Poor Nottingham Prognostic Index Research Articles

Clinicopathological Significance of Cyclin-Dependent Kinase 2 (CDK2) in Ductal Carcinoma In Situ and Early-Stage Invasive Breast Cancers.

Cyclin-dependent kinase 2 (CDK2) is a key cell cycle regulator, with essential roles during G1/S transition. The clinicopathological significance of CDK2 in ductal carcinomas in situ (DCIS) and early-stage invasive breast cancers (BCs) remains largely unknown. Here, we evaluated CDK2's protein expression in 479 BC samples and 216 DCIS specimens. Analysis of CDK2 transcripts was completed in the METABRIC cohort (n = 1980) and TCGA cohort (n = 1090), respectively. A high nuclear CDK2 protein expression was significantly associated with aggressive phenotypes, including a high tumour grade, lymph vascular invasion, a poor Nottingham prognostic index (all p-values < 0.0001), and shorter survival (p = 0.006), especially in luminal BC (p = 0.009). In p53-mutant BC, high nuclear CDK2 remained linked with worse survival (p = 0.01). In DCIS, high nuclear/low cytoplasmic co-expression showed significant association with a high tumour grade (p = 0.043), triple-negative and HER2-enriched molecular subtypes (p = 0.01), Comedo necrosis (p = 0.024), negative ER status (p = 0.004), negative PR status (p < 0.0001), and a high proliferation index (p < 0.0001). Tumours with high CDK2 transcripts were more likely to have higher expressions of genes involved in the cell cycle, homologous recombination, and p53 signaling. We provide compelling evidence that high CDK2 is a feature of aggressive breast cancers. The clinical evaluation of CDK2 inhibitors in early-stage BC patients will have a clinical impact.

Relationship of Nottingham Prognostic Index with prognostic parameters of breast carcinoma

Background: Breast cancer (BC) is the commonest malignancy in the female and it is gaining its significance due to worldwide rising incidence. It is also important due to 2.5% higher incidence in Pakistan as compared to neighbouring countries. Nottingham prognostic index (NPI) is an important prognostic factor of BC. It provides information about survival and morbidity. There are significant variations in different studies. Aim: To carry out current study relating NPI with various histopathological parameters of BC. Methods: This was a descriptive cross-sectional study. The study was done at the Department of Pathology, King Edward Medical University Lahore with the collaboration of four surgical units of Mayo Hospital Lahore from 2010 to 2019. Total 137 cases of breast carcinoma were included. Information about age, grade, primary tumor size, axillary lymph node status and stage was entered in the pre designed proforma. NPI was calculated as 0.2xtumor size(cm)+lymph node grade. NPI was scored as excellent, good, moderate and poor and its correlation was calculated against primary tumor size, lymph node grade, tumor grade and stage. Results: We studied 137 cases of breast carcinoma with mean age 49.32±11.64 years. Mean NPI was 5.4±1.4 with range of 2.4 to 9.4. NPI scores in poor 65(47.4%) and moderate 61(44.5%) groups were significantly high as compared to good 10(7.3%) and excellent scores 1(0.7%). Most of the cases of poor NPI were in p T3 and p T4 whereas this was p T2 with moderate score. Poor score of NPI was significant in grade 3 which is in contrast to moderate score where grade 2 dominated the picture. Correlation of NPI with LNG was in favor of LNG 1 with good and moderate scores while LNG3 dominated in the poor group. In stage III, 49 cases (35.8%) were seen with poor score of NPI. Conclusion: NPI is an important prognostic parameter and it can be studied with different histopathological parameters to see correlation between them. In the current study majority of the cases of NPI scored at poor and moderate levels. Correlation coefficient was linear, strong and positive especially with LNG. Mean NPI has ascending correlation with these parameters. Thus NPI can be used as a prognostic indicator when comparing with histopathological parameters of BC. Keywords: Breast cancer, NPI, tumor grade, tumor stage, LNG

Abstract 5405: Expression of cathepsin D in early-stage breast cancer and its prognostic and predictive value

