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Clinicopathological classification and individualized treatment of breast
cancer
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HU Hui , LIU Yin-hua , XU Ling , ZHAO Jian-xin , DUAN Xue-ning , YE Jing-ming , LI Ting ,
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ZHANG Hong , ZHANG Shuang and XIONG Yan
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Breast Disease Center and Department of Pathology, Peking University First Hospital,
No.8 XiShiKu Street, Beijing, 100034, China
Correspondence to：Dr. YE Jing-ming，Breast Disease Center, Peking University First
Hospital, No.8 XiShiKu Street, Beijing, 100034, China Tel & Fax: +86 (0) 106-655-2566,
E-mail: [email protected]
Keywords：breast cancer ; clinicopathogical classification; tumor-nodal-metastatic
staging ; histopathological grade ; individualized treatment
Abstract
Background The clinicopathological classification were proposed in the St. Gallen
consensus report 2011.We conducted a retrospective analysis of breast cancer subtype
and tumor-nodal-metastatic (TNM) staging and histopathological grade to investigate the
value of these parameters in the treatment strategies of invasive breast cancer.
Methods A retrospective analysis of breast cancer subtype, TNM staging, and
histopathological grade of 213 cases has been performed by the methods recommended in
the St. Gallen International Expert Consensus report 2011. The estrogen receptor (ER),
progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), and Ki-67
of 213 tumor samples have been investigated by immunohistochemistry according to methods
for classifying breast cancer subtypes proposed in the St. Gallen consensus report 2011.
Results The luminal A subtype was found in 53 patients (24.9%), the luminal B subtype
was found in 112 patients (52.6%), the HER2-positive subtype was found in 22 patients
(10.3%), and the triple-negative subtype was found in 26 patients (12.%).
Histopathological grade and TNM staging differed significantly among the four subtypes
of breast cancer (P< 0.001).
Conclusions It is important to consider TNM staging and histopathological grading in
the treatment strategies of breast cancer based on current clinicopathogical
classification methods.
Abbreviations
ER
estrogen receptor
PR
progesterone receptor
HER2
human epidermal growth factor receptor-2
TNM
tumor-nodal-metastatic
IHC
immunohistochemistry
FISH
fluorescence in situ hybridization
th
Experts attending the 12 International St. Gallen Breast Cancer Conference in March
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2011 Error! No bookmark name given., acknowledged that molecular typing is useful
to help understand the intrinsic biological nature of breast cancer. The conference
reached a consensus that the immunohistochemical (IHC) technique proposed by Cheang
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should be used to analyze the expression of four markers [estrogen receptor (ER),
progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67]
to determine the clinicopathological subtype of breast cancer, representing a similar
but more practical approach than molecular typing. Although the conference did not
exclude established clinical risk factors or treatment recommendations, it has prompted
much debate on whether identification of the four clinicopathological subtypes (luminal
A, luminal B, HER2-positive, and triple-negative) by IHC and the associated treatment
recommendations will affect individualized treatment of breast cancer.
Following the introduction of these criteria, the Breast Cancer Center in conjunction
with the Department of Pathology at our hospital re-examined and classified the
histological specimens from patients with newly diagnosed invasive breast cancer who
were admitted between January and December 2010. We investigated whether
tumor-nodal-metastatic (TNM) staging and histopathological grading should be used in
combination with the clinicopathological classification proposed in the St. Gallen
consensus report 2011.
METHODS
Patients
Patients who were newly diagnosed with invasive breast cancer at the Breast Disease
Center, Peking University First Hospital, between January and December 2010 were
enrolled in this study. All patients met the following criteria: the clinical data were
complete and evaluable for TNM staging; and the re-examined pathological material was
a pathological specimen of the primary breast cancer lesion that had not been previously
treated. All pathologic specimens were reviewed by two experienced pathologists who
determined the following tumor characteristics : primary tumor size, histologic and
nuclear grades, and the expression of ER, PR, HER2, and Ki67. The data collected also
included demographic features and clinicopathological classification.
Tissue processing
From January 2008, surgical clinicians and pathologists at our institute have reached
a consensus on processing of breast tumor specimens (including core needle biopsy and
excisional biopsy specimens) as follows: tissue specimens are sent to the Department
of Pathology within 30 min of collection; the specimens are cut at 5 mm intervals and
fixed in 10 volumes of 10% neutral-buffered formalin solution for 6–48 h; fixed
specimens are then embedded in paraffin and sectioned to 5-µm-thick slices. In this
study, the re-examination involved re-sectioning of specimens previously embedded in
paraffin and subsequent IHC analyses. IHC for ER, PR, and Ki67 was performed on sequential
sections using established methods. HER2 status was determined by IHC and/or
fluorescence in situ hybridization (FISH) assays.
