Evaluation Of Estrogen Receptor Research Articles

Abstract 3707: Characterization of estrogen receptor expression on CTCs during CDK4/6i treatment in HR+/HER2- metastatic breast cancer: Results from the PACE phase II study

Abstract Background Circulating tumor cells (CTCs) are associated with worse survival in metastatic breast cancer (MBC). The PACE study (NCT03147287) enrolled patients (pts) with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) MBC after progression on CDK4/6 inhibitor (CDK4/6i) and endocrine therapy, and randomized pts to fulvestrant (ful) alone; ful with palbociclib; or ful, palbociclib, and avelumab [Mayer et al., SABCS 2022]. Pts with ≥5 CTCs appear to derive benefit from treatment combinations vs ful alone. In this feasibility analysis, we evaluated estrogen receptor (ER) expression on CTCs to further investigate their monitoring/predictive potential.Methods Blood samples were collected from pts enrolled in the PACE study at: baseline (T1), first tumor assessment (T2) and progression (T3). CTCs were enumerated using the CellSearch platform and samples were classified as CTChigh or CTClow (cutoff ≥5 CTCs). CTChigh samples underwent ER expression quantification with the ACCEPT software [Zeune et al. 2017]. ER expression intensity (ERint) was measured through the Marker Characterization function for each CTC; the average was calculated for each sample. Results From the 220 enrolled pts, a total of 409 samples (166, 153 and 90 collected at T1, T2, and T3, respectively) were analyzed for ER. Overall, 236 samples were CTClow (T1 = 91, T2 = 97, T3 = 48) and 173 were CTChigh (T1 =75, T2 =56, T3 =42). ER was quantified on 3928, 1853, and 2209 CTCs collected at T1, T2, and T3, respectively. Overall, 32.2% of CTCs were ER negative (ER-).The samples’ median ERint showed a numerical decrease from T1 to T3 (T1 = 7.27, T2 = 4.58, T3 = 1.31). Similarly, the % of ER positive (ER+) CTCs per sample decreased from baseline to progression: 26.3%, 14.0%, 5.5% at T1, T2, T3, respectively.CTChigh samples were then classified as ER+ or ER- (ER+ = mean ER_int >0). At T1, 91 (54.8%) samples were CTClow, 67 (40.4%) were CTChigh/ER+, and 8 (4.8%) were CTChigh/ER-. At progression, 48 (53.3%) samples were CTClow, 26 (28.9%) were CTChigh/ER+, and 16 (17.8%) samples were CTChigh/ER-. A numerical increase in the proportion of CTChigh/ER- samples was thus observed from baseline to progression (4.8 to 17.8%).Conclusions Herein we demonstrated the feasibility of evaluating and quantify ER expression on CTCs with a software-assisted approach to reduce inter-operator variability. In the PACE study, ER expression on CTCs was decreased at progression compared to baseline, possibly suggesting a mechanism associated with treatment resistance. Future analyses are needed to investigate the correlation between ER expression levels on CTCs with survival and treatment response. This, together with information about the mutational status of ESR1 by ctDNA sequencing, might provide a new perspective on the development of resistance to ful and CDK4/6i in HR+/HER2- MBC. Citation Format: Mara Serena Serafini, Carolina Reduzzi, Lorenzo Gerratana, Rinath Jeselsohn, Reshma L. Mahtani, Cynthia X. Ma, Angela DeMichele, Jane Lowe Meisel, Kathy D. Miller, Yara Abdou, Elizabeth C. Riley, Rubina Qamar, Priyanka Sharma, Sonya Reid, Harold J. Burstein, Sara M. Tolaney, Michelle K. DeMeo, Yuan Liu, Eric Gauthier, Yue Ren, Meredith M. Regan, Huiping Liu, Erica L. Mayer, Massimo Cristofanilli. Characterization of estrogen receptor expression on CTCs during CDK4/6i treatment in HR+/HER2- metastatic breast cancer: Results from the PACE phase II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3707.

