Estrogen Receptor Negative Research Articles

Abstract P5-05-01: Metabolite profiling and RNA-seq identifies novel metabolomic-genomic biomarker and therapeutic options for rapidly proliferating breast cancers

Abstract Metabolic dysregulation is one of the distinctive features of breast cancer, yet remains under-characterized in different subtypes of breast cancer. In this study, we performed full metabolome profiling and RNA-seq gene expression analyses on patient samples comprised of Triple Negative Breast Cancer (TNBC) and Estrogen Receptor (ER) positive breast cancers, as well as TNBC patient-derived xenografts (PDX). We identified two major metabolic groups using hierarchical clustering analysis of global metabolite levels: a Nucleotide/Carbohydrate-Enriched group and a Lipid/Fatty Acid-Enriched group. The Nucleotide/Carbohydrate-Enriched group is populated by the majority of TNBCs and all TNBC PDX samples, and shows high levels of energy consumption and nucleotide biosynthesis related metabolites, while the Lipid/Fatty Acid-Enriched group contained all ER+ cancers (and normal breast tissues) and showed high levels of lipids and fatty acids. Using these two metabolite-defined groups, we compared metabolic signatures to RNA-seq expression data and identified gene expression signatures that correlated with each metabolic group. This novel integrated signature identified classic proliferation-associated genes as highly expressed in the Nucleotide/Carbohydrate-Enriched metabolomics group. We next sought to therapeutically target the Nucleotide/Carbohydrate-Enriched group through targeting of nucleotide metabolism using a pyrimidine biosynthesis inhibitor (DHODH inhibitor, Brequinar), and/or a glutaminase inhibitor (CB-839), and observed tumor volume reductions and improved survival times using the TNBC PDX models. Notably,. when the DHODH inhibitor Brequinar was tested on four different immune-competent TNBC mouse models, it showed significant single agent activity, and in 3/4 cases had better activity than carboplatin/paclitaxel combination, and with less toxicity. Our study reveals a new molecularly targeted therapy for rapidly proliferating TNBCs, guided by a novel set of metabolic-genomic biomarkers, which might be translated quickly as DHODH inhibitors are already FDA approved for use in other diseases. Citation Format: Cherise R Glodowski, Chengheng Liao, Cheng Fan, Juan Liu, Kevin R Mott, Akash Kaushik, Hieu Vu, Jason W Locasale, Samuel K McBrayer, Ralph J DeBerardinis, Charles M Perou, Qing Zhang. Metabolite profiling and RNA-seq identifies novel metabolomic-genomic biomarker and therapeutic options for rapidly proliferating breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-05-01.

Abstract OT1-04-01: ATNEC: A multi-centre, randomised trial investigating whether axillary treatment can be avoided in T1-3N1M0 breast cancer patients with no residual cancer in the lymph glands after neoadjuvant chemotherapy (clinicaltrials.gov: nct04109079)

Abstract Background: For patients who are node positive to start at presentation and are found to have a complete nodal tumour response (ypN0) post neoadjuvant chemotherapy (NACT), we do not yet know whether local axillary therapy can be modified based on the response to NACT. ATNEC randomised trial specifically address axillary management following NACT in patients with proven axillary node metastases. Methods: Design: ATNEC is a phase III, randomised (1:1), multi-centre trial, with embedded economic evaluation. Patients with proven axillary node metastases on needle biopsy receive NACT followed by sentinel node biopsy (SNB). If the sentinel nodes have converted to benign (ypN0), ATNEC randomly assigns patients to axillary treatment (nodal radiotherapy or axillary nodal clearance) vs. no axillary treatment (without further surgery). Aims: To assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy - who after NACT have no residual nodal disease on SNB - is non-inferior to axillary treatment in terms of disease free survival, and reduces the risk of lymphoedema at 5 years. Stratification: Institution, type of surgery (breast conserving surgery [BCS] vs mastectomy), receptor status (triple negative vs HER2 positive vs ER status positive and/or PR status positive and HER2 negative). Inclusion criteria:. • Age ≥ 18. • Male or female. • T1-3N1M0 breast cancer at diagnosis (pre-NACT). • FNA or core biopsy confirmed axillary nodal metastases at presentation. • ER and HER2 status evaluated on primary tumour. • Received standard NACT as per local guidelines. • Imaging assessment of the axilla at completion of NACT. • Dual tracer SNB after NACT and at least 3 nodes removed (sentinel nodes and marked node). o If a single tracer is used, the patient is eligible if the involved node is marked before NACT and at least 3 nodes removed (including the marked node). o If axillary node sampling is performed following failed localisation of sentinel nodes, patient is eligible if at least 3 nodes removed (including the marked node). o If node is not marked, or marked node is not removed, patient is eligible if the histology report shows evidence of down-staging with complete pathological response in at least one node and at least 3 nodes removed. • No evidence of nodal metastases post NACT (ypN0). Exclusion criteria:. • Bilateral invasive breast cancer. • SNB prior to NACT. • Previous ipsilateral axillary nodal surgery. • Previous cancer within last 5 years or concomitant malignancy. Radiotherapy Quality Assurance: ATNEC has in-built radiotherapy QA programme that is coordinated by National Radiotherapy Trials QA (RTTQA) group. Target accrual: 1900 Number of sites: 100 Trial Status: Recruiting. Trial is open to new sites. Disclaimer: This study is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (Reference - HTA NIHR128311). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Citation Format: Amit Goyal, Sophie Cramp, Andrea Marshall, Duncan Wheatley, Natalie Hammonds, Shama Puri, Tara Homer, Luke Vale, Roeum Butt, Romaana Mir, Janice Rose, Helen Teresa Edwards, Samreen Ahmed, Abeer Shaaban, Beatrix Elsberger, Julie Bruce, Sophie Gasson, Valerie Speirs, Jacqui Shaw, Helen Higgins, Janet Dunn. ATNEC: A multi-centre, randomised trial investigating whether axillary treatment can be avoided in T1-3N1M0 breast cancer patients with no residual cancer in the lymph glands after neoadjuvant chemotherapy (clinicaltrials.gov: nct04109079) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-04-01.

