
Medical Centre, Kuala Lumpur, Malaysia
5
Department of Pathology, University Malaya Medical Centre,
Kuala Lumpur, Malaysia
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The University Malaya Medical Centre (UMMC) Breast
Cancer Registry, which prospectively collects clinicopathological data from women newly diagnosed with
breast cancer since 1993 was used for this study. The
registry was approved by the Ethical Review Committee of
UMMC. Because PR and HER2 were only routinely done
from 2004, 2821 consecutive Malaysian patients who were
newly diagnosed with invasive breast cancer in University
Malaya Medical Centre (UMMC), Malaysia between 1st
Jan 2005 and 31st Dec 2011 were included in this study.
The patients’ age at onset, self-reported ethnicity, stage
of disease, size, tumour grade, ER, PR, and HER2 status
were evaluated from pathological and clinical reports. The
patients were staged according to the American Joint
Commission on Cancer (AJCC) Cancer Staging Manual
6th Ed. [5]. Patients’ survival status was confirmed by
obtaining the data from National Registration Department.
Of the 2821 patients, 324 (11.5 %) had de novo metastatic
breast cancer. In the metastatic breast cancer group, 15.1 %
were not tested for HER2, while 7.7 and 10.5 % did not have
known ER or PR status, respectively. Hence, metastatic
breast cancer was excluded from further analysis since this
would hamper interpretation. Of the remaining 2497 patients
with Stage 1–3 breast cancer, only 2.4, 2.9, and 4.3 % had
unknown ER, PR, and HER2 status, respectively. 426
patients (17.8 %) had an equivocal HER2 status. Given that
fluorescence in situ hybridization (FISH) was not done for a
large proportion of patients in this group, they were excluded
leaving 1957 patients for further analysis.
Immunohistochemistry for ER, PR, and HER2
Immunohistochemistry using standard Envision methodology (DAKO kit, performed manually) for estrogen and
progesterone receptor protein expression, and c-erbB-2/
HER-2 overexpression was performed on 4-micron-thick
microtomed sections of formalin-fixed paraffin-embedded
tumor biopsies or excised tumor tissue. The primary antibodies were obtained commercially and dilutions used were
ER clone SP1 (Neomarkers, USA) at 1:100 dilution, PR
clone PgR636 (DAKO, Denmark), at 1:200 dilution; c-erbB2 (HER2) (DAKO, Denmark Code A0485) at 1:600 dilution.
The antigen retrieval solution was Tri-EDTA at pH9.
The tumor was deemed ER or PR positive when 10 % or
more of the invasive tumor nuclei were stained for the
respective antibody, regardless of staining intensity.
The c-erbB2/HER-2 expression was categorized
according to ASCO CAP guidelines 2007 [6] as 0 (no
World J Surg
staining), 1? (weak incomplete membrane staining in any
proportion or weak, complete membrane staining in\10 %
of cells), 2? (weak, complete membrane staining in[10 %
of cells, or complete intense membrane staining of [10 %
but \30 % of invasive tumor cells), or 3? (complete
intense membrane staining of [30 % of invasive tumor
cells). Expressions of 0 or 1? were regarded as negative.
Only tumors with 3? expressions were regarded as HER2
overexpressed (positive). Expressions of 2? were regarded
as equivocal for overexpression and would require further
in situ hybridization testing for HER2 gene amplification.
However, since no in situ hybridization testing (with FISH
or SISH) was available during the period of this study, this
category was excluded from analysis.
Table 1 Breast cancer clinicopathological features: Jan 2007–Dec
2011
Characteristics
Overall n = 1957
Age, n (%)
\ 35
120 (6.1)
35–50
734 (37.5)
51–65
805 (41.1)
[ 65
298 (15.2)
Race, n (%)
Chinese
Malay
949 (48.5)
747 (38.2)
Indian
245 (12.5)
Others
16 (0.8)
Stage, n (%)
Statistical analysis
From the three biomarkers, patients were grouped into 4
IHC subtypes i.e., ER and/or PR positive HER2 negative
(ER?PR?HER2-, ER?PR-HER2-, or ER-PR?HER2-), ER and/or PR positive HER2 positive
(ER?PR?HER2?, ER?PR-HER2?, or ER-PR?HER2?), ER negative PR negative HER2 positive
(ER-PR-HER2?), and ER negative PR negative HER2
negative (ER-PR-HER2-, or triple negative). The
demography and tumor characteristics between the subtypes were compared using v2 test.
