Clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes
The aim of the present study was to investigate the clinical and morphological features of nonspecific invasive breast cancer according to its molecular subtypes. Materials and Methods: 163 women with nonspecific invasive breast cancer (T1–4N0–3M0) were included in the present study. Luminal A type...
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| Zitieren: | Clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes / M. Zavyalova, S. Vtorushin, N. Telegina, N. Krakhmal, O. Savelieva, L. Tashireva, O. Bragina, E. Denisov, E. Kaigorodova, E. Slonimskaya, E. Choynzonov, V. Perelmuter // Experimental Oncology. — 2016 — Т. 38, № 2. — С. 122–127. — Бібліогр.: 24 назв. — англ. |
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irk-123456789-1379962018-06-18T03:04:54Z Clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes Zavyalova, M. Vtorushin, S. Telegina, N. Krakhmal, N. Savelieva, O. Tashireva, L. Bragina, O. Denisov, E. Kaigorodova, E. Slonimskaya, E. Choynzonov, E. Perelmuter, V. Original contributions The aim of the present study was to investigate the clinical and morphological features of nonspecific invasive breast cancer according to its molecular subtypes. Materials and Methods: 163 women with nonspecific invasive breast cancer (T1–4N0–3M0) were included in the present study. Luminal A type of breast cancer was detected in 101 women, luminal B type — in 23 women, overexpression of HER2/neu was identified in 14 women and triple-negative cancer — in 25 women. Results: The study revealed that various molecular subtypes of breast cancer differ in the morphological structure, the expression characteristics of the primary tumor and the rate of lymphogenous and hematogenous metastasis. Lymphogenous metastases were more frequently (in 71%) detected in HER2/neu overexpressing breast cancer than in luminal A (41%), luminal B (39%) and triple-negative tumors (40%). Hematogenous metastasis did not depend on the morphological structure of carcinoma infiltrative component, the state of tumor stroma as well as the proliferative activity in all the investigated groups. Conclusion: The revealed clinicopathological characteristics of different molecular subtypes of invasive breast cancer allow to predict the possible outcome of the disease and select personalized treatment strategy for patients more reasonably. 2016 Article Clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes / M. Zavyalova, S. Vtorushin, N. Telegina, N. Krakhmal, O. Savelieva, L. Tashireva, O. Bragina, E. Denisov, E. Kaigorodova, E. Slonimskaya, E. Choynzonov, V. Perelmuter // Experimental Oncology. — 2016 — Т. 38, № 2. — С. 122–127. — Бібліогр.: 24 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/137996 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions Zavyalova, M. Vtorushin, S. Telegina, N. Krakhmal, N. Savelieva, O. Tashireva, L. Bragina, O. Denisov, E. Kaigorodova, E. Slonimskaya, E. Choynzonov, E. Perelmuter, V. Clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes Experimental Oncology |
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The aim of the present study was to investigate the clinical and morphological features of nonspecific invasive breast cancer according to its molecular subtypes. Materials and Methods: 163 women with nonspecific invasive breast cancer (T1–4N0–3M0) were included in the present study. Luminal A type of breast cancer was detected in 101 women, luminal B type — in 23 women, overexpression of HER2/neu was identified in 14 women and triple-negative cancer — in 25 women. Results: The study revealed that various molecular subtypes of breast cancer differ in the morphological structure, the expression characteristics of the primary tumor and the rate of lymphogenous and hematogenous metastasis. Lymphogenous metastases were more frequently (in 71%) detected in HER2/neu overexpressing breast cancer than in luminal A (41%), luminal B (39%) and triple-negative tumors (40%). Hematogenous metastasis did not depend on the morphological structure of carcinoma infiltrative component, the state of tumor stroma as well as the proliferative activity in all the investigated groups. Conclusion: The revealed clinicopathological characteristics of different molecular subtypes of invasive breast cancer allow to predict the possible outcome of the disease and select personalized treatment strategy for patients more reasonably. |
