Receptor Expression In Breast Cancer Research Articles

The prognostic and immune significance of Rab11A in pan-cancer and its function and mechanism underlying estrogen receptor targeting in breast cancer.

Rab11A is an important molecule for recycling endosomes and is closely related to the proliferation, invasion, and metastasis of tumors. This study investigated the prognostic and immune significance of Rab11A and validated its potential function and mechanism in breast cancer (BRCA). RNA sequencing data for 33 tumors were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression databases. Correlation analysis was used to evaluate the relationship between Rab11A expression and immune characteristics. Potential pathways were identified using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis. Immunohistochemical analysis, colony formation assay, bromodeoxyuridine incorporation assay, immunofluorescence, and Western blot were used to explore potential function and mechanism. Analysis of the TCGA database showed significant upregulation of Rab11A expression in a variety of cancers. Rab11A was up-regulated in 82.4% of BRCA. High Rab11A expression is associated with poor survival in cancer patients and is a predictor of poor prognosis. CIBERSORT analysis showed that Rab11A was negatively associated with almost all immune cycle activity scores pan-cancer. The results of the TCGA-BRCA cohort were further confirmed by using pathological samples from clinical BRCA patients. The results showed that Rab11A expression was correlated with estrogen receptor (ER) and progesterone receptor expression in BRCA (p<0.05). Knockdown and overexpression of Rab11A affected the proliferation of BRCA cells. Further mechanistic studies revealed that down-regulation of ER alpha (ERα) and up-regulation of ER beta (ERβ) mediated Rab11A-induced inhibition of BRCA cell proliferation. Rab11A expression in pan-cancer is associated with poor prognosis and immune profile. In particular, in BRCA, Rab11A expression regulates cell proliferation by targeting ERα and ERβ. High Rab11A expression is tightly associated with immune characteristics, tumor microenvironment, and genetic mutations. These results provide a reference for exploring the role of Rab11A in pan-cancer and provide a new perspective for revealing potential therapeutic targets in BRCA.

Analyzing Androgen Receptor Expression in Breast Cancer: Insights into Histopathological Parameters and Hormone Receptor Status Among Indian Women

Analyzing Androgen Receptor Expression in Breast Cancer: Insights into Histopathological Parameters and Hormone Receptor Status Among Indian Women

Abstract PO5-06-01: Loss of hormone receptor expression in breast cancer is associated with increased brain tropism and accelerated progression of leptomeningeal disease

Abstract The four breast cancer subtypes—luminal A, luminal B, HER2-overexpressing, and triple-negative breast cancer (TNBC) – are classified based on gene expression profiles of hormone receptors (HRs) (estrogen receptor (ER) and progesterone receptor (PR)) and human epidermal growth factor receptor 2 (HER2/ERBB2). Negative hormone receptor status is known to be associated with more aggressive breast cancer. Compared to other breast cancer subtypes, the HR-negative TNBC and HER2-overexpressing subtypes are characterized by high rates of recurrence and a notable increase in brain metastases and in particular, leptomeningeal disease (LMD). LMD – the most aggressive form of central nervous system (CNS) metastasis, in which cancer cells infiltrate leptomeninges of the brain and spine – carries a dismal prognosis due to a rapid progression, poor detection, and no effective treatment. Several studies that investigated the link between HR status and LMD suggest that HR-negative breast cancers have a shorter time to LMD diagnosis. This shortened timeline is consistent with higher migratory capabilities reported for TNBC and HER2 breast cancer cells. However, as it is known that breast cancers exhibit subtype-specific metastatic tropism (i.e., luminal subtypes tend to metastasize to bone and liver, while TNBCs metastasize to the CNS), the longer time between primary breast cancer diagnosis and LMD diagnosis for HR-positive breast cancers may also reflect a longer metastatic route that first includes a non-CNS location. In this study, we performed a retrospective analysis on 141 breast cancer patients with LMD treated at Stanford Hospital between 2008-2020. The Stanford LMD cohort was analyzed using linear regression analysis, Cox regression analysis, and Chi-squared analysis. HR status was recorded (when available) for local recurrences and distant metastases, and was included in our regression models as a time-dependent HR covariate. We tested if: (1) HR-negative breast cancers had shorter time between primary and LMD diagnosis as well as worse survival after LMD diagnosis versus HR-positive breast cancers, and if (2) HR loss (i.e., HR status changing from positive to negative) increased likelihood of the metastasis to CNS. In agreement with published studies, the Stanford LMD cohort showed that HR-negative cancers had shorter time to development of LMD (p = 0.0004 for ER, p = 0.0001 for PR) and increased mortality following LMD (p = 0.010 for ER, p = 0.009 for PR). We found that HR-negative status at primary breast cancer diagnosis increased risk of first metastasis to CNS versus non-CNS locations (p = 0.021 for ER, p = 0.043 for PR). HR status switch (also known as hormone discordance) between primary diagnosis and metastasis occurred in 15% of patients in Stanford cohort, consistent with other studies. Importantly, accounting for HR status switch strengthened the association between HR-negative status and the risk of CNS metastasis [Hazard Ratio = 2.506 (1.395 - 4.500) for “baseline ER status” versus Hazard Ratio = 3.509 (1.890 - 6.515) for “time-dependent ER status”, Hazard Ratio = 2.420 (1.310 - 4.471) for “baseline PR status” versus Hazard Ratio = 3.407 (1.815 - 6.395) for “time-dependent PR status”]. In conclusion, HR-negative status was associated with shorter time to development of LMD, higher CNS tropism, and shorter survival following LMD diagnosis. Taking into consideration hormone discordance between the primary tumor and metastatic sites strengthened this association. Our results suggest a potential value in testing HR status at all recurrences and advanced CNS monitoring following HR loss. Citation Format: Sophia Pribus, Maxine C. Umeh-Garcia, Bo Gu, Bryanna Godfrey, Summer Han, Sophia Chernikova, Melanie Hayden Gephart. Loss of hormone receptor expression in breast cancer is associated with increased brain tropism and accelerated progression of leptomeningeal disease [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-01.