IHC
Monoclonal antibodies for ER (clone: SP1, dilution: 1:200; Dako, Glostrup, Denmark),
Ki-67 (clone: MIB-1, dilution: 1:200; Dako, Denmark), PR (clone: 16SAN27, dilution:
1:200; Novocastra，DE), and HER2(clone: 4B5; Ventana, Tucson, AZ, USA) were used for
IHC analyses on a Ventana automated staining system. ER and PR positivity were defined
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as any level of positive nuclear staining (i.e. ≥ 1%). HER2expression was evaluated
in terms of its cell membrane localization. The intensity of membrane staining was
semi-quantitatively analyzed (0–3+). Briefly, 3+ staining (HER2overexpression) was
defined as uniform and intense membrane staining in > 30% of invasive breast cancer cells.
No staining (0) or weak (1+) and incomplete membrane staining was considered a negative
result. Specimens with HER2IHC expression graded as 2+ underwent FISH to confirm
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HER2positivity . Ki67 positivity was defined in terms of its nuclear staining; the Ki67
labeling index was calculated as the percentage of MIB-1-positive cells in a total of
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1000 malignant cells observed at high-power magnification (×400). The results were
evaluated by three experienced pathologists. Consensus was reached on controversial
cases through discussion.
FISH
The target area was selected based on the results of histopathological and
immunohistochemical analyses; only sections with ≥ 20 tumor cells were used. The
intraductal component of the carcinoma was excluded from the analysis. The HER2gene
detection kit was purchased from Beijing GP Medical Technologies Co., Ltd. (Beijing,
China). Proteinase K (0.1 mg/ml) digestion was performed at 37°C, followed by
degradation at 83°C for 5 min and hybridization at 42°C for 16 h in a hybridization
instrument. Sections were double-stained with 4’,6-diamidino-2-phenylindole. A tissue
sample from a patient with confirmed invasive breast cancer was used as a positive control.
HER2was visualized as orange-red fluorescence, while chromosome 17 centromere was
visualized as green fluorescence. The FISH score was determined as the ratio of the
average copy number of the HER2 gene to that of the chromosome 17 centromere in 20
–60 nuclei/case. Specimens with a signal ratio > 2 were scored as HER2-positive
(HER2amplified) and those with a signal ratio of < 1.8 were scored as HER2-negative.
Samples scoring between 1.8 and 2.2 were considered borderline and were re-evaluated.
The heterogeneity of HER2gene amplification was objectively assessed when the
fluorescence signal was unevenly distributed.
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TNM staging
Pathologic stage was determined in patients that received no neoadjuvant therapy, while
the highest level of clinicopathological stage was recorded for patients who received
neoadjuvant therapy. TNM staging was performed according to the 7
American Joint Committee on Cancer TNM staging system.
th
edition of the
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Histopathological grading
The histopathological grade was determined using the modified Scarff–Bloom–Richardson
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grading system (Nottingham grading). The Nottingham grading system is based on
microscopic evaluation of the morphologic and cytologic features of tumor cells,
including the degree of tubule formation, nuclear pleomorphism, and mitotic count.
The clinicopathological classification
The clinicopathological classification used here was based on the IHC staining of ER,
PR, HER2, and Ki67, and established four subtypes of breast cancer. The luminal A subtype
was defined as ER- and/or PR-positive, HER2negative, and Ki-67 expression in < 14% of
cells. The luminal B subtype was defined as ER- and/or PR-positive, Ki-67 expression
in ≥ 14% of cells, or HER2-positive. The HER2-positive subtype was defined as
HER2-positive, and ER- and PR-negative. The triple-negative subtype was defined as ER-,
PR-, and HER2-negative.
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Statistics
Non-parametric tests (Mann–Whitney test and the Kruskal–Wallis test) were used to test
the differences in clinical characteristics between the individual subtypes of breast
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cancer. X tests were used to compare categorical variables. Values of P < 0.05 were
considered statistically significant. Analyses were conducted using SPSS software
version 16.0 (IBM-SPSS, Chicago, IL, USA).
RESULTS
General clinical characteristics
Between January and December 2010, 277 patients with newly diagnosed breast cancer,
including two patients with bilateral breast cancer, were admitted to our hospital. Of
these, 32 patients with ductal carcinoma in situ, lobular carcinoma in situ, or
microinvasive cancer, and 4 patients with other types of malignant tumors were excluded
from the analysis. Of the remaining 241 patients with invasive breast cancer, there were
9 patients in whom the primary tumor was removed by lumpectomy at another hospital or
the primary tumor size could not be evaluated for another reason, 4 patients were not
treated at our hospital, and 15 patients had a HER2 IHC value of 2+ but refused to undergo
the FISH test; these patients were excluded from the analysis. Therefore, a total of
213 patients with invasive breast cancer were included in this study, including 211
females and 2 males, aged 25–88 years (mean age, 52.3 years).
