Effect of Ki-67 Expression Levels and Histological Grade on Breast Cancer Early Relapse in Patients with Different Immunohistochemical-based Subtypes

Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with poor prognosis and limited treatment options. Hypoxia is a key hallmark of TNBC. Metabolic adaptation promotes progression of TNBC cells that are located within the hypoxic tumor regions. However, it is not well understood regarding the precise molecular mechanisms underlying the regulation of metabolic adaptions by hypoxia. Methods RNA sequencing was performed to analyze the gene expression profiles in MDA-MB-231 cell line (20% O2 and 1% O2). Expressions of Slc6a8, which encodes the creatine transporter protein, were detected in breast cancer cells and tissues by quantitative real-time PCR. Immunohistochemistry was performed to detect SLC6A8 protein abundances in tumor tissues. Clinicopathologic correlation and overall survival were evaluated by chi-square test and Kaplan-Meier analysis, respectively. Cell viability assay and flow cytometry analysis with Annexin V/PI double staining were performed to investigate the impact of SLC6A8-mediated uptake of creatine on viability of hypoxic TNBC cells. TNBC orthotopic mouse model was used to evaluate the effects of creatine in vivo. Results SLC6A8 was aberrantly upregulated in TNBC cells in hypoxia. SLC6A8 was drastically overexpressed in TNBC tissues and its level was tightly associated with advanced TNM stage, higher histological grade and worse overall survival of TNBC patients. We found that SLC6A8 was transcriptionally upregulated by p65/NF-κB and mediated accumulation of intracellular creatine in hypoxia. SLC6A8-mediated accumulation of creatine promoted survival and suppressed apoptosis via maintaining redox homeostasis in hypoxic TNBC cells. Furthermore, creatine was required to facilitate tumor growth in xenograft mouse models. Mechanistically, intracellular creatine bolstered cell antioxidant defense by reducing mitochondrial activity and oxygen consumption rates to reduce accumulation of intracellular reactive oxygen species, ultimately activating AKT-ERK signaling, the activation of which protected the viability of hypoxic TNBC cells via mediating the upregulation of Ki-67 and Bcl-2, and the downregulation of Bax and cleaved Caspase-3. Conclusions Our study indicates that SLC6A8-mediated creatine accumulation plays an important role in promoting TNBC progression, and may provide a potential therapeutic strategy option for treatment of SLC6A8 high expressed TNBC.

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The Value of Ultrasound Diagnosed Axillary Lymph Node in Avoiding Axillary Surgery in Early Breast Cancer Patients

10.21203/rs.3.rs-81453/v1 ◽

2020 ◽

Author(s):

Na Liu ◽

Liu Yang ◽

Xinle Wang ◽

Meiqi Wang ◽

Ruoyang Li ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Cancer Patients ◽

Axillary Lymph Node ◽

Histological Grade ◽

False Negative ◽

Axillary Lymph ◽

Breast Cancer Patients ◽

Ki 67 ◽

Axillary Surgery

Abstract Background: Axillary lymph node dissection can be avoided in early stage breast cancer patients with negative sentinel lymph node biopsy. However, the possibility of avoiding axillary surgery in patients without axillary lymph node metastasis (ALNM) by preoperative imaging is still under exploration. Thus, the objectives of this study were to investigate the high-risk factors of false negative of ALNM diagnosed by preoperative ultrasound (US) and to find out who could be avoided axillary surgery in the US negative ALNM patients.Methods: This study retrospectively analyzed 3,361 patients with primary early breast cancer diagnosed in the Breast Center of the Fourth Hospital of Hebei Medical University from January 2010 to December 2012. All patients had undergone routine preoperative US and then axillary lymph node dissected. This study investigated the clinicopathological features of axillary lymph node (ALN) negative patients diagnosed by preoperative US and its correlation with prognosis. The follow-up data for disease-free survival (DFS) and overall survival (OS) were obtained from 2,357 patients. Results: The sensitivity, specificity and accuracy of axillary US in this cohort were 66.24%, 76.62% and 73.87%. The proportion of patients in the false negative group was higher than that in true negative in the group of age < 50 years old (P = 0.002), tumor size > 2cm (P = 0.008), estrogen receptor (ER) positive (P = 0.005), progesterone receptor (PR) high expression (P = 0.007), nuclear-associated antigen Ki-67 (Ki-67) >20% (P = 0.030), visible vascular tumor thrombus (P < 0.001) and histological grade>2 (P < 0.001). Prognostic analysis of false negative and true negative ultrasonographic diagnosis of ALN metastasis: when ALNM was not found by preoperative ultrasound, there was no significant difference in patients with ALNM≤3 compared with patients without lymph node metastasis in patients of age ≥ 50 years old, tumor size ≤ 2cm, Ki-67 ≤ 20%, or histological grade ≤ 2. Conclusion: The surgery of ALN may be avoided for the preoperative US diagnosed ALNs negative in early breast cancer patients who had advanced age, small tumor size, low expression of Ki-67 and low histological grade.