Abstract P2-08-11: How reliable are biomarkers assessed on a core needle biopsy? A study of paired core needle biopsies and surgical specimens in early breast cancer

Abstract Background: The conventional biomarkers estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki67, and Nottingham histologic grade (NHG) are used to classify breast cancer into its molecular subtypes, determine prognosis, and guide treatment. A preoperative core needle biopsy (CNB) is used to confirm the diagnosis and invasiveness of a breast lesion and forms the basis for characterizing the tumor in the case of neoadjuvant primary treatment, emphasizing the importance of obtaining reliable biomarker assessment from a diagnostic CNB. Aim: The aim of this study was to determine the similarity between biomarker status assessed on a CNB compared to a medically untreated surgical specimen. Methods: Paired CNB and surgical specimens from 267 patients that were part of the prospective Sweden Cancerome Analysis Network- Breast (SCAN-B) cohort were studied. The concordance for the five biomarkers: ER, PgR, Ki67, HER2 and molecular subtype, between paired CNB and surgical specimen were investigated using immunohistochemistry (IHC) and gene expression-based analytical methods (GEX). IHC data were collected from patient medical records and gene expression was measured by RNA sequencing. Cohen’s kappa and Mcnemar’s test were used to compare the concordance of biomarkers.Results: Moderate to very good levels of concordance were observed between the biomarker status obtained on a CNB compared with the paired surgical specimen for IHC (κappa range 0.474-0.917) and GEX (κappa range 0.528-0.776), respectively. However, a significant drift from low to high Ki67 status and from negative to positive HER2 status between the CNB and surgical specimen was observed when using IHC and GEX, respectively (McNemar p < 0.05 for both comparisons). Moderate to good concordance levels of biomarker status were generally obtained when comparing GEX and IHC status measured from the same type of sample (κappa range 0.484-0.649) except for Ki67 which consistently displayed poor concordance levels between IHC and GEX for both CNB and surgical specimen comparisons (κappa range 0.158-0.198). Notably, a significant shift from positive to negative ER status and high to low Ki67 status was observed when comparing IHC with GEX classification (McNemar p <0.001 for both comparisons). Conclusion: The tissue sampling and the method of biomarker analysis may affect the results of biomarker status and ultimately affect treatment decisions. The implications of using a preoperative CNB to determine biomarker status, prognosis, and treatment choice should be taken into consideration in neoadjuvant treatment settings. Citation Format: Hani Saghir, Srinivas Veerla, Martin Malmberg, Lisa Rydén, Anna Ehinger, Lao Saal, Johan Vallon-Christersson, Åke Borg, Cecilia Hegardt, Ingrid Hedenfalk, Susanne Dieroff-Hay, Christer Larsson, Niklas Loman, Siker Kimbung. How reliable are biomarkers assessed on a core needle biopsy? A study of paired core needle biopsies and surgical specimens in early breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-11.