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| author |
Zavyalova, M. Vtorushin, S. Telegina, N. Krakhmal, N. Savelieva, O. Tashireva, L. Bragina, O. Denisov, E. Kaigorodova, E. Slonimskaya, E. Choynzonov, E. Perelmuter, V. |
| author_facet |
Zavyalova, M. Vtorushin, S. Telegina, N. Krakhmal, N. Savelieva, O. Tashireva, L. Bragina, O. Denisov, E. Kaigorodova, E. Slonimskaya, E. Choynzonov, E. Perelmuter, V. |
| author_sort |
Zavyalova, M. |
| title |
Clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes |
| title_short |
Clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes |
| title_full |
Clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes |
| title_fullStr |
Clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes |
| title_full_unstemmed |
Clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes |
| title_sort |
clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2016 |
| topic_facet |
Original contributions |
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http://dspace.nbuv.gov.ua/handle/123456789/137996 |
| citation_txt |
Clinicopathological features of nonspecific invasive breast cancer according to its molecular subtypes / M. Zavyalova, S. Vtorushin, N. Telegina, N. Krakhmal, O. Savelieva, L. Tashireva, O. Bragina, E. Denisov, E. Kaigorodova, E. Slonimskaya, E. Choynzonov, V. Perelmuter // Experimental Oncology. — 2016 — Т. 38, № 2. — С. 122–127. — Бібліогр.: 24 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
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2025-07-10T02:46:28Z |
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2025-07-10T02:46:28Z |
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| fulltext |
122 Experimental Oncology 38, 122–127, 2016 (June)
CLINICOPATHOLOGICAL FEATURES OF NONSPECIFIC INVASIVE
BREAST CANCER ACCORDING TO ITS MOLECULAR SUBTYPES
M. Zavyalova1, 2, 3, S. Vtorushin1, 2, N. Telegina2, N. Krakhmal1,2, O. Savelieva1, 3,*, L. Tashireva1,
O. Bragina4, E. Denisov3, 4, E. Kaigorodova1, 3, E. Slonimskaya5, 6, E. Choynzonov6, 7, V. Perelmuter1, 2
1Department of Pathological Anatomy and Cytology, Tomsk Cancer Research Institute, Tomsk 634050, Russian Federation
2Department of Pathological Anatomy, Siberian State Medical University, Tomsk, Russian Federation
3Laboratory of Translational Cell and Molecular Biomedicine, National Research Tomsk State University,
Tomsk, Russian Federation
4Laboratory of Molecular Oncology and Immunology, Tomsk Cancer Research Institute, Tomsk 634050, Russian Federation
5Department of General Oncology, Tomsk Cancer Research Institute, Tomsk 634050, Russian Federation
6Department of Oncology, Siberian State Medical University, Tomsk, Russian Federation
7Department of Head and Neck Cancer, Tomsk Cancer Research Institute, Tomsk 634050, Russian Federation
The aim of the present study was to investigate the clinical and morphological features of nonspecific invasive breast cancer according
to its molecular subtypes. Materials and Methods: 163 women with nonspecific invasive breast cancer (T1–4N0–3M0) were in-
cluded in the present study. Luminal A type of breast cancer was detected in 101 women, luminal B type — in 23 women, overexpres-
sion of HER2/neu was identified in 14 women and triple-negative cancer — in 25 women. Results: The study revealed that various
molecular subtypes of breast cancer differ in the morphological structure, the expression characteristics of the primary tumor and the
rate of lymphogenous and hematogenous metastasis. Lymphogenous metastases were more frequently (in 71%) detected in HER2/neu
overexpressing breast cancer than in luminal A (41%), luminal B (39%) and triple-negative tumors (40%). Hematogenous metastasis
did not depend on the morphological structure of carcinoma infiltrative component, the state of tumor stroma as well as the prolifera-
tive activity in all the investigated groups. Conclusion: The revealed clinicopathological characteristics of different molecular subtypes
of invasive breast cancer allow to predict the possible outcome of the disease and select personalized treatment strategy for patients
more reasonably.