Abstract 6267: Evaluating estrogen receptor signaling modifications at bone marrow related stiffnesses in metastatic breast cancer

Abstract Bone metastasis is highly prevalent in breast cancer (BC) patients with metastatic disease and can increase the risk of hypercalcemia and pathological fractures. Several studies have evaluated the mechanisms of metastasized BC cells’ involvement in bone destruction, but how the bone marrow (BM) microenvironment contributes to this process remains ambiguous. Recent studies have shown that as BC cells experience increased stiffnesses outside of the primary microenvironment, there is higher expression of epithelial-to-mesenchymal transition (EMT) markers, increased expression of osteolytic proteins, and decreased drug responses. However, these changes have not been evaluated at stiffnesses relative to the BM. Estrogen receptor (ER) status also plays a pivotal role in BC patient survival. Clinical studies have indicated that the majority of ER+ patients with metastatic disease have more incidences of bone metastases compared to ER- patients. There is some evidence that suggests that the physical properties can also affect estrogen receptor signaling at the primary site, however, there is minimal work to establish how the physical factors of the BM can affect ER sensitivity after metastasis. We hypothesize that higher stiffness ranges of the BM can alter the estrogen receptor sensitivity of metastasized tumor cells and increase osteolysis. To analyze this question, we seeded ER+ BC cell lines (MCF7s and T47Ds) on CytoSoft® Rigidity Plates that mimicked the stiffness of the BM (0.5 - 32 kPa). After 2 days in culture, we probed the expression of downstream estrogen signaling factors, GREB1, PGR, and TIFF1, to evaluate estrogen activity using western blot. Our results show an increase in downstream estrogen signaling at higher stiffnesses (32 kPa) compared to lower stiffnesses (0.5 kPa) at the protein level but not at the transcriptional level. In the future, we will analyze factors associated with osteolysis (ITGB3, TGFB-RII, and PTHLH). Additionally, we plan to conduct RNA sequencing to analyze any larger transcriptional changes at different stiffnesses. Overall, this work gives insight into how estrogen signaling changes in the BM compared to the primary site. It will also give us insight into potential therapeutic targets for ER+ BC after metastasis to the bone. Citation Format: Logan Alexander Northcutt, Marjan Rafat, Julie Rhoades. Evaluating estrogen receptor signaling modifications at bone marrow related stiffnesses in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6267.

Comparing Heat-Induced Antigen Retrieval Methods for ER Expression in Invasive Breast Carcinoma

In the realm of cancer diagnosis and treatment, immuno-histochemical staining has become a pivotal tool for discerning molecular markers within tissue samples. Objective: To comprehensively compare different heat-induced antigen retrieval methods for evaluating estrogen receptor (ER) expression in female invasive breast carcinoma of no special type. Methods: A cross-sectional design was employed utilizing 250 formalin-fixed paraffin-embedded (FFPE) tissue samples from confirmed cases of invasive breast carcinoma. The study was conducted within Histopathology Department in CMH Peshawar. The study spanned from January 6, 2022 to June 30, 2023. Three heat-induced antigen retrieval methods were evaluated: conventional microwave-based retrieval, pressure cooking retrieval, and water bath heating. ER expression was assessed through immune-histo-chemical staining, and scores were analyzed using descriptive statistics and ANOVA. A post hoc Tukey's Honestly Significant Difference (HSD) test was conducted to identify which specific retrieval methods exhibited significant differences in ER expression scores. Results: The pressure-cooking retrieval method exhibited significantly higher mean ER expression scores (7.52) compared to the conventional microwave-based (6.87) and water bath heating methods (6.65). Post hoc analysis confirmed the substantial differences. Standard deviations and interquartile ranges were consistent with each method. Conclusions: The study underscores the pivotal role of retrieval techniques in accurate ER expression assessment in female invasive breast carcinoma of no special type. The pressure cooking method emerges as a potent enhancer of ER expression, advocating for standardized protocols to ensure consistent diagnostic outcomes and informed therapeutic decisions. Despite limitations, this research contributes to the refinement of patient care in the management of invasive breast carcinoma.

