Joint Prediction of Breast Cancer Histological Grade and Ki-67 Expression Level Based on DCE-MRI and DWI Radiomics

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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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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Discussion of relationships among changes of pathological indicators, postoperative lymphedema of the upper limb, and prognosis of patients with breast cancer

Bioscience Reports ◽

10.1042/bsr20190231 ◽

2019 ◽

Vol 39 (4) ◽

Author(s):

Xiping Zhang ◽

Binbin Tang ◽

Dehong Zou ◽

Hongjian Yang ◽

Enqi Qiao ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Lymph Node Metastasis ◽

Upper Limb ◽

Pathologic Complete Response ◽

Complete Response ◽

Expression Level ◽

Ki 67 ◽

Node Metastasis ◽

Ptnm Stage

Abstract Objectives: The present study aimed to discuss the impacts of changes to pathological indicators of patients with breast cancer upon the incidence of postoperative lymphedema of the upper limb and prognosis. Methods: 2597 female patients with breast cancer who received surgical treatment in our hospital were enrolled in the present study to evaluate the incidence of these patients’ postoperative lymphedema of the upper limb. Results: For patients with breast cancer, the incidence of postoperative lymphedema of the upper limb was related to T stage of breast cancer, lymph node metastasis, the number of metastatic lymph nodes, pTNM stage, and pathological types of breast cancer (P<0.05). Lymph node metastasis was an independent risk factor of lymphedema of the upper limb; lymph node metastasis and Ki-67 expression level were independent factors that impacted pathologic complete response rate of neoadjuvant chemotherapies. Patients’ mortality was correlated to pathological and molecular subtypes, Ki-67 expression level, ER expression level, PR expression level, and pTNM stage (P<0.05), among which the pTNM stage, Ki-67 expression level, and PR expression level were independent factors that affected prognosis of patients with breast cancer. Conclusion: Patients with lymph node metastasis were more prone to lymphedema of the upper limb, while it was easier for those whose Ki-67 expression level was high and who were not subject to lymph node metastasis to get a pathological complete response after receiving neoadjuvant chemotherapies. The prognosis was poorer among patients whose progesterone receptors were negative and Ki-67 expression levels were high at the advanced pTNM stage.

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Prediction of histological grade in breast cancer by combining DCE-MRI and DWI features

Medical Imaging 2019: Imaging Informatics for Healthcare, Research, and Applications ◽

10.1117/12.2513126 ◽

2019 ◽

Author(s):

Lihua Li ◽

Wenrui Zhao ◽

Ming Fan ◽

Maosheng Xu

Keyword(s):

Breast Cancer ◽

Histological Grade ◽

Dce Mri

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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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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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A retrospective study of immunohistochemical detection of Ki67 and correlation with ER, PR, and HER2-neu status in invasive breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e21132 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e21132-e21132

Author(s):

Deepa Meda Prakash ◽

Swarna Shivakumar ◽

P P Bapsy

Keyword(s):