Key Words: invasive breast cancer, molecular subtype, HER2/neu, triple-negative cancer, intratumor heterogeneity.
In recent years the molecular genetic classifica-
tion of breast tumors offered by C.M. Perou et al.
(2000) is used to determine appropriate treatment for
patients on an individual basis [1]. This classification
is based on cluster analysis of 465 genes and enables
to differentiate between the following breast cancer
subtypes: luminal A, luminal B, HER2/neu-positive
overexpression and triple-negative. Each molecular
genetic subtype is associated with specific molecular
and clinical signs and is characterized by features of tu-
mor response to chemotherapy, metastatic behavior
and different outcomes [2, 3].
Luminal A tumors are highly sensitive to hormone
therapy, have low risk of recurrence and high survival
rates [2, 4, 5]. Luminal B tumors in comparison with
luminal A ones are often accompanied by metastases
in lymph nodes and recurrence risk. These tumors are
usually not sensitive to chemotherapy and hormone
therapy, but they are sensitive to trastuzumab in cases
with positive HER2/neu expression [6, 7].
HER2/neu-positive breast cancer is characterized
by the large size of the primary tumor, frequent involve-
ment of lymph nodes in the metastatic process and
low survival rates. HER2/neu-positive tumors are not
sensitive to hormone therapy, however administration
of trastuzumab in the adjuvant setting is effective for
them [6–8].
Triple-negative cancer is found among younger
women and is often associated with BRCA1 mutations.
Low differentiation grade, necrosis and inflamma-
tory infiltration in the tumor stroma characterize the
histological structure of this cancer subtype. These
tumors have big size, they often metastasize to lymph
nodes and distant organs and have lower survival rates.
Triple-negative tumors are sensitive to anthracycline-
taxane-based chemotherapy [9, 10].
Classification of breast cancers described above
is still relevant. Evaluation of estrogen receptors (ER),
progesterone receptors (PR), HER2/neu and Ki-67 ex-
pression is considered to be the gold standard in im-
munohistochemical diagnosis of breast cancer. In ca-
ses of triple-negative cancer cytokeratins CK5/6 and
epidermal growth factor receptor 1 or vimentin are
further detected. Knowledge of this biomarker status
enables to determine therapeutic schemes for breast
cancer patients [6, 7, 11, 12]. However, using this
biomarker panel in some cases leads to considerable
difficulties in interpretation of immunohistochemical
reactions. It may be explained by tumor heterogene-
ity, which underlies simultaneous detection of luminal
and basal signs. It is also the reason for distinguishing
the so-called “basal-and-luminal” tumors which are
considered to have cell clones responding to treat-
Submitted: April 21, 2016.
*Correspondence: Fax: +7 3822 41-80-60;
E-mail: olga.sav.1980@gmail.com
Abbreviations used: CK — cytokeratin, EGFR1 — epidermal growth fac-
tor receptor; ER — estrogen receptors; PR — progesterone receptors.
Exp Oncol 2016
38, 2, 122–127
Experimental Oncology 38, 122–127, 2016 (June)38, 122–127, 2016 (June) (June) 123
ment differently. This expression peculiarity deserves
special attention [13].
In addition, detailed analysis of tumor morphologi-
cal structure in different molecular subtypes of breast
cancer is required. Recent data regarding this issue
are scarce and are limited to identification of tumor
histological variant and differentiation grade only.
The aim of the present study was to investigate the
clinical and morphological features of nonspecific inva-
sive breast cancer according to its molecular subtypes.
MATERIALS AND METHODS
Patients. 163 women (mean age — 55.9 ±
11.1 years) with nonspecific invasive breast cancer T1–
4N0–3M0, who were treated in General Oncology De-
partment of Tomsk Cancer Research Institute (Tomsk,
Russia) from January 1999 to January 2007, were
included in the present study (Table 1).