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The expression and clinical significance of GADD45A in breast cancer patients

PeerJ ◽

10.7717/peerj.5344 ◽

2018 ◽

Vol 6 ◽

pp. e5344 ◽

Cited By ~ 4

Author(s):

Junnan Wang ◽

Yiran Wang ◽

Fei Long ◽

Fengshang Yan ◽

Ning Wang ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Patients ◽

Clinical Significance ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Breast Cancer Patients ◽

Ki 67 ◽

Expression Levels ◽

Cancer Tissues

BackgroundGrowth arrest and DNA-damage-inducible protein 45 alpha (GADD45A) was previously found to be associated with risk of several kinds of human tumors. Here, we studied the expression and clinical significance of GADD45A in breast cancer.MethodsWe performed an immunohistochemical study of GADD45A protein from 419 breast cancer tissues and 116 adjacent non-neoplastic tissues.ResultsSignificantly high GADD45A expression were observed in breast cancer tissues compared with adjacent non-neoplastic tissues (P < 0.001) and were independently correlative with estrogen receptor negative (P = 0.028) and high Ki-67 index (P < 0.001). Kaplan–Meier survival analysis revealed that patients with high GADD45A expression levels had a worse long-term prognosis in triple negative breast cancer (P = 0.041), but it was not an independent prognostic factor in multivariate analysis (P = 0.058).ConclusionsGADD45A expression levels are significantly correlative with estrogen receptor status and Ki-67 index in human breast cancer. Patients with triple negative breast cancer might be stratified into high risk and low risk groups based on the GADD45A expression levels.

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Analysis of Low Estrogen Receptor (ER+) Breast Carcinomas in a Large Community Breast Cancer Center in Northern California

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqab191.051 ◽

2021 ◽

Vol 156 (Supplement_1) ◽

pp. S26-S27

Author(s):

