The Clinicopathological Significance of Basal Markers in Early-Stage Invasive Carcinoma of No Special Type of the Breast
Fikret DIRILENOÐLU1, Demet ARIKAN ETIT2, Halil TAÞKAYNATAN3, Ferhan ELMALI4
1Department of Pathology, Near East University, Faculty of Medicine, NICOSIA, CYPRUS
2Department of Pathology, Katip Celebi University Izmir Ataturk Training and Research Hospital, IZMIR, TURKEY
3Department of Oncology, Katip Celebi University Izmir Ataturk Training and Research Hospital, IZMIR, TURKEY
4Department of Biostatistics, Katip Celebi University Izmir Ataturk Training and Research Hospital, IZMIR, TURKEY
Keywords: Basal marker, Cytokeratin 5/6, EGFR, Early-stage breast cancer, Molecular subtype
Basal markers [cytokeratin 5/6 (CK5/6) and epidermal growth factor receptor (EGFR)] are used in identifying the basal-like breast
carcinoma subtype, which is associated with a poor prognosis. However, the clinicopathological significance in early-stage invasive carcinoma of
no special type (IC, NST) has not been well established.
Material and Method: In a five-year period, 133 female patients with early-stage IC, NST with a median follow-up time of 89 months were
included. The immunohistochemistry-based molecular subtypes were identified according to ASCO/CAP guidelines in 2013. The cutoff values
for basal positivity were determined as 10% for each marker.
Results: Basal positivity was recorded in 83.3% (5/6) of triple-negative breast cancers, 50% (2/4) of HER2-enriched, 18.6% (13/70) of luminal B,
and 8.3% of luminal A (4/48) subtype. CK5/6 and EGFR positivity were significantly associated with ER negativity (p < 0.001). EGFR positive
cases were significantly associated with PR negativity and HER2 positivity compared to negative cases. However, basal positivity was not
associated with the patient outcome (p = 0.006 and p = 0.004, respectively).
Conclusion: Basal positive IC, NSTs were associated with hormone receptor negativity and HER2 overexpression; these patients would therefore
be less likely to respond to hormonotherapy and more likely to benefit from anti-HER2 treatment as well as dual-kinase inhibitors. The lack
of standardization of the definition of basal marker positivity may contribute to the conflicting results of prognostic studies. Hence, further
studies focusing on developing a standard protocol for determining basal marker positivity are needed not only for IC, NST but also for other
histological types of breast cancer.
Staging is a powerful tool for determining the prognosis and
treatment choice in breast cancer (1). With the advances in
screening and increasing awareness of breast cancer, the
majority of tumors are detected in the early stage (2). The
more precise estimation of outcome is also dependent on
other prognostic and predictive factors, such as histological
type, histological grade, and the hormone receptor and
HER2 status. Nevertheless, some of the patients with earlystage
disease still experience recurrence and metastasis
unpredictably, largely due to the biological heterogeneity
of the disease (3). An extensive search for new biomarkers
therefore persists to improve prognostic and predictive
As a result of global gene expression profiling studies
conducted by Perou and Sorlie, breast carcinomas are divided into five distinct intrinsic molecular profiles with
different biological and clinical characteristics: luminal A,
luminal B, HER2, basal-like, and normal breast-like (4).
Basal-like breast cancer (BLBC) is a subgroup of triplenegative
breast cancer (TNBC) that expresses high levels
of certain proteins, such as keratins (CK5/6, CK14, CK17),
epidermal growth factor receptor (EGFR), c-Kit, and
vimentin. All of these BLBC-associated proteins have been
proposed as “basal markers” (5). Immunohistochemically,
a combination of estrogen receptor (ER) negativity, HER2
negativity, and CK5/6 and/or EGFR positivity has been
reported to demonstrate a sensitivity of 76% and specificity
of 100% in identifying BLBCs (6). Following this study,
CK5/6 and EGFR stains have been commonly used in
pathology practice and in research to identify BLBC cases
Since BLBC has been found to be associated with a poor
prognosis, the basal markers used in the identification of
this subtype have attracted much interest to reveal their
prognostic significance in breast carcinomas. Although
some of the studies reported that these markers were
associated with a poor patient outcome, others found no
In this study, our goal was to determine the clinical and
pathological value of basal positivity (CK5/6 and/or EGFR),
specifically in a subset of patients with early-stage invasive
carcinoma of no special type of the breast (IC, NST).
Our study was approved by our institution’s Noninterventional
Ethics Committee with decision number 92
dated 24 August 2016. Informed consent was obtained from
each patient included in this manuscript. We performed
this study according to the principles of the ethical
guidelines established in the World Medical Association’s
Declaration of Helsinki.