Evaluation of estrogen receptor, progesterone receptor, and Ki 67 immunoexpression in epithelial ovarian tumors with histopathological correlation

Abstract Background: Ovarian cancer ranks sixth among women’s cancers globally and seventh among cancer-related deaths. Around 90% of ovarian cancers have an epithelial genesis. Steroid hormones like progesterone and estrogen largely influence the development of ovarian cancers. In ovarian neoplasms, the proliferation marker Ki 67 helps forecast the course of the disease. Objective: To study the immunohistochemical expression pattern of estrogen receptor (ER), progesterone receptor (PR), and Ki 67 in the surface epithelial ovarian tumors (SEOTs) and correlate the findings with the standard histopathological. Materials and Methods: This prospective study was conducted in the Department of Pathology, MKCG Medical College and Hospital, Brahmapur, from November 2020 to October 2022 on 62 surface epithelial ovarian tumor cases. All the patients were evaluated for standard histopathological parameters and immuno-histochemistry (IHC) status using ER, PR, and Ki 67 as primary antibodies. Results: A total of 62 cases of SEOTs constituted the study group, of which 42 (67.74%) were benign, 5 (8.06%) were borderline, and 15 (24.2%) were malignant on histopathological evaluation: serous SEOTs (41, 66.12%), mucinous SEOTs (18, 29.03%), endometrioid SEOTs (2, 3.22%), and clear cell carcinoma (1, 1.61%). ER expression was more in malignant tumors (10/15; 66.66%) than in borderline (3/5; 60%) and benign (11/42; 26.19%), but the expression of PR was more in benign (27/42; 64.28%), followed by borderline (3/5; 60%) and malignant (8/15; 53.33%) SEOTs. Expression of Ki 67 was found to be more malignant (14/15; 93.33%) than borderline (4/5; 80%) and benign (2/42; 4.76%) SEOTs. Conclusion: ER and Ki 67 were expressed more in malignant, followed by borderline and benign, whereas PR expression was more innocent than borderline and malignant.

Tributyltin Exposure Is Associated With Recognition Memory Impairments, Alterations in Estrogen Receptor α Protein Levels, and Oxidative Stress in the Brain of Female Mice.

Tributyltin (TBT) is a persistent organometallic pollutant widely used in several agricultural and industrial processes. TBT exposure is associated with various metabolic, reproductive, immune, and cardiovascular abnormalities. However, few studies have evaluated the effects of TBT on behavior. In the present study, we aimed to investigate whether TBT exposure results in oxidative, neuroendocrine, and behavioral alterations. TBT was administered to adult female mice (250, 500, or 750 ng/kg/day or veh for 14 days), and their recognition memory was assessed. We have also evaluated estrogen receptor (ER)α protein expression and oxidative stress (OS) in brain areas related to memory, as well as the correlation between them. A reduction in short- and long-term recognition memory (STM and LTM) performance, as well as in total exploration time was observed in TBT mice. Reduced ERα protein expression was observed in the prefrontal cortex (PFC) and hippocampus of TBT mice, while an increase in TBARS concentration was observed in the PFC of treated animals. Collectively, these data suggest that TBT exposure impairs recognition memory in female mice as a result of, at least in part, its toxicological effects on ERα expression and OS in specific brain areas related to memory.

Mucinous Breast Carcinoma: Clinicopathological Comparison With Invasive Ductal Carcinoma.