Abstract Purpose: Cathepsin D is a proteolytic enzyme that is normally localized in the lysosomes and is involved in the malignant progression of breast cancer. The expression of Cathepsin D is regulated by steroid hormones including oestrogen and growth factors. There are conflicting results between different studies regarding Cathepsin D significance as prognostic and predictor marker in breast cancer. Furthermore, Cathepsin D has not been recommended for clinical use by the American Society of Clinical Oncology because of insufficient evidence. This study was aimed to fill the gap in the lack of recent and large studies on prognostic significance of Cathepsin D expression by studying a large well-characterized series of primary breast cancer for cathepsin D expression using immunohistochemistry. Methods: Expression of Cathepsin D was assessed by immunohistochemical staining of tissue microarrays, in a large well-characterized series of early-stage operable breast cancer (n=954) from Nottingham Primary Breast Carcinoma Series between the period of 1988 and 1998 who underwent primary surgery. Correlation of cathepsin D expression with clinicopathological parameters and prognosis was evaluated. Results: Cathepsin D expression was positive in 28.8% (275/954) of breast cancer tumors. Positive expression of cathepsin D was significantly associated with high histological grade (p=0.007), pleomorphism (p=0.002), poor Nottingham Prognostic Index score (NPI) (p&amp;lt;0.002), recurrence (p=0.005) and distant metastasis (p&amp;lt;0.0001). Kaplan-Meier analysis showed that Cathepsin D expression was significantly associated with shorter breast cancer specific survival (BCSS) (p=0.001), higher risk of recurrence (p=0.001) and distant metastasis (p&amp;lt;0.0001). Cathepsin D positive tumors with ER positive staining who were treated with tamoxifen were associated with lower BCSS and higher risk of developing distant metastasis (p=0.001). Conclusion: This study shows Cathepsin D expression as a promising prognostic biomarker for early operable invasive breast cancer. Our results indicate that Cathepsin D expressing tumors are associated with shorter breast cancer specific survival and higher risk of recurrence and metastasis. Cathepsin D could be clinically useful to predict response to tamoxifen treatment. Targeting Cathepsin D either through inhibition of action or interference with the proteolytic pathway could be used to treat metastatic breast cancers expressing Cathepsin D. Citation Format: Inas M. Alhudiri, Christopher C. Nolan, Ian O. Ellis, Emad A. Rakha, Adam Elzagheid, Andrew R. Green, Caroline J. Chapman. Expression of cathepsin D in early-stage breast cancer and its prognostic and predictive value [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5405.

Significance of CD133 Expression in Invasive Ductal Carcinoma of the Breast

Background and Aim: Cancer stem cells (CSCs) are thought to be responsible for tumor initiation, progression, and resistance to chemotherapy and radiotherapy. CD133 is a trans-membrane glycoprotein which is considered as a putative CSCs marker. Emerging evidence suggests that CD133 may be a critical factor in tumor development, progression and metastasis. The aim of this study was to evaluate the expression of CD133 in mammary infiltrating ductal carcinoma (IDC), and to correlate its expression with some known clinicopathological parameters. Methods: Fifty patients with mammary IDC who underwent modified radical mastectomy were included in this study. From each specimen, two tissue sections were obtained; one was stained by hematoxylin and eosin (H&amp;E) stain to determine the histologic subtype, grade and indicators of local aggressiveness. The second tissue section was immunohistochemically stained by anti-human CD133 antibody. Results: The study revealed statistically significant associations between CD133 expression and poorly differentiated, advanced stage tumors with poor Nottingham Prognostic Index (NPI), triple negative phenotype, lymphovascular invasion (LVI) and lymph node metastasis (LNM). Conclusion: The current study revealed that CD133 is strongly associated with poor prognostic indices; it is positively correlated to poorly-differentiated tumors with high histologic grade and advanced stage&#x0D;

Prognostic significance of heat shock protein 90AA1 (HSP90α) in invasive breast cancer

AimsThe mechanisms that drive breast cancer (BC) progression and poor outcome are not fully understood. The human heat shock protein 90 alpha family class A member 1 (HSP90α) encoded by...

The ITIM-Containing Receptor: Leukocyte-Associated Immunoglobulin-Like Receptor-1 (LAIR-1) Modulates Immune Response and Confers Poor Prognosis in Invasive Breast Carcinoma.