Clinical pathological subtype
The breast cancers in the 213 patients were classified as luminal A in 53 patients (24.9%),
luminal B in 112 (52.6%), HER2-positive in 26 (12.2%), and triple-negative in 22 (10.3%).
In terms of pathological grading, the cancers in 66 (31.0%), 94 (44.1%), and 53 (24.9%)
patients were classified as grade I, II and III respectively. On TNM staging, 78 (36.6%),
92 (43.2%), 41 (19.2%), and 2 (0.9%) patients were classified with stage I, II, III and
IV breast cancer, respectively (Table 1).
Clinicopathological classification and histopathological grading
On histopathological grading, the 53 luminal A subtype breast cancers included 39 (73.6%)
of grade I, 14 (26.4%) of grade II, and none of grade III. The 112 luminal B subtype
breast cancers were of grade I in 24 (21.4%), grade II in 63 (56.3%), and grade III in
25 (22.3%). Among 22 triple-negative cancers, 2 (7.7%) were of grade I, 7 (26.9%) of
grade II, and 17 (65.4%) of grade III. The 26 HER2-positive cancers included 1 (4.5%)
of grade I (4.5%), 10 (45.5%) of grade II, and 11 (50.0%) of grade III. (Table 1)
Among the four subtypes, the proportion of patients histopathologically classified as
grade I was highest for the luminal A subtype, whereas the proportion of patients
classified as grade II was highest for the luminal B subtype and the proportion of
patients classified as grade III was highest for the triple-negative subtype. Only 4.5%
of patients with the HER2-positive subtype were classified as grade I, while the
proportions of patients with grade II or grade III cancer were fairly similar (45.5%
and 50.0%, respectively).
The distribution of the histopathological grades in patients with the luminal A subtype
was significantly different from those in patients with the luminal B, HER2-positive,
or triple-negative subtypes (P < 0.001). The distribution of histopathological grades
in patients with the luminal B subtype was also significantly different from that in
patients with the HER2-positive or triple-negative subtypes (P < 0.001). By contrast,
the distribution of histopathological grades was not significantly different between
patients with the HER2-positive and triple-negative subtypes of breast cancer (P> 0.05).
Clinicopathological classification and TNM staging
The TNM staging in 53 patients with the luminal A subtype was stage I in 29 patients
(54.7%), stage II in 18 (34.0%), and stage III in 6 (11.3%); none had stage IV cancer.
The TNM staging in 112 patients with the luminal B subtype was stage I in 37 patients
(33.0%), stage II in 48 (42.9%), stage III in 25 (22.3%), and stage IV in 2 (1.8%). In
26 patients with triple-negative breast cancer, the TNM staging was stage I in 8 patients
(30.8%), stage II in 14 (53.8%), and stage III in 4 (15.4%); none had stage IV cancer.
The TNM staging in 22 patients with HER2-positive breast cancer was stage I in 4 patients
(18.2%), stage II in 12 (54.5%), and stage III in 6 (27.3%); none had stage IV cancer
(Table 1).
The distribution of TNM staging in patients with the luminal A subtype was significantly
different from the distributions in the luminal B and HER2-positive subtypes (P < 0.001),
but not the triple-negative subtype (P > 0.05). There were no significant differences
in the distribution of TNM staging among the luminal B, triple-negative, and
HER2-positive subtypes of breast cancer ( P > 0.05).
DISCUSSION
Breast cancer is the most common malignant tumor in women. Because of its high
heterogeneity, there are significant variations in its racial distribution, morphology,
and molecular genetic characteristics, as well as its response to treatment and
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prognosis. In addition to traditional prognostic indicators such as TNM staging and
pathological grade, researchers are continuing to explore other biological indicators
that may aid clinical practice and research into breast cancer. It is also debated whether
the recommendations for individualized treatment can provide the maximum benefits to
all patients with breast cancer. The four editions of the St. Gallen International Expert
Consensus reports published between 2005 and 2011 have progressed from the risk
assessment of recurrence to clinicopathological classification.
Error! Reference source not found.
These changes suggest that a more precise individualized treatment program will dominate
the treatment of breast cancer.