IntroductionInvasive ductal carcinoma (IDC) is the most common histological subtype of breast cancer. Conversely, many special types of breast carcinoma were described with varying prognosis and hormone receptor status. Mucinous carcinoma (MC) is a rare special subtype of breast cancer, and only a few studies have evaluated the clinicopathological and hormone receptor profile of this type of breast cancer. Therefore, in this study, we compared the clinicopathological characteristics of MC with IDC in our population.MethodsA retrospective observational study was conducted in the Department of Histopathology, Liaquat National Hospital and Medical College, from January 2013 till December 2020, for eight years. During this period, 38 cases of MC were diagnosed and 1268 cases of IDC were identified. All specimens were grossed according to standard protocols and representative sections were submitted from tumors, resection margins, and lymph nodes. Slides were examined by histopathologists to determine tumor type and grade. Immunohistochemical (IHC) stains were applied to evaluate estrogen receptor (ER), progesterone receptor (PR), Ki67, and human epidermal growth factor receptor 2 (HER2/neu) statuses.ResultsThe mean age of the patients with MC was 56.47±13.90 years, and most of the patients were above 50 years of age. The mean tumor size was 34.89±19.70 mm. Most tumors were grade 1 (68.4%) with a low mean Ki67 index (15.21±14.06%). Axillary metastasis was present in 31.6% of cases and all of them were nodal (N)-stage N1. ER, PR, and HER2/neu positivity were noted in 94.7%, 78.9, and 10.5% cases, respectively. Compared with IDC, a significant association of MC was noted with age, Ki67 index, tumor (T)-stage, N-stage, and tumor grade. MC cases had a higher mean age than IDC cases. Comparative analysis revealed that MC had a lower frequency of axillary metastasis, a lower mean Ki67 index, and a lower tumor grade than IDC. About biomarker status, MC was noted to have a higher frequency of ER and PR expression, and a lower frequency of HER2/neu expression than IDC.ConclusionMC is a rare subtype of breast cancer. However, it is important to recognize this subtype of breast cancer as it is associated with a prognostically better pathological profile, such as lower tumor grade and Ki67 index, lower frequency of axillary metastasis, higher expression of ER and PR, and lower expression of HER2/neu.

Endometrial changes in estrogen and progesterone receptor expression during implantation in an oocyte donation program.

Implantation is the final and most important stage of embryogenesis and is of paramount importance in achieving a successful pregnancy. Progesterone and estrogen are steroid hormones responsible for the regulation of the implantation window and the current study hypothesised that their receptors may be implicated in women undergoing oocyte donation. A total of 15 women aged 25-32 years old (mean ± SD, 28.9±2.89) undergoing oocyte donation were recruited into the present study. Participants underwent ovarian stimulation with gonadotrophin-releasing hormone antagonist and recombinant follicle-stimulating hormone. Endometrial aspiration biopsy was performed on the day of oocyte retrieval and after 5 days (on days 0 and 5, respectively). Endometrial histology and evaluation of estrogen receptor (ER)α and progesterone receptor (PR)-B were performed on days 0 and 5. The ER nodal staining percentage on day 0 was age-associated, with patients aged <30 years demonstrating 100% staining and those aged >30 years exhibiting 90% staining. Pathological staining revealed statistically significant differences between days 0 and 5 following all staining procedures. Wilcoxon signed-rank test resulted in the following P-values, for ER (nodes % and stromal %) day 0/5, P=0.0001; for PR (nodes % and stromal %) day 0/5, P=0.0001 and P=0.035, respectively; for ER (grade nodes and stromal %) day 0/5, P=0.0001; and PR (grade nodes and stromal %) day 0/5 P=0.0001 and P=0.016, respectively. Synchronization between blastocyst development and the acquisition of endometrial receptivity is a prerequisite for the success of in vitro fertilisation (IVF). Aside from the recent discovery of molecules that are considered crucial for successful embryo implantation, assessing the functional characteristics of the endometrium may offer unique insights into this process, thus improving IVF results.