Abstract P2-08-16: The cross-talk between nuclear p-ser294-FOXO3a and cytoplasmic MMP-2 in breast cancer survival and treatment response

Abstract Background The forkhead protein FOXO3a, the member of the forkhead box O (FOXO) transcription factors, controls a wide spectrum of carcinogenesis, therapy response and progression in human cancer. Emerging evidence suggest that phosphorylation of FOXO3a by ERK and p38 at Serine 294 induces its nuclear localization or exclusion to the cytosol, therefore regulating FOXO3a transcriptional activity and consequently promoting cell proliferation and tumorigenesis. Several proteins regulated by FOXO3a, such as MMP-2,9 and 13, are involved in metastasis. We aim to explore the potential role of p-ser294-FOXO3a and MMPs, and interplay between both in breast cancer. Materials and Methods Paraffin-embedded tissue microarrays from 350 breast cancer patients were enrolled. Immunohistochemical analysis was performed, and the expression patterns of p-ser294-FOXO3a, MMP-2, MMP-9, MMP-13 were categorized by semiquantitative method and further correlated with the clinicopathological parameters using the x2 test. Survival curves were calculated using the Kaplan-Meier method, while the significance was determined by log rank test. The biological impacts and underlying mechanisms of p-ser294-FOXO3a were analyzed by transwell assay, RT-PCR, western blotting immunofluorescence staining. co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) assay in breast cancer cells upon transfection with FOXO3a and FOXO3a mutant (S294A). Results Our results showed that nuclear p-Ser294-FOXO3a index was inversely correlated with tumor grade (p=0.011) and relapse (p=0.053), but positively correlated only with cytoplasmic MMP-2 intensity (p=0.010). It is noted that cytoplasmic MMP-2 intensity was positively correlated with tumor grade (p=0.032) and size (p=0.028). Intriguingly, decreased nuclear p-Ser294-FOXO3a index was significantly associated with an improved overall survival rate (p=0.004) and of those patients bearing high MMP-2 staining (p<0.001) or negative ER status (p=0.006), and those receiving hormone therapy (HT) (p=0.030) or chemotherapy (p=0.001). Ectopic FOXO3a overexpression increased invasion rate which was inhibited by tamoxifen (TAM) in only ER-positive MCF-7 cells. In addition, TAM inhibited the invasion rates of ERα-negative MDA-MB-231 cells when co-expressed FOXO3a and ERα, and Ser294Ala-FOXO3a mutant (S294A) is incompetent for TAM-mediated suppression of invasion. Real time qPCR showed that TAM decreased FOXO3a-induced MMP-2 mRNA expression in MCF-7 cells and in MDA-MB-231 cells co-expressed with ERα. Co-immunoprecipitation and immunofluorescent staining showed that Ser294 phosphorylation of FOXO3a might be essential for its nuclear localization and protein-protein interaction with ERα in response to TAM. Conclusion The present study highlights that the real index of nuclear p-ser294-FOXO3a can predict a better survival rate and treatment response of HT and chemotherapy in breast cancer. Furthermore, the specific interplay among p-ser294-FOXO3a, ERα, and MMP-2 might be involved in breast cancer metastasis and treatment response. A better understanding of the underlying mechanism may improve the treatment strategy of specific breast cancer subtype. Citation Format: Ming-Feng Hou, Sheau-Fang Yang, Yu-Chun Huang, Fang-Ming Chen, Yao-Tsung Yeh. The cross-talk between nuclear p-ser294-FOXO3a and cytoplasmic MMP-2 in breast cancer survival and treatment response [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-16.

Costus speciosus J Koenig (Costaceae) exerts anti-proliferative effect on breast cancer cells via induction of cell cycle arrest and inhibition of activity of metalloproteinase-2


 
 
 
 Purpose: To Investigate the antiproliferative effect of n-hexane-diethyl ether fraction of Costus speciosus (NP) on triple negative breast cancer (MDA-MB-231) cells, and the mechanism involved.
 Methods: Maceration with methanol (CH3OH) was used for extraction of Costus speciosus rhizomes. Chromatographic separation was used to obtain the non-polar fraction (NP) via elution with n-hexane:(C2H5)2O at a volume ratio of 9:1. The cytotoxic effect of NP was evaluated against two breast cancer cell lines i.e., triple negative (MDA-MB-231) and positive ER (MCF-7) employing 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) MTT) assay, and the IC50 values were estimated. Cell cycle was determined with flow cytometry, while the likely mechanism involved in the cytotoxic effect was investigated using comet assay, immunofluorescence, clonogenic and scratch assays, zymography and detection of the antioxidant markers.
 Results: NP produced potent cytotoxicity against MDA-MB-231, with IC50 value of 4 ± 0.03 μg/mL, whereas its IC50 for MCF-7 was 27 ± 1.3 μg/mL. It induced apoptosis via cell cycle arrest at G1 phase. Moreover, NP markedly decreased levels of superoxide dismutase (SOD), reduced glutathione (GSH), and matrix metalloprotease-2 (MMP-2), in MDA-MB-231 cells. Moreover, it inhibited cancer cell migration and colony formation.
 Conclusion: Non-polar fraction of Costus speciosus (NP) exerted cytotoxic effect on triple negative breast cancer cells (MDA-MB-231) and positive ER (MCF-7). It inhibited cancer cell migration and colony formation. Interestingly, NP arrested the breast cancer cell cycles at sub-G1 phase, inhibited SOD and MMP-2, and decreased GSH levels. It induced apoptosis via DNA damage, downregulation of mutant p53, and over-expressions of the cell cycle inhibitors p21 and p27.
 