Patients were followed up from the date of diagnosis, to
date of death (all-cause), or censored on the date of last
mortality update with the National Registration Department (31st March 2014). Overall survival of patients was
compared between different IHC subtypes using Kaplan–
Meier method [7]. To adjust for baseline differences in
demography, tumor characteristics, and treatment between
the IHC groups, we used Cox regression analysis [8].
Prognostic factors that were included in the multivariable
Cox model was selected based on a priori knowledge of
their associations with breast cancer survival; age at diagnosis, ethnicity, tumor size, number of pathologically
positive axillary lymph nodes, tumor grade, lymphovascular invasion, locoregional treatment, neoadjuvant
chemotherapy, and adjuvant chemotherapy.
Two-tailed p value of less than 0.05 and 95 % confidence intervals (CI) for HR not including 1 was considered
statistically significant. All statistical analyses were performed using SPSS for Windows version 20.0
Results
Table 1 shows the demographic features of the 1957
patients with Stage 1–3 breast cancer. The majority were
Chinese (48.5 %). The median age was 53 years old. Of
1
559 (28.6)
2
862 (44.6)
3
536 (27.4)
Lymph node, n (%)
Negative
1079 (57.4)
Positive
801 (42.6)
Unknown
77
Grade, n (%)
1
155 (9.7)
2
786 (49.1)
3
Unknown
660 (41.2)
355
Tumour Size, n (%)
B 2 cm
756 (39.4)
[ 2–5 cm
921 (47.9)
[ 5 cm
244 (12.7)
Unknown
36
Estrogen Receptor, n (%)
Positive
1159 (59.2)
Negative
798 (40.8)
Progesterone Receptor, n (%)
Positive
1022 (52.2)
Negative
935 (47.8)
Human Epidermal Growth Receptor, n (%)
Positive
644 (32.9)
Negative
1313 (67.1)
IHC subtypes, n (%)
ER and/or PR positive HER2 negative
929 (47.5)
ER and/or PR positive HER2 positive
293 (15.0)
ER negative PR negative HER2 positive
351 (17.9)
ER negative PR negative HER2 negative
384 (19.6)
those who had axillary dissection done, 40.9 % were lymph
node positive. Approximately 50 and 40 % were Grade 2
and 3, respectively. The majority of patients (55.7 %) had
tumors measuring more than 2 cm, while 44.6 % had Stage
2 disease.
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Table 2 Comparison of four subtypes of breast cancer: Jan 2007–Dec 2011
ER and/or PR positive
HER2 negative (%)
ER and/or PR positive
HER2 positive (%)
ER negative PR negative
HER2 positive (%)
ER negative PR negative
HER2 negative (%)
p Value
Chinese
466 (49.1)
140 (14.8)
164 (17.3)
179 (18.9)
0.269
Malays
328 (43.9)
123 (16.5)
135 (18.1)
161 (21.6)
Indians
126 (51.4)
029 (11.8)
048 (19.6)
042 (17.1)
Others
009 (56.2)
001 (06.2)
004 (25.0)
002 (12.5)
037 (04.0)
349 (37.6)
019 (06.5)
118 (40.3)
023 (06.6)
135 (38.5)
041 (10.7)
132 (34.4)
Race
Age
\ 35
35–50
51–65
369 (39.7)
116 (39.6)
161 (45.9)
159 (41.4)
[65
174 (18.7)
040 (13.7)
032 (09.1)
052 (13.5)
1
305 (32.8)
86 (29.4)
67 (19.1)
101 (26.3)
2
391 (42.1)
119 (40.6)
170 (48.4)
182 (47.4)
3
233 (25.1)
88 (30)
114 (32.5)
101 (26.3)
\0.001
Stage
\0.001
Size
B 2 cm
406 (44.4)
123 (42.7)
96 (28.2)
131 (34.7)
[ 2–5 cm
426 (46.6)
122 (42.4)
178 (52.4)
195 (51.6)
[ 5 cm
083 (09.1)
043 (14.9)
066 (19.4)
052 (13.8)
Negative
513 (57.1)
152 (55.1)
180 (54.1)
234 (62.7)
Positive
385 (42.9)
124 (44.9)
153 (45.9)
139 (37.3)
\0.001
Lymph node
Grade
1
123 (16.3)
17 (6.9)
6 (2.1)
10 (3.1)
2
461 (61.2)
135 (54.4)
104 (37)
86 (26.9)
