Clinical and immunohistochemical features of primary breast cancer and metachronous ovarian and endometrial tumors
The aim of the study was to assess the patterns of development of metachronous cancer (endometrial cancer, EC, and ovarian cancer, OC) in breast cancer (BC) patients dependent of receptor phenotype of breast tumors. Materials and Methods: In the study, 63 patients with ВС, who developed metachronous...
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irk-123456789-1455692019-01-25T01:23:07Z Clinical and immunohistochemical features of primary breast cancer and metachronous ovarian and endometrial tumors Kryzhanivska, A.E. Dyakiv, I.B. Kyshakevych, I. Original contributions The aim of the study was to assess the patterns of development of metachronous cancer (endometrial cancer, EC, and ovarian cancer, OC) in breast cancer (BC) patients dependent of receptor phenotype of breast tumors. Materials and Methods: In the study, 63 patients with ВС, who developed metachronous EC (n = 47) or OC (n = 16) were enrolled. Expression of estrogen receptor (ER), progesterone receptor (PR), HER/2neu was assessed using immunohistochemical approach. Results: BC in patients with metachronous EC and OC was characterized by a different frequency of molecular subtypes with the dominance of luminal A (36%) and B (43%) subtypes. In primary BC, we have established a correlation between ER expression and regional lymph nodes status (r = −0.50, p < 0.05); negative correlation between HER2/neu expression and tumor stage (r = −0.48, p < 0.05); between the molecular subtype of BC and its size (r = −0.33, p <0.05), the molecular subtype of primary BC and metastases in regional lymph nodes (r = 0.27, p <0.05). In the patients with luminal subtype BC metachronous tumors developed with the highest frequency (OC — 50%, EC — 50%). After treatment of primary BC metachronous tumors developed at different period: EC (22.2%) — most often in 3–5 years, OC (11.0%) — after 10 years and more. Conclusion: Our data evidence on the clinical significance of the individual characteristics of the BC, especially its molecular subtype, and the need to calculate the personalized risk of development of metachronous tumors of the reproductive system in patients with the BC. Key Words: breast cancer, metachronous endometrial cancer, metachronous ovarian cancer, hormonal receptors, HER2/neu, immunohistochemistry. 2018 Article Clinical and immunohistochemical features of primary breast cancer and metachronous ovarian and endometrial tumors / A.E. Kryzhanivska, I.B. Dyakiv, I. Kyshakevych // Experimental Oncology. — 2018 — Т. 40, № 2. — С. 124–127. — Бібліогр.: 11 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/145569 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions Kryzhanivska, A.E. Dyakiv, I.B. Kyshakevych, I. Clinical and immunohistochemical features of primary breast cancer and metachronous ovarian and endometrial tumors Experimental Oncology |
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The aim of the study was to assess the patterns of development of metachronous cancer (endometrial cancer, EC, and ovarian cancer, OC) in breast cancer (BC) patients dependent of receptor phenotype of breast tumors. Materials and Methods: In the study, 63 patients with ВС, who developed metachronous EC (n = 47) or OC (n = 16) were enrolled. Expression of estrogen receptor (ER), progesterone receptor (PR), HER/2neu was assessed using immunohistochemical approach. Results: BC in patients with metachronous EC and OC was characterized by a different frequency of molecular subtypes with the dominance of luminal A (36%) and B (43%) subtypes. In primary BC, we have established a correlation between ER expression and regional lymph nodes status (r = −0.50, p < 0.05); negative correlation between HER2/neu expression and tumor stage (r = −0.48, p < 0.05); between the molecular subtype of BC and its size (r = −0.33, p <0.05), the molecular subtype of primary BC and metastases in regional lymph nodes (r = 0.27, p <0.05). In the patients with luminal subtype BC metachronous tumors developed with the highest frequency (OC — 50%, EC — 50%). After treatment of primary BC metachronous tumors developed at different period: EC (22.2%) — most often in 3–5 years, OC (11.0%) — after 10 years and more. Conclusion: Our data evidence on the clinical significance of the individual characteristics of the BC, especially its molecular subtype, and the need to calculate the personalized risk of development of metachronous tumors of the reproductive system in patients with the BC. Key Words: breast cancer, metachronous endometrial cancer, metachronous ovarian cancer, hormonal receptors, HER2/neu, immunohistochemistry. |