Comparative Immunofluorescent Analysis of Estrogen Receptor Beta Expression in Ovarian and Breast Cancer Cell Lines

Comparative quantitative evaluation of estrogen receptors β (ERβ) expression is performed by the immunofluorescence method using flow cytometry in the ovarian cancer cell lines COLO-704, OVCAR-3, EFO-21, and SK-OV-3, as well as the breast cancer cell line MCF-7. A high level of ERβ expression (88–91%) is revealed in all the cell cultures investigated, and significant differences were observed in the intensity of the marker’s expression between ovarian cancer cell cultures (in OVCAR-3, EFO-21, and SK-OV-3 they are higher than in COLO-704 cells by factors of 1.6, 2.3, and 3.5, respectively). Moreover, the intensity of ERβ expression was significantly higher in SK-OV-3, EFO-21, and OVCAR-3 than in MCF-7 cells: in 2.7; 1.4 and 1.9 times, respectively. The authors suggest that in contrast to breast cancer patients, ERβ rather than ERα could be the main target for antiestrogens in ovarian cancer patients. The revealed differences in the ERβ expression in a number of widely used ovarian cancer cell cultures lead us to recommend them for further fundamental research on ERβ to study the biological effects of antiestrogens.

The Evaluation of Estrogen Receptor β as a Potential Prognosis Factor in Melanoma

Differences across sexes in cutaneous melanoma incidence, metastatic pathways and disease outcome are consistently observed, with women having a significant survival advantage compared with men. This suggests that gender could play a role as a prognostic indicator through sex hormone signaling, but the mechanism is still unclear. This article focuses on available literature data concerning the influence of estrogen receptor beta (ERβ) expression as a host-related biological protective factor for female patients with melanoma. Furthermore, it highlights the potential role of estrogen receptor beta (ERβ) as a prognostic biologic marker in cutaneous melanoma. Keywords: melanoma, sex, hormone receptors, estrogen receptor β

Survey of low ER-positive expression and its correlation with other clinical and pathological factors in breast cancer.

Breast cancer is the most common cancer in women. Owning to the prominent role of biomarkers in molecular classification of breast cancer in recent years, evaluation of estrogen receptor (ER), progesterone receptor (PR), and Her2/neu seems to be required for prognosis and treatment of patients. One-hundred twenty two patients with primary breast carcinoma were selected and immunohistochemistry staining for ER, PR, and Her2/neu were performed on representative paraffin blocks. ER level can be semi-quantified by immunohistochemistry using the H-score. The score, given as the sum of the percent of tumor cells staining multiplied by the intensity level, ranges from 0 to 300 as low, intermediate, and high grades. The statistical association of ER expression with the level of PR and Her2/neu, tumor size, necrosis, microscopic grade, vascular invasion, and lymph node involvement were analyzed using SPSS16 software. Results showed that among 122 studied patients, 44.3% were in the low ER-positive group where most of these cases (22.1%) were Her2/neu negative. Although there was a reciprocal interplay between the expression of ER and Her2/neu, increased expression of ER had a direct relation with PR level. However, there was no statistical relation between ER level with age, tumor size, necrosis, microscopic grade, vascular invasion, and lymph node involvement. The study clearly indicated that low ER group encompasses the high frequency of breast cancer patients. Furthermore, the most cases of low ER patients were in Her2/neu negative group.

Breast Cancer Biomarkers: Challenges in Routine Estrogen Receptor, Progesterone Receptor, and HER2/neu Evaluation.

Evaluation of estrogen receptor (ER), progesterone receptor (PR), and HER2/neu (HER2) biomarkers is standard of care for all cases of newly diagnosed invasive, recurrent, and metastatic breast cancer. Repeat analysis is also performed in select cases per College of American Pathologists/American Society of Clinical Oncology guidelines and other clinical indications. However, in specific scenarios, preanalytic and analytic variables may pose distinct challenges to testing. To provide a review of select challenges in the testing of commonly performed breast cancer biomarkers ER, PR, and HER2 and outline best practices for overcoming these challenges. Review of College of American Pathologists/American Society of Clinical Oncology recommendations, current literature, and personal experience of the author. Attention must be given to specimen handling to ensure accurate ER, PR, and HER2 biomarker assessment and appropriate management of breast cancer patients.