Patients and Clinical Information
Between January 2007 and October 2011, female patients
with a diagnosis of early-stage (stage I, II, IIIA) IC, NST
of the breast were retrospectively analyzed from the
electronic database systems of the Department of Pathology
and Oncology (Probel Software, Izmir, Turkey) (12).
Age, menopausal status, tumor location, type of surgery,
number of tumor foci, histological grade, presence of
ductal carcinoma in situ (DCIS) or lobular carcinoma in
situ (LCIS), status of surgical margins, stage of the disease,
status of axillary lymph nodes, immunohistochemical
(IHC) stains (ER, PR, HER2, and Ki-67), treatments
received [hormonotherapy (HT), chemotherapy (CT),
radiotherapy (RT), and other targeted treatment agents such
as trastuzumab)], and the clinical follow-up and survival
data were documented for each case. Menopausal status
was recorded as premenopausal and postmenopausal. The
types of operation were breast conservative surgery, simple
mastectomy, and modified radical mastectomy. The number
of tumor foci was divided into single or multiple. The lymph
node status was divided into three groups as N0, N1, N2. The
cases with accompanying fatal disease were not included in
the study. The cases who did not have sufficient clinical and
follow-up data or pathology material of sufficient quality
and quantity were excluded from the study.
Re-Assessment of Histopathological and IHC
Characteristics of Tumors
All the slides of the cases with sufficient clinical information
were obtained from the archives of the Department of
Pathology. Two pathologists (FD and DAE) reviewed all the H&E and IHC slides. The histological grade of the
tumors was determined according to the Modified Scarff-
For ER and PR, 1% or more staining was considered
positive. In assessing HER2 status, IHC and fluorescence
in situ hybridization (FISH) analyses were performed
according to the updated American Society of Clinical
Oncology/College of American Pathologists guideline in
2013. The Ki-67 proliferation index was assessed using a
40X objective lens in the highest area of staining (hot spot).
The cases with HER2 score 2+ were tested by FISH analysis
and recorded as HER2 positive or negative. At least 50 cells
were counted in FISH analysis and the cases with HER2
signal/CEP17 (chromosome 17 centromere) signal ratio of
>2 were determined as HER2 positive.
Technical Properties of the IHC Studies
According to standard tissue processing and staining
procedures in our laboratory, all the specimens were fixed
in 10% neutral-buffered formaldehyde solution for 24-48
hours. Tissue samples were processed in an automated
closed-system tissue processor and embedded in paraffin.
Four-micron sections from the prepared paraffin blocks
were mounted on poly-L-lysin slides. For CK5/6 and
EGFR, one formalin-fixed, paraffin-embedded (FFPE)
block containing sufficient tumor tissue was selected
from each case during the histopathological review. Two
sections were obtained from each of the selected blocks
and transferred on two separate poly-L-lysin slides.
The staining procedure was carried out according to the
manufacturer’s instructions. The antibodies were visualized
by the streptavidin-biotin-peroxidase method using
ER (Novocastra, Leica Biosystems, Wetzlar, Germany;
mouse monoclonal antibody, SP1 clone, 1:40 dilution), PR
(Novocastra, mouse monoclonal antibody, SP2 clone, 1:100
dilution), HER2 (Novocastra, mouse monoclonal antibody,
CB11 clone, EGFR (Novocastra, mouse monoclonal
antibody, EGFR.25 clone, 1: 100 dilution), CK5/6 (Dako,
mouse monoclonal antibody, D5/16 B4 clone, ready-touse),
and Ki-67 (Novocastra, mouse monoclonal antibody,
MIB1 clone, 1:100 dilution). For positive controls, normal
breast parenchyma adjacent to tumor was used for ER,
PR, and CK5/6. An additional section from breast cancer
tissues that was positive for the respective stains was used
for each of HER2, Ki-67 and EGFR.
Identification of IHC-Based Molecular Subtypes
All cases were divided into subtypes consistent with
intrinsic breast carcinoma subtypes as outlined in the
results of the International Breast Cancer Conference in St.
Gallen in 2013.
Evaluation of CK5/6 and EGFR Staining
Percentage of cytoplasmic and/or membranous staining in
invasive tumor cells was recorded. The cutoff values were
determined as 10% for both stains. The cases with at least
one marker positivity were designated as “basal positive”.
