|Year : 2022 | Volume
| Issue : 2 | Page : 210-218
Evaluation of immunohistochemical expression of topoisomerase II alpha protein in patients with breast cancer and its correlation with different prognostic factors
Mohammed Saeed Sharif Fadhil Al-Alawchi1, Haider Abdul Ridha Alkafaji2
1 Department of Histopathology, Iraqi Board for Medical Specialties, Babil Center, University of Babylon, Iraq
2 Department of Pathology, Babil College of Medicine, University of Babylon, Iraq
|Date of Submission||14-Dec-2021|
|Date of Acceptance||08-Feb-2022|
|Date of Web Publication||30-Jun-2022|
Mohammed Saeed Sharif Fadhil Al-Alawchi
Department of Histopathology, Iraqi Board for Medical Specialties, Babil Center
Source of Support: None, Conflict of Interest: None
Background: There are indications to support the knowledge about the prognosis of breast cancer. One of these markers is regarded as a prognostic factor and related to the proliferation rate. Topoisomerase IIα (TOP2A), encoded by the TOP2A gene, is a molecular target for anthracycline therapy. Aims: The aim of this article is to establish any association of the status of topoisomerase IIa immunohistochemistry with different prognostic clinicopathological and molecular parameters in breast cancer. Settings and Design: A cross-sectional retrospective study was carried out in the Department of Pathology and Forensic Medicine, Faculty of Medicine, Babylon University, during the period from January 2020 through December 2020. Materials and Methods: Fifty cases with invasive breast carcinoma have been obtained from surgical modified radical mastectomy specimens from the Laboratory of Histopathology in Al-Kafeel Specialized Hospital, Karbala for the last 3 years (2017–2019). Different clinicopathological variables were estimated. The expression of TOP2A was stained by using the PathnSitu PolyExcel Detection System of Immunostaining. Statistical Analysis Used: Immunostaining with TOP2A expression used a cut-off value of 10%. The results were considered statistically significant if the P-value was ≤ 0.05. Results: Fifty cases of TOP2A overexpression were classified as follows: 28 cases (56%) had 3+ expression, 4 cases (8%) with 2+ expression, and 4 cases (8%) with 1+ expression, whereas 14 cases had no expression of TOP2A (28%). TOP2A overexpression was shown to be associated with a higher grade (P = 0.023) and molecular subtypes (P = 0.057), but not with other clinicopathological parameters (age of patients, type of histology, number of lymph nodes involved, tumor size). Conclusion: According to these results, TOP2A plays a major role in the aggressive nature of tumors. This may support the suggestion to be used as a prognosis marker.
Keywords: Breast cancer, breast cancer prognosis, topoisomerase IIa (TOPA2)
|How to cite this article:|
Al-Alawchi MS, Alkafaji HA. Evaluation of immunohistochemical expression of topoisomerase II alpha protein in patients with breast cancer and its correlation with different prognostic factors. Med J Babylon 2022;19:210-8
|How to cite this URL:|
Al-Alawchi MS, Alkafaji HA. Evaluation of immunohistochemical expression of topoisomerase II alpha protein in patients with breast cancer and its correlation with different prognostic factors. Med J Babylon [serial online] 2022 [cited 2022 Dec 7];19:210-8. Available from: https://www.medjbabylon.org/text.asp?2022/19/2/210/349470
| Introduction|| |
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among women.
Worldwide, in 2020, female breast cancer has now surpassed lung cancer as the leading cause of global cancer incidence in both sexes combined, with an estimated 2.3 million new cases, representing 11.7% of all cancer cases. It is the fifth leading cause of cancer mortality worldwide. So among women, breast cancer accounts for one in four cancer cases and one in six cancer deaths.
In Iraq, in 2020, breast cancer is the first one to rank among the malignancies in all populations; it accounted for 22.2% of total cancer cases and 37.9% of all new cancer cases among females of all ages. Breast cancer ranks the first among the total cancer deaths, and it is established as 15.3%.
The highest incidence of mortality from cancer in females was breast cancer (4.79/100,000 female populations).
Breast cancers show considerable variation in the sense of their histological features and molecular alterations, and such factors are known to influence the patient outcome and clinical behavior.
The changes in molecules that classify breast carcinogenesis have been established. Therefore, four subtypes of breast cancer were distinguished by group tumors: luminal A, luminal B, enriched human epidermal growth factor receptor 2 (HER2), and triple-negative breast cancer (basal-like). This classification has changed from tumor burden to biology-centered approaches to clinical management of breast cancer.