 
 

Quantitative CK19 biomarker detection in breast cancer cell lines.

Cytokeratin19 (CK19) was detected as the most related marker for circulating tumor cells, which was assessed in specific cell lines. MCF7, SKBR3, T47D, and MDA-MB-231, and HeLa cell line as negative control were used. CK19 expression was confirmed by using mouse monoclonal anti-human CK19 antibody. CK19 detection in MDA-MB-231 was not observed. CK19 marker expression was compared in T47D, MCF7, and SKBR3 cell lines. T47D and MCF7 belonged to the luminal subtype of breast cancer (BC) that CK19 expression regulated with an ER marker. SKBR3 belonged to the HER2 positive subtype of BC. However, MDA-MB-231 belonged to the claudin-low subtype of BC that lack of CK19 expression strongly is related to negative ER, PR, and HER2. Therefore, there are not only quantitative differences in CK19 expression, but its expression could also link to the other markers of BC that should be considered in the molecular classification of breast carcinoma. Different expression levels related to cell classification could be useful in the prognosis and treatment of cancers with epithelial origins.

Scoping Review: Relationship between Overweight and Obesity with Triple Negative Breast Cancer in Woman

Breast cancer is still one of the main problems for global public health. Breast cancer has several pathological characteristics, including triple negative breast cancer (TNBC) characterized by negative ER, PR, HER2 results and has a poor prognosis. Risk factors for TNBC are closely related to Body Mass Index (BMI) as an individual description of obesity. It is known in women, overweight and obesity can trigger breast cancer. This study aims to analyze the relationship between overweight and obesity based on BMI with the incidence of TNBC in women. This study used a scoping review to analyze scientific writings from three data sources, they are PubMed, ScienceDirect and SpringerLink. In the initial search, 797 articles were generated, then adjusted according to the inclusion, exclusion and eligibility criteria to produce 5 articles summarized in the PRISMA diagram. Of the five articles that were predominantly conducted in Asia, four articles stated that women with a BMI ≥25 kg/m2 had a higher risk of TNBC. One article stated that the risk factors for TNBC can be assessed from waist circumference other than BMI. In addition, there is one article that mentioned the opposite, there is no relationship between BMI at the age of 25-54 years and TNBC. The conclusion of this study is that obesity have a relationship with the incidence of TNBC in women.

Nucleolus assessment in invasive breast carcinoma, an objective parameter for histological grading.

The nucleolus has the potential to provide insight into how many types of cancer will progress. In this study, we examined the evaluation of the nucleolus with a microscope in widespread breast cancer tumors and whether this value contributes to tumor grading as an objective clinicopathological parameter. In our study, the nucleolus was evaluated retrospectively in resections with a diagnosis of invasive breast carcinoma of the cases between January 2010 and April 2021. In total, the tumor nucleolus of 377 cases of invasive breast carcinoma was evaluated. Nucleolus evaluation was performed with light microscopy using four different modes (modified Helpap method, in 1, 5, and 10 high power fields at 40x magnification). The relationship between nucleolar scores and clinicopathological parameters was examined separately. Regrading was performed by replacing nuclear pleomorphism with the nucleolar score in the classically used histological grading system and utilizing the nucleolus score as the fourth parameter in this grading system. There was no significant correlation between the prognosis of the patients and the nucleolar score. When nuclear pleomorphism and nucleolar score were replaced in the classical grading system, disease-free and overall survival were correlated with the new grading system. In addition, a relationship was found between high nucleolus score and other clinicopathological parameters (such as estrogen receptor negativity, progesterone receptor negativity, high Ki-67, triple negative, and human epidermal growth factor receptor-2 status). The presence of nucleolus is associated with disease-free survival and overall survival of patients, and it can be evaluated with a light microscope at no extra cost and time. Therefore, in the classical grading, using it instead of nuclear pleomorphism with low reproducibility among pathologists may provide more objective results in predicting patient prognosis.

Association of vitamin D deficiency and inflammatory cytokines with the clinicopathological features of breast cancer in female Saudi patients