Table 1. Clinicopathological characteristics of breast cancer patients
Characteristics
Tumorsubtype
Luminal A, %
(n = 101)
Luminal B, %
(n = 23)
Triple-nega-
tive, %
(n = 14)
HER2/neu-
positive, %
(n = 25)
Mean age, years 55.9 ± 10.5 53.4 ± 12.1 59.1 ± 11.7 53.7 ± 12.3
Menopausal sta-
tus
66 65 76 64
Tumor localization
Outer quadrants 54 71 63 60
Internal quad-
rants
46 29 37 40
ER
Positive 9 87 0 0
Negative 91 13 100 100
PR
Positive 11 74 0 0
Negative 89 26 100 100
HER2
Positive 0 0 0 100
Negative 100 100 100 0
Ki-67
Expression ≥20% 0 100 52 50
Expression <20% 100 0 48 50
Tumor stage
0 0 0 0 0
I 33 22 4 0
II 54 65 80 64
III 9 13 16 36
IV 4 0 0 0
Tumor size (cm)
T1 (< 2) 52 43 12 14
T2 (2–5) 40 52 84 64
T3 (> 5) 8 5 4 22
Node status
N0 59 61 60 29
N1 24 26 8 43
N2 11 7 20 7
N3 6 6 12 21
Lymph node involvement
Positive 41 39 40 71
Negative 59 61 60 29
Histological grade
Low grade
(I and II)
98 91 96 86
High grade (III) 2 9 4 14
The study was approved by the Local Medical Ethics
Committee, and informed consents were obtained
from all the patients prior to analysis. The patients did
not receive preoperative treatment. 99 (61%) patients
went through radical mastectomy, and 64 (39%) women
underwent sectoral resection of breast cancer with axil-
lary lymph node dissection. In the postoperative period
122 women received adjuvant chemotherapy schemes
CMF (cyclophosphamide + methotrexate + fluorouracil),
FAC (fluorouracil + doxorubicin + cyclophosphamide),
CAX (cyclophosphamide + doxorubicin + capecitabine).
Antiestrogen therapy with tamoxifen was prescribed
for 41 postmenopausal women. Postoperatively 40 pa-
tients were treated with remote gamma-therapy on the
postope rative scar and/or regional lymph outflow zones
in the standard mode. The period of patient monitoring
was from 5 to 10 years.
Methods. Morphological examination of the surgi-
cal specimens was performed by the standard method
using a light microscope “Carl Zeiss Axio Lab.A1”.
The histological type of breast cancer was defined
according to recommendations of the World Health
Organization (Geneva, 2012). The study included only
cases with nonspecific invasive carcinoma. The ma-
lignancy grading was estimated according to the
modified Scarff — Bloom — Richardson grading sys-
tem. Previously we described the diversity of invasive
growth patterns of tumor cells probably resulted in high
intratumor morphological heterogeneity, which (e.g.
in breast cancer) is represented by different morpho-
logical structures: tubular, alveolar, trabecular, solid
structures (patterns), and discrete (small) groups
of tumor cells [14–17].
Expression of hormone receptors and oncoproteins
was assessed by immunohistochemistry: DAKO Clone
1D5 was used for ER, DAKO Clone PgR 636 — for
PR and DAKO Clone MIB-1 — for Ki-67. Expression
of sex hormone receptors was determined by Histo-
Score. Assessment of Ki-67 was based on the percen-
tage of positive cell nuclei in each variant of paren-
chymal component structures of primary nonspecific
invasive carcinoma, regardless of staining intensity.
HER2/neu protein overexpression was determined
by immunohistochemistry: DAKO polyclonal rabbit
anti-human antibodies were used for c-erB-2 (dilution
1:500) and it was semi-quantitated based on staining
of the cytoplasmic membrane rather than cytoplasm it-
self. HER2/neu overexpression was rated negative (0+
and 1+), indeterminate (2+) or positive (3+). In cases
of 2+, women were not included in the study. The posi-
tivity cut-off value for HER2/neu was set at 30%.