Recognition of best prognostic and predictive indicators is the main challenge in clinical oncology practice. For that reason, selection of better techniques for evaluating each indicator will influence the tumor therapy and prognosis.
DNA topoisomerase IIa (TOP2A) is a nucleic enzyme that affects the topological structure of DNA by interacting with the double-helix DNA, thus playing an important role in DNA replication, transcription, recombination, condensation, and segregation.
TOP2A expression in tumor cells is reported to be a direct molecular target for anthracycline-containing therapy; cells with a lower degree of an enzyme are less sensitive to the drug and cells containing a high amount are more responsive.
There is growing evidence that TOP2A protein expression is a strong prognostic factor, and TOP2A gene amplification might be a predictive marker (particularly used for anthracyclines therapy). Therefore, it is considered as a prognosis marker for breast cancer aggressiveness.
| Materials and Methods|| |
This study is a cross-sectional retrospective study carried out in the Department of Pathology and Forensic Medicine, Faculty of Medicine, University of Babylon, Iraq, during the period from January 2020 through December 2020.
Specimen selection and data collection
Fifty formalin-fixed and paraffin-embedded tissue blocks from archived tissue specimens of female patients diagnosed with invasive breast carcinoma have been obtained from surgical modified radical mastectomy specimens from the Laboratory of Histopathology in Al-Kafeel Specialized Hospital, Karbala for the last 3 years (2017–2019).
The primary diagnosis was established by using slides stained with (hematoxylin/eosin). Furthermore, molecular subclassification was done by re-examination of the slides stained with immunohistochemistry (IHC) for ER, PR, and HER2, which were all extracted from the archive.
The cases were evaluated by two pathologists, and also the authors re-examined them for histological diagnosis, pathological parameters including lymph node status, tumor grade, tumor size, histological subtypes, and IHC (ER, PR, and HER-2).
The selection of cases
Sample from patients with axillary dissection diagnosed as carcinoma with invasion to or beyond the basement membrane, regardless of histological classification (ductal or lobular or other types), different ages, grades, stages, molecular subtypes, was selected.
Cases with true cut biopsy, lumpectomy, and radical mastectomy specimens were excluded due to deficient data regarding the parameters of involved lymph nodes and tumor size. Furthermore, cases with total lymph node numbers less than 10 in axillary clearance were excluded.
New 5 μm thickness histological sections were made from each of the paraffin-embedded blocks fixed on positively charged slides to be processed and stained to be subjected to conduct IHC procedures to detect topoisomerase IIA.
The internal control group involved 10 blocks consisting of known five positive and five negative tissues from patients with non-breast cancer, whereas an external control group included two blocks of tonsils and spleen. All are used for topoisomerase IIA IHC evaluation.
Parallel positive control sections were processed with each set of immunostaining, which is known to express topoisomerase IIa, and were used with each run.
Sections untreated with primary antibody (topoisomerase IIa) were considered as negative controls for each set of slides.
The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki. It was carried out with patients’ verbal and analytical approval before sample was taken. The study protocol and the subject information and consent form were reviewed and approved by a local Ethics Committee according to the document number 88 on the 23rd of November 2020.
| Results|| |
Clinicopathological parameters of patients with breast cancer
The distribution of patients by age ranged from 20 to 90 years. The overall (mean ± SD) patients’ age was 52.06 ± 12.89 years; most of the patients are between fifth and sixth decades (32%) 16 cases for each one, whereas decades of third (4%) 2 cases, fourth (12%) 6 cases, seventh (10%) 5 cases, eighth (8%) 4 cases, and ninth (2%) 1 case.
The distribution of patients by tumor-related factors
Seventeen (34%) cases were grades I and II (66%) and 33 cases had grade III.
Type of histology
Forty-two (84%) cases had ductal non-specific type carcinoma in the breast, 5 (10%) cases had lobular and 3 (6%) cases had different histological types of breast cancer.
According to (ER, PR, Her2) IHC-based molecular subtypes, 34 (68%) cases had luminal A, 4 (8%) cases had luminal B, 6 (12%) cases of Her2-enriched, and 6 (12%) cases had basal-like (triple-negative).