Breast cancer is the leading cause of cancer-related death among women in Saudi Arabia. Many studies have suggested a strong correlation between vitamin D and multiple types of cancer. This study included 100 female Saudi patients with early or locally advanced breast cancer. Patients were recruited from King Faisal Hospital in Taif City, Saudi Arabia, from January 2020 to September 2020. We aimed to study the association between serum vitamin D, calcium, interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and chemerin and breast cancer progression. The control group consisted of 100 healthy individuals. Serum levels of vitamin D, calcium, IL-6, TNF-α and chemerin were measured in all participants. Vitamin D was significantly decreased in patients with high-grade tumours ( p < 0.0001), obesity ( p = 0.013), negative oestrogen receptors ( p < 0.0001), negative progesterone receptors ( p < 0.0001) and positive HER2 receptors ( p < 0.0001). Vitamin D was also decreased in patients with large tumours ( p < 0.0001), axillary lymph node involvement ( p < 0.0001) and advanced-stage cancers ( p < 0.0001). Moreover, higher levels of IL-6, TNF-α and chemerin were significantly associated with the presence of breast cancer, particularly in its advanced stages. Vitamin D deficiency and elevated levels of IL-6, TNF- α and chemerin were associated with adverse clinicopathological features of breast cancer. Vitamin D deficiency and elevated inflammatory cytokines (IL-6, TNF-α and chemerin) were associated with the clinicopathological features of breast cancer in female Saudi patients.

Prognostic Factors in Patients with Breast Cancer Liver Metastases (BCLM) Undergoing Liver Resection: Systematic Review and Meta-Analysis

Introduction: Surgical treatment of Breast Cancer Liver Metastasis (BCLM) is debated. We perform a systematic review and meta-analysis of prognostic factors on survival after hepatic resection for BCLM. Methods: An electronic search was performed using PubMed/MEDLINE and Cochrane library databases. Two independent reviewers screened the titles and abstracts. Qualitative and quantitative evaluation of included studies was performed. The pooled effect was calculated using the random-effects model. Results: Thirty-five publications reported analysis on the role of prognostic factors influencing survival after hepatic resection for BCLM and were included in the meta-analysis. Two thousand seven hundred eighty-two patients underwent liver resection for BCLM. The positivity of the axillary lymph nodes at breast cancer diagnosis and the negative Estrogen Receptor status were survival unfavorable factors (HR 1.74, CI 95% 1.25 to 2.41, I2=0% and HR 2.09, CI 95% 1.40 to 3.12, I2=0%). Cumulative HR for predictive factors (multiple liver metastases, size of the metastasis, short interval between primary tumour and onset of liver disease, resection margin and presence of extrahepatic disease) related to the BCLM pattern was 1.32 (CI 95% 1.17 to 1.48, I2=71%) and 1.51 (CI 95% 1.15 to 1.98, I2=76%) for surgical and pathological features. Conclusion: Surgical treatment of BCLM is an option with survival advantages for selected patients. For better long-term results, surgical selection should consider both primary tumour and BCLM features. N0 stage at breast diagnosis, metachronous disease limited to the liver, single BCLM, and highly achievable R0 liver resection may determine the ideal candidate to resection.

Outcome of Breast Cancer Management Comparative Cross Sectional Study in Sudan and Greece

Introduction: Prognosis of breast cancer depends mainly on early detection of the disease it is also well known the stage at diagnosis is inversely associated with the five-year survival rate nodal involvement is main prognostic factor. Other factors are associated with the prognosis of breast cancer like the molecular subtype of the tumor, socioeconomic status of the patient, and the modalities of treatment received. The management of the patient is going to be planned according to stage at diagnosis, aggressiveness of the breast cancer disease; of course, the timing of investigation and treatment is influenced by the socioeconomic status of the patient. We have recorded invasive or non- invasive breast cancer at the time of diagnosis, site of the disease right, left or bilateral, type of surgery. Comparison of these factors in two countries both of them they have no national screening program for breast cancer like Sudan and Greece, but there is difference in population education. The breast cancer patients in Greece are treated at specialized breast units and in Sudan patients are treated in general hospitals by general surgeons. General objectives: To evaluate different modalities of breast cancer treatment set up and outcomes of breast cancer in both countries Sudan and Greece. Methods: The study is a comparative cross sectional case control study performed at Bashair Alneelain University Teaching & Elsharif Hospitals in Sudan, Hippokrateion General Hospital of the University of Athens and Alexandra General Hospital of the University of Athens in Greece. Inclusion criteria: included female patients that were diagnosed with breast cancer underwent appropriate treatment and with five years survival rate. The study compared 100 breast cancer patients from Sudan and 94 breast cancer patients from Greece. Control 100 female patients from Sudan and 66 female patients from Greece diagnosed with a benign disease of the breast. Informed consent was obtained in all cases. Results: The first result we found more invasive breast cancer in Sudan than in Greece (42.27%), and (9.28%) for noninvasive than Greece (29.8%), and (19.07%) respectively, the p-value of chi-square test (.001) more bilateral breast cancer in Greek patients. There is significant increase of mastectomy in Sudan than in Greece, more chemotherapy on the other hand more conservative breast surgery and hormonal therapy in Greece and recurrence occurs on the contralateral breast. Conclusion: Breast cancer patients in Sudan presents at late stage, younger age group with negative estrogen receptors tumors and higher rate of local recurrence. Breast cancer cases in Greece are diagnosed at earlier stage and old age group than in Sudan, bilateral, estrogen receptors positive treated with hormonal therapy and conservative breast surgery. Management of breast cancer at specialized breast clinics gives better outcome even in countries where there is no national screening program for early detection of breast cancer.