Notch, SUMOylation, and ESR-Mediated Signalling Are the Main Molecular Pathways Showing Significantly Different Epimutation Scores between Expressing or Not Oestrogen Receptor Breast Cancer in Three Public EWAS Datasets.

Oestrogen receptor expression in breast cancer (BC) cells is a marker of high cellular differentiation and allows the identification of two BC groups (ER-positive and ER-negative) that, although not completely homogeneous, differ in biological characteristics, clinical behaviour, and therapeutic options. The study, based on three publicly available EWAS (Epigenetic Wide Association Study) datasets, focuses on the comparison between these two groups of breast cancer using an epimutation score. The score is calculated not only based on the presence of the epimutation, but also on the deviation amplitude of the methylation outlier value. For each dataset, we performed a functional analysis based first on the functional gene region of each annotated gene (we aggregated the data per gene region TSS1500, TSS200, first-exon, and body-gene identified by the information from the Illumina Data Sheet), and then, we performed a pathway enrichment analysis through the REACTOME database based on the genes with the highest epimutation score. Thus, we blended our results and found common pathways for all three datasets. We found that a higher and significant epimutation score due to hypermethylation in ER-positive BC is present in the promoter region of the genes belonging to the SUMOylation pathway, the Notch pathway, the IFN-γ signalling pathway, and the deubiquitination protease pathway, while a higher and significant level of epimutation due to hypomethylation in ER-positive BC is present in the promoter region of the genes belonging to the ESR-mediated pathway. The presence of this state of promoter hypomethylation in the ESR-mediated signalling genes is consistent and coherent with an active signalling pathway mediated by oestrogen function in the group of ER-positive BC. The SUMOylation and Notch pathways are associated with BC pathogenesis and have been found to play distinct roles in the two BC subgroups. We speculated that the altered methylation profile may play a role in regulating signalling pathways with specific functions in the two subgroups of ER BC.

Comprehensive characterization of androgen receptor expression in breast cancer.

1035 Background: The androgen receptor ( AR) is a hormone-regulated transcription factor that plays an important role in breast cancer (BC) pathogenesis. While estrogen receptor inhibitors are well-studied in BC, the role of AR on prognosis and therapy is less well-known. Here we aim to characterize the clinicopathologic and molecular features of AR expression in BC. Methods: 27,169 BC samples were tested by NGS (592, NextSeq; WES, NovaSeq), WTS (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Microsatellite-instability (MSI) was tested by IHC and NGS. Tumor mutational burden (TMB) totaled somatic mutations per tumor (high≥10 mt/MB). Tumors with AR-high(H) and AR-low(L) expression were classified by top and bottom quartile, respectively. Real world overall survival (OS) and treatment-associated survival was obtained from insurance claims and calculated from tissue collection or treatment start to last contact using Kaplan-Meier estimates. Statistical significance was determined by chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q&lt;0.05). Results: Median AR expression was higher in lobular compared to ductal carcinoma (2.2-fold) and in HR+/HER2- compared to TNBC (13.9-fold). Compared to AR-L, AR-H BC had higher frequency of PIK3CA (50.6% vs 12.7%), CDH1 (20% vs 2.2%), ESR1 (12.8% vs 1.4%), MAP3K1 (9.4% vs 1.4%), GATA3 (11.2% vs 2.7%), AKT1 (5.7% vs 1.4%), NF1 (8.6% vs 3.6%), ARID1A (6.9 vs 3.6), SPEN (2.8% vs 1.5%), and PTEN (7.9% vs 6.2%) mutations and TMB high (9.5% vs 7.7%), but lower frequency of dMMR/MSI-H (0.6% vs 1.7%) and PD-L1 (18.7% vs 45.3%) positivity (all p&lt;0.05). AR-H tumors also showed enrichment of the IL2-STAT5 pathway (NES: 1.33, FDR: 0.24). Further, AR-H BC had higher expression of immune checkpoint genes ( CD274, PDCD1LG2, LAG3, HAVCR2, FOXP3, FC: 1.1-1.4, all p&lt;0.05) and T cell inflamed scores (32.5% vs 26.2%, p&lt;0.05). AR-H BC had increased immune cell infiltration of B cells (6% vs 4%), M2 Mφ (5% vs 2%), and NK cells (3% vs 2%), but decreased infiltration of M1 Mφ (2% vs 3%) (all p&lt;0.05). AR-H BC had upregulation of M2 Mφ related genes ( ARG1, IL10, CCL17, CXCR1, FC: 1.2-1.8, all p&lt;0.05) and downregulation of M1 Mφ related genes ( CCL2, CCL5, CXCL9, CXCL10, FC: 1-1.5, all p&lt;0.05). AR-H BC was associated with improved OS compared to AR-L BC (mOS: 1843 vs 1096 days; HR 0.6, 95% CI 0.5-0.7, p&lt;0.00001), and with doxorubicin (2294 vs 2054 days; HR 0.7, 95% CI 0.5-0.9, p&lt;0.001) , paclitaxel (2239 vs 1967 days; HR 0.7, 95% CI 0.5-0.9, p&lt;0.001) and trastuzumab (inf vs 2351 days; HR 0.6, 95% CI 0.4-0.9, p&lt;0.01) treatment. Conclusions: Our data suggest a strong association between AR expression and increased mutations in several cancer related genes, immune checkpoint markers, the IL2-STAT5 pathway, differential immune cell infiltration, and improved overall survival.