Synthesis of a benzoxazinthione derivative of tanaproget and pharmacological evaluation for PET imaging of PR expression

BackgroundThe histological evaluation of estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer lesions from biopsy tissue can stratify patients to receive endocrine therapy. Furthermore, PR expression can predict response to selective estrogen receptor modulators (SERMs). Current immunohistochemical approaches to PR detection are limited by sampling error associated with biopsy and lack of standardised protocols; positron emission tomography (PET) using receptor targeted radiopharmaceuticals to provide quantitative, whole-body imaging may overcome these limitations. PR expression has been successfully imaged with PET in the clinical setting, however investigation into new radioligands with improved pharmacokinetics and metabolic stability is desirable.ResultsWe report the synthesis of a focused library of non-steroidal PR ligands evaluated for use as PET radioligands. A lead candidate ([18F]2) with low nanomolar activity was selected and radiolabelled with a radiochemical yield of 2.29 ± 2.31% (decay-corrected), radiochemical purity (RCP) > 95% and a molar activity of 2.5 ± 1.6 GBq/μmol. Cell uptake studies showed a significant and specific accumulation of [18F]2 in T47D (PR++) breast cancer cell compared to MDA-MB-231 (PR-) control; however, in vivo evaluation was confounded by rapid defluorination of the radioligand. In vitro metabolite analysis of 2 in MLM confirmed defluorination and oxidative metabolism of the thiocarbamate to oxocarbamate moiety by mass spectrometry.ConclusionsA route to access [18F]2 was developed to allow in vitro and in vivo evaluation, albeit with low radiochemical yield and modest molar activity. [18F]2 demonstrated selective uptake in PR++ T47D cells which could be blocked in a dose dependent manner with progesterone. However, [18F]2 showed poor in vivo metabolic stability with rapid defluorination within the time frame of the imaging protocol.

Evaluation of Estrogen Receptor α and ß Genes Expression in Normal and Neoplastic Mammary Gland in Dogs by Real-time PCR

Background: Estrogen and progesterone play a key role in mammary tumorigenesis of female dogs. Malignant tumors are considered hormone-dependent neoplasms, which may reappear after surgical removal or might spread to other organs such as liver, lymph nodes, and lungs. Objective: The purpose of this study was to evaluate the expression of estrogen receptor α and ß genes in normal and neoplastic mammary glands of female dogs. Methods: Ten neoplastic tumors (benign and malignant) and 10 normal samples were selected. After RNA extraction and cDNA synthesis, ERα and ERβ genes were amplified by Real-time PCR based on SYBR green related to β-actin reference gene. Results: The obtained Ct and ΔCt values were analyzed by GLM procedure of SAS software v9.2. The results showed that the expression of ERα and ERβ genes in neoplastic cases was over- and down-expressed respectively as compared with normal samples (p < 0.01). Conclusion: The findings indicated that these genes could be used as reference genes for screening and also for early diagnosis of patients, and this method could be helpful for patient selection and monitoring of the anti-estrogen therapy.

An Optimized Workflow to Evaluate Estrogen Receptor Gene Mutations in Small Amounts of Cell-Free DNA

The detection of mutated genes in cell-free DNA (cfDNA) in plasma has emerged as an important minimally invasive way to obtain detailed information regarding tumor biology. Reliable determination of circulating tumor-derived DNA, often present at a low quantity amidst an excess of normal DNA in plasma, would be of added value for screening and monitoring of cancer patients and for hypothesis-generating studies in valuable retrospective cohorts. Our aim was to establish a workflow to simultaneously assess four hotspot estrogen receptor mutations (mESR1) in cfDNA isolated from only 200 μL of plasma by means of uniplex or multiplex pre-amplification combined with digital PCR. This workflow was then applied in metastatic breast cancer (MBC) patients receiving systemic therapies for MBC. In accordance with previous studies, estrogen receptor mutations were more frequently detected in endocrine-treated MBC patients at progressive disease [34.1% (15/44)] than before the start of endocrine therapy [3.9% (2/51); P=0.001]. For a subset of samples, results were compared with analysis of these mutations by Oncomine-targeted next-generation sequencing, which, although requiring a higher cfDNA input, yielded concordant results. The data establish development and validation of a digital PCR workflow for the simultaneous detection of several tumor-derived mutations in minute amounts of cfDNA and show the potential of this workflow for use on archived volume-limited blood samples.