All statistical analyses were performed using the IBM SPSS
Statistics 22.0 package program (IBM Corp., Armonk, New
York, USA). The frequencies of clinical and histological
variables were presented using cross-tabulations. A twosided
Fisher’s Chi-Square exact test for rxc tables was
applied to compare the differences between the groups for
categorical variables. The normal distribution of variables
was examined visually (histogram and probability plots)
and with analytical methods (Shapiro-Wilk tests). If the
distribution was not normal or there were ordinal variables,
the groups were compared by using the Mann-Whitney
U test. If at least one of the variables was not normally
distributed or ordinal, the correlation coefficients and
statistical significance were calculated by the Spearman test
for inter-variable relationships. Kaplan-Meier analysis was
used for survival analysis and the log-rank test was used for
comparison of the survival curves. A value of p <0.05 was
|Patients and Clinical Information
One hundred and eighty cases diagnosed as early-stage
IC, NST between October 2007 and October 2011 were
re-evaluated. Twenty-seven cases without available FFPE
blocks (consultation cases), and 20 cases with histologically
inadequate quality and quantity of tissue and/or with no
invasive tumor area after the sections for CK5/6 and EGFR
stains were excluded from the series. A total of 133 cases in
which at least one basal marker staining could be evaluated
were included in the study.
All cases were female and the median age was 50 (range, 33 -
77). Seventy-four (55.6%) of the cases were premenopausal
and 59 (44.4%) were postmenopausal. Fifty-seven (43.2%)
tumors were located in the right breast, 75 (56.8%) were
in the left breast, and the location was unknown in one
case. Breast conservative surgery was performed in 79 cases
(65.3%), MRM in 38 cases (31.4%), and simple mastectomy
in four cases (3.3%). The type of operation was not known
in 12 cases. Of the 131 tumors, 116 (88.5%) were in a single
focus and 15 (11.5%) were in multiple foci. The median
tumor size was 2 cm (range, 0.6 - 7 cm). Fifty-eight (43.6%)
were stage I, 57 (42.9%) were stage II, and 18 (13.5%) were stage IIIA. Axillary lymph node metastasis was present in 57
(42.9%) of the cases: N1 in 40 (30.1%) and N2 in 17 (12.8%).
One hundred and twenty-one cases (91%) received HT,
115 (86.5%) received CT, and 107 cases (80.5%) received
RT. Median follow-up time was 89 months (range, 27 -
117 months). During follow-up, progression occurred in
16 (12%) of the patients while 8 patients (7.1%) deceased.
The median progression-free survival (PFS) time was 88
months (range, 14 - 117 months) and the median overall
survival (OS) time was 92 months (range, 27-117 months).
Histopathological Analyses and IHC-Based Molecular
Among 130 cases, histological grade was grade 1 in 17
(13.1%), grade 2 in 95 (73.1%), and grade 3 in 18 (%13.8)
cases. Of 128 cases, 42 (32.8%) had DCIS and one of these
cases was found to have LCIS. Among 125 cases, surgical
margin positivity was found in three (2.4%). According
to the results of ER, PR, HER2, Ki-67, CK5/6, and EGFR
staining, 49 cases (35.8%) were classified as luminal A, 48
(36.9%) were luminal B-HER2 (-), 23 (17.7%) were luminal
B-HER2 (+) [19 (14.6%) were luminal B-HER2 PR (+),
four (3.1%) were luminal B-HER2 PR (-)], four (3.1%) were
HER2-enriched, and six (4.4%) were triple-negative breast
carcinoma. All triple-negative cases included in this study
were classified as BLBC because they showed at least one
basal marker positivity. Three tumors with an “ER (-), PR
(+), and HER2 (-)” profile were unclassified.
Staining Properties of CK5/6 and EGFR
Both stains were interpretable in 131 cases out of 133 cases.
Due to the technical issues, two cases with CK5/6 and one
case with EGFR stain could not be evaluated.
CK5/6 showed staining in basal and/or luminal epithelial
cells in the normal breast parenchyma. Cytoplasmic and/
or membranous staining was observed. Among 131 cases, 9
(6.9%) were CK5/6 positive. When any positivity in invasive
tumor cells was recorded, 76 cases (58%) were positive for
CK5/6. The percentage of staining of the tumors varied
between 0 and 100% (Figure 1A-D).
Click Here to Zoom
|Figure 1: CK5/6 positivity in invasive breast carcinoma, no special type. A) Isolated cell staining (IHC; x200). B) Focal, membranouspredominant
staining. (IHC; x200). C) Diffuse staining (IHC; x40). D) Mixed staining pattern, areas of extensive cytoplasmic -
membranous staining and isolated cell staining (IHC; x40).