Gerdes J et al. found that Ki67 is a nuclear antigen expressed in proliferating cells,
and its expression reflects the proliferation rate of malignant tumors. Ki67 is now
considered to be the most reliable indicator for determining the proliferative
activities of tumor cells.
Error! Reference source not found.
At the 12
th
International St. Gallen
Breast Cancer Conference in 2011, it was proposed that the clinical types of breast cancer
could be distinguished based on IHC staining of four markers (ER, PR, HER2, and Ki67).
In this subtyping system, the Ki-67 labeling index is mainly used to differentiate
between the luminal A and luminal B (HER2-negative) subtypes, which require different
treatment options and also influence prognosis.
7
Following the introduction of these
criteria, we re-examined breast cancer specimens from 213 patients with invasive breast
cancer. The resulting subtypes were luminal A in 53 patients (24.9%), luminal B in 112
(52.6%), HER2-positive in 26 (12.2%), and triple-negative in 22 (10.3%). The proportions
of patients with the luminal (luminal A and B), HER2-positive, and triple-negative
subtypes were similar to those reported in other studies, although the proportions of
patients with the luminal A and luminal B subtypes differed from those in other studies.
Error! Reference source not found.
This difference may be due to our inclusion of patients from a
single medical center, the relatively small number of patients, and/or ethnic
differences.
In this study, the luminal A and B subtypes accounted for 77.5% of all subtypes of breast
cancer. As both subtypes are positive for ER and/or PR expression and can benefit from
endocrine therapy, our results support the importance of endocrine therapy in most
patients with breast cancer.
The St. Gallen consensus reports published between 2005 and 2009 recommend that it is
important to evaluate the prognosis of breast cancer patients to help select the most
appropriate treatment, and that endocrine therapy is recommended for pathological grade
I, TNM staging I, ER- and/or PR-positive, and HER2-negative patients. The St. Gallen
consensus report published in 2011 clearly stated that, except for some particularly
high-risk circumstances (e.g., lymph node involvement), only patients with the luminal
A subtype of breast cancer should receive endocrine therapy. Overall, 41.5% (22/53) of
patients with the luminal A subtype were classified as having histopathological grade
I and TNM staging I breast cancer (Table 2), for which endocrine therapy is the best
choice. However, many patients were classified as histopathological grade II (26.4%),
or worse, TNM staging II (45.3%) and TNM staging III (11.3%) (Table 1). In our study,
there are 5 patients in Luminal A subtype, TNM staging II or III were received
neo-adjuvant chemotherapy, one patient quit because of clinical progressive disease,
4 patients completed all cycles. The pathologic response according to the Miller-Payne
histopathological grading system was as follows:1 G1,1 G4,2 G3. Error! Reference source not found.
Therefore, we suggest that clinicians should pay careful attention to the St. Gallen
consensus report 2011, regarding the treatment recommendations for the luminal A subtype
of breast cancer. In particular, for patients with the luminal A subtype and additional
risk factors, such as axillary lymph node metastasis, secondary cytotoxic chemotherapy
is not contraindicated and should be selected on a patient-by-patient basis.
The St. Gallen consensus report 2011, also recommended that cytotoxic adjuvant
chemotherapy or cytotoxic chemotherapy combined with anti-HER2therapy should be used
as the basic treatment for patients with triple-negative, HER2-positive, or luminal B
breast cancer. In the present study, these three subtypes included 95.5%, 92.3%, and
78.6% of patients with a histopathological grade of II or III, and 69.2%, 81.8%, and
67% of patients with a TNM staging of II or III. These findings confirmed the presence
of significant risk factors in most of the patients with these subtypes of breast cancer,
as well as the need for auxiliary cytotoxic chemotherapy.
Before the introduction of the clinicopathological classification proposed by the St.
Gallen consensus report 2011, the prognosis and treatment decisions were essentially
based on histopathological grade and TNM stage, which had achieved some consensus.
Reference source not found.
Error!
Clinical guidelines also suggested that cytotoxic chemotherapy could
be beneficial for patients with TNM staging II/worse and/or histopathological grade III
breast cancer. Therefore, the clinicopathological classification proposed by the St.
Gallen consensus report 2011, should be considered as supplementary to the established
recommendations. In this study, none of the patients with the luminal A subtype were
classified as histopathological grade III, indicative of high-grade tumor
differentiation and a low degree of malignancy in this group of patients. However,
several patients with luminal A subtype breast cancer were lymph node-positive and
several had TNM staging III disease. Therefore, the St. Gallen consensus report
emphasized that lymph node status, tumor size, and other factors should also be
considered when selecting the appropriate chemotherapy. With respect to luminal B,
triple-negative, and HER2-positive breast cancer, the selection of cytotoxic
chemotherapy is particularly important to achieve clinical benefits in patients with
more severe histopathological grade and TNM staging.