Simple SummaryBreast cancer exhibits significant genetic and clinical heterogeneity. Given the importance of understanding tumour-immune interactions to enable the development of novel immunotherapies, identification of novel prognostic biomarkers is important for accurate predictions of the breast cancer patient’s outcome and treatment decisions. The aim of this retrospective study was to assess the potential prognostic value of the leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1), a collagen-binding immunoreceptor tyrosine-based inhibition motifs (ITIM)-bearing inhibitory receptor, that plays an important role in the regulation of the immune system and tumour progression. Our study highlights the importance of LAIR-1 expression and the role of the immune microenvironment in breast cancer progression and worse clinical outcome. Further functional investigation warrants understanding the crosstalk between immune checkpoint blocking agents, immune microenvironment and its underlying mechanisms for targeted therapy development.Background: The leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) plays a role in immune response homeostasis, extracellular matrix remodelling and it is overexpressed in many high-grade cancers. This study aimed to elucidate the biological and prognostic role of LAIR-1 in invasive breast cancer (BC). Methods: The biological and prognostic effect of LAIR-1 was evaluated at the mRNA and protein levels using well-characterised multiple BC cohorts. Related signalling pathways were evaluated using in silico differential gene expression and siRNA knockdown were used for functional analyses. Results: High LAIR-1 expression either in mRNA or protein levels were associated with high tumour grade, poor Nottingham Prognostic Index, hormone receptor negativity, immune cell infiltrates and extracellular matrix remodelling elements. High LAIR-1 protein expression was an independent predictor of shorter BC-specific survival and distant metastasis-free survival in the entire BC cohort and human epidermal growth factor receptor 2 (HER2)+ subtype. Pathway analysis highlights LAIR-1 association with extracellular matrix remodelling-receptor interaction, and cellular proliferation. Depletion of LAIR-1 using siRNA significantly reduced cell proliferation and invasion capability in HER2+ BC cell lines. Conclusion: High expression of LAIR-1 is associated with poor clinical outcome in BC. Association with immune cells and immune checkpoint markers warrant further studies to assess the underlying mechanistic roles.

Relationship of Oncotype Dx score with tumor grade, size, nodal status, proliferative marker Ki67 and Nottingham Prognostic Index in early breast cancer tumors in Saudi Population

BackgroundOncotype Dx is a 21-gene recurrence score, which is used as a diagnostic tool for the recurrence of breast cancer. It is also used to determine the benefit of chemotherapy for breast cancer in early stages. This study investigates the relationship of Oncotype Dx with pathological prognostic markers of protein Ki 67, Nottingham Prognostic Index (NPI) and tumor grade. MethodsData for early breast cancer patients treated at our tertiary care center was collected for statistical analysis. Data for patients from 2014 to 2018 was recorded for patient's age, ER/PR status, Ki 67, nodal status, tumor grade, NPI along with Oncotype Dx score. Metric measurements were described as mean ± SD and the non-metric data was represented by frequency (%). Chi-square or Fisher's exact tests as well as logistic regression was applied to assess the associations at 95% CI. ResultsAmong 156 breast cancer patients, the mean age was 55.7 ± 9.4 years. The tumors were classified into Grade-I (12.8%), Grade-II (67.3%) and Grade-III (19.9%). Ki67 score was 12.8 ± 12.0 and NPI score was 3.7 ± 0.8. The mean Oncotype Dx score was 17.0 ± 9.1; it was 14.1 ± 6.8 for Grade-I tumors; 15.7 ± 7.5 for grade -II tumors; and 23.2 ± 12.3 for grade-III tumors [Mean Oncotype Dx score across Tumor grades was compared by ANOVA (η = 0.121), p < 0.001]. While logistic regression analyses for the dichotomized Oncotype Dx higher score (≥25) was significantly associated with grade-III tumors odds ratio (OR) = 13.72 (95% CI: 1.62–115.89), higher Ki67 (>20) OR = 14.40, (95% CI: 1.44–143.71), average NPI score (2.41–3.40), OR = 13.60, (95% CI: 1.57–117.94) to poor NPI (>5.4). The association of Oncotype Dx with age, tumor size and nodal status was statistically not significant. ConclusionsThis study revealed that age, Ki67, tumor size and nodal status did not have a statistically significant impact on Oncotypye Dx recurrence score in the targeted patient population. There was a significant correlation of low grade node negative patients with Oncotype Dx while high grade node negative patients had poor correlations with Oncotype Dx. The use of Oncotype Dx has shown to be less cost-effective and has no noticeable association with improved life expectancy in the targeted patient population (i.e., hormone positive, node negative cases) in comparison with current clinical practices in Saudi Arabia and it is less likely to be cost-effective in this group of patients.