Abstract P3-05-11: Breast cancer characteristics in premenopausal women by contraception method

Abstract INTRODUCTION: Our knowledge regarding the levonorgestrel intra-uterine device (LNG-IUD) and breast cancer (BC) risk is limited. As the LNG-IUD is a widely used contraception method, we here explored receptor expression in BC, in women &amp;lt; 56 years, by having a LNG-IUD at diagnosis. We aim to validate the findings of a previous cohort treated in the University Hospitals Leuven, where we observed proportionally more progesterone receptor (PR), lower human epidermal growth factor receptor 2 (HER2) expression and more ER+PR+HER2- subtypes in LNG-IUD users compared to non-LNG-IUD users. MATERIALS AND METHODS: We conducted a retrospective observational monocentric study from 2015 until 2020. We included patients &amp;lt; 56 years consulting the University Hospitals Leuven for primary invasive BC, who were treated with primary breast surgery or neoadjuvant therapy. We compared patient and tumor characteristics, especially receptor subtypes in LNG-IUD users at diagnosis with non- LNG-IUD users. Group comparisons with regards to receptor subtypes were performed by the Chi-square test, all tests were evaluated at a two-sided 5% significance level. RESULTS: Of the 1347 patients with BC included in this study, 272 had a LNG-IUD at diagnosis. The LNG-IUD users were more likely ER (85.29% vs 77.77%, p=0.006) and PR positive (80.88% vs 70.95%, p&amp;lt; 0.001) compared to the control group. Additionally, we observed more ER+PR+HER2- (68.75% vs 58.62%, p=0.002) and fewer ER-PR- HER2- (10.29% vs 15.66%, p=0.025) subtypes when comparing with the control group. CONCLUSION: This internal validation study confirmed invasive BC, diagnosed in women under age 56, to be more likely PR+ and ER+PR+HER2- if they used a LNG- IUD at BC diagnosis when compared to non-LNG-IUD users. Citation Format: Inés De Maeyer, Eline Borowski, Karen Van Baelen, Annouschka Laenen, Ines Nevelsteen, Hans Wildiers, Sileny Han, Ann Smeets, Thaïs Baert, Kevin Punie, Patrick Neven. Breast cancer characteristics in premenopausal women by contraception method [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-11.

CD103+ Cells and Chemokine Receptor Expression in Breast Cancer.

Mucosal environments harbour lymphocytes, which express several adhesion molecules, including intestinal homing receptors and integrin αE/β7 (CD103). CD103 binds E-cadherin, an integrin receptor expressed in intestinal endothelial cells. Its expression not only enables homing or retention of T lymphocytes at these sites but is also associated with increased T lymphocyte activation. However, it is not yet clear how CD103 expression is related to the clinical staging of breast cancer, which is determined by factors such as the size of the tumor (T), the involvement of nearby lymph nodes (N), and presence of metastasis (M). We examined the prognostic significance of CD103 by FACS in 53 breast cancer patients and 46 healthy controls enrolled, and investigated its expression, which contributes to lymphocyte recruitment in tumor tissue. Patients with breast cancer showed increased frequencies of CD103+, CD4+CD103+, and CD8+CD103+ cells compared to controls. CD103 was expressed at a high level on the surfaces of tumor-infiltrating lymphocytes in patients with breast cancer. Its expression in peripheral blood was not correlated with clinical TNM stage. To determine the localisation of CD103+ cells in breast tissue, tissue sections of breast tumors were stained for CD103. In tissue sections of breast tumors stained for CD103, its expression in T lymphocytes was higher compared to normal breast tissue. In addition, CD103+ cells expressed higher levels of receptors for inflammatory chemokines, compared to CD103- cells. CD103+ cells in peripheral blood and tumor tissue might be an important source of tumor-infiltrating lymphocyte trafficking, homing, and retention in cancer patients.