High grade breast ductal carcinomas have high density of tumor-associated macrophages.

The role of tumor-associated macrophages (TAMs) is double-natured and still controversial. Depending on different settings, macrophages may suppress or promote tumor growth. TAM density may be one of the predictive factors of treatment outcome in cancer patients. To evaluate the density of tumor-associated macrophages in breast cancer and its relationship with various histopathologic findings. 55patients with invasive ductal carcinoma of breast who underwent mastectomy were enrolled. Sections of tumor samples were stained and the density of CD68+ cells was evaluated. There was anassociation between estrogen receptor (ER) expression and CD68density (p = 0.010) as the higher densities of CD68were seen inER negative tumors. Moreover, there was a significant relationship between histological grade and CD68density (p =0.006). The higher TAM density is associated with higher tumor grade and negative ER expression in breast cancer tissues. These findings revealed that inflammation could have an important role in malignancies.

Clinical Significance of Serglycin Expression in Human Breast Cancer Patients.

Serglycin plays a crucial role in the aggressiveness of several types of malignancies, including breast cancer. In this study, we aimed to investigate the prognostic impact of serglycin expression in breast cancer patients, which has not been previously reported. Immunohistochemical analyses were performed on 348 resected specimens of invasive carcinomas, using antibodies against serglycin. Low serglycin expression was observed in 23% of specimens (80/348) and significantly correlated with high histological grade (p=0.001) and negative ER (p=0.013). The log-rank test showed that low serglycin expression correlated with shorter distant metastasis-free survival (DMFS) (p=0.016) and disease-specific survival (DSS) (p=0.037) in node-positive breast cancer patients. Cox's multivariate analysis revealed that low serglycin expression was an independent factor for shorter DMFS (p=0.017) and DSS (p=0.020) in node-positive breast cancer patients. Low serglycin expression is an independent predictor of unfavorable prognosis in node-positive breast cancer patients.

Correlation of breast cancer microcirculation construction with tumor stem cells (CSCs) and epithelial-mesenchymal transition (EMT) based on contrast-enhanced ultrasound (CEUS).

This study is to explore the correlation between the contrast-enhanced ultrasound (CEUS) characteristics of breast cancer and the epithelial-mesenchyme transformation (EMT). Totally 119 patients of breast cancer underwent CEUS. Tissues in the active area were collected and subjected to the immunohistochemical detection, PT-PCR and Western blot. Correlation analysis was conducted between the clinical pathological parameters and the CEUS indicators. The expression levels of CD44, N-cadherin, and β-catenin in breast cancer tissues were higher than those in adjacent tissues (P<0.05). However, the expression levels of CD24 and E-cadherin in breast cancer tissues were lower than those in adjacent tissues (P<0.05). There was no significant difference in E-cadherin mRNA and Vimentin levels between cancer and adjacent tissues (P>0.05). The expressions were up-regulated in the CSCs, with higher histological grade, lymph node metastasis, and negative estrogen receptor (ER) expression. Smaller breast tumors, with no lymph node metastasis, lower clinical stage, and positive ER expression, tended to exhibit the up-regulated epithelial phenotype. Breast tumors, with high histological grade, lymph node metastasis, high clinical staging grade, and negative ER expression, tended to exhibit the up-regulated interstitial phenotype. The peak intensity of the time-intensity curve (TIC) for the CEUS was positively correlated with the CSC marker CD44 and the interstitial phenotype marker N-cadherin. The starting time of enhancement was negatively correlated with the N-cadherin. Area under the curve was positively correlated with the expression of CD44 and N-cadherin, while negatively correlated with the epithelial phenotype marker β-catenin. The time to peak was negatively correlated with the interstitial phenotypes Vimentin and N-cadherin, with no correlation with the E-cadherin or β-catenin. Breast cancers show the enlarged lesions after enlargement and perfusion defect for the CEUS. The fast-in pattern, high enhancement, and high perfusion in the TIC are correlated with the CSCs and EMT expressions, suggesting poor disease prognosis.