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Article |
| author |
Kryzhanivska, A.E. Dyakiv, I.B. Kyshakevych, I. |
| author_facet |
Kryzhanivska, A.E. Dyakiv, I.B. Kyshakevych, I. |
| author_sort |
Kryzhanivska, A.E. |
| title |
Clinical and immunohistochemical features of primary breast cancer and metachronous ovarian and endometrial tumors |
| title_short |
Clinical and immunohistochemical features of primary breast cancer and metachronous ovarian and endometrial tumors |
| title_full |
Clinical and immunohistochemical features of primary breast cancer and metachronous ovarian and endometrial tumors |
| title_fullStr |
Clinical and immunohistochemical features of primary breast cancer and metachronous ovarian and endometrial tumors |
| title_full_unstemmed |
Clinical and immunohistochemical features of primary breast cancer and metachronous ovarian and endometrial tumors |
| title_sort |
clinical and immunohistochemical features of primary breast cancer and metachronous ovarian and endometrial tumors |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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2018 |
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Original contributions |
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http://dspace.nbuv.gov.ua/handle/123456789/145569 |
| citation_txt |
Clinical and immunohistochemical features of primary breast cancer and metachronous ovarian and endometrial tumors / A.E. Kryzhanivska, I.B. Dyakiv, I. Kyshakevych // Experimental Oncology. — 2018 — Т. 40, № 2. — С. 124–127. — Бібліогр.: 11 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
AT kryzhanivskaae clinicalandimmunohistochemicalfeaturesofprimarybreastcancerandmetachronousovarianandendometrialtumors AT dyakivib clinicalandimmunohistochemicalfeaturesofprimarybreastcancerandmetachronousovarianandendometrialtumors AT kyshakevychi clinicalandimmunohistochemicalfeaturesofprimarybreastcancerandmetachronousovarianandendometrialtumors |
| first_indexed |
2025-07-10T21:58:27Z |
| last_indexed |
2025-07-10T21:58:27Z |
| _version_ |
1837298849755955200 |
| fulltext |
124 Experimental Oncology 40, 124–127, 2018 (June)
CLINICAL AND IMMUNOHISTOCHEMICAL FEATURES
OF PRIMARY BREAST CANCER AND METACHRONOUS OVARIAN
AND ENDOMETRIAL TUMORS
A.E. Kryzhanivska, I.B. Dyakiv*, I. Kyshakevych
Ivano-Frankivsk National Medical University, Ivano-Frankivsk 76018, Ukraine
The aim of the study was to assess the patterns of development of metachronous cancer (endometrial cancer, EC, and ovarian
cancer, OC) in breast cancer (BC) patients dependent of receptor phenotype of breast tumors. Materials and Methods: In the
study, 63 patients with ВС, who developed metachronous EC (n = 47) or OC (n = 16) were enrolled. Expression of estrogen re-
ceptor (ER), progesterone receptor (PR), HER/2neu was assessed using immunohistochemical approach. Results: BC in patients
with metachronous EC and OC was characterized by a different frequency of molecular subtypes with the dominance of luminal
A (36%) and B (43%) subtypes. In primary BC, we have established a correlation between ER expression and regional lymph
nodes status (r = −0.50, p < 0.05); negative correlation between HER2/neu expression and tumor stage (r = −0.48, p < 0.05);
between the molecular subtype of BC and its size (r = −0.33, p <0.05), the molecular subtype of primary BC and metastases
in regional lymph nodes (r = 0.27, p <0.05). In the patients with luminal subtype BC metachronous tumors developed with the
highest frequency (OC — 50%, EC — 50%). After treatment of primary BC metachronous tumors developed at different period:
EC (22.2%) — most often in 3–5 years, OC (11.0%) — after 10 years and more. Conclusion: Our data evidence on the clinical
significance of the individual characteristics of the BC, especially its molecular subtype, and the need to calculate the personalized
risk of development of metachronous tumors of the reproductive system in patients with the BC.
Key Words: breast cancer, metachronous endometrial cancer, metachronous ovarian cancer, hormonal receptors, HER2/neu,
immunohistochemistry.
Over recent years, breast cancer (BC) has re-
mained the most common malignant disease among
women both in Ukraine and in most countries of West-
ern Europe and America. Analyzing the survival rates
of patients with BC in recent decades, one may
conclude that improvement of BC treatment results
is achieved. According to Surveillance, Epidemiology
and End Results data, the statistical database of the
National Cancer Institute in the USA, 5-year survival
constitutes 83.4–98.4% in case of localized forms
of BC and 23.3% in case of metastatic BC. Such results
have been achieved due to a personified approach
to BC treatment [4].