Nucleolar protein 10 (NOP10) predicts poor prognosis in invasive breast cancer

PurposeNucleolar protein 10 (NOP10) is required for ribosome biogenesis and telomere maintenance and plays a key role in carcinogenesis. This study aims to evaluate the clinical and prognostic significance of NOP10 in breast cancer (BC).MethodsNOP10 expression was assessed at mRNA level employing the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n = 1980) and Cancer Genome Atlas (TCGA) BC cohorts (n = 854). Protein expression was evaluated on tissue microarray of a large BC cohort (n = 1081) using immunohistochemistry. The correlation between NOP10 expression, clinicopathological parameters and patient outcome was assessed.ResultsNOP10 expression was detected in the nucleus and nucleolus of the tumour cells. At the transcriptomic and proteomic levels, NOP10 was significantly associated with aggressive BC features including high tumour grade, high nucleolar score and poor Nottingham Prognostic Index. High NOP10 protein expression was an independent predictor of poor outcome in the whole cohort and in triple-negative BC (TNBC) class (p = 0.002 & p = 0.014, respectively). In chemotherapy- treated patients, high NOP10 protein expression was significantly associated with shorter survival (p = 0.03) and was predictive of higher risk of death (p = 0.028) and development of distant metastasis (p = 0.02) independent of tumour size, nodal stage and tumour grade.ConclusionHigh NOP10 expression is a poor prognostic biomarker in BC and its expression can help in predicting chemotherapy resistance. Functional assessments are necessary to decipher the underlying mechanisms and to reveal its potential therapeutic values in various BC subtypes especially in the aggressive TNBC class.

Tumor-infiltrating lymphocytes are associated with poor prognosis in invasive lobular breast carcinoma

The prognostic impact of tumor-infiltrating lymphocytes (TILs) within invasive lobular carcinoma (ILC) remains to be better characterized. In estrogen receptor (ER)-negative invasive ductal carcinomas of no special type (IDC-NST), TILs are associated with good prognosis. The aim of this study was to examine TILs in ILC, with particular focus on prognostic and clinicopathologic features. A cohort comprising 459 consecutive ILCs diagnosed in a single institution from 2005 to 2008 met the eligibility criteria for this study. The percentage of tumor area occupied by TILs was quantified by two breast pathologists and categorized into three groups: no TILs, ≤5%, >5%. Clinicopathologic features were tested by Fisher's exact tests or Chi2 tests. Overall survival (OS) and invasive disease-free survival (iDFS) were estimated by Kaplan–Meier and Cox proportional hazard statistics. There were 239 TIL-negative cases, 185 cases with ≤5% TILs, and 35 cases with >5% TILs. TILs were associated with younger age, larger tumors, lymph node involvement, poor Nottingham prognostic index, HER2 amplification, multinucleation, and prominent nucleoli (p < 0.05). Poor OS was significantly associated with increasing TILs in the univariate Cox proportional hazards model (p < 0.001) and Kaplan–Meier estimator (p < 0.05, log-rank test). Similar results were observed for iDFS (p = 0.004 for Cox univariate and p = 0.005 for log-rank test). Notably, TILs can identify a subset of ILC patients with poor OS independently of molecular subtype and lymph node metastases (multivariate Cox, p < 0.001, OS hazard ratio (HR) = 4.38 and HR = 6.15, for ≤5% and >5% TILs, respectively, vs. absence of TILs). Prominent nucleoli was the only nuclear feature associated with poor OS (p = 0.05) and iDFS (p = 0.05) in univariate Cox survival analysis. TILs represent a promising new morphologic biomarker associated with poor outcome of ILC, in contrast with that observed in ER-negative IDC-NST.

Clinical Significance of Immunohistochemical Expression of Neuropeptide Y1 Receptor in Patients With Breast Cancer in Egypt.