EGFR positivity was generally weak in epithelial and
myoepithelial cells in the normal breast although rarely
it was strong. Positive cases had cytoplasmic and/or
membranous staining in various intensities (Figure 2AC).
EGFR was positive in 26 (19.7%) of 132 cases. When
any positivity in invasive tumor cells was included, 69 cases
(52.3%) were positive for EGFR.
Click Here to Zoom
|Figure 2: EGFR staining in various intensities in invasive breast
carcinoma, no special type. A) (1+) intensity (IHC; x200). B) (2+)
intensity (IHC; x100). C) (3+) intensity (IHC; x200).
The correlation between CK5/6 and EGFR positivity was
moderate (rho = 0.559; p < 0.001). However, significant differences between staining percentages were noted in
some cases in which both markers were positive. The cases
that showed positivity with CK5/6 (n=9) were also found
to be positive with EGFR, but not vice versa. The number
of basal positive (CK5/6 and/or EGFR positive) cases was
therefore the same as the EGFR positive cases. When any
staining in invasive tumor cells was taken into account,
93 cases (69.9%) were basal positive and both stains were
found to be positive in 52 cases (40%).
The Relationship Between the Basal Marker Positivity
and the Clinical and Pathological Data
Each basal marker was correlated with the clinical and
pathological data. All CK5/6 positive cases were also
positive for EGFR, but not vice versa, and concordant
statistical results were therefore obtained in the analyses for EGFR and basal positivity. CK5/6 positivity and EGFR
positivity were found to have a significant association with
histological grade (p = 0.001 and p = 0.008, respectively).
CK5/6 and EGFR were significantly associated with IHCbased
subtypes (p = 0.037 and p < 0.001, respectively). Basal
positivity was recorded in 83.3% (5/6) of TNBC, 50% (2/4)
of HER2-enriched, 18.6% (13/70) of luminal B, and 8.3%
of luminal A (4/48) subtype. CK5/6 and EGFR positivity
were significantly associated with ER negativity (ERnegative
vs. ER-positive cases; for CK5/6, 35.3% vs. 2.6%;
for EGFR, 77.8% vs. 10.5%, p < 0.001). EGFR positive cases
were significantly associated with PR negativity and HER2
positivity (47.1% vs. 15.7% in PR negative vs. PR positive
cases, p = 0.006; and 14.3% vs. 40.7% in HER2 negative vs.
HER2 positive cases, p = 0.004) compared to negative cases. Although not statistically significant, CK5/6 positive cases
were also more likely to be PR negative and HER2 positive
(18.8% vs. 5.2% in PR negative vs. PR positive cases, p =
0.08; and 4.8% vs. 14.8% in HER2 negative vs. HER2
positive cases, p = 0.086) (Table I).
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|Table I: The relationship between basal markers and clinical and pathological data.
Univariate analyses showed that tumor size (p = 0.003),
surgical margin positivity (p = 0.011), stage (p < 0.001),
lymph node stage (p < 0.001), IHC-based molecular
subtypes (p = 0.002), and ER status (p = 0.045) were
significantly associated with the OS. Menopausal status (p
= 0.031), type of operation (p = 0.017), increase in tumor
size (p < 0.001), surgical margin status (p = 0.046), increase
in stage (p < 0.001), lymph node involvement (p = 0.009),
increase in lymph node stage (p < 0.001), and IHC-based
molecular subtypes (p = 0.007) were significantly associated with the PFS. Log-rank test results for all the clinical and
pathological features are presented in Table II.
Because all CK5/6 positive cases were also found to be
positive for EGFR, outcome analyses for the cases with
EGFR positivity yielded results that were concordant with
those from cases with basal positivity (CK5/6 and/or EGFR
positivity). In univariate analyses, EGFR positive cases
compared to negative cases showed slightly poorer OS and
PFS but this association was not statistically significant
(p > 0.05). CK5/6 positivity was not associated with the
OS and PFS as well (p > 0.05). However, CK5/6 positive
cases showed slightly better OS compared to the negative
cases (Figure 3). Notably, CK5/6 was negative in all cases
who died of the disease, and in all but one case who had
progressive disease. EGFR was negative in five out of eight
cases who died of the disease and 10 out of 15 cases who
had progressive disease.
Click Here to Zoom
|Figure 3: These diagrams display Kaplan-Meier survival curves comparing overall survival and progression-free survival between basal
marker positive and negative cases.
Our study focused on the clinical and pathological utility
of the basal markers in early-stage IC, NST of the breast.