G Bulusu ◽

K Duncan ◽

A Wheeler

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Histological Grade ◽

Statistical Significance ◽

Cancer Center ◽

Pathology Report ◽

Breast Cancers ◽

Breast Carcinomas ◽

Ki 67 ◽

Er Positive

Abstract Introduction/Objective Estrogen Receptor (ER) expression in breast cancers is a crucial factor for endocrine therapy in patients with tumors expressing ER in ≥1% of tumor cells. The 2019 guidelines published by ASCO/CAP states that breast cancers that have a 1% to 10% of cells staining Estrogen Receptor (ER) positive should be reported as ER Low Positive cases. This study aims to address this subset of low-positive ER tumors and compare the clinical features to other known breast cancer subtypes. Methods/Case Report We conducted a retrospective review of a prospectively maintained breast cancer registry from 2013 to 2021 at Mills-Peninsula Medical Center, a Sutter Health Affiliate. The study reviewed patient charts with respect to the pathology report, operative report, chemotherapy regimen, and clinical outcomes. Statistical analyses were conducted using R Project for Statistical Coding, with The Student’s T-test used to compare continuous variables. Two-sided P values less than 0.05 indicate statistical significance. Results (if a Case Study enter NA) Our study identified 1316 cases of invasive breast carcinomas, of which 29 (2.16%) demonstrated ER Low-Positive expression. We aimed to evaluate the clinical and pathological features, such as histological grade, ER, PR, HER-2, Ki-67%, and patient age for these tumors. We found that ER Low-Positive tumors demonstrated higher mean histological grade morphology (2.5 out of 3, p<0.001) that was similar to that of Triple Negative Breast Cancers (TNBC) (3 of 3, p<0.001) than to High ER-Positive (1.6 of 3, p<0.001) cancers. Further observations, through examining proliferation rates by utilizing the Ki-67 index, indicate comparative trends between the ER Low-Positive cohort and the TNBC cohort. Conclusion The results suggest that the ER Low-Positive carcinomas, despite reported as ER-positive cases, present with similar clinicopathological features to those of ER-negative tumors. Through this study and future research, we would like to emphasize a stricter set of guidelines that can be adopted to reduce variability for reporting biomarkers. This standardization will allow oncologists to provide more appropriate treatment options and improve the quality of patient care.

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Progesterone Receptor Status and Ki-67 Index May Predict Early Relapse in Luminal B/HER2 Negative Breast Cancer Patients: A Retrospective Study

PLoS ONE ◽

10.1371/journal.pone.0095629 ◽

2014 ◽

Vol 9 (8) ◽

pp. e95629 ◽

Cited By ~ 14

Author(s):

Yu Zong ◽

Li Zhu ◽

Jiayi Wu ◽

Xiaosong Chen ◽

Ou Huang ◽

...

Keyword(s):

Breast Cancer ◽

Retrospective Study ◽

Progesterone Receptor ◽

Cancer Patients ◽

Progesterone Receptor Status ◽

Breast Cancer Patients ◽

Ki 67 ◽

Early Relapse ◽

Receptor Status ◽

Luminal B

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The Analysis of bcl-2 in Association with p53 and Ki-67 in Triple Negative Breast Cancer and Other Molecular Subtypes in Ghana

Journal of Oncology ◽

10.1155/2021/7054134 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Charity Ameh-Mensah ◽

Babatunde Moses Duduyemi ◽

Kweku Bedu-Addo ◽

Elijah Atta Manu ◽

Francis Opoku ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Subtypes ◽

Histological Grade ◽

Her2 Overexpression ◽

Luminal A ◽

Ki 67 ◽

Cross Sectional ◽

Luminal B ◽

Protein P53

Background. Little is known about the role of apoptosis in the tumorigenesis and prognosis of breast cancer in Ghana. Chemotherapeutic drug efficacy partially relates to apoptosis induction, rendering it a vital target in cancer therapy with unique biomarker opportunities that have not been exploited. Aberrations in this pathway are central to tumorigenesis, tumor progression, overall tumor growth, and regression during treatment therapies. Antiapoptotic bcl-2 (gene) and p53 are known to play roles in apoptosis while Ki-67 is a proliferative marker. The aim of our study is to determine the association of bcl-2 (protein) with p53 and Ki-67 in 203 consecutive breast cancer cases over a 10-year period. Method. A retrospective cross-sectional study on archival FFPE tissue blocks over a 9-year period with abstraction of clinicopathologic data. Two hundred and three consecutive and suitable FFPE blocks were selected for tissue microarray (TMA) construction, and IHC (bcl-2 (protein), Ki-67, p53, cyclin D, pan cytokeratins A and E, ER, PR, and HER2/neu) was done. Expressions of bcl-2 (protein), p53, and Ki-67 were related to histological grade, lymphovascular invasion, and molecular subtypes. SPSS version 23 was used to analyze results. Results. Most of our cases were in the fifth decade of life (31%); invasive carcinoma of no special type (NST) was predominant (87%); histological grade III (38%) was the highest; and Luminal A (19.8%), Luminal B (9.9%), HER2 (16%), and TNBC (54.3%) constituted the molecular classes. bcl-2 expression was found in 38% of the cases. Our cases also showed mutation in p53 (36.7%) and ki-67 expression (62.5%). bcl-2 (protein) and p53 significantly correlated with Luminal B and TNBC ( p < 0.01 ). Ki-67 also correlated significantly with Luminal A and B and HER2 overexpression ( p < 0.01 ). Premenopausal age (40–49) and histological grade inversely correlated with bcl-2 (protein) expression. p53 statistically correlated with Ki-67 ( p < 0.05 ). Conclusion. Our results show high expression of bcl-2 (protein) suggesting an important role of apoptosis in Ghanaian breast cancer cases. bcl-2 (protein), p53, and Ki-67 expressions emerged interdependently from this research and can thus be manipulated in prediction and prognosis of breast cancers in our setting.