The analysis of the relationship between transferrin receptor 1 (TfR1) and clinical, morphological and immunophenotypic characteristics of breast cancer: retrospective cohort study

Background. Transferrin receptor 1 (TfR1) expression has been identified in a number of malignant tumors. It is noted that its overexpression gives growth advantages to cancer cells. Estimation of transferrin receptor expression in breast cancer (BC) might be an important component in disease prognosis, choice of treatment, also might be an attractive target for targeted therapy.&#x0D; Aim. To evaluate the expression of TfR1 by BC cells and to study its relationship with the clinical, morphological and immunophenotypic characteristics of the tumor.&#x0D; Materials and methods. This study included 82 patients with BC who received treatment at the Blokhin National Medical Research Center of Oncology (Moscow). The expression of TfR1 on primary tumor cells was studied, the relationship of TfR1 with clinical, morphological and immunophenotypic characteristics of BC was analyzed. Immunophenotyping of the primary tumor was performed by the immunohistochemical method (immunofluorescent staining) on cryostat sections. Antibodies to CD71, CD95, CD54, CD29, MUC1, Pgp170 were used. The reaction was evaluated using a luminescent microscope (AXIOSKOP, Germany). The study was dominated by patients with stage IIB 54% and IIIB 21%. Infiltrative ductal BC was diagnosed in 67% (n=55) of patients, infiltrative-lobular in 22% (n=18) of cases, other types in 11.0% (n=9).&#x0D; Results. BC cells expressed TfR1 in most cases (64.4%; n=61). A combination of TfR1 monomorphic expression with MUC1 monomorphic expression (74.4%; n=47) was noted. CD29 is presented both mosaic (38.7%) and monomorphic (51.6%). The Pgp170 antigen was monomorphically observed in 27.5% of cases. As the proportion of TfR+ cells increased, the expression frequency of the adhesion molecule CD54 increased from 10.5 to 33.3%, a positive correlation was established (r=0.293; p=0.008). In the group with TfR1 monomorphic expression, the frequency of tumors expressing the CD95 apoptosis molecule decreased: 25.0% vs 13% (p=0.042).&#x0D; Conclusion. BC cells overexpress TfR1. TfR1 expression is associated with tumor immunophenotype.

Commentary on "Application of Photoshop-based Image Analysis to Quantification of Hormone Receptor Expression in Breast Cancer".

Commentary on "Application of Photoshop-based Image Analysis to Quantification of Hormone Receptor Expression in Breast Cancer".

DOG1 expression is in common human tumors: A tissue microarray study on more than 15,000 tissue samples

Abstract Introduction/Objective Introduction: DOG1 (Discovered on GIST1) is a voltage-gated calcium-activated chloride and bicarbonate channel that is highly expressed in interstitial cells of Cajal and in gastrointestinal stromal tumors (GIST) derived from Cajal cells. Methods/Case Report Methods: To systematically determine in what tumor entities and normal tissue types DOG1 may be further expressed, a tissue microarray (TMA) containing 15,965 samples from 121 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results (if a Case Study enter NA) Results: DOG1 immunostaining was found in 67 tumor types including GIST (95.7%), esophageal squamous cell carcinoma (31.9%), pancreatic ductal adenocarcinoma (33.6%), adenocarcinoma of the Papilla Vateri (20%), squamous cell carcinoma of the vulva (15.8%) and the oral cavity (15.3%), mucinous ovarian cancer (15.3%), esophageal adenocarcinoma (12.5%), endometrioid endometrial cancer (12.1%), neuroendocrine carcinoma of the colon (11.1%) and diffuse gastric adenocarcinoma (11%). Low level-DOG1 immunostaining was seen in 17 additional tumor entities. DOG1 expression was unrelated to histopathological parameters of tumor aggressiveness and/or patient prognosis in cancers of the breast (n=1,002), urinary bladder (975), ovary (469), endometrium (173), stomach (233), and thyroid gland (512). Conclusion High DOG1 expression was linked to estrogen receptor expression in breast cancer (p&amp;lt;0.0001) and absence of HPV infection in squamous cell carcinomas (p=0.0008). In conclusion, our data identify several tumor entities that can show DOG1 expression levels at similar levels as in GIST. Although DOG1 is tightly linked to a diagnosis of GIST in spindle cell tumors, the differential diagnosis is much broader in DOG1 positive epithelioid neoplasms.