For the purpose of the present study breast
cancer was classified into four subtypes based
on estrogens and progesterone hormone receptors,
HER2 and Ki-67 values: luminal A (ER+PR+HER2–,
Ki-67 expression < 20%), luminal B (ER+PR+HER2–,
Ki-67 expression ≥ 20%), HER2/neu-positive over-
expression (ER–PR–HER2+) and triple-negative
(ER–PR–HER2–). Luminal A type of breast cancer was
detected in 101 women, luminal B type — in 23 women,
overexpression of HER2/neu — in 14 women and triple-
negative cancer — in 25 women.
The presence of metastatic lesions was assessed
in the lymph nodes, and the number of lymph nodes
with metastases was counted. Information about the
frequency and timing of hematogenous metastasis was
received from patient case histories or outpatient cards.
124 Experimental Oncology 38, 122–127, 2016 (June)
Statistical analysis. Qualitative variables were
expressed as “n” and percentage, whereas quantita-
tive variables were expressed as their mean (M) value
and standard deviation (SD). In order to compare
qualitative variables, the χ2-test was implemented.
Mean values were compared using ANOVA. Statisti-
cal significance was set at p < 0.05, using two-tail
approach. Statistical analysis was performed using
STATISTICA 8.0 for Windows (StatSoft Inc., USA).
RESULTS
Such clinical parameters as age and menstrual
status of women were analyzed in the present study.
The mean age of patients with various breast cancer
molecular subtypes did not differ (luminal A sub-
type — 55.9 ± 10.5 years, luminal B subtype — 53.4 ±
12.1 years, triple-negative cancer — 59.1 ± 11.7 years
and HER2/neu overexpressing tumors — 53.7 ±
12.3 years). In all the investigated groups of patients
menopausal status was as follows: in patients with
luminal A subtype — in 66% of cases; with luminal
B subtype — in 65% of cases; with triple-negative
cancer — in 76% of cases; with HER2/neu overex-
pression — in 64% of cases. Unilateral lesion of the
breast was detected in most cases. Tumors were more
frequently localized in the outer quadrants (luminal
A tumors — 54%, luminal B tumors — 71%, triple-
negative cancer — 63%, HER2/neu overexpressing tu-
mors — 60%). The detection rate of multicenter tumor
growth did not differ in all the patient groups as well
(luminal A — 21%, luminal B — 22%, triple-negative
cancer — 13% HER2/neu overexpression — 21%).
Small tumors (< 2 cm in diameter) were more pre-
valent in patients with luminal cancer types, whereas
larger tumors were typical of patients with triple-nega-
tive and HER2/neu overexpressing tumors (Fig. 1).
0
20
40
60
80
100
Luminal A Luminal B Triple-negative HER2/neu-
positive
Tumor size
Nu
m
be
r o
f p
at
ie
nt
s,
%
<2 cm
2–5 cm
>2 cm
52
43
12 14
40
52
84
64
8 5 4
22
Fig. 1. Tumor size in patients with various molecular breast
cancer subtypes
The morphological examination of the primary
tumor in most cases revealed the second grade of ma-
lignancy: in 90% of cases in luminal A breast cancer,
in 80% of cases in luminal B subtype, in 95% of cases
in triple-negative and in 86% of cases in HER2/neu
overexpressing tumors. The frequency of ductal struc-
ture detection did not differ in the investigated groups.
The histological investigation of primary tumor infil-
trative component revealed a number of features spe-
cific to each molecular breast cancer subtype. It turned
out that the infiltrative component in luminal A and
B molecular subtypes was very diverse, all five types
of the structures classified by us (alveolar, trabecular,
tubular, solid and discretely spaced groups of tumor
cells) were detected in them more often (in 13 and 22%
of cases, respectively). In the meantime, histological
monomorphic neoplasms were detected in triple-
nega tive and HER2/neu overexpressing tumors
(in 16 and 14% of cases, accordingly), the infiltrative
component in them had only one variant of structures.