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Monoclonal Antibodies for Immunohistochemical Diagnosis of Breast Cancer

The Open Biotechnology Journal ◽

10.2174/1874070702115010157 ◽

2021 ◽

Vol 15 (1) ◽

pp. 157-163

Author(s):

Aigerim Turgimbayeva ◽

Assel Issabekova ◽

Assylbek Zhylkibayev ◽

Saule Eskendirova

Keyword(s):

Breast Cancer ◽

Monoclonal Antibodies ◽

Molecular Genetic ◽

Tumour Response ◽

Progesterone Receptors ◽

Pass Rate ◽

Ki 67 ◽

Proliferation Markers ◽

Expression Levels ◽

Immunohistochemical Diagnosis

Breast cancer is a leading malignant disease in women worldwide, although its pathology is visually localised. Currently, it has been proven that the parameters of molecular genetic biomarkers, including oncoprotein HER2, proliferation markers Ki-67, oestrogen receptors ER, and progesterone receptors PgR, are associated with breast carcinogenesis and are a reflection of the biological aggression of the tumour. The significance of these biomarkers in signalling pathways and genetic mechanisms of carcinogenesis has been described, as well as the relationship between the expression levels of each biomarker and the tumour response to appropriate therapy. The primary antibody that imparts specificity to IHC is based on the monoclonal antibodies (mAbs) as the main immunoreagent that enables reliable identification of breast cancer cells. The most commonly used antibodies to molecular biomarkers for IHC were determined in accordance with indicators of laboratory use and efficiency (pass rate) of HER2, Ki-67, ER, PgR assessments in the NordiQC breast cancer module. The discovery of the complete structure of these biomarkers and the design of their domains and subdomains by genetic engineering methods enable the synthesis of effective monoclonal antibodies. Quantitative indicators of the expression levels of tumour biomarkers of breast cancer were determined using mAb, depending on epitope specificity and affinity.

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PREDICTIVE RELAPSE MODEL IN PATIENTS WITH LUMINAL HER2-NEGATIVE BREAST CANCER

Ulyanovsk Medico-biological Journal ◽

10.34014/2227-1848-2020-4-61-73 ◽

2020 ◽

pp. 61-73

Author(s):

M.Kh. Torosyan ◽

T.V. Shevchenko ◽

V.V. Rodionov ◽

Yu.G. Savinov ◽

Yu.A. Veryaskina ◽

...

Keyword(s):