3
169 (22.4)
96 (38.7)
171 (60.9)
224 (70)
31 (3.3)
17 (5.8)
21 (6)
18 (4.7)
0.089
\0.001
Type of Surgery
No surgery
Mastectomy
645 (69.4)
198 (67.6)
269 (76.6)
270 (70.3)
Lumpectomy
253 (27.2)
78 (26.6)
61 (17.4)
25 (25)
No
366 (42.3)
96 (35.7)
83 (26.1)
78 (22.7)
Yes
500 (57.7)
173 (64.3)
235 (73.9)
266 (77.3)
No
51 (5.8)
15 (5.5)
275 (93.9)
279 (91.2)
Yes
829 (94.2)
260 (94.5)
18 (6.1)
27 (8.8)
0.005
Chemotherapy
\0.001
Hormone therapy
The majority of patients had ER and/or PR positive
HER2 negative (47.5 %) tumors, whereas 19.6 % had ER
negative PR negative HER2 negative. The remainder
(32.9 %) was HER2 positive, either ER and/or PR positive
HER2 positive, (15 %) or ER negative PR negative HER2
positive (17.9 %). Table 2 shows the association of ethnicity, age, stage, size, lymph node involvement, and grade
with the four IHC subtypes. In univariable analysis, ethnicity and lymph node involvement was not significantly
associated with IHC subtypes. However, patients with ER
123
\0.001
negative PR negative HER2 negative (triple negative breast
cancer) and ER negative PR negative HER2 positive
tumors were younger, and had tumors, which were larger,
of higher grade, and of more advanced stages compared to
the other subtypes. Patients with ER negative PR negative
HER2 positive cancers had larger tumors and later stages
than their counterparts with triple negative breast cancer
(TNBC), whereas TNBC were younger and had higher
grade tumors. Overall, 62.1 % of patients received
chemotherapy; ER negative PR negative HER2 positive
World J Surg
and TNBC were more likely to receive chemotherapy.
94.4 % of women who were ER and/or PR positive
received tamoxifen. Only 62 out of 646 HER2 positive
patients (9.6 %) received trastuzumab.
Median survival in the overall cohort of patients with
stage I to III breast cancer was 7.7 years (95 % CI
7.6–7.9 years). Figure 1 shows the cumulative overall survival of the four subtypes of breast cancer. The 5-year overall
survival in ER and/or PR positive HER2 negative, ER
and/or PR positive HER2 positive, ER negative PR negative HER2 positive, and ER negative PR negative HER2
negative subtype were 87.1 %(95 % CI 84.5–89.5 %),
83.1 %(95 %CI 78.6–87.6 %), 75.1 %(95 %CI 70.4–79.8 %),
and 74.4 %(95 %CI 69.7–79.7 %), respectively.
Following multivariable Cox regression as in Table 3,
the difference in overall survival of the ER and/or PR
positive HER2 positive subtypes against the ER and/or PR
positive HER2 negative subtypes was not found to be
significant (HR 1.26 (95 %CI 0.91,1.74). However, compared to ER and/or PR positive HER2 negative subtype,
both the ER negative PR negative HER2 positive and ER
negative PR negative HER2 negative subtypes were associated with substantially higher risk of mortality ranging
between 2- and 2.5-fold; HR 1.97 (95 %CI 1.47,2.63), and
2.51(95 %CI 1.88, 3.35), respectively.
Discussion
Testing for ER, PR, and HER2 is considered critical to the
management of breast cancer in this current day and age. In
low- and middle-income countries, testing may still be not
routine and quality assurance remains a problem. Resource
limitations may impact tissue handling and processing that
can result in falsely negative results in the receptors [9]. It
has been noted that inter-laboratory variations in assessment of ER and PR exist even in developed countries [10].