DOG1 expression is common in human tumors: A tissue microarray study on more than 15,000 tissue samples

DOG1 (Discovered on GIST1) is a voltage-gated calcium-activated chloride and bicarbonate channel that is highly expressed in interstitial cells of Cajal and in gastrointestinal stromal tumors (GIST) derived from Cajal cells. To systematically determine in what tumor entities and normal tissue types DOG1 may be further expressed, a tissue microarray (TMA) containing 15,965 samples from 121 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. DOG1 immunostaining was found in 67 tumor types including GIST (95.7%), esophageal squamous cell carcinoma (31.9%), pancreatic ductal adenocarcinoma (33.6%), adenocarcinoma of the Papilla Vateri (20%), squamous cell carcinoma of the vulva (15.8%) and the oral cavity (15.3%), mucinous ovarian cancer (15.3%), esophageal adenocarcinoma (12.5%), endometrioid endometrial cancer (12.1%), neuroendocrine carcinoma of the colon (11.1%) and diffuse gastric adenocarcinoma (11%). Low level-DOG1 immunostaining was seen in 17 additional tumor entities. DOG1 expression was unrelated to histopathological parameters of tumor aggressiveness and/or patient prognosis in cancers of the breast (n = 1002), urinary bladder (975), ovary (469), endometrium (173), stomach (233), and thyroid gland (512). High DOG1 expression was linked to estrogen receptor expression in breast cancer (p < 0.0001) and absence of HPV infection in squamous cell carcinomas (p = 0.0008). In conclusion, our data identify several tumor entities that can show DOG1 expression levels at similar levels as in GIST. Although DOG1 is tightly linked to a diagnosis of GIST in spindle cell tumors, the differential diagnosis is much broader in DOG1 positive epithelioid neoplasms.

Androgen receptor expression in breast cancer: Implications on prognosis and treatment, a brief review

Approximately 70%–85% of breast cancers express androgen receptors (ARs). The role of AR in breast cancer pathogenesis is currently in exploration. Both androgens and anti-androgens have demonstrated variable inhibitory and stimulatory effects in AR-positive breast cancer depending on estrogen receptor and HER2 co-expression. Androgen signaling pathways interact with other critical cellular pathways, such as the PI3K/AKT/mTOR, Ras/Raf/MAPK/ERK, Wnt/β-catenin, and estrogen signaling pathways. Therapeutic exploitation of AR has been the crux of management of prostate cancer for decades. In recent years there has been increasing interest in AR as a novel therapeutic target in breast cancer. There have been many early phase clinical trials evaluating the safety and efficacy of various AR-targeted agents in breast cancer. Some of these studies have shown promising clinical benefits. Studies of biomarkers to identify the patients likely to benefit from AR-targeted therapies are currently in progress. Besides, AR expression may be an important prognostic and predictive marker for breast cancer, which needs to be defined better in future studies.

2020 RSNA Outstanding Researcher.

HomeRadiologyVol. 298, No. 1 Next CommunicationsFree AccessSpecial Communications2020 RSNA Outstanding ResearcherJames P. BorgstedeJames P. BorgstedeJames P. BorgstedePublished Online:Dec 1 2020https://doi.org/10.1148/radiol.2020209023MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In David Mankoff, MD, PhDDownload as PowerPointOpen in Image Viewer As one of the foremost authorities in nuclear medicine/PET, David Mankoff, MD, PhD, is a leader in molecular imaging science and a pioneer in the development of whole-body PET imaging.“Dr Mankoff is a true renaissance imaging specialist,” said RSNA President James P. Borgstede, MD. “He is a researcher, an inventor, an educator and a clinical specialist. All of imaging is fortunate to have Dr Mankoff as a colleague.”Dr Mankoff is the Gerd Muehllehner Professor of Radiology and vice chair of research at the University of Pennsylvania (Penn) Perelman School of Medicine and associate director of education and research at the Abramson Cancer Center, both in Philadelphia.While earning a PhD in bioengineering, Dr Mankoff worked with his thesis advisor, the late Gerd Muehllehner, PhD, to develop a commercial version of the scanner that later formed the basis for the PennPET Explorer, a whole-body PET imaging system recently developed at Penn.After earning his PhD and MD at Penn, Dr Mankoff completed his residency in internal medicine and nuclear medicine at the University of Washington in Seattle. He remained there, eventually becoming a full professor of radiology, medicine, and bioengineering.During his time in Seattle, Dr Mankoff developed research interests in translational cancer molecular imaging and quantitative PET imaging and image analysis. In 2013, he returned to Penn School of Medicine as a professor of radiology and the PET Center director.A leading researcher with a particular interest in breast cancer, Dr Mankoff has maintained more than 20 years of continuous funding from federal sources and has been recognized as a Susan G. Komen Scholar since 2012.Key research achievements include defining applications of FDG PET to breast cancer staging and response evaluation, translating novel tracers to early human trials, studying the in vivo biology of cancer metabolism, and imaging estrogen receptor expression in breast cancer using PET.At the national level, Dr Mankoff has served as a committee leader and scientific planning co-chair of the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network (ECOG-ACRIN). He is a former steering committee chair of the NCI Quantitative Imaging Executive Committee, former member of the NCI Clinical Trials Advisory Committee, and former past president of the American Board of Nuclear Medicine.Dr Mankoff is associate editor for RSNA’s newest journal, Radiology: Imaging Cancer. He also serves on the editorial boards of several scientific journals. Dr Mankoff is co-chair of the RSNA Vice Chairs of Research Group and a member of the RSNA Committee on Scientific Affairs. He has also been active in the RSNA Clinical Trial Methodology Workshop and he has served as workshop co-director.Recognized for his many contributions to the field, Dr Mankoff was named an RSNA Honored Educator in 2013, 2018, and 2019. He received the Distinguished Investigator Award from the Academy of Radiology Research in 2018.Article HistoryPublished online: Dec 01 2020Published in print: Jan 2021 FiguresReferencesRelatedDetailsRecommended Articles Linda Moy, MD, Named New Editor of RadiologyRadioGraphics2022Volume: 42Issue: 2pp. E37-E38Linda Moy, MD, Named New Editor of RadiologyRadiology2022Volume: 303Issue: 1pp. 3-4PET Molecular Imaging as a Tool for Precision OncologyRadiology2020Volume: 296Issue: 2pp. 379-380Bruce G. Haffty, MD, President, Radiological Society of North America, 2022Radiology2022Volume: 302Issue: 3pp. 492-493Mutation Profiles of Urothelial Cancer: Will Genomics Change Radiology or Vice Versa?Radiology2020Volume: 295Issue: 3pp. 581-582See More RSNA Education Exhibits Breast Cancer in Younger Women: Screening and Diagnostic Imaging ExaminationsDigital Posters2018Non-BRCA Early Onset Breast Cancer in Young Women: Challenges and OpportunitiesDigital Posters2020Assessing Immunotherapy with Functional and Molecular Imaging and Radiomics: Whence and WitherDigital Posters2019 RSNA Case Collection Occult Breast CancerRSNA Case Collection2022Inflammatory breast cancerRSNA Case Collection2020Primary breast lymphomaRSNA Case Collection2020 Vol. 298, No. 1 Metrics Altmetric Score PDF download