Our results suggested that basal positive cases, as compared
to negative cases, may differ from each other in terms of
treatment choice and therapy resistance because they
significantly tend to be hormone receptor negative and
HER2 positive. Basal positivity did not correlate with the
significant prognostic factors, i.e., TNM stage, tumor size,
and nodal status (13). Accordingly, basal positivity was
not found to be associated with the patient outcome in our
Regardless of cutoff value selection, basal positivity
(positivity for CK5/6 and/or EGFR) has been reported in 15.6% of all invasive breast carcinomas on average (6,14-
16). Among the subtypes, these markers were found to
be expressed most frequently in TNBC (50-80%) (14) .
HER2-enriched is the other subtype with remarkable basal
positivity rates, and EGFR (HER1) has shown positivity in
up to 58% in particular (16). It was also reported that basal
positivity is significantly more common in HER2-positive
compared to HER2-negative breast cancers overall (16,17).
However, basal positivity was found to be associated
with HER2 negativity in ER-negative tumors (18,19). In
accordance with these findings, our results supported
that basal markers, especially EGFR, are most frequently
found to be positive in TNBC, but are also associated with
HER2 positivity in non-TNBC. Besides, basal positive breast carcinomas are more likely to be hormone receptor
negative. Considering these associations, these patients
would less likely respond to HT but more likely benefit
from anti-HER2 therapy as well as dual-kinase inhibitors
(such as lapatinib), which target both EGFR and erb-B2
and are promising in HER2- and EGFR-expressing
breast carcinomas (20,21). In hormone receptor positive
subtypes (luminal A and luminal B), the basal positivity
rate was lower (17/118, 14.4%) and this is compatible with
the previous studies with rates ranging from 1% to 18%
Prognostic use of these markers has yet to be established
since there is a lack of standardization in defining basal
marker positivity. Some of the previous studies have
used one basal marker only, while others have used more
than one marker. The variations in the types, clones, and
evaluation methods of basal markers have been confusing
(5,19). For instance, cutoff value selection has varied
significantly in prognostic and predictive studies. Some
studies that investigated the prognostic and predictive
value of basal markers in breast carcinomas have regarded
any weak cytoplasmic or membranous staining as positive,
while some others determined positivity based on the
intensity of staining or a cutoff value of up to 10% (6,11,15).
We used the cutoff value of 10% for both markers instead
of any cell staining basically for two reasons: i) lower cutoff
values showed poor reproducibility in interpretation;
ii) basal markers are also positive in other non-invasive
lesions, such as DCIS, or normal parenchyma. We often
encountered weak staining in a very small number of cells
within the tumor area and were then unable to discriminate
whether the staining was present in invasive tumor cells or
not (23,24). Using this cutoff value, 19.7% of the cases were
EGFR positive and 6.9% were CK5/6 positive. However,
when any invasive tumor cell staining was counted, the
positivity rates increased to 52.3% for EGFR and 58% for
CK5/6. Another issue is the variation in cutoff values for
predictive breast cancer markers. For instance, the cutoff
value for ER positivity was determined as 5% in one study
and 10% in another (25,26). In our study, we used a cutoff
value for ER of 1%, as currently recommended by the
ASCO/CAP guidelines (27). The cutoff value for the Ki-
67 proliferation index in the distinction of the luminal B
from the luminal A subtype is 14% for some authors and
20% for the others (28). In this case, the distribution and
clinical characteristics of these groups would vary from
one study to another. These observations may explain the
disparities between the rates of basal marker positivity and
the differences in prognostic estimates reported in breast
We aimed to evaluate the utility of basal markers in earlystage
invasive breast carcinoma cases with a diagnosis of
IC, NST. Basal positive IC, NSTs were associated with
hormone receptor negativity and HER2 overexpression;
therefore, these patients may not benefit from HT but may
respond to anti-HER2 treatment as well as dual-kinase
inhibitors, such as lapatinib. In our study population
including the most common histological type of breast
cancer and with a median follow-up time of 89 months,
previously established strong prognostic factors remained
significant. However, basal positivity was not associated
with the patient outcome. The lack of standardization of
the definition of basal marker positivity may contribute to
the conflicting results of prognostic studies. Hence, further
studies focusing on establishing a standard protocol for
determining basal marker positivity is needed not only
for IC, NST but also for other histological types of breast
This research paper was generated from the thesis of Dr.
Fikret Dirilenoglu and received a grant from the Board
of Scientific Research of the Izmir Ataturk Training and
Research Hospital (Grant No: 6/2016).
CONFLICT of INTEREST
The authors declare no conflict of interest.
We would like to thank Dr. Yuksel Kucukzeybek, Ayhan
Kancar, and Hulya Goren for their generous time and great
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