Seventeen (34%) cases had tumor size equal to or less than 20 mm, 30 (60%) cases of tumor size between 21 and 50 mm, and 3 (6%) cases had tumor size >50 mm.
The number of axillary lymph nodes involved
About 34% of the cases had metastasis of lymph node numbers between 1 and 3 nodes involved, 14% of the cases had metastasis of lymph node numbers between 4 and 9, and 10% had lymph node metastasis numbers 10 or more. The excluded total lymph nodes number in axillary clearance is less than 10. These parameters are shown in [Table 1].
IHC results in breast carcinoma
IHC-positive results for topoisomerase IIa were determined as nuclear staining of malignant cells and accordingly, we categorized the results by using H-score, which is a semi-quantitative assessment that involves the nuclear staining intensity and percentage of stained tumor cells.
Accordingly, the H-score ranged from 0 to 300 in this study.
The study results were recorded as positive when H-score was cut-off by more than 10%.
Topoisomerase IIa in breast carcinoma at that score was 36 out of 50 cases (72%). All positive staining results were non-focal, and in most cases, 64% (32/50) show diffuse moderate-to-strong staining [Table 2] and [Figure 1].
|Table 2: Topoisomerase IIa immunoreactivity in breast carcinoma at variable H-score cut-off values|
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|Figure 1: Topoisomerase IIa reactivity in breast carcinoma at variable H-score cut-off values|
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The result of the study
There were 28 cases (56%) with staining intensity 3+ expression in topoisomerase II alpha which represents 225–300 from H-score as in [Figure 2], 4 cases (8%) with 2+ expression which represents 150–225 from H-score as in [Figure 3], and 4 cases (8%) with 1+ expression which represents 10–150 from H-score as in [Figure 4], whereas 14 cases had no expression of TOP2 II alpha (28%), which was less than 10% of cut-off value of H-score as in [Figure 5].
|Figure 2: Invasive ductal carcinoma non-specific type (NST), grade 3. (a) H&E-stained slide section (×400). (b) Topoisomerase 2a-stained slide section with (H-score >225) strong +3 dark brown nuclear (red arrow) (×400)|
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|Figure 3: Invasive ductal carcinoma non-specific type (NST), grade 1. (a)H&E-stained slide section (×400). (b) Topoisomerase 2a-stained slide section with (H-score between 150 and 225) moderate +2 brown nuclear (red arrow) (×400)|
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|Figure 4: Invasive ductal carcinoma non-specific type (NST), grade 2. (a) H&E-stained slide section (×400). (b) Topoisomerase 2a-stained slide section with (H-score between 10 and 150) mild +1 faint brown nuclear (red arrow) (×400)|
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|Figure 5: Invasive ductal carcinoma non-specific type (NST), grade 3. (a) H&E-stained slide section (×400). (b) Topoisomerase 2a-stained slide section with (H-score <10) (negative) loss of stain expression (red arrow) (×400)|
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Note that we found strong brown cytoplasmic staining in invasive papillary carcinoma.
The association between age of patients with breast cancer and topoisomerase IIa expression
IHC analysis of topoisomerase IIa expression with ages of patients having breast carcinoma revealed that (+3) 28 cases were reported more common (about 9 cases) in each age between 41 and 50, 8 cases in ages between 51 and 60, whereas (+2) 4 cases were reported to be more common (about 2 cases) in ages 31 and 40 and (+1) 4 cases were reported to be more common (about 2 cases) in ages 51 and 60. Out of the 14 cases, negative expressions were reported more commonly in about 6 cases in each age range 41–50 and 51–60, as shown in [Figure 6]. No significant association between topoisomerase IIa immunostaining and age was found, as shown in [Table 3].
|Figure 6: Association between the age of patients with breast cancer and topoisomerase IIa expression|
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|Table 3: Association between topoisomerase IIa expression and the age of patients|
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The association between grade of breast cancer and topoisomerase IIa expression
IHC analysis of topoisomerase IIa expression with a grade of breast carcinoma revealed that 17 (34%) cases were grades I and (66%) II, and 33 cases had grade III including the following.
(+3) was reported in 8 cases of grades I and II and 20 cases of grade III tumors.
(+2) was reported in 2 cases of grades I and II and 2 cases of grade III tumors.
(+1) was reported in 4 cases of grades I and II and no cases of grade III tumors.