Breast Cancer ◽

Prognostic Model ◽

Prognostic Index ◽

Cancer Recurrence ◽

Disease Stage ◽

Luminal Breast Cancer ◽

Her2 Overexpression ◽

Ki 67 ◽

Expression Levels

Luminal HER2-negative breast cancer (BC) detected at early stages is characterized by a relatively favorable course. However, in some cases, there may be a relapse of the disease regardless of the treatment. The aim of the study was to identify predictors of recurrence of primary resectable luminal HER2-negative breast cancer. Materials and Methods. The authors examined biopsies of patients’ breast tumors (n=158) with luminal HER2-negative breast cancer, stage T1-2N0-1M0, as well as anamnestic data of patients. All women were divided into 2 groups: with disease recurrence within the next 5 years after surgery (n=53) and relapse-free patients (n=105). Macroscopic tumor characteristics, its malignancy, total malignancy score, Nottingham prognostic index, Ki-67, expression of receptors for estrogen and progesterone and their influence on relapse were studied. The authors analyzed expression levels of miRNA (miRNA-21, miRNA-221, miRNA-222, miRNA-155, miRNA-205, miRNA-20a, miRNA-125b, miRNA-146b, miRNA-200a) in tumor tissues. Statistical data processing was performed using Statistica 7 (StatSoft Inc., USA) and MedCalc (version 15.2) software. Results. Comparative analysis of miRNA expression levels between groups of patients with recurrent breast cancer (n=21) and relapse-free patients (n=20) revealed a statistically significant increase in the expression levels of miRNA-21, miRNA-205, miRNA-146b, and miRNA-200a in the group with recurrent disease. The authors established the predictive role of the ratios of the expression levels of potentially oncogenic and tumor suppressive miRNA-21/miRNA-155 and miRNA-21/miRNA-205, as well as the role of miRNA-20a in breast cancer recurrence in combination with Ki-67, disease stage, and primary tumor size. Based on the data obtained, they developed a prognostic model to determine the recurrence of primary operable luminal HER2-negative breast cancer. Conclusion. The created prognostic model allows to clearly stratify the prognosis of primary operable luminal HER2-negative breast cancer. Keywords: primary resectable luminal breast cancer without HER2 overexpression, recurrence prognosis, miRNA. Люминальный HER2-негативный рак молочной железы (РМЖ), выявленный на ранних стадиях, характеризуется относительно благоприятным течением. Однако в ряде случаев возникает рецидив заболевания независимо от проведенного лечения. Цель исследования – выявить предикторы рецидивирования первично операбельного люминального HER2-негативного РМЖ. Материалы и методы. Исследовались биоптаты опухолей молочной железы пациенток (n=158) с люминальным HER2-негативным РМЖ стадии T1-2N0-1M0, а также анамнестические данные пациенток. Все женщины были разделены на 2 группы: с рецидивом заболевания в течение последующих 5 лет после проведения операции (n=53) и с безрецидивным течением (n=105). Изучены макроскопические характеристики опухоли, степень злокачественности, суммарный балл злокачественности, Ноттингемский прогностический индекс, Ki-67, экспрессия рецепторов к эстрогену и прогестерону и их влияние на возникновение рецидива. Проведен анализ уровней экспрессии миРНК (миРНК-21, миРНК-221, миРНК-222, миРНК-155, миРНК-205, миРНК-20а, миРНК-125b, миРНК-146b, миРНК-200a) в тканях опухолей. Статистическая обработка данных произведена с помощью программ Statistica 7 (StatSoft Inc., США) и MedCalc (версия 15.2). Результаты. Сравнительный анализ уровней экспрессии миРНК между группами пациенток с рецидивом РМЖ (n=21) и безрецидивным течением (n=20) выявил статистически значимое повышение уровней экспрессии миРНК-21, миРНК-205, миРНК-146b и миРНК-200a в группе с рецидивом заболевания. Установлена предсказывающая роль соотношений уровней экспрессии потенциально онкогенных и онкосупрессорных миРНК-21/миРНК-155 и миРНК-21/миРНК-205, а также роль миРНК-20a в возникновении рецидива РМЖ в сочетании с Кi-67, стадией заболевания, размером первичной опухоли. На основе полученных данных разработана прогностическая модель определения рецидива первично операбельного люминального HER2-негативного РМЖ. Выводы. Созданная прогностическая модель позволяет четко стратифицировать прогноз первично операбельного люминального HER2-негативного РМЖ. Ключевые слова: первично операбельный люминальный рак молочной железы без гиперэкспрессии HER2, прогноз рецидива, миРНК.