Histopathological grading helps us to evaluate the degree of malignancy, while TNM
staging provides a useful system to ascertain the tumor stage. Using both systems
together can provide clinicians with valuable information to aid prognostic evaluation.
In addition, clinicopathological classification based on the analysis of tumor marker
expression can help to distinguish between breast cancer subtypes, and provide a more
scientific basis to predict treatment efficacy and to determine individualized treatment.
The established systems used for subtyping, staging, and grading of breast cancers should
not be abandoned, as TNM staging and histopathological grade provide foundations for
individualized treatment of breast cancer, and cancer subtype complements rather
replaces these well validated systems.
Acknowledgments We wish to thank our colleagues at the Department of Pathology for their
technical support.
Funding The study was supported by funding from the Beijing Municipal Science and
Technology commission (D090507043409010) and the capital foundation of medical
development and Research (2009-1011)
Conflict of Interest The authors declare that they have no conflict of interest.
Open Access This article is distributed under the terms of the Creative Commons
Attribution Noncommercial License, which permits any noncommercial use, distribution,
and reproduction in any medium, provided the original authors and the source are
credited.
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Table 1. Distribution of histopathological grade and TNM stage according to breast
cancer subtype
Characteristics
Total Tissue cases
Luminal A
Luminal B
TNBC
HER2+
No. of Pt(%)
No. of Pt (%)
No. of Pt (%)
No. of Pt(%)
No. of Pt(%)
213 (100.0)
53 (24.9)
112 (52.6)
26 (12.2)
22 (10.3)
52.3
52.3
53.1
52.8
52.8
Age
Median (years)
Histologic grade
P Value
I
66 (31.0)
39 (73.6)
24 (21.4)
2 (7.7)
1 (4.5)
II
94 (44.1)
14 (26.4)
63 (56.3)
7 (26.9)
10 (45.5)
III
53 (24.9)
0 (0)
25 (22.3)
17 (65.4)
11 (50.0)
I
78 (36.6)
29 (54.7)
37 (33.0)
8 (30.8)
4 (18.2)
II
92 (43.2)
18 (34.0)
48 (42.9)
14 (53.8)
12 (54.5)
III
41 (19.2)
6(11.3)
25 (22.3)
4 (15.4)
6 (27.3)
IV
2 (0.9)
0 (0)
2 (1.8)
0 (0)
0 (0)
T1
100 (46.9)
32 (60.4)
53 (47.3)
10 (38.5)
5 (22.7)
T2
92 (43.2)
18 (34.0)
47 (42.0)
15 (57.7)
12 (54.5)
T3
20 (9.4)
3 (5.7)
12 (10.7)
1 (3.8)
4 (18.2)
T4
1 (0.5)
0 (0)
0 (0)
0 (0)
1 (4.5)
N0
124 (58.2)
37 (69.8)
60 (53.6)
16 (61.5)
11 (50.0)
N1
52 (24.4)
11 (20.8)
29 (25.9)
6 (23.1)
6 (27.3)
N2
26 (12.2)
4 (7.5)
14 (12.5)
4 (15.4)
4 (18.2)
N3
11 (5.2)
1 (1.9)
9 (8.0)
0 (0)
1 (4.5)
M1
2 (0.9)
0
2 (0.9)
0
0
M0
211 (99.1)
53 (24.9)
110 (51.6)
26 (12.2)
22（10.3)
<0.001
TNM stage
0.003
T stage
<0.001
Node
<0.001
M stage
0.610
Table 2. Classification of patients according to breast cancer subtype
Grade/TNM
Subtypes
Luminal A
Luminal B
No. of Pt (%)
No. of Pt (%)
TNBC
HER2+
No. of Pt (%)
53
112
26
I/I
22 (41.5)
11 (9.8)
0
I/II
12 (22.6)
10 (8.9)
2 (7.7)
I/III
5 (9.4)
3 (2.7)
0
No. of Pt (%)
22
0
0
1 (4.55)
II/I
7 (13.2)
23 (20.5)
1 (3.8)
1 (4.55)
II/II
6 (11.3)
25 (22.3)
1 (3.8)
6 (27.3)
II/III
1 (1.9)
14 (12.5)
0
3 (13.6)
II/IV
0
1 (0.9)
0
0
III/I
0
3 (2.7)
1 (3.8)
3 (13.6)
III/II
0
13 (11.6)
8 (30.8)
6 (27.3)
III/III
0
8 (7.14)
4 (15.4)
2 (9.1)
III/IV
0
1 (0.9)
0
0