The high methylation level of a novel 151-bp CpG island in the ESR1 gene promoter is associated with a poor breast cancer prognosis

BackgroundThe ESR1 gene suffers methylation changes in many types of cancers, including breast cancer (BC), the most frequently diagnosed cancer in women that is also present in men. Methylation at promoter A of ESR1 is the worse prognosis in terms of overall survival; thus, the early detection, prognostic, and prediction of therapy involve some methylation biomarkers.MethodsTherefore, our study aimed to examine the methylation levels at the ESR1 gene in samples from Mexican BC patients and its possible association with menopausal status.ResultsWe identified a novel 151-bp CpG island in the promoter A of the ESR1 gene. Interestingly, methylation levels at this CpG island in positive ERα tumors were approximately 50% less than negative ERα or control samples. Furthermore, methylation levels at ESR1 were associated with menopausal status. In postmenopausal patients, the methylation levels were 1.5-fold higher than in premenopausal patients. Finally, according to tumor malignancy, triple-negative cancer subtypes had higher ESR1 methylation levels than luminal/HER2+ or luminal A subtypes.ConclusionsOur findings suggest that methylation at this novel CpG island might be a promising prognosis marker

Low thyroid hormone receptor alpha-2 (THR\u03b1-2) tumor expression is associated with unfavorable tumor characteristics and high breast cancer mortality

BackgroundThe active thyroid hormone triiodothyronine (T3) has been found to have an estrogen-like effect on breast cancer cells. Thyroid hormone receptor alpha-2 (THRα-2) acts as an antagonist for triiodothyronine (T3) signaling, and a low expression has been associated with unfavorable tumor characteristics and a higher mortality in breast cancer. However, the evidence are not conclusive. The present study evaluates tumor-specific THRα-2 expression in invasive breast cancers and its association with tumor characteristics and long-term mortality in a large population.MethodThe Malmö Diet and Cancer Study (MDCS), a population-based cohort in Sweden that included 17,035 women from 1991 to 1996, was used. Women diagnosed with breast cancer during 1991–2010 were eligible for inclusion. A tissue micro array was constructed from stored tumor material and stained for THRα-2 using immunohistochemistry. Tumors from 654 patients were scored regarding the intensity and the fraction of cells stained, then dichotomized into low or high expression. Date and cause of death were collected up until 2018-12-31. Tumor- and patient characteristics were available from the MDCS. Missing data was imputed using chained equations. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for low vs high expression of THRα-2 related to specific tumor factors. Mortality was evaluated with Kaplan–Meier curves and Cox regression, rendering hazard ratios (HRs). Analyses were also stratified for estrogen receptor (ER) status.ResultsWe found strong evidence of an association between low THRα-2 and unfavorable tumor characteristics, including estrogen receptor negativity: OR 4.04 (95% CI 2.28–7.15) and tumor size > 20–50 mm: OR 2.20 (95% CI 1.39–3.49). We found evidence of increased breast cancer-specific mortality for women with low THRα-2, HR 1.38 (95% CI 0.96–1.99), which remained after adjusting for age at diagnosis, HR 1.48 (95% CI 1.03–2.14), but not after adjusting for relevant prognostic factors, HR 0.98 (95% CI 0.66–1.45). THRα-2 expression in ER-negative tumors had an inverse correlation with overall mortality, HR 0.27 (95% CI 0.11–0.65).ConclusionLow tumor-specific THRα-2 expression was in this study associated with prognostically unfavorable tumor characteristics and a higher mortality in breast cancer, but not independent from other prognostic factors.

Breast Cancer in Chinese Females Aged 25 Years and Younger.

Background Breast cancer has both aggressive clinicopathological characteristics and a poor prognosis in young females. However, limited information is available for breast cancer in Chinese females aged ≤25 years. Therefore, we aimed to explore prognostic factors for invasive disease-free (iDFS) and overall survival (OS) among breast cancer patients aged ≤25 years. Methods We retrospectively analyzed data from 174 Chinese females aged ≤25 years with invasive breast cancer treated in the Cancer Hospital of the Chinese Academy of Medical Sciences from January 1, 1999, to December 31, 2018. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors. Results The median follow-up time was 75 months (ranging from 1 to 236 months). Breast cancer patients aged ≤25 years exhibited aggressive clinicopathological characteristics, including advanced tumor stage (21.8%), lymph node metastasis (47.1%), lymphovascular invasion (24.1%), estrogen receptor negativity (44.3%), progesterone receptor (PR) negativity (42.5%), and triple-negative breast cancer (25.3%). Among them, 50 cases had locoregional recurrence and metastasis, 20 had bilateral invasiveness, and 33 had breast cancer-specific deaths. Cox multivariate analysis identified that diagnosis delay, PR status, and radiotherapy were significant prognostic factors for both iDFS and OS (P < 0.05). The risk of recurrence and metastasis was five times higher in N3 than in N0 (HR: 6.778, 95% CI: 2.268–17.141, P < 0.001). Patients with lymphovascular invasion had a threefold increase in the risk of breast cancer-specific death (HR: 4.217, 95% CI: 1.956–9.090, P < 0.001). No differences were observed between mastectomy and breast-conserving surgery (BCS) plus radiotherapy for iDFS or OS (iDFS: χ2 = 0.678, P=0.410; OS: χ2 = 0.165, P=0.685). Conclusions Breast cancer in females ≤25 years old was associated with aggressive clinical features and a worse prognosis. Young females with breast lumps should receive timely diagnosis and treatment. Young breast cancer patients with lymphovascular invasion, PR-negative status, and lymph node metastasis have an increased risk of experiencing recurrence and metastasis and should hence be closely monitored. Age at diagnosis should not be the sole deciding factor for surgical treatment methods.