The emergence of metachronous tumors, namely
ВС, еndometrial cancer (EC) and ovarian cancer (OC),
has become particularly relevant over the last decade.
Numerous studies have shown that BC is a hormone-
dependent cancer associated with a chronic effect
of estrogens related to an impaired estrogen-proges-
terone balance. According to the estrogen theory, es-
trogens and their receptors play an essential role in the
initiation and promotion of the process of malignant
transformation, since hyperestrogenism is one of the
factors modulating genes expression leading to dys-
regulation of cellular signaling and the development
of metachronous BC [1–4].
A well-known fact is that BC represents a hetero-
geneous tumor group. According to the molecular
genetic classification, four subtypes of BC are dis-
tinguished: luminal A, luminal B, HER-2/neu positive,
basal or triple-negative. According to modern studies,
the presence of steroid hormones receptors is an im-
portant biological feature of malignant tumors and can
determine the course of the disease. In addition, the
disruption of hormonal balance in the body of women
is also associated with the ЕС and ОС onset. Clinical
course of hormone related tumors depends on de-
crease or loss of expression of both progesterone
receptors (PR) and estrogen receptors (ER), which
manifests itself in a greater aggressiveness of the
tumor process: more invasion, metastasis and unfa-
vorable course of disease [5–7]. But at present time,
no clear relation between the clinical-biological fea-
tures of BC receptor phenotype and the development
of subsequent metachronous hormone related can-
cers has been established. The above mentioned data
suggest the expediency of studying the ER, PR and
HER-2/neu status in patients with primary BC tumors
and metachronous OC and EC. This will allow to assess
the receptor status in these neoplasms and evaluate
its significance in the course of the tumor disease.
MATERIALS AND METHODS
In the study, 63 patients with BC, in which, after
the completion of treatment, another oncological
disease has developed, were enrolled: EC deve-
loped in 47 patients, OC — in 16 patients. The study
did not include BC patients with BC progression
or metastasis. The verification of BC and the second
oncological disease was carried out by histological
examination of the biopsy and/or surgical material
of biological specimens. The clinical diagnostics
of BC was performed according to the TNM clas-
Submitted: December 5, 2017.
*Correspondence: E-mail: irynadjakiv@ukr.net
Abbreviations used: BC — breast cancer; EC — endometrial can-
cer; ER — estrogen receptor; OC — ovarian cancer; PR — proges-
terone receptor; RLN — regional lymph nodes.
Exp Oncol 2018
40, 2, 124–127
Experimental Oncology 40, 124–127, 2018 (June) 125
sification (2002) and the diagnostics of second
oncological disease was carried out by histologi-
cal examination (World Health Organization, 2003)
of the biopsy and/or surgical material of biological
specimens.
The patients received combined treatment: sur-
gical, chemotherapeutic, radiological, hormonal
therapy (if necessary). 86% of patients received
hormone therapy with tamoxifen (20 mg once a day
for 5 years). All patients were cured at the Communal
Institution “Precarpathian Clinical Cancer Center”
from 1986 to 2016, treatment, according to the order
of the Ministry of Health of Ukraine No. 396 “On Ap-
proval and Implementation of Medical-Technological
Documents for the Standardization of Medical Assis-
tance of Cancer Patients”. The study was approved
by the Ethics Commission of Ivano-Frankivsk National
Medical University (conclusion No. 83).
To assess ER, PR and HER2/neu expression
in the samples of BC, EC and OC, 4 µm histologic
slides were prepared from paraffin blocks of tumors.
Immunohistochemical study was performed using
the following monoclonal antibodies: antiER — clone
1D5, antiPR — clone PgR636, antiHER/2neu — clone
c-erbB-2 (Dako Cytomation, Denmark). The degree
of immunohistochemical reaction was assessed
as «+++» — strong, «++» — moderate, «+» — low
or no expression (0). The number of cells with
> 10% with a strong and moderate expression was
considered as positive expression of the examined
markers.
The statistical analysis of the data was performed
using Microsoft® Office Excel® 2007 and Statis-
tica v.6.1 (Statsoft Inc., USA) programs for variation
statistics, correlation, regression, multiple correla-
tion-regression analysis. Changes were considered
to be significant at p < 0.05.