Another issue is that the definition of ER and PR positivity
has changed with the recent guideline stating that 1 %
rather than 10 % should be the cutoff used to define ER and
Fig. 1 Comparison of overall survival in four subtypes of breast cancer
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Table 3 Factor associated with overall survival of breast cancer patients in Asian setting
Variable
Univariable odds ratio (95 % CI)a
Multivariable odd ratio (95 %CI)b
Molecular subtype
ER and/or PR positive HER2 negative
1.00
1.00
ER and/or PR positive HER2 positive
1.43 (1.05 1.95)c
1.26 (0.91, 1.74)
ER negative PR negative HER2 positive
1.95 (1.49, 2.56)c
1.97 (1.47, 2.63)c
c
2.51 (1.88, 3.35)c
c
1.02 (1.01, 1.02)
1.01 (1.00, 1.02)c
Chinese
1.00
1.00
Malay
1.12 (0.89, 1.40)
ER negative PR negative HER2 negative
Age, years
2.04 (1.57, 2.65)
Race
Indian
Others
Tumor size, cm
1.01 (0.80, 1.28)
c
1.36 (1.00, 1.85)
1.25 (0.91, 1.71)
1.52 (0.62, 3.72)
1.16 (1.13, 1.18)c
1.21 (0.49, 3.00)
1.09 (1.06, 1.13)
1.00
1.00
Axillary lymph nodes
0
1–3
4–9
c
3.14 (2.30, 4.29)c
c
4.04 (2.85, 5.74)c
c
3.01 (2.26, 4.01)
4.19 (3.05, 5.76)
10 or more
7.38 (5.46, 9.98)
5.84 (4.11, 8.30)c
Unknown
–
–
1
1.00
1.00
2
1.65 (1.01, 2.69)c
1.20 (0.72, 2.00)
3
2.15 (1.32, 3.50)c
1.19 (0.70, 2.01)
Unknown
–
–
Tumor grade
Lymphovascular invasion
Absent
1.00
1.00
2.09 (1.66, 2.64)
1.52 (1.17, 1.96)c
–
–
Yes
3.06 (2.23, 4.21)c
1.13 (0.71, 1.80)
No
1.00
1.00
Unknown
–
–
Present
Unknown
Neoadjuvant chemotherapy
c
Locoregional treatment
No
1.00
1.00
Mastectomy
2.34 (0.17, 0.32)c
0.64 (0.39, 1.03)
Breast conserving therapy
0.12 (0.08, 0.17)c
0.49 (0.29, 0.83)c
1.00 (0.80, 1.25)
0.52 (0.39, 0.67)c
Chemotherapy
Yes
No
1.00
1.00
Unknown
–
–
a
Derived using a enter univariable logistic regression model
b
Derived using a enter multivariable logistic regression model
c
Statistically significant
PR positivity [11]. However for this study, a cut-off point
of 10 % was used, as this was the standard criteria during
the years of the study.
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Guidelines have been set for the standardized testing and
reporting of HER [2, 12] but these are in use in high
income countries. Data on the prevalence of HER2 positive
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breast cancer in Asia is limited. Most studies use
immunohistochemistry to assess HER2 status but vague
definitions of positivity and the lack of a standard reliable
HER2 assessment method available to patients across Asia
has been reported, leading to a rather wide variation of
positive rates from 6 to 65 % [13]. In the current study,
17.8 % had an equivocal HER2 result, which in high
income countries would lead to reflexive testing by FISH.
Unfortunately, FISH was not available in UMMC for a
large proportion of patients during the study period. Hence
the dilemma would be where to place these equivocal
cases. The proportion of equivocal cases should not exceed
15 % [14] and can be reduced further with the use of more
specific antibodies [15]. Because we were unable to resolve
where these equivocal cases actually belong to, equivocal
HER2 results were excluded from further analysis.
In the metastatic setting, where surgery is not carried out
or the tumor is inoperable, all three molecular markers may
not be carried out, especially HER2 because of the extra costs
incurred. Although hormonal therapy with tamoxifen for
hormone positive breast cancer is fairly cheap and affordable, the same is not true of treatment with the anti-HER2
therapy such as trastuzumab, which is not given to patients in
the metastatic setting unless the patients are able to pay for
the treatment themselves. Trastuzumab was not provided by
the health services in Malaysia both in the adjuvant or
metastatic setting during the years of the study because of the
high cost incurred. However trastuzumab was available to
those who could afford to pay for the treatment themselves.
Since knowing the HER2 status will not change the management of the patient, the need to know is more for academic rather than practical reasons. Because the HER2 status
was not available for a significant proportion of the metastatic breast cancers (15.1 %) in our study, metastatic breast
cancers were excluded from the analysis.
Since all the three markers in our study were done by a
single laboratory which subscribes to the UK National
External Quality Assessment Scheme (UK NEQAS) for
immunocytochemistry, we believe that the results of the
markers are accurate especially as the rates of HER2 positive cancers (32.9 % after excluding the equivocal HER2)
and triple negative breast cancer (19.6 %) is similar to
other reports on Asian women [16, 17].