Predicting axillary response to neoadjuvant chemotherapy: the role of diffusion weighted imaging.

The aim of this study is to investigate whether the primary tumour response to neoadjuvant chemotherapy (NAC), based on the increase in the ADC-values (apparent diffusion coefficient) within the breast lesion, could help to predict axillary complete response. We retrospectively included 74 patients who were treated with NAC followed by surgery at Lucus Augusti Hospital between January 2015 and September 2020. Simple logistic regression was used to evaluate the factors associated with axillary pathological complete response, including the changes in breast tumour ADC-values due to the treatment. Axillary complete response was correlated with negative oestrogen receptor status, Her2 positivity and response of primary tumour. It was achieved in 31% of the patients. In addition, the increase in the tumour ADC-values with NAC was higher for responders. Among the tumours that demonstrated an increase in ADC-value >0.92 ×10-3 mm2/s, 42.8% (15/35) showed axillary complete response. Eight (20.5%) breast cancers with an increase in ADC below the cut-off value were found to have no metastatic nodes after treatment (p = 0.038). Our results suggest that the performance of models predicting axillary response to NAC can be improved by adding the tumour response determined also using diffusion-weighted imaging. For the fist time, we investigate the relation between tumour response to NAC, assessed using diffusion-weighted imaging, and axillary pathologic complete response.

ASSOCIATION OF STEROID RECEPTOR EXPRESSION WITH THE CLINICAL AND HISTOLOGICAL FINDINGS IN PATIENTS WITH ENDOMETRIAL CANCER

Objective: To determine the association of estrogen and progesterone receptor expression with the clinical and histological findings of endometrial cancer.&#x0D; Study Design: Prospective observational study.&#x0D; Place and Duration of Study: Jinnah Postgraduate Medical Centre, Karachi between Sep 2017 to Oct 2019.&#x0D; Methodology: A total of 130 patients were diagnosed with endometrial carcinoma. Data from patient files were collected regarding tumour histology, grade, stage, tumour receptor expression, and the clinical characteristics: parity, menopausal status. The receptor expression profile was documented for each patient. Data were analyzed using SPSS version 25. The association between ER/PR expression categories and clinical/histological features were explored using the chi-square test.&#x0D; Results: The estrogen and progesterone receptor expressions were significantly associated with low-grade (Grade I and II) tumours and with Stage I and Stage II endometrial carcinoma with p&lt;0.001. About 34 (34.7%) cases of endometrioid histology were negative for both estrogen and progesterone receptors. The ER and PR negativity was strongly associated with Grade III endometrial cancer (p=0.003). The majority of the stage IV cancers were negative for both the ER and PR receptors with a p&lt;0.001.&#x0D; Conclusion: Estrogen and progesterone positivity was associated with endometrioid adenocarcinoma, well-differentiated, and less advanced stage of endometrial cancer at the time of diagnosis.

Prognostic value of metabolic activity of the psoas muscle evaluated by preoperative 18F-FDG PET-CT in breast cancer: a retrospective cross-sectional study

BackgroundThis study aimed to evaluate the potential of metabolic activity of the psoas muscle measured by 18F-fluorodeoxyglucose positron emission tomography-computed tomography to predict treatment outcomes in patients with resectable breast cancer.MethodsThe medical records of 288 patients who had undergone surgical resection for stages I–III invasive ductal carcinoma of the breast between January 2014 and December 2014 in Pusan National University Hospital were reviewed. The standardized uptake values (SUVs) of the bilateral psoas muscle were normalized using the mean SUV of the liver. SUVRmax was calculated as the ratio of the maximum SUV of the average bilateral psoas muscle to the mean SUV of the liver. SUVRmean was calculated as the ratio of the mean SUV of the bilateral psoas muscle to the mean SUV of the liver.ResultsUnivariate analyses identified a higher T stage, higher N stage, estrogen receptor negativity, progesterone receptor negativity, human epidermal growth factor receptor 2 positivity, triple-negative breast cancer, mastectomy (rather than breast-conserving surgery), SUVRmean > 0.464, and SUVRmax > 0.565 as significant adverse factors for disease-free survival (DFS). Multivariate Cox regression analysis revealed that N3 stage (hazard ratio [HR] = 5.347, P = 0.031) was an independent factor for recurrence. An SUVRmax > 0.565 (HR = 4.987, P = 0.050) seemed to have a correlation with shorter DFS.ConclusionsA higher SUVRmax of the psoas muscle, which could be a surrogate marker of insulin resistance, showed strong potential as an independent prognostic factor for recurrence in patients with resectable breast cancer.