The received data demonstrate different grades of in-
tratumoral morphological heterogeneity in women with
different breast cancer molecular subtypes (Table 2).
Table 2. Number of different structure types in the infiltrative component of non-
specific invasive carcinoma according to the molecular subtypes of breast cancer
Number of struc-
ture types in the
infiltrative com-
ponent
Molecular subtype, n (%)
Luminal A
(n = 101)
Luminal B
(n = 23)
Triple-nega-
tive (n = 25)
HER2/neu-
positive
(n = 14)
1 4/101
(4)
1/23
(4)
4/25
(16)
р1 = 0.01
р2 = 0.08
2/14
(14)
р1 = 0.05
2 17/101
(17)
4/23
(17)
6/25
(24)
4/14
(29)
3 45/101
(44)
8/23
(35)
8/25
(32)
5/14
(36)
4 22/101
(22)
5/23
(22)
6/25
(24)
3/14
(21)
5 13/101
(13)
5/23
(22)
1/25
(4)
р2 = 0.03
0/14
(0)
р1 = 0.07
р2 = 0.03
Note: p1 — compared with luminal A group; p2 — compared with luminal B group.
In patients with triple-negative and HER2/neu over-
expressing cancer the tubular structures were observed
rarely: in 16 and 21% of cases as opposed to luminal
A (45%; p = 0.004 and p = 0.004, accordingly) and
in luminal B (52%; p = 0.005 and p = 0.03, accordingly)
tumor subtypes. Our results indirectly indicate low
differentiation grade of triple-negative and HER2/neu
overexpressing tumors and do not conflict with data
of other researchers about low-grade triple-negative
cancer [18]. The other tumor structures (alveolar, tra-
becular, solid and discretely spaced groups of cells)
were detected with approximately identical frequency.
The morphological study of the stromal tumor com-
ponent showed that stromal fibrosis with parenchymal
component ≤ 10% did not take place in triple-negative
tumors in contrast to luminal A (13%; p = 0.02), luminal
B (9%; p = 0.06) and HER2/neu overexpressing (14%;
p = 0.03) cancer subtypes. More significant inflam-
matory stroma infiltration was found in triple-negative
breast cancer (36%) as opposed to luminal A (8%; p =
0.0002) and luminal B (13%; p = 0.03) subtypes.
The study of tumor cell proliferative activity in different
breast cancer molecular subtypes showed that Ki-67 ex-
pression in luminal A tumors was 2.00 (1.00–5.00)%,
in luminal B tumors — 20.00 (2.30–21.00)%, in triple-
negative cancer subtype — 2.00 (1.00–3.00)% and
in HER2/neu-positive tumors — 2.50 (1.50–5.15)%.
Lymphogenous metastases were more frequently
(in 71% of cases) detected in women with HER2/neu
overexpressing cancer subtype in comparison with
Experimental Oncology 38, 122–127, 2016 (June)38, 122–127, 2016 (June) (June) 125
luminal A (41%; p = 0.01), luminal B (39%; p = 0.03) and
triple-negative tumors (40%; p = 0.03). The number
of metastatic lymph nodes in women with luminal A,
luminal B and HER2/neu overexpressing tumors did
not differ (p > 0.05). Metastatic lesion of four and more
lymph nodes (criteria N2–3) was more often diagnosed
in patients with triple-negative cancer subtype (Fig. 2).
The average number of regional lymph nodes involved
in the metastatic process did not differ among various
molecular subtypes of breast cancer (p > 0.05).