Androgen Receptor and ALDH1 Expression Among Internationally Diverse Patient Populations.

PurposePopulation-based incidence rates of breast cancers that are negative for estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2/neu (triple-negative breast cancer [TNBC]) are higher among African American (AA) compared with white American (WA) women, and TNBC prevalence is elevated among selected populations of African patients. The extent to which TNBC risk is related to East African versus West African ancestry, and whether these associations extend to expression of other biomarkers, is uncertain.MethodsWe used immunohistochemistry to evaluate estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2/neu, androgen receptor and aldehyde dehydrogenase 1 (ALDH1) expression among WA (n = 153), AA (n = 76), Ethiopian (Eth)/East African (n = 90), and Ghanaian (Gh)/West African (n = 286) patients with breast cancer through an institutional review board–approved international research program.ResultsMean age at diagnosis was 43, 49, 60, and 57 years for the Eth, Gh, AA, and WA patients, respectively. TNBC frequency was higher for AA and Gh patients (41% and 54%, respectively) compared with WA and Eth patients (23% and 15%, respectively; P < .001) Frequency of ALDH1 positivity was higher for AA and Gh patients (32% and 36%, respectively) compared with WA and Eth patients (23% and 17%, respectively; P = .007). Significant differences were observed for distribution of androgen receptor positivity: 71%, 55%, 42%, and 50% for the WA, AA, Gh, and Eth patients, respectively (P = .008).ConclusionExtent of African ancestry seems to be associated with particular breast cancer phenotypes. West African ancestry correlates with increased risk of TNBC and breast cancers that are positive for ALDH1.

Can Histological Grade and Mitotic Index Replace Ki67 to Determine Luminal Breast Cancer Subtypes?

Introduction:Breast cancer can be classified into subtypes based on immunohistochemical markers, with Ki67 expression levels being used to divide luminal BC tumors in luminal A and B subtypes; however, Ki67 is not routinely determined due to a lack of standardization.Objective:To evaluate histological grade and Eliminate: the mitotic index to determine if they can be used as an alternative method to Ki67 staining for luminal subtype definition.Methods:We evaluated estrogen receptor positive breast cancer tissue samples. Pathological analysis included determination of Ki67. A low level of Ki67 was defined as <14% positive cells.Results:We evaluated 151 breast cancer samples; 24 (15,9%) were classified as I; 74 as HG II (49%), and 53 (35,1%) as HG III. The median value for Ki67 was 13% (range: <1% - 82%) and for MI was 2 (0-12). Histological grade I tumors exhibited Ki67 values significantly lower than HG II and III tumors (Anova, Tamhane test p=0,001). A higher Ki67 value was related to a higher MI (Rho Sperman p=0,336; R2= 0,0273). ROC curve analysis determined that a MI ≥ 3 had a sensibility of 61.9% and specificity of 66.7% in predicting a high Ki67 value (≥14%) (area under the curve: 0,691; p =0,0001). A HG I tumor or HG II-III with MI ≤2, had a high probability of corresponding to a LA tumor (76,3%), as defined using Ki67 expression, while the probability of a LB subtype was higher with HG II-III and a MI ≥3 (57.4%). Global discrimination was 68.1%.Conclusions:For the LA subtype, our predictive model showed a good correlation of HG and MI with the classification based on Ki67<14%. In the LB subtype, the model showed a weak correlation; therefore Ki67 determination seems to be needed for this group of patients.