Estrogen and Progesterone Receptor Expression in Breast Carcinoma and Its Association With Clinicopathological Variables Among the Pakistani Population.

IntroductionThe prognosis of breast cancer depends on the histological type, size of the tumor, tumor necrosis, skin, nipple and chest wall invasion, lymphovascular invasion, grade, stage, the status of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2), cell proliferation marker (ki-67), and type of therapy. Estrogen receptor and progesterone receptor expression in breast cancer is, so far, the most useful predictive marker. We have undertaken this study to find the expression of ER and PgR in breast carcinoma and its association with other prognostically important clinicopathological variables.Materials and methodsIn this cross-sectional study, a total of 130 cases of modified radical mastectomy that have been diagnosed as malignant on histopathology were collected from the pathology department of Allama Iqbal Medical College, Lahore, from January 2016 to May 2018. The demographic data and gross and microscopic findings were recorded. Immunohistochemistry (ER, PgR) was applied to suitable tumor sections and their status was evaluated semi-quantitatively by histopathologists using College American Pathologist (CAP) guidelines.ResultMost of the breast cancer patients (69; 53.1%) were below 50 years of age. Fifty-nine (45.4%) and 48 (36.9%) cases were positive for ER and PgR, respectively, showing lower hormonal receptor positivity than that reported in the western population where ER expression has been found in 50%-80% of cases and PR expression is found in 60%-70% of cases of invasive ductal carcinoma. The association of the expression of hormone receptors with a clinicopathological variable was demonstrated. ER-/PgR- tumors showed a higher histologic grade, greater tumor size, and more lymph node involvement by metastasis.ConclusionLow hormone receptor positivity is associated with young patients, advanced stage at presentation, and higher grade in our population. The tumor characteristics are different as compared to the western population. This suggests more consideration to the screening, early diagnosis, and molecular or immunohistochemical typing of this cancer in our population.

Contribution of Immune Cells to Glucocorticoid Receptor Expression in Breast Cancer.

Breast cancer (BC) patients experience increased stress with elevated cortisol levels, increasing risk of cancer recurrence. Cortisol binds to a cytoplasmic receptor, glucocorticoid receptor (GR) encoded by GR gene (NR3C1). We hypothesized that not only cancer cells, but even immune cells in the tumor microenvironment (TME) may contribute to GR expression in bulk tumor and influence prognosis. To test this, mRNA expression data was accessed from METABRIC and TCGA. “High” and “low” expression was based on highest and lowest quartiles of NR3C1 gene expression, respectively. Single-cell sequencing data were obtained from GSE75688 and GSE114725 cohorts. Computer algorithms CIBERSORT, Gene Set Enrichment Analysis and TIMER were used. GR-high BC has better median disease-free and disease-specific survival. Single cell sequencing data showed higher GR expression on immune cells compared to cancer and stromal cells. Positive correlation between GR-high BC and CD8+ T-cells was noted. In GR-high tumors, higher cytolytic activity (CYT) with decreased T-regulatory and T-follicular helper cells was observed. High GR expression was associated with lower proliferation index Ki67, enriched in IL-2_STAT5, apoptosis, KRAS, TGF-β signaling, and epithelial-to-mesenchymal transition. Immune cells significantly contribute to GR expression of bulk BC. GR-high BC has a favorable TME with higher CYT with favorable outcomes.

Vitamin D pathway related polymorphisms and vitamin D receptor expression in breast cancer.