58
67
20
60
42
33
80
40
0
20
40
60
80
100
Luminal A Luminal B Triple-negative HER2/neu-
positive
Node status
N1
N2–3
Nu
m
be
r o
f p
at
ie
nt
s,
%
Fig. 2. Nodal metastasis rate in women with various molecular
breast cancer subtypes. p1 = 0.01 — compared with lumi-
nal A group; p2 = 0.03 — compared with luminal B group; p3 =
0.04 — compared with HER2/neu-positive group
There was no relation between the lymphogenous
metastatic process and patient’s age. The rate of lym-
phogenous metastasis was studied in various molecu-
lar breast cancer subtypes in the groups of women
with different menstrual status. It was revealed that
lymphogenous metastases did not occur (0%) in the
investigated patients with luminal B subtype and intact
menstrual function, while in postmenopausal women
it was detected in 60% of cases (p = 0.005).
Research of lymphogenous metastatic features
depending on the morphological structure of primary
tumor tissue was carried out. Among patients with
luminal A and luminal B subtypes, lymphogenous me-
tastases were more prevalent in cases with more varied
morphological tumor constitution, which infiltrative com-
ponent consisted of three or more different structure
types. Such regularity was not observed in triple-nega-
tive and HER2/neu overexpressing tumors (Table 3).
Table 3. Lymphogenous metastasis rate in patients with various molecu-
lar breast cancer subtypes according to the number of different structure
types in the infiltrative tumor component
Number of struc-
ture types in the
infiltrative com-
ponent
Molecular subtype, n (%)
Luminal A
(n = 101)
Luminal B
(n = 23)
Triple-nega-
tive (n = 25)
HER2/neu-
positive
(n = 14)
1 0/41 (0) 0/9 (0) 1/10 (10) 1/10 (10)
2 3/41 (7) 0/9 (0) 3/10 (30) 3/10 (30)
3 21/41 (51)
р1 < 0.001
р2 < 0.001
3/9 (33)
р1 = 0.03
р2 = 0.03
4/10 (40) 3/10 (30)
4–5 17/41 (42)
р1 < 0.001
р2 < 0.001
6/9 (67)
р1 = 0.004
р2 = 0.004
2/10 (20) 3/10 (30)
Note: p1 — compared with patients with one structure type in the infiltrative
component; p2 — compared with patients with two structure types in the in-
filtrative component.
No significant distinctions in the incidence of hema-
togenous metastasis depending on patients’ age, men-
strual status, size and grade of tumors were revealed
(p > 0.05) in any molecular breast cancer subtype.
Hematogenous metastasis did not depend on the
morphological structure of the carcinoma infiltrative
component, the state of tumor stroma as well as the
proliferative activity in all the investigated groups.
In women with luminal cancer subtypes the probability
of hematogenous metastasis was not associated with
any percentage of ER+- and PR+-cells or ER and PR ex-
pression index (on the Histo-Score scale).
The dependence of distant metastasis on status
of regional lymph nodes was found only in patients with
triple-negative breast cancer: all women with tumor
lymph node lesion had hematogenous dissemination
process (χ2 = 9.3; p = 0.002) at various stages of moni-
toring. Such regularity was not observed in other
breast cancer subtypes (Fig. 3).
41
37
25
70
45
50
100
75
0
20
40
60
80
100
120
Luminal A Luminal B Triple-negative HER2/neu-
positive
N0
N+
Node status
Nu
m
be
r o
f p
at
ie
nt
s,
%
Fig. 3. Hematogenous dissemination rate according to the
pre sence of lymph node metastases in women with various
molecular breast cancer subtypes; p = 0.002 — compared with
triple-negative patients with N0 node status
DISCUSSION
The present study revealed that various molecular
subtypes of breast cancer differ in the morphological
structure, the expression profile of the primary tumor
and the rate of lymphogenous and hematogenous
metastasis. It should be emphasized that these diffe-
rences are found within one nosological form of non-
specific invasive breast cancer (ICD-O code 8500/3).
In our opinion one important distinction between
the molecular subtypes of breast cancer is the promi-
nence of morphological heterogeneity. According
to our research, phenotypic drift takes place in non-
specific invasive cancer. It consists in the increase
in time of various types of breast cancer infiltrative
component structures. It turned out that luminal sub-
types were often characterized by the most prominent
heterogeneity. At the same time in triple-negative and
HER2/neu overexpressing tumors the cases with one
type of infiltrative component structures prevailed [15].