Breast Cancer ◽

Prognostic Factor ◽

Tumor Size ◽

Histological Grade ◽

Biological Behavior ◽

Proliferation Index ◽

Poor Correlation ◽

Nuclear Staining ◽

Ki 67 ◽

Therapeutic Decisions

e21132 Background: Carcinoma breast is a heterogeneous group of disease. Several prognostic factors are known to predict the biological behavior and clinical outcome of breast cancer, including proliferation index, tumor size, age, histological grade, hormone receptors and Her2Neu status. Of theses proliferative index is the most important parameter in predicting tumor aggressiveness and prognosis. Ki67 is a nuclear protein, tightly linked to the cell cycle and is a marker of cell proliferation. High Ki67 usually correlates with a poor prognosis in breast cancer. Methods: This exploratory study is initiated whether Ki67 will be an additional prognostic factor. Immunohistochemical staining of Ki 67 was performed on formalin fixed paraffin embedded blocks of 50 cases of histologically confirmed breast cancer. Ki 67 expression based on distinct nuclear staining of tumor cells was assessed semiquantitatively as, nil (no immunostaining), low (≤10% immunopositivity), high (>10% immunopositivity) by light microscope. ER, PR, Her 2neu status and clinico-pathological parameters were analyzed and correlated with Ki67 immunostaining using the x2 test. Results: Our study showed high Ki 67 staining in 24 cases(48%), low immunostaining in 18 cases(36%) and was nil in 5 cases (10%) and was inconclusive in 3 cases(6%) (core biopsies). There was an inverse correlation of Ki 67 with ER, PR scores in 32 cases (64%) and positive correlation was seen in 28 cases (56%) with Her2 neu status. A good correlation was also observed with mitotic index in 37cases (74%) and histological grade in 29 cases (58%). Good correlation was seen with large tumor size in 24 cases(48%) and metastatic disease 9 cases (64%). Poor correlation was observed with node positive 22 cases (44%). High Ki 67 expression with good treatment response was seen in 13 cases (26%). Conclusions: Based on our study, Ki 67 score may prove to be an important prognostic factor in breast cancer and thereby, useful in making therapeutic decisions. But this is being explored in a large prospective study.

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

Scientific Reports ◽

10.1038/s41598-020-64523-1 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Qin Liang ◽

Ding Ma ◽

Run-Fang Gao ◽

Ke-Da Yu

Keyword(s):

Breast Cancer ◽

Histological Grade ◽

Ki 67 ◽

Early Relapse ◽

Expression Levels

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Associations Between Dynamic Contrast Enhanced Magnetic Resonance Imaging and Clinically Relevant Histopathological Features in Breast Cancer. A Multicenter Analysis

10.21203/rs.3.rs-111377/v1 ◽

2020 ◽

Author(s):

Alexey Surov ◽

Maciej Pech ◽

Jin You Kim ◽

Marco Aiello ◽

Wei Huang ◽

...

Keyword(s):

Breast Cancer ◽

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Hormone Receptor ◽

Hormone Receptor Status ◽

Resonance Imaging ◽

Ki 67 ◽

Dce Mri ◽

Dynamic Contrast Enhanced ◽

Contrast Enhanced

Abstract Background: To provide evident data regarding relationships between quantitative dynamic contrast enhanced magnetic resonance imaging (DCE MRI) and prognostic factors in breast cancer (BC).Methods: Data from 4 centers (200 female patients, mean age, 51.2 ± 11.5 years) were acquired. The following data were collected: histopathological diagnosis, tumor grade, stage, hormone receptor status, KI 67, and DCE MRI values including Ktrans (volume transfer constant), Ve (volume of the extravascular extracellular leakage space (EES) and Kep (diffusion of contrast medium from the EES back to the plasma). DCE MRI values between different groups were compared using the Mann–Whitney U test and by the Kruskal-Wallis H test. The association between DCE MRI and Ki 67 values was calculated by Spearman’s rank correlation coefficient. Results: DCE MRI values of different tumor subtypes overlapped significantly. There were no statistically significant differences of DCE MRI values between different tumor grades. All DCE MRI parameters correlated with KI 67: Ktrans, r = 0.44, p=0.0001; Ve, r = 0.34, p=0.0001; Kep, r = 0.28, p=0.002. ROC analysis identified a Ktrans threshold of 0.3 min-1 for discrimination of tumors with low KI 67 expression (<25%) and high KI 67 expression (≥25%): sensitivity, 75.5%, specificity, 73.0%, accuracy, 74.0%, AUC, 0.78. DCE MRI values overlapped between tumors with different T and N stages.Conclusion: Ktrans, Kep, and Ve cannot be used as reliable a surrogate marker for hormone receptor status, tumor stage and grade in BC. Ktrans may discriminate lesions with high and lower proliferation activity.

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