Vitamin D deficiency is an emerging risk factor for breast cancer suggesting its role in breast cancer pathogenesis. Recent evidence suggests vitamin D receptor (VDR) expression is a prognosis predictor in breast cancer. We set out to determine the status of VDR expression in histologically characterized breast cancers, and whether common genetic variants modify VDR expression in breast cancer. One-hundred and twenty Kuwaiti female breast cancer fixed tissues were assessed for VDR expression to identify the level and location of its expression by immunohistochemistry. VDR variants (rs731236, rs2228570), and vitamin D binding protein (VDBP) variants (rs4588, rs7041) genotypes were ascertained in breast cancer specimens using Taqman genotyping assays. VDR nuclear expression correlated with low grade tumors (p=0.01), whereas cytoplasmic expression correlated with lymph node positive tumors (p=0.03). Absence of VDR expression was a marker for high-grade dedifferentiated tumors (p=0.01). VDBP rs7041 associated with breast cancer risk (OR 1.92, 95% CI: 1.34 - 2.73; p=0.0004), and VDR rs2228570 correlated with increased VDR cytoplasmic expression (p<0.0001). In conclusion, VDR expression is altered in breast cancer confirming its involvement in breast cancer progression. Genetic factors appear to play a role in breast cancer risk, and may modify tumor sensitization to vitamin D.

Helical and kinase domain mutations of PIK3CA, and their association with hormone receptor expression in breast cancer.

Breast cancer is one of the major causes of female morbidity and mortality, accounting for ~25% of the total cancer cases in women. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic α subunit (PIK3CA) mutations serve a major role in downstream signaling of receptor tyrosine kinases. The present study aimed to elucidate the frequency of exon 9 and 20 mutations of PIK3CA and their role in disease progression. A total of 118 tumor samples from confirmed breast cancer patients were collected from the histopathology laboratory at King Fahd Hospital of the University (Al-Khobar, Saudi Arabia). Sanger sequencing was performed on extracted DNA to identify the mutations on exons 9 and 20 of PIK3CA. The results were further validated by competitive allele-specific TaqMan polymerase chain reaction. Three mutations, namely E542K and E545K within exon 9, and H1047R within exon 20, were observed in 25 patients (21.2%). Among these, 18 patients carried the H1047R mutation of the kinase domain, while the remaining 7 patients carried mutations in the helical domain. PIK3CA mutations were associated with the estrogen receptor-positive/progesterone receptor-positive (ER+/PR+) group of tumors in contrast to the ER−/PR− group (P=0.021). Furthermore, it was observed that the PIK3CA mutation was associated with a poor disease prognosis. Taken together, the current study emphasized the potential of PIK3CA mutations as an important biomarker for breast cancer classification and the possible use of PIK3CA inhibitor as targeted therapy for breast cancer.

Abstract P5-05-11: Clinical significance of androgen receptor expression in breast cancer

Abstract Background Breast cancer is highly heterogeneous and immunohistochemistry (IHC) is used to determine breast cancer subtypes using estrogen and progesterone receptor (ER and PgR), HER2 and Ki-67. The androgen receptor (AR) is frequently expressed in breast cancer, but evaluation of AR has not been standardized and the oncogenic activity in breast cancer is still unclear. The objectives of this study were to assess the clinical significance of AR expression in breast cancer patients with primary (pretreatment and posttreatment) and recurrent breast cancer in relation to breast cancer subtype. Methods Primary and recurrent breast cancer patients who underwent treatment from March 2017 to May 2018 were enrolled in this study. A total of 591 primary breast cancer cases and 52 recurrent cases were analyzed. Thirty-four primary cases received treatment before surgery. The factors investigated included nodal status, tumor size, nuclear grade, ER/PgR and HER2 status, p53 overexpression, and the Ki-67 index value. The AR expression was evaluated using IHC and the expression was divided into 3 groups; negative, low (&amp;lt;10%) and high (≥10%). Breast cancer subtypes were categorized based on the IHC data derived from ER/PgR, HER2 and Ki-67 (cutoff point: 20%) in invasive tumors. Results The AR expression rates were 69.7%(low: 33.9% and high: 35.8%)in all primary cases. Patients who received treatment before surgery had an AR rate of 38.2% which was significantly different from the untreated cases (p=0.002). In the cases with neoadjuvant chemotherapy, the positive rate significantly decreased after chemotherapy in the cases with non-pCR (pathological complete response). The positive rate of recurrent/metastatic cases was 57.7% (low: 34.6% and high: 23.1%). Higher AR expression significantly correlated with smaller tumor size, positive ER/PgR, lower Ki-67 values and nuclear grade and negative p53 overexpression. The AR expression rate was 72.5% in Luminal A, 73.2% in Luminal B, 80% in Luminal HER2, 56.8% in HER2 enriched and 43.5% in triple negative (TN) cases. Moreover, in the TN tumor cases, AR expression significantly correlated with postmenopausal status and a higher degree of malignancy determined by Ki-67, p53, and nuclear grade. However, there was no significant relationship between these factors and the other subtypes. Conclusion The AR expressions were higher in the primary breast cancer cases than in the pretreated and recurrent cases. The AR expression significantly correlated with a lower degree of malignancy and postmenopausal status only in the TN breast cancer cases. These findings suggest that the TN cases with AR-positive tumors have a more favorable prognosis compared with the cases with AR-negative tumors. However, further studies are needed to determine the predictive and prognostic factors for clinical use. Citation Format: Arima N, Nishimura R, Osako T, Okumura Y, Nakano M, Fujisue M. Clinical significance of androgen receptor expression in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-11.