RESULTS AND DISCUSSION
The conducted research is based on the results
of clinical and immunohistochemical investigation
of 63 patients with BC, in which after the comple-
tion of treatment, another oncological disease was
arized (ЕС or ОС). The age of BC patients varied
from 25 to 83 years (at average 53.9 ± 11.8 years)
(Table 1). BC cases were assessed according
to the TNM classification (2002) (Table 2), and
BC was mostly of stages I and II (27.0 and 50.8%,
respectively), and stage III (19.0%). All 63 patients
with BC were operated because of the second
oncological disease: EC developed in 47 patients,
OC — in 16 patients.
Table 1. Distribution of patients with primary BC by age
Age, years n = 63 100%
25 1 1.6
30–39 6 9.5
40–49 12 19.0
50–59 18 28.6
60–69 15 23.8
70–79 9 14.3
80–83 2 3.3
Total 63 100.0
Average age 53.9 ± 11.8
Table 2. Distribution of patients with primary BC according to TNM clas-
sification (2002)
Stage of primary BC n %
I stage: Т1N0М0 17 27.0
II stage: T0–3N0–1M0 32 50.8
III stage: T0–4N0–3M0 12 19.0
IV stage: T0–4N0–3M1 2 3.2
Total 63 100.0
All patients underwent surgical treatment. Mastec-
tomy by Madden was performed in 36 (57.2%) patients
with BC, mastectomies by Halstead — in 14 (22.2%),
and by Petit — in 9 (14.3%). Organ-preserving opera-
tion (quadrantectomy) was done in 4 (6.3%) patients
(Table 3).
Table 3. Distribution of patients with primary BC according to surgical
treatment
Surgical trearment n %
Quadrantectomy 4 6.3
Mastectomy by Maden 36 57.2
Mastectomy by Petit 9 14.3
Mastectomy by Halsted 14 22.2
Total 63 100.0
After surgical treatment 86% of patients received
hormone therapy (tamoxifen 20 mg once a day for
5 years). Metachronous EC occurred mainly in the pe-
riod from 3 to 5 years after the treatment of BC (14 pa-
tients (22.2%)), and metacharonic OC — in period
longer than 10 years (in 7 patients (11.0%)) (Table 4).
Table 4. Period of development of metachronous ЕС and OC
Cases of development of metachronous tumors after treatment
of primary BC (n = 63/100%)
Terms after treatment
of BC
EC, n (%)
47 (74.6)
OC, n (%)
16 (25.4)
Up to 1 year 6 (9.5) 1 (1.6)
From 1 to 3 years 5 (7.9) 2 (3.2)
From 3 to 5 years 14 (22.2) 3 (4.8)
From 5 to 10 years 10 (15.9) 3 (4.8)
More than 10 years 12 (19.1) 7 (11.0)
The stage of the metachronous tumors was the fol-
lowing: EC was of stage I in 34 (54.0%) cases, stages
II and III — in 9 (14.3%) and 4 (6.3%) cases, respec-
tively; OC — of stage III in 8 (12.7%) cases, stage II —
in 5 (7.9%) cases, and stage I — in 3 (4.8%) patients.
According to the immunohistochemical features,
the breast tumors were of 4 molecular subtypes: lu-
minal A subtype constituting 36%; luminal B subtype
with the highest frequency constituting 43%; Her2/
neu-positive subtype — 7%; and basal-like subtype
(or triple-negative subtype, ER−PR−Hеr2/neu−) —
14% cases (Table 5). In the patients with luminal
subtype BC metachronous tumors developed with the
highest frequency (OC — 50%, EC — 50%).
One of the most important clinical characteristics
is the presence of metastases in RLN or organs distant
from the tumor. In the majority of patients with BC they
were absent regardless of the tumor molecular sub-
type: luminal A — 67.9%, luminal B — 68.6%, triple
negative — 85.7%.
Statistical analysis of the data showed that there
is a significant correlation between ER expression
and RLN status (r = −0.50, p < 0.05); expression
of HER2/neu and the stage of the disease (r = −0.48,
p < 0.05). The relation between the molecular subtype
of the primary BC with its size (r = −0.33, p < 0.05) and
126 Experimental Oncology 40, 124–127, 2018 (June)
the presence of metastases in RLN (r = 0.27, p < 0.05)
were also found.