It appears that the tumor is growing faster in triple-
negative and HER2/neu positive breast cancers than
in the luminal subtypes: a series of indirect signs indi-
cate it. Cases with one variant of infiltrative component
structures are more common in triple-negative and
HER2/neu positive breast cancers than in the luminal
126 Experimental Oncology 38, 122–127, 2016 (June)
subtypes. The combination of minimal morphological
structure heterogeneity with greater tumor size and
greater parenchymal component volume in triple-
negative cancer can be taken as an argument in favor
of accelerated tumor growth in this subtype in com-
parison with the luminal ones.
Significant distinctions between various molecu-
lar breast cancer subtypes related to lymphogenous
metastasis. In luminal subtypes of breast cancer, lym-
phogenous metastases were more frequent at higher
morphological tumor heterogeneity. Apparently, higher
morphological tumor heterogeneity, reflecting pheno-
typic diversity of tumor elements, makes emergence
of a cell clone with lymphatic metastasis capacity
more probable.
It was found that in patients with luminal B sub-
type the rate of lymphogenous metastases depends
on the menstrual status being significantly higher
in menopausal women. We have previously shown that
invasive ductal breast carcinoma in women older than
35 years with intact menstrual function has significant
clinicopathological and molecular genetic features
as opposed to menopausal patients [19].
Triple-negative invasive breast cancer particularly
differs in the parameters of lymphogenous metastasis.
The lesions of four or more lymph nodes are mostly
diagnosed exactly in these patients. The interest
in studying lymphogenous metastatic mechanisms
does not fade away. The search for the informative
parameters of this process associated with the overall
survival rate continues. It was agreed that an unfavo-
rable prognostic sign is high percentage of lymph node
lesions [20, 21]. However, until now the causes and
the mechanisms of involvement of different number
of lymph nodes in the metastatic process are unknown.
The prediction of the likelihood of axillary lymph
node metastatic lesions in breast cancer in cases where
sentinel lymph node is affected with metastases is a dif-
ficult problem. This problem has not been solved despite
creation of several nomogram variants aiming to predict
the lesion of non-sentry lymph nodes upon metastasis
detection in the sentinel node [22, 23]. In this regard, the
regular involvement of a large number of lymph nodes
in the metastatic process in some patients with triple-
negative breast cancer may be a promising model sys-
tem for studying widespread lymphogenous metastasis.
Another feature of triple-negative breast cancer
is obvious relation between lymphogenous and hema-
togenous metastasis. Hematogenous dissemination
was detected in all cases with lymph node meta-
static lesion only in this molecular subtype. For other
molecular subtypes of breast cancer the possibility
of hematogenous metastasis did not depend on the
presence of lymphogenous metastasis.
The explanation of these distinctions may be found
in S. Paget’ “Seed and Soil” concept [24]. It can
be suggested that the emergence of tumor cell clones
with the ability to metastasize (“seed”) in triple-
negative breast cancer subtype coincides with the
formation of optimal cellular and molecular microen-
vironment in the regions of hematogenous metastasis
development (“soil”). Moreover, tumor cells are ca-
pable of adapting not only to the premetastatic niches
in the regional lymph nodes, but, probably, to the areas
of hematogenous metastases formation as well.
Apparently, triple-negative nonspecific invasive
breast cancer may be a suitable model for studying
the link between lymphogenous and hematogenous
metastasis. The environment for emergence of “seed”
and “soil” has more independent nature in luminal
and HER2/neu positive breast tumors than in triple-
negative cancer subtype.
Thus, different molecular genetic subtypes of breast
cancer are characterized by significant morphologi-
cal diversity and severity of intratumor morphological
heterogeneity, which may be associated with regularity
of lymphogenous and hematogenous metastasis.
ACKNOWLEDGMENTS
This work was supported by the Russian Founda-
tion for Basic Research (project No. 15–34–20864 and
16–34–00415).
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