Expression of estrogen receptor beta correlates with adverse prognosis in resected pancreatic adenocarcinoma

BackgroundThe relevance of estrogen receptor (ER) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Clinical trials targeting ER with selective estrogen receptor modulators in pancreatic cancer did not show any benefit. Here, we analyze the impact of recently characterized ER isoform beta on survival in a cohort of patients with resected PDAC.MethodsEighty-four patients having undergone pancreatic resection for PDAC at a single institution were identified. Tissue microarrays were constructed of archival tumor specimens. The expression of ER beta was determined by immunohistochemistry and quantified by a system established for estrogen receptor expression in breast cancer. ER beta expression was then correlated with clinicopathological parameters, and univariate and multivariate survival analyses were performed.ResultsNuclear expression of ER beta was found in 31% of tumors. No significant correlation was found between ER beta expression and TNM status, tumor grade, age or sex. Univariate analysis revealed nodal metastasis and the expression of ER beta as factors correlating with a shorter overall survival and disease free survival. When comparing ER beta expression in patients surviving more than 24 months with those who died from the tumor within 12 or 24 months, respectively, a significantly lower ER beta expression was found in the long term survivors. In multivariate analysis, ER beta expression was demonstrated to be an independent predictor of shorter overall survival.ConclusionsIn resected PDAC, expression of ER beta seems to correlate with poor prognosis. These data may help to identify patients who may benefit from additional systemic therapy including selective estrogen receptor modulators.

Abstract 2211: Patient level polygenic risk scores and continuous estrogen receptor expression in breast cancer

Abstract Introduction: Genome-wide association studies over the past 10 years have identified over 100 common variants associated with breast cancer risk. The association of these polymorphisms varies according to estrogen receptor status of the tumor, with some associated primarily with ER+ or ER- disease, or both subtypes. However, ER expression in breast cancer cells is continuous. The aim of this study was to establish whether the association between polygenic risk scores and ER expression in breast cancer is continuous in nature. Methods: Data were taken from the international Breast Cancer Association Consortium (BCAC). Germline genotype data for 75 SNPs previously reported to be associated with breast cancer were available for 4,999 breast cancer cases for which ER expression data were also available. Automated ER expression on a continuous scale was measured using two image analysis algorithms: Astrogrid and Ariol. A third form of ER expression score, the manual Allred ordinal, was used. Genotype data were used to calculate polygenic risk scores using the equation: PRS = ∑ βx where β is the log-odds of the odds ratio (OR) of breast cancer associated with that single nucleotide polymorphism (SNP), and x is the number of variant alleles at a SNP locus. Five different PRSs were calculated: i) SNPs associated with both ER+ and ER- disease (PRS-A, n= 74) ii) SNPs associated with ER+ disease at P&amp;lt;0.01 (PRS-B, n= 65) iii) SNPs associated with ER- disease at P&amp;lt;0.01 (PRS-C, n= 43) iv) SNPs associated with ER+ but not ER- disease (PRS-D, n= 30) v) SNPs associated with ER- but not ER+ disease (PRS-E, n = 8) The ER-specific weights for the PRS were taken from previous OR estimates. Linear regression models adjusted for study were used to test for a relationship between the five PRSs and ER expression measured on the Ariol, Astrogrid and Allred scales. Results: There was a strong positive correlation found between PRS-B against Astrogrid (β=0.0176, P=4.06x10-4), a weak negative correlation found with PRS-C (β=-0.012, P=0.019) and a weak positive correlation for PRS-A (β=0.012, P=0.0144). PRS-D and E showed far stronger association with Astrogrid than PRS-B and C, respectively (β=0.0186 and -0.017, P=1.97x10-4 and 8.1x10-4). There was a qualitatively similar association when the PRSs were correlated with Ariol and Allred, apart from the stronger correlations with PRS-B (β=91.2 and 0.0853, P=5.52x10-4 and 1.33x10-3). Conclusion: We have shown a robust association between PRS and ER expression in the directions we predicted. This suggests that the continuous variation in ER expression is biologically plausible and linked to genetic polymorphism. The weakening of association with PRS-A and the stronger associations with PRS-D and E show that having SNPs that are associated with both ER subtypes in the same PRS weakens significance, and suggests that subtype-specific PRSs may be improved on by using SNPs exclusive to the respective subtype. Citation Format: Anamay H. Shetty, Raza Ali, Fiona Blows, Carlos Caldas, Nicholas Inard, Javier Benítez, Jenny Chang-Claude, Georgia Chenevix-Trench, Fergus Couch, Angela Cox, Peter Devilee, Douglas Easton, Montserrat Garcia-Closas, Arto Mannermaa, Heli Nevanlinna, Marjanka Schmidt, Paul Pharoah. Patient level polygenic risk scores and continuous estrogen receptor expression in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2211.