Breast cancer (BC) is the most common malignancy in female individuals worldwide. It constitutes about 38.8% of all malignant tumors among Egyptian female individuals. Neuropeptide Y1 receptor (NPY1R) is one of the most abundant peptides in the central and peripheral nervous systems of mammals. It has been found to promote proliferation, vascularization, and stimulate migration in several cell types and tissues and some types of tumor. This the first immunohistochemical study to evaluate the expression of NPY1R in BC and its correlation with clinicopathologic parameters and patient survival. This study included 92 patients with BC. Immunohistochemical staining for NPY1R was done on paraffin-embedded formalin-fixed tissue sections. Statistically significant increases in NPY1R expression was seen in malignant (46/92; 50%) versus non-neoplastic tissue (12/29; 20.7%) (P<0.001). The receiver operating characteristic curve showed that NPY1R is a poor diagnostic test for BC (P<0.001, area under the curve=0.686) in breast tissue. Membranous was the most common pattern of positivity in carcinoma cases (24/46; 52.2%). Statistically significant associations were found between positive NPY1R expression and the presence of metastatic disease (P<0.001), clinical stage (P=0.0003), perineurial invasion (P=0.003), estrogen receptor expression (P=0.004), molecular subtype (P=0.015), Nottingham Prognostic Index risk group (P=0.04), radiotherapy treatment (P=0.01), hormonal treatment (P=0.015), and type of endocrine therapy (P=0.011). Although no significant association was detected between NPY1R-positive and NPY1R-negative cases regarding overall survival and progression-free survival, cases with non-nuclear (membranous+cytoplasmic) expression showed near significantly shorter survival (P=0.063). This study shows that NPY1R was identified in about 50% of malignant BC cases. Its expression correlates with some features of the aggressive disease being associated with metastasis, perineurial invasion, advanced stages, and poor Nottingham Prognostic Index. This suggests a potential prognostic role of NPY1R in BC. Non-nuclear expression of NPY1R seems to be more important in terms of prognosis of BC.

Expression of CD 133 in Invasive Ductal Carcinoma of Breast.

Background:CD133 is a commonly used cancer stem cell (CSC) marker in breast cancer. However, the association between CD133 expression, with clinicopathological features and prognosis in breast cancer, is poorly understood in the Indian subcontinent. This study was designed to explore the expression of CD 133 in breast carcinoma and to know its association between CD133 and clinicopathological characteristics. Methods:A total of fifty seven cases were included in the study. All the clinicopathological parameters were collected from Department of Pathology archives. Slides, blocks, clinical information, tumor size and axillary lymph node status were obtained from medical records and the pathology reports. Immunohistochemistry was done using CD 133 antibodies. Both Cytoplasmic and membranous staining was taken a positive. Scoring was done based on percentage of positive cells and intensity of staining. MS Excel, SPSS version 22 (IBM SPSS Statistics, Somers NY, USA) was used to analyze data.p value < 0.05 was considered as statistically significant. Results:Statistically significant association between the CD 133 expression and nodal metastasis, tumor stage and Nottingham prognostic index was analysed. There was no statistical correlation between CD 133 expression age, tumor grade and tumor size. The disease free survival showed the mean disease free survival of CD 133 positivity cases was 16months. And the patients who were negative for CD 133 expression had mean survival of 30 months. By the Kaplan Mayer graph it was evident that the more the CD 133 expression the lesser was the disease free survival of the patients. Conclusion: CD 133 expression was seen in 77.08% cases and was associated with tumor stage, lymph node metastasis, poor Nottingham prognostic index and worse disease free survival. An increasing trend of association was seen between CD 133 expression and Age, Tumor Size and Tumor grade.

The prognostic significance of ALDH1A1 expression in early invasive breast cancer.

Aldehyde dehydrogenase family 1 member A1 (ALDH1A1) is reportedly a key ALDH isozyme linked to the cancer stem cells (CSC) of many solid tumours, where it is involved in self-renewal, differentiation and self-protection. In this study, the prognostic significance of ALDH1A1 expression in early invasive breast cancer (BC) and its role as a BC stem cell (BCSC) were evaluated. ALDH1A1 expression was assessed, using immunohistochemistry and tissue microarrays, in a large well-characterised BC cohort. ALDH1A1 mRNA expression was also assessed at transcriptomic levels, utilising data from the Molecular Taxonomy of Breast Cancer International Consortium. The associations of ALDH1A1 with clinicopathological parameters, other stem cell markers and patient outcomes were determined. ALDH1A1 was expressed in 71% of BC cases at both the protein and mRNA levels. High ALDH1A1 expression was associated with poor prognostic features, including high grade, poor Nottingham Prognostic Index (NPI), lymph node metastasis and highly proliferative ER+ (luminal B) and triple-negative (TNBC) subtypes. ALDH1A1 expression was positively correlated with the expression of CD44, CD24, TWIST, SOX9, EPCAM and CD133. The high immunoexpression of ALDH1A1 was significantly associated with poor BC-specific survival (P<0.001), and specifically in the luminal B and TNBC subtypes (P=0.042 and P=0.003, respectively). The immunoexpression of ALDH1A1 was an independent predictor of poor prognosis (P=0.015). ALDH1A1, as assessed using immunohistochemistry, seems to act as a BCSC marker associated not only with other BCSC markers but also with poor prognostic characteristics and poor outcomes, particularly in the luminal B and TNBC subtypes.