The Core Needle and Surgical Biopsy Concordance to Detect Estrogen, Progesterone, and Her-2 Receptors in Breast Cancer: A Comparative Study

Evaluation of estrogen receptor (ER), progesterone receptor (PR), and (human epidermal growth factor receptor-2) Her-2 on core needle biopsies (CNBs) is increasingly in use to diagnosis early breast cancer, but its concordance with surgical excision (SE) is not well documented. The study included 100 formalin fixed, paraffin-embedded specimens of invasive breast carcinoma archived in Pathology Department of Cancer Institute, Tehran, Iran, from 2011 to 2014. Immunohistochemistry was applied to detect ER, PR, and Her-2. The current study findings indicated a significant correlation of 90% between CNB and SE specimens for ER expression. The correlation between CNB and SE specimens was estimated as 81% and 97.3% for PR and Her-2, respectively. CNB can be performed confidently to determine ER and Her-2. For PR, results obtained from CNB should be considered.

Endometrial Cancers With Activating KRas Mutations Have Activated Estrogen Signaling and Paradoxical Response to MEK Inhibition.

The aims of this study were to determine if activating KRas mutation alters estrogen signaling in endometrial cancer (EC) and to explore the potential therapeutic impact of these alterations. The Cancer Genome Atlas was queried for changes in estrogen-regulated genes in EC based on KRas mutation status. In vitro studies were conducted to evaluate estrogen receptor α (ERα) phosphorylation changes and related kinase changes in KRas mutant EC cells. The resulting effect on response to MEK inhibition, using trametinib, was evaluated. Immunohistochemistry was performed on KRas mutant and wild-type EC tumors to test estrogen signaling differences. KRas mutant tumors in The Cancer Genome Atlas showed decreased progesterone receptor expression (P = 0.047). Protein analysis in KRas mutant EC cells also showed decreased expression of ERα (P < 0.001) and progesterone receptor (P = 0.001). Although total ERα is decreased in KRas mutant cells, phospho-ERα S118 was increased compared with wild type. Treatment with trametinib in KRas mutant cells increased phospho-ERα S167 and increased expression of estrogen-regulated genes. While MEK inhibition blocked estradiol-stimulated phosphorylation of ERK1/2 and p90RSK in wild-type cells, phospho-ERK1/2 and phospho-p90RSK were substantially increased in KRas mutants. KRas mutant EC tumor specimens showed similar changes, with increased phospho-ERα S118 and phospho-ERα S167 compared with wild-type EC tumors. MEK inhibition in KRas mutant cells results in activation of ER signaling and prevents the abrogation of signaling through ERK1/2 and p90RSK that is achieved in KRas wild-type EC cells. Combination therapy with MEK inhibition plus antiestrogen therapy may be necessary to improve response rates in patients with KRas mutant EC.

Epithelial cadherins and associated molecules in invasive lobular breast cancer

to estimate the expression of cell adhesion molecules E- and P-cadherin, as well as that of cadherin-catenin complexes in invasive lobular breast cancer (BC) cells. 250 cases of postoperative material from patients diagnosed with invasive lobular BC were studied. The expressions of cell adhesion molecules E-cadherin, P-cadherin, β-catenin, p120 catenin, and vimentin were determined by immunohistochemical assay in all cases. The examined cases were divided into molecular biological subtypes, based on the evaluation of estrogen receptors (ER), progesterone receptors (PR), HER-2/neu, and Ki-67 proliferative index. The membrane expression of E-cadherin on the tumor cells was found to be preserved in 93%; the cytoplasmic expression of β-catenin and p120-catenin appeared in 60 and 72% of cases, respectively. The expression of P-cadherin was detected in 82% of cases. The coexpression of E- and P-cadherin was noted in 90% of all the examined cases. There was a correlation between the expression of E- and P-cadherins (V=0.34; p<0.05). The BC cells showed the coexpression of E- and P-cadherins, as well as release of the molecules β- and p120-catenins into the cytoplasm of tumor cells, which leads to the activation of intracellular mechanisms for changing the structure of the cytoskeleton and the level of proliferation. The above-mentioned mechanisms are accompanied by the activation of epithelial-mesenchymal transition. The intracellular mechanisms resulted in progressive cancer and its metastasis.

Reliability of Core Needle Biopsy in Evaluating Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2, and Ki-67 Status

Reliability of Core Needle Biopsy in Evaluating Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2, and Ki-67 Status