The negative expression was reported in 3 cases of grades I and II and 11 cases of grade III tumors. There is a significant association between topoisomerase IIa immunostaining and the grade of the tumor, as shown in [Table 4].
|Table 4: Association between topoisomerase IIa expression and the grades of breast cancers|
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The association between histology types of breast cancer and topoisomerase IIa expression
IHC analysis of topoisomerase IIa expression with a type of histology revealed the following:
(84%) 42 cases had a ductal type of breast carcinoma, including (+3) 24 cases, (+2) 3 cases, and (+1) 4 cases;
(10%) five cases had a lobular type, with topoisomerase IIa including (+3) three cases, whereas (+1) and (+2) no case;
(6%) three cases had different histological types of breast cancers, (+1) and (+2) had one case;
14 cases had no expression of topoisomerase IIa including 11 ductal cases, 2 lobular cases, 1 other case as in [Figure 7].
|Figure 7: Association between histological type breast cancer and topoisomerase IIa expression|
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No significant association between topoisomerase IIa immunostaining and types of histology is shown in [Table 5].
|Table 5: Association between Topoisomerase IIa expression and types of histology of breast cancer|
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The association between (ER, PR, Her2) IHC-based molecular subtypes of breast cancer and topoisomerase IIa expression
Topoisomerase IIa expression in (ER, PR, Her2) IHC-based molecular subtypes includes the following:
(68%) 34 breast cancer cases had luminal A including (+3) 20 cases, (+2) 3 cases, (+1) no case;
(8%) 4 cases had luminal B including (+3) 2 cases, (+1) 2 cases, and (+2) no case;
(12%) 6 cases had Her2-enriched including (+3) 4 cases, (+2) no case, and (+1) 1 case;
(12%) 6 cases had basal-like (triple-negative), (+3) 3 cases, (+2) 2 cases, and (+1) no case;
no topoisomerase IIa expression in 14 cases, including 11 cases luminal A, no case luminal B, 2 cases Her2-enriched, 1 case triple-negative.
A significant association was found between topoisomerase IIa immunostaining and (ER, PR, Her2) IHC-based molecular subtypes of the tumor, as shown in [Table 6].
|Table 6: The association between (ER, PR, Her2) immunohistochemical-based molecular subtypes of breast cancer and topoisomerase IIa expression|
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The association between the number of axillary lymph nodes involved in breast cancer and topoisomerase IIa expression
IHC analysis of topoisomerase IIa expression with number of axillary lymph nodes involved is as follows:
lymph node metastasis numbers between 1 and 3 nodes were involved in 17 (34%) cases with topoisomerase IIa expression being (+3) in 10 cases, (+2) 1 case, and (+1) 2 cases;
lymph node metastasis numbers between 4 and 9 were involved in 7 (14%) cases with topoisomerase IIa expression being (+3) in 4 cases, (+2) no case, and (+1) 1 case;
lymph node metastasis numbers 10 or more were involved in 5 (10%) cases with topoisomerase IIa expression being (+3) in 3 cases and (+1) and (+2) no cases;
21 (42%) cases of no involvement of lymph nodes had an expression of topoisomerase IIa, which were about (+3) in 11 cases, (+2) 3 cases, (+1) 1 case;
no expression of topoisomerase IIa in 4 cases in pN1 (1–3) lymph nodes, 2 cases in pN2 (4–9) lymph nodes, 2 cases in pN3 (10 or more) lymph nodes, and 6 cases with no lymph nodes, as in [Figure 8].
|Figure 8: Association between topoisomerase IIa expression and lymph nodes involved with breast cancer|
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No significant correlation was found between topoisomerase IIa immunostaining and the number of lymph nodes involved, as shown in [Table 7].
|Table 7: Association between Topoisomerase IIa expression and number of axillary lymph nodes involved in breast cancer|
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The association between tumor size of breast cancer and topoisomerase IIa expression
IHC analysis of topoisomerase IIa expression with tumor size is as follows:
(34%) 17 cases had a tumor size equal to or less than 2 cm (T1), with an expression of topoisomerase IIa about (+3) being 9 cases, (+2) 2 cases, and (+1) 1 case;
(60%) 30 cases had a tumor size between 21 and 50 mm (T2), with an expression of topoisomerase IIa about (+3) being 17 cases, (+2) 2 cases, and (+1) 3 cases;
(6%) 3 cases had a tumor size >50 mm, with the expression of topoisomerase IIa about (+3) being 2 cases, (+1) and (+2) no cases, as shown in [Figure 9].
|Figure 9: Association between the size of breast cancer and topoisomerase IIa expression|
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No significant correlation was found between topoisomerase IIa immunostaining and size of the tumor, as shown in [Table 8].
|Table 8: Association between topoisomerase IIa expression and number of lymph nodes involved in breast cancer|
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| Discussion|| |
Breast cancer is the most prevalent form of cancer in women worldwide, and it is also the leading cause of cancer mortality in women. It has a huge burden on the global health authorities.