The nucleolar-related protein Dyskerin pseudouridine synthase 1 (DKC1) predicts poor prognosis in breast cancer

BackgroundHypertrophy of the nucleolus is a distinctive cytological feature of malignant cells and corresponds to aggressive behaviour. This study aimed to identify the key gene associated with nucleolar prominence (NP) in breast cancer (BC) and determine its prognostic significance.MethodsFrom The Cancer Genome Atlas (TCGA) cohort, digital whole slide images identified cancers having NP served as label and an information theory algorithm was applied to find which mRNA gene best explained NP. Dyskerin Pseudouridine Synthase 1 (DKC1) was identified. DKC1 expression was assessed using mRNA data of Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1980) and TCGA (n = 855). DKC1 protein expression was assessed using immunohistochemistry in Nottingham BC cohort (n = 943).ResultsNuclear and nucleolar expressions of DKC1 protein were significantly associated with higher tumour grade (p < 0.0001), high nucleolar score (p < 0.001) and poor Nottingham Prognostic Index (p < 0.0001). High DKC1 expression was associated with shorter BC-specific survival (BCSS). In multivariate analysis, DKC1 mRNA and protein expressions were independent risk factors for BCSS (p < 0.01).ConclusionDKC1 expression is strongly correlated with NP and its overexpression in BC is associated with unfavourable clinicopathological characteristics and poor outcome. This has been a detailed example in the correlation of phenotype with genotype.

The effect of postoperative complications on survival and recurrence after surgery for breast cancer: A systematic review and meta-analysis.

This systematic review investigated the impact of complications on long term outcomes for patients with primary invasive operable breast cancer. A systematic review was performed using appropriate keywords, and meta-analysis using a random effects model completed. Ten retrospective cohort studies, including 37,657 patients were included. Five studies identified a relationship between wound complications, infection and pyrexia and recurrence or recurrence-free survival. Risk of recurrence, 1-year and 5-year recurrence-free survival and overall survival were related to complications, particularly for patients with poor Nottingham Prognostic Index. Five studies failed to demonstrate a relationship between complications and prognosis. Complication was found to significantly affect 5-year recurrence-free survival (HR 1.48 95 % CI 1.02-2.14, p = 0.04) but not recurrence (HR 2.39, 95 %CI 0.94-6.07, p = 0.07), with a high degree of heterogeneity amongst analysed studies (I2 = 95 %). Further research is needed to quantify the effects of postoperative complication on prognosis following surgery for breast cancer.

Expression of Vascular Cell Adhesion Molecule-1 (VCAM-1) in Invasive Ductal Carcinoma of the Breast

AbstractBackground and Aim: VCAM-1 (CD106) expressed mainly on activated endothelial cells in response to pro-inflammatory cytokines. Recent evidences suggest that it is closely correlated with tumor formation, angiogenesis and cancer progression. The aim of the current study was to evaluate expression status of VCAM-1 in mammary invasive ductal carcinoma (IDC), and to correlate its expression with some known clinicopathological data. Methods: Formalin-fixed paraffin embedded tissue blocks of 58 specimens of IDC were evaluated for VCAM-1 expression by immunohistochemistry (IHC). Correlation of VCAM-1 expression with different clinicopathological data was measured statistically.Results: Up-regulation of VCAM-1 expression was frequently observed in less differentiated tumors and within advanced stages with poor Nottingham prognostic index (NPI). VCAM-1 overexpression was significantly associated with the presence of lymph node metastasis (LNM), lymphovascular invasion (LVI), and prominent lymphocytic infiltration. There was no significant association of VCAM-1 expression with patients' age, tumor laterality, tumor size, muscle or skin invasion, and presence of in situ component.Conclusion: VCAM-1 molecule could promote LVI and LNM. VCAM-1 is a potential independent prognostic factor for breast carcinoma.