It seemed appropriate to analyze further the re-
lation between ER, PR and HER2/neu expression
in these patients with the clinical and pathological
features of tumor growth which are important for the
estimation of the disease prognosis: stage, tumor size,
metastases of RLN, BC molecular subtype.
The largest number of ER+ and HER2/neu-positive
tumors was detected in patients with stage I (100% and
100%, respectively) of both BC and EC in comparison
with stages II and III of BC and EC (83 and 54%, respec-
tively); in patients with BC and EC of stage II or III —
67 and 33%, respectively. The significant difference
in PR expression depending on the stage of the tumor
process was not detected. The statistical analysis
of the data indicated the existence of an inverse re-
lationship between ER, Her2/neu expression and the
disease stage. Positive expression of steroid hormone
receptors was detected in 12 and 50% of patients with
stages II and III of metachronous OC.
Recurrence-free and overall survival is in reverse
correlation with RLN metastases [7–11]. Taking this
into consideration, we conducted a research on the
relation between the receptor status of BC, EC and
OC tumor cells and metastasis. ER expression (100%
of tumor tissue samples) was observed in patients
without metastases in RLN. HER2/neu expression
was noted in somewhat lower number of cases (83%).
Even less number of studied tumors samples (67%)
were PR positive.
In case of RLN metastases, different frequency
of expression of steroid hormone receptors in the
primary tumors was noted. Namely, ER and PR ex-
pression was detected in 75% of cases in the group
of patients with RLN N1 status. This was higher in com-
parison with patients with RLN N3 (50%). The statistical
analysis showed the existence of an inverse correla-
tion between RLN status and ER, PR and HER2/neu
expression in a primary tumor.
The relation between the receptors expression (ER,
PR) and HER2/neu and the age of patients in case
of secondary oncology onset was also analyzed.
In particular, the age of patients with positive recep-
tor status (ER+PR+HER2/neu+) was higher in case
of secondary oncology disease onset in comparison
with the absence of expression of these molecules.
Thus, secondary cancer occurred at the age
of 63.9 years in patients with ER-positive BC. This was
about 6 years higher on average compared to a group
of patients (57.5 years) with ER-negative primary
tumors. The same regularity was noted in patients
with PR and HER-positive BC. It should be noted that
the development of metachronous cancer occurred
10 years later in patients with HER2/neu-positive
BC in comparison with patients with HER2/neu-ne-
gative BC (Table 6).
Table 6. Expression of immunohistochemical markers in tumor tissue of pri-
mary ВС and average age of development of metachronous ЕС or ОС
Markers Positive expression of markers Negative expression
Average age of patients, years
RE 63.9 ± 1.2 57.5 ± 1.0
RP 64.2 ± 4.1 60.2 ± 3.5
HER2/neu 67.3 ± 2.2 57.9 ± 2.7
The statistical analysis of the data indicated the
correlation between ER expression and the stage of the
tumor process, RLN status, HER2/neu expression and
RLN status in BC patients. The relation between the
molecular subtype of BC and metastasis in RLN was
also detected.
CONCLUSION
The BC cases with metachronous EC and OC are
characterized by a different frequency of BC molecular
subtypes with the dominance of luminal A (36%) and
B (43%) subtypes. Statistical analysis of the obtained
results revealed correlation between the different
clinical characteristics of the BC. In the primary
BC, we have established a correlation between
ER expression and RLN status (r = −0.50, p < 0.05);
negative correlation between HER2 / neu expression
and stage (r = −0.48, p <0.05); between the molecular
subtype of BC and its size (r = −0.33, p < 0.05), the
molecular subtype of primary BC and metastases
in RLN (r = 0.27, p < 0.05). The highest frequency
of metastases is noted in patients with triple negative
BC. In the patients with luminal subtype BC metachro-
nous tumors developed with the highest frequency.
Metachronous tumors developed at different period
after treatment of primary tumors: EC (22.2%) —
most often in 3–5 years, OS (11%) — most often after
10 years or more. Our data evidence on the clinical
significance of the individual characteristics of the
BC, especially its molecular subtype and the need
to calculate the personalized risk of development
of metachronous tumors of the reproductive system
in patients with the BC.
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Table 5. The frequency of molecular subtypes of primary tumors and meta-
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Patients (n/%)
Molecular subtype, n = 63
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