The most commonly used and the simplest way to detect the TOP2A protein expression is IHC, although no standard antibodies, methods of staining, or scoring system was recommended.
This study presents 50 cases of breast cancers graded using the Nottingham Histologic Score System and staged according to TNM (TNM is a system to describe the amount and spread of cancer in a patient’s body. T describes the size of the tumor and any spread of cancer into nearby tissue; N describes spread of cancer to nearby lymph nodes; and M describes metastasis [spread of cancer to other parts of the body].)/American Joint Committee on Cancer (AJCC) to test multiple clinical-pathological parameters with TOP2A expression (age, grade, molecular subtypes, histopathological forms, size of tumor, lymph node number involved).
A number of studied cases and different cut-off values used to define overexpression, whether 5%, 10%,,, 15%, 20%, 25%, and 30%, have been used in various studies.
TOP2A expression was identified through IHC in up to 50–80% of the cases (detection according to the 10% cut-off).,,
In the current analysis, 10% cut-off value is used to define overexpression. We noted a strong positive association between the staining strengths of nuclear TOP2A in the positive cells, and the TOP2A expression identified about 72% (36 cases with TOP2A overexpression from 50 cases), which was consistent with worldwide studies in the same subject.
There is still debate about the prognostic effect of TOP2A protein expression on breast cancer, and the role of TOP2A in breast cancer prognosis is uncertain.
Some studies have shown that overexpression of TOP2A has been connected to poor outcomes., Others have proved a strong effect., In contrast, others who failed to show an association of this form have reported a restricted prognostic effect.
This difference among studies could be explained by different antibody clones used, whether monoclonal or polyclonal with different specificities and sensitivities; the absence of the standard procedure and the description of IHC of TOP2A protein, as described earlier, may be one explanation. Another possible cause might be owing to either using automated analysis of quantitative images or using subjective analysis, for the measurement of protein expression.
The different prognostic effects of protein TOP2A for different subtypes of breast cancers may be another possible reason.
The intensity of staining and the proportion of positive cells in the TOP2A status given have been taken into account in other studies.
To help in such a debate, we evaluated the association of TOP2A expression with some prognostic clinicopathological parameters.
There is significant evidence that breast cancer is a heterogeneous disease rather than a single disease, and there are breast cancer subtypes that appear with different prognoses, i.e., specific clinicopathological characteristics.,,
This study evaluated TOP2A expression protein with some of these parameters.
We found that higher grade tumor was strongly linked with the expression of the TOP2A protein, suggesting that tumors with a higher TOP2A expression were more aggressive; this is consistent with some previous studies that stated that the protein TOP2A was significantly linked to a high grade of the tumor, and inconsistent with other different studies.,
In our study, TOP2A expression (ER, PR, Her2) IHC-based molecular subtyping was evaluated in breast cancer women who expressed it: (68%) 34 cases had luminal A, (8%) 4 cases had luminal B, (12%) 6 cases had Her2-enriched, (12%) 6 cases had basal-like (triple-negative), which verified that there was a significant expression of protein TOP2A related to (ER, PR, Her2) IHC molecular subtypes. This was consistent with studies that stated that protein, TOP2A, was substantially linked to molecular subtypes and separated ER and PR individually,,, HER-2 status.
So, our study was consistent with demonstrating the higher TOP2A expression protein, which was a poor predicting factor for luminal breast cancer, and this was consistent with the previous study.
In our study, there is no relationship between the expression of TOP2A and age, tumor size, the status of lymph nodes, histological type, consistent with age, tumor size, the status of lymph nodes and inconsistent with some studies which mentioned that the TOP2A protein has been frequently associated with node metastasis and tumor size.,
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al
. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin2021;71:209-49.
Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, et al
. Cancer statistics for the year 2020: An overview. Int J Cancer2021. doi: 10.1002/ijc.33588..