Ki 67 Expression in Molecular Sub types of Breast Cancer in Patients of Zagazig University Hospitals

Ki67 representing the proliferation of the cells for the active tumors. Moreover, a lot of studies performed to determine its prognostic role. This study evaluated the significance and prognostic role of Ki67 among molecular subtypes of breast cancer.Methods: Ki67 was measured in 58 cases of primary breast cancers in pathology department of Zagazig University from 2016-2018. These patients were evaluated for Estrogen Receptor, Progesterone Receptor, and HER2. Ki67 was divided to high and low according to percentage levels: < 20% and ≥ 20%.Result: Among 58 cases studied, the patients’ age ranged from 22 to 72 years, (50%) cases were classified luminal A subtype, (24.1%) cases as luminal B, (15.5%) cases as HER2 enriched, and (10.3%) cases triple-negative. Luminal tumors featured a prevalence of lower tumor grades (grades 1and 2), whereas high tumor grade (grade 3) predominated among the HER2-enriched and triple-negative subtypes (66.7% for each). Triple-negative was significantly associated with younger ages. We observed that high expression of Ki67 appears to be associated with tumor size, high histological grade & stage, positive lymph node, distant metastasis, histological type, hormonal receptor negativity and poor Nottingham Prognostic Index. Conclusion: We concluded that Luminal A breast cancer is the most common molecular subtype in patients of Zagazig University Hospitals, similar to other international and local studies, triple-negative subtype is the most aggressive subtype associated with poorer prognostic parameters, and Ki67 may be considered as a valuable biomarker in breast cancer patients.Key words: breast cancer, Ki67, molecular subtypes, prognosis

Phosphorylation of EphA2 receptor and vasculogenic mimicry is an indicator of poor prognosis in invasive carcinoma of the breast.

The occurrence of vasculogenic mimicry (VM) and EphA2-mediated tumour progression are associated with poor prognosis in various solid tumours. Here, we aimed to investigate the prognostic implications of VM and its association with phosphorylated EphA2 receptor in invasive carcinoma of the breast. The patients were stratified based on CD-31/PAS dual staining and subsequently the expression status of phospho-EphA2 (S897), FAK, phospho-ERK1/2 and Laminin 5Ƴ2 was analysed by immunohistochemistry. Survival of patients was correlated within the stratified cohort. The pathologically defined VM phenotype and phospho-EphA2 (S897) expression status were significantly associated with lower disease-free survival (DFS) and overall survival (OS). Both the features were also found to be significantly associated with higher nodal status, poor Nottingham Prognostic Index (NPI) and were more prevalent in the triple-negative breast cancer (TNBC) group. Incidentally, there were no significant association between age of the patient, grade and size of the tumour with VM and phospho-EphA2 (S897). The effector molecules of phospho-EphA2 (S897) viz., Focal Adhesion Kinase (FAK), phospho-ERK1/2 and Laminin 5Ƴ2 were significantly upregulated in the VM-positive cohort. Survival analysis revealed that the VM and phospho-EphA2 (S897) dual-positive cohort had poorest DFS [mean time = 48.313 (39.992-56.633) months] and OS [mean time = 56.692 (49.055-64.328) months]. Individually, VM-positive [Hazard Ratio (HR) 6.005; 95% confidence interval (CI) 2.002-18.018; P = 0.001 for DFS and HR 11.654; 95% CI 3.195-42.508; P < 0.0001 for OS] and phospho-EphA2 (S897)-positive (HR 4.342; 95% CI 1.717-10.983; P = 0.002 for DFS and HR 5.853; 95% CI 1.663-20.602; P = 0.006 for OS) expression proved to be independent indicators of prognosis. This study evaluated tumour dependency on oncogenic EphA2 receptor regulation and VM in invasive carcinoma of the breast and their prognostic significance. Significant correlations between VM, phospho-EphA2 and several clinicopathologic parameters of breast cancer were found. Subsequently, the occurrence of VM or phospho-EphA2 expression proved to be major contributors for poor prognosis in patients with breast cancer but their simultaneous expression failed to be an independent risk factor.

Immunohistochemical Expression of Microfibrillar-associated Protein 5 (MFAP5) in Invasive Breast Carcinoma of No Special Type.