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Predictors of Response and Survival Outcomes of Triple Negative Breast Cancer Receiving Neoadjuvant Chemotherapy

Chemotherapy ◽

10.1159/000509638 ◽

2020 ◽

Vol 65 (3-4) ◽

pp. 101-109

Author(s):

Meizhen Zhu ◽

Yang Yu ◽

Xiying Shao ◽

Liang Zhu ◽

Linbo Wang

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Histological Grade ◽

Disease Free Survival ◽

Complete Response ◽

Survival Outcomes ◽

Ki 67 ◽

Pre Treatment

Background: In triple negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NACT), pre-treatment predictors for pathological complete response (pCR) have been reported; however, those for progressive disease (PD) remain unidentified. Methods: We investigated pre-treatment clinicopathological predictors associated with pCR and PD by retrospectively reviewing data for 165 patients treated between 2015 and 2018. Patients with pCR and PD were compared to those without pCR and PD, respectively, using logistic regression and Kaplan-Meier methods. Results: Lack of androgen receptor (AR) was an independent predictor of pCR, while high histological grade, low Ki-67 index, and incomplete NACT courses were independent predictors of PD. Mean disease-free survival and overall survival were significantly poorer in PD patients than in pCR patients (15.7, 21.3 vs. 52.4, 56.3 months). Conclusions: Insights into the chemo-resistance mechanisms and exploration of novel targeted agents in subgroups as per AR and Ki-67 status are needed to improve survival outcomes in TNBC patients.

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Multivariate analysis of expression of the microtubule-associated protein, tau, predicts improved progression free and overall survival in patients with metastatic HER-2-negative breast cancers treated with docetaxel and vinorelbine plus filgrastim

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.543 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 543-543

Author(s):

A. M. Gown ◽

L. C. Goldstein ◽

P. L. Porter ◽

R. B. Livingston ◽

S. Tam ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Multivariate Analysis ◽

Progression Free Survival ◽

High Expression ◽

Breast Cancers ◽

Beta Tubulin ◽

Ki 67 ◽

Expression Levels ◽

Her 2

543 Background: Drugs that poison the mitotic spindle, including taxanes and vinca alkaloids, are active agents against breast cancer. Preliminary evidence showed that high expression levels of tau predicted improved PFS and OS in patients with metastatic HER-2-negative breast cancers treated with docetaxel and vinorelbine plus filgrastim. We now tested whether levels of tau and another microtubule associated protein, beta-tubulin, could predict PFS and OS in multivariate analysis using other prognostic marker studies, including ER, PR, p53 and Ki-67 on a tissue microarray (TMA) obtained from patients in the SWOG S0102 trial. Materials and Methods: Immunohistochemistry (IHC) using antibodies to tau, beta-tubulin, ER, PR, p53, and Ki-67 was performed on a TMA constructed from the S0102 paraffin blocks. All markers were scored semiquantitatively from 0 to 3. Progression free survival (PFS) and overall survival (OS) were evaluated using multivariate analysis. Results: A total of 38 patients (41.3%) were evaluated. Tau was positively correlated with ER (r=0.36; p=0.0325) and PR (r=0.63; p<0.0001), but not with beta tubulin (p=0.34), Ki-67 (p=0.58), or age (p=0.73). Beta tubulin was not significantly correlated with any other markers. Adjusting for age, there was a significant effect of tau expression on OS (HR=0.667, p= 0.0193) and PFS (HR=0.653; p=0.0035), with higher tau associated with longer survival. When adjusted for both age and PR, there was a marginally significant effect of tau on OS (HR=0.582; p=0.056) and PFS (HR=0.604; p= 0.065). Beta tubulin was not associated with OS (HR=0.909; p=0.66) and PFS (HR=0.904; p=0.58) adjusted for age. Conclusions: In multivariate analysis, identification of breast cancer specimens showing high expression levels of tau predicts improved PFS and OS in patients with metastatic HER-2-negative breast cancers treated with docetaxel and vinorelbine plus filgrastim. High expression of tau also correlated with PR and ER expression. These results confirm and expand earlier studies of the predictive power of tau in a multivariate analysis using a panel of IHC markers for breast cancer. No significant financial relationships to disclose.

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