Ministry of Health (Iraq).Iraq Annual Statistical Report 2016.2017. Ministry of Health. Available from: https://ghdx.healthdata.org/record/iraq-annual-statistical-report-2016
Tsuda H Individualization of breast cancer based on histopathological features and molecular alterations. Breast Cancer 2008;15:121-32.
Prat A, Pineda E, Adamo B, Galván P, Fernández A, Gaba L, et al
. Clinical implications of the intrinsic molecular subtypes of breast cancer. Breast2015;24(Suppl 2):S26-35.
Cardoso F, Cataliotti L, Costa A, Knox S, Marotti L, Rutgers E, et al
. European Breast Cancer Conference manifesto on breast centers/units. Eur J Cancer 2017;72:244-50.
Chen JR, Chien HP, Chen KS, Hwang CC, Chen HY, Yeh KY, et al
. Amplification of HER2 and TOP2A and deletion of TOP2A genes in a series of Taiwanese breast cancer. Medicine (Baltimore) 2017;96:e5582.
Santin AD, Zhan F, Bignotti E, Siegel ER, Cané S, Bellone S, et al
. Gene expression profiles of primary HPV16- and HPV18-infected early stage cervical cancers and normal cervical epithelium: Identification of novel candidate molecular markers for cervical cancer diagnosis and therapy. Virology 2005;331:269-91.
Qiao JH, Jiao DC, Lu ZD, Yang S, Liu ZZ Clinical significance of topoisomerase 2a expression and gene change in operable invasive breast cancer. Tumour Biol 2015;36:6833-8.
Rody A, Karn T, Ruckhäberle E, Müller V, Gehrmann M, Solbach C, et al
. Gene expression of topoisomerase II alpha (TOP2A) by microarray analysis is highly prognostic in estrogen receptor (ER) positive breast cancer. Breast Cancer Res Treat 2009;113:457-66.
An X, Xu F, Luo R, Zheng Q, Lu J, Yang Y, et al
. The prognostic significance of topoisomerase II alpha protein in early stage luminal breast cancer. BMC Cancer 2018;18:331.
Fountzilas G, Valavanis C, Kotoula V, Eleftheraki AG, Kalogeras KT, Tzaida O, et al
. HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy. J Transl Med 2012;10:10.
Zaczek A, Markiewicz A, Supernat A, Bednarz-Knoll N, Brandt B, Seroczyńska B, et al
. Prognostic value of TOP2A gene amplification and chromosome 17 polysomy in early breast cancer. Pathol Oncol Res 2012;18:885-94.
Iyikesici MS, Basaran G, Dane F, Ekenel M, Yumuk PF, Cabuk D, et al
. Associations between clinicopathological prognostic factors and pAkt, pMAPK and topoisomerase II expression in breast cancer. Int J Clin Exp Med 2014;7:1459-64.
Romero A, Martín M, Cheang MC, López García-Asenjo JA, Oliva B, He X, et al
. Assessment of topoisomerase II α status in breast cancer by quantitative PCR, gene expression microarrays, immunohistochemistry, and fluorescence in situ
hybridization. Am J Pathol 2011;178:1453-60.
Fritz P, Cabrera CM, Dippon J, Gerteis A, Simon W, Aulitzky WE, et al
. c-erbB2 and topoisomerase IIα protein expression independently predict poor survival in primary human breast cancer: A retrospective study. Breast Cancer Res 2005;7: R374-84.
Depowski PL, Rosenthal SI, Brien TP, Stylos S, Johnson RL, Ross JS Topoisomerase iiα expression in breast cancer: Correlation with outcome variables. Mod Pathol 2000;13:542-7.
Chen S, Huang L, Liu Y, Chen CM, Wu J, Shao ZM The predictive and prognostic significance of pre- and post-treatment topoisomerase iiα in anthracycline-based neoadjuvant chemotherapy for local advanced breast cancer. Eur J Surg Oncol 2013;39:619-26.
Olszewski WT, Pieńkowski T, Olszewski W, Mrozkowiak M, Bauer-Kosińska B, Piaścik A, et al
. Topoisomerase 2α status in invasive breast carcinoma - comparison of its clinical value according to immunohistochemical and fluorescence in situ hybridization methods of evaluation. Pol J Pathol 2014;65:283-90.
Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, et al
. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 2009;27:1160-7.
Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, et al
. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006;295:2492-502.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]