Breast cancer (BC) remains the most prevalent female cancer in Egypt and worldwide. Microfibrillar-associated protein 5 (MFAP5) is a multifunctional glycoprotein. Although MFAP5 gene was among the genes that found globally expressed in human cancers, it had been only recently reported in few cancer research studies. This is a retrospective study that has been conducted on 66 Egyptian patients who had invasive carcinoma of no special type. Immunohistochemical staining for MFAP5 was applied on the archival formalin-fixed paraffin-embedded blocks. Staining was assessed semiquantitatively and correlated with the available clinicopathologic parameters and immunohistochemical subtypes of BC. MFAP5 epithelial cytoplasmic expression was observed in 89.4% (59/66) of cases. In contrast, nuclear expression was seen in non-neoplastic breast lobules and premalignant lesions adjacent to tumors that also exhibited constant staining in myoepithelial layer. Statistical analysis of epithelial cytoplasmic expression revealed association of MFAP5 expression with tumor size (P=0.046), high histologic grade (P=0.007), presence of lymph node metastasis (P=0.014), poor Nottingham Prognostic Index (NPI) (P=0.001), late stage (P=0.008), immunohistochemical subtypes of BC (P=0.018), and increased microvessel density using CD34 immunostianing (P=0.04). MFAP5 cytoplasmic expression was also observed in an adjacent duct carcinoma in situ component in 37/45 cases (82.2%). This study showed that MFAP5 is a novel myoepithelial cell marker that appears to be upregulated in duct epithelium in duct carcinoma in situ and invasive carcinoma of no special type during tumorogenesis and that its cytoplasmic expression in invasive tumors seems to have a poor prognostic role manifested by its association with poor prognostic parameters such as high grade, late stage, lymph node invasion, and increased microvessel density.

Expression of Lamin A/C in early-stage breast cancer and its prognostic value.

Lamins A/C, a major component of the nuclear lamina, play key roles in maintaining nuclear integrity, regulation of gene expression, cell proliferation and apoptosis. Reduced lamin A/C expression in cancer has been reported to be a sign of poor prognosis. However, its clinical significance in breast cancer remains to be defined. This study aimed to evaluate expression and prognostic significance of lamin A/C in early-stage breast cancer. Using immunohistochemical staining of tissue microarrays, expression of lamin A/C was evaluated in a large well-characterised series of early-stage operable breast cancer (n = 938) obtained from Nottingham Primary Breast Carcinoma Series. Association of lamin A/C expression with clinicopathological parameters and outcome was evaluated. Positive expression rate of lamin A/C in breast cancer was 42.2% (n = 398). Reduced/loss of expression of lamin A/C was significantly associated with high histological grade (p < 0.001), larger tumour size (p = 0.004), poor Nottingham Prognostic Index score (p < 0.001), lymphovascular invasion (p = 0.014) and development of distant metastasis (p = 0.027). Survival analysis showed that reduced/loss of expression of lamin A/C was significantly associated with shorter breast cancer-specific survival (p = 0.008). This study suggests lamin A/C plays a role in breast cancer and loss of its expression is associated with variables of poor prognosis and shorter outcome.

Connexin 43 is an independent predictor of patient outcome in breast cancer patients

PurposeGap junctions are specialized membrane structures that form channels between adjacent cells allowing cell communication. Gap junctions and specifically Connexin 43 (Cx43) are down-regulated in cancer; however, there are contrasting reports on how this effects breast cancer patient survival. This paper is the first large-scale tissue microarray analysis of Cx43 expression in breast cancer patients with an associated clinical long-term follow-up.MethodsUsing a validated TMA of 1118 primary breast cancers, coupled to a comprehensive database of clinicopathological variables, the expression levels and subcellular localisation of Cx43 was assessed by immunohistochemistry. Its impact in terms of survival, distant metastasis-free survival, and clinicopathological variables was determined.ResultsPatients whose tumors expressed high levels of Cx43 had significantly better survival (p < 0.001) than patients with low levels. High Cx43 expression within tumors was associated with an 18-month survival advantage. Loss of Cx43 expression was associated with markers of poor prognosis, namely large tumor size, high grade, high proliferation status, high pleomorphism, high mitosis, poor Nottingham Prognostic Index (NPI), and triple negative tumors. Cx43 expression was independent of tumor size, grade, stage and ER-status in predicting poor survival on multivariate analysis (p = 0.004).ConclusionConnexin 43 (Cx43) is an independent predictor of breast cancer survival and distant metastasis-free survival. High expression of Cx43 was seen in only 13% of tumors, suggesting that drugs to increase Cx43 expression may result in prolonged patients survival.