HER2 ? breast cancers have been reported to be higher
in Asians compared to Caucasians. The HER2 positive rate
was reported to be 36 % in Koreans in the California
Breast Cancer Registry. (odds ratio (OR) 1.8, 95 % confidence interval (CI) 1.5–2.2, compared to non-Hispanic
White women) [16]. In China, a triple negative breast
cancer incidence of 17 % has been reported in a large
series of Chinese women with breast cancer [17]. A study
in Sarawak, Malaysia showed that HER2 positive and triple
negative breast cancer predominate in the Asian region,
with significant differences among the different ethnic
groups, with Malays having significantly more HER2
positive tumors than Chinese [18]. However in the current
study, there were no significant differences in the proportions of the IHC subtypes among the Malay, Chinese, and
Indian women. It has been hypothesized that risk factors
for different subtypes vary markedly, and Westernized
populations are more likely to have factors that increase the
risk of ER and/or PR positive HER2 negative breast cancer
[19].
Because of the controversies regarding the IHC surrogates for the molecular subtypes, for this study, to avoid
any confusion, we decided to study the different categories
of breast cancer according to the expression of ER, PR, and
HER2 by IHC. While HER2 overexpressing and triple
negative are clearly represented by the IHC subgroups of
ER negative PR negative HER2 positive and ER negative
PR negative HER2 negative respectively, the IHC surrogates of Luminal A and Luminal B are still under debate.
To add to the confusion, the St Gallens guidelines suggest
using Ki67 or the percentage of PR positivity to differentiate between Luminal A and Luminal B, both of which are
not practical in a low resource setting [3].
The IHC subtypes are associated with age and grade,
with HER2 overexpressing and triple negative breast cancer being significantly associated with high grade [20, 21].
In the current study, as well as being younger and higher
grade, ER negative PR negative HER2 positive, and triple
negative breast cancers were also associated with larger
size, but there is no significant difference in involved
lymph nodes among the different subgroups. In fact, triple
negative breast was the least likely subtype to have
involved lymph nodes in the current study. The paradox of
larger size and less lymph node involvement in triple
negative breast cancer has been reported before [22]. IHC
subtypes are also significantly related to stage of disease,
with the ER negative PR negative HER2 positive subtype
presenting with more advanced stages in this study.
Because ER negative PR negative HER2 positive and
triple negative breast cancer are more likely to be associated with poor prognostic factors, survival has been
reported to be poorer in these subtypes in several studies. A
study on 496 incident cases of breast cancer from the
Carolina Breast Cancer Study (between May 1993 and Dec
1996), where the IHC surrogates for each subtype is similar
to the current study, showed that breast cancer specific
survival differed by subtype with the poorest survival in the
ER negative PR negative HER2 positive subtype and the
triple negative subtype. This was before the era of antiHER2 therapy [2]. With wider use of trastuzumab, the
survival of HER2 overexpressing breast cancer has
improved significantly [23]. The current study shows no
difference in survival between the ER negative PR negative
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HER2 positive and the ER negative PR negative HER2
negative subtype, which is expected since there was very
limited access to trastuzumab during this period. Without
targeted therapy for the HER2 positive group, the prognosis would be similar to the ER negative PR negative
HER2 negative subtype where there is no targeted therapy
available. A trial to investigate the effect of adding a targeted therapy, bevacizumab, which is a monoclonal antibody against the vascular endothelial growth factor
(EGFR), showed no effect on survival [24].
It is also of interest that the survival of hormone receptor
negative breast cancer is poorer than that of hormone
receptor positive breast cancer regardless of HER2 status,
which means that hormone receptor status rather than
HER2 status has more impact on survival. This is also seen
in another study where ER negativity was a stronger predictor of poor survival than HER2 positivity [25].
Conclusion
Breast cancer subtypes as defined by ER, PR, and HER2
showed that the ER negative PR negative HER2 positive
and ER negative PR negative HER2 negative presented
with more aggressive clinicopathological features and
poorer overall survival compared to the ER and/or PR
positive HER2 negative and ER and/or PR positive HER2
positive subtypes. There was no difference in overall survival between the ER negative PR negative HER2 positive
and ER negative PR negative HER2 negative subtypes, in
the absence of targeted therapy with trastuzumab in the ER
negative PR negative HER2 positive subtype. Survival
from breast cancer depends on optimal access to treatment
[26], and in low- and middle-income countries, targeted
therapy is limited by financial constraints, and hence survival of women with ER negative PR negative and HER2
positive breast cancer will not be better than those with
triple negative breast cancer.
Acknowledgments This paper is supported by HIR Grant UM.C/
HIR/MOHE/06 from the Ministry of Education Malaysia.
Compliance with Ethical Standards
Conflict of interest
peting interests.
The authors declare that they have no com-
Ethics Approval This study was approved by the Ethics Review
Committee of the University Malaya Medical Centre.
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