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Several studies have investigated the link between beta blockers (BB) and breast cancer outcomes but have reported mixed results. Our aim was to investigate the relationship between BB and breast cancer outcomes. Literatures investigating the relationship between BB and breast cancer outcomes were searched through PubMed and Embase. A total 43 articles were included by meta-analysis. We found BB increased breast cancer risk (n = 22, RR: 1.169, 95% CI: 1.063-1.285). We also found BB were associated with a lower overall survival (OS, n = 19, RR: 1.125, 95% CI: 1.078-1.173) and a higher recurrence risk (n = 8, RR: 1.130, 95% CI: 1.040-1.227) for breast cancer. Interestingly, subgroup analyses found only selective BB increased breast cancer risk (n = 5, RR: 1.766, 95% CI: 1.148-2.718) and recurrence risk (n = 2, RR: 1.168 -, 95% CI: 1.026-1.328) while only nonselective BB were associated with a lower OS (n = 4, RR: 1.135, 95% CI: 1.073-1.202) for breast cancer. Moreover, we found BB were associated with a significantly lower OS (n = 3, RR: 2.751, 95% CI: 1.213-6.238) and higher recurrence (n = 2, RR: 1.284, 95% CI: 1.102-1.497) only in luminal breast cancer while with a higher PFS (n = 2, RR: 0.585, 95% CI: 0.343-0.997) in Her2+ breast cancer. No significant differences in terms of CSM (n = 19, RR: 1.009, 95% CI: 0.947-1.077), PFS (n = 4, RR: 0.932, 95% CI: 0.616-1.305), and DFS (n = 2, RR: 0.776, 95% CI: 0.512-1.176) were observed. Our results provide evidence of the relationship between BB and breast cancer incidence and prognosis., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Gene expression profiling (GEP)-based prognostic signatures are being rapidly integrated into clinical decision making for systemic management of breast cancer patients. However, GEP remains relatively underdeveloped for locoregional risk assessment. Yet, locoregional recurrence (LRR), especially early after surgery, is associated with poor survival., Patients and Methods: GEP was carried out on two independent luminal-like breast cancer cohorts of patients developing early (≤5 years after surgery) or late (>5 years) LRR and used, by a training and testing approach, to build a gene signature able to intercept women at risk of developing early LRR. The GEP data of two in silico datasets and of a third independent cohort were used to explore its prognostic value., Results: Analysis of the first two cohorts led to the identification of three genes, CSTB, CCDC91 and ITGB1, whose expression, derived by principal component analysis, generated a three-gene signature significantly associated with early LRR in both cohorts (P value <0.001 and 0.005, respectively), overcoming the discriminatory capability of age, hormone receptor status and therapy. Remarkably, the integration of the signature with these clinical variables led to an area under the curve of 0.878 [95% confidence interval (CI) 0.810-0.945]. In in silico datasets we found that the three-gene signature retained its association, showing higher values in the early relapsed patients. Moreover, in the third additional cohort, the signature significantly associated with relapse-free survival (hazard ratio 1.56, 95% CI 1.04-2.35)., Conclusions: Our three-gene signature represents a new exploitable tool to aid treatment choice in patients with luminal-like breast cancer at risk of developing early recurrence., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Nuclear receptor coactivator 5 (NCOA5) is known to modulate ERα-mediated transcription and has been found to be involved in the progression of several malignancies. However, the potential correlation between NCOA5 and clinical outcome in patients with luminal breast cancer remains unknown. In the present study, we demonstrated that NCOA5 was significantly up-regulated in luminal breast cancer tissues compared with adjacent non-cancerous tissues both in validated cohort and TCGA cohort. Moreover, Kaplan-Meier analysis indicated that patients with high NOCA5 expression had significantly lower overall survival ( P = 0.021). Cox regression analysis indicated that the high NOCA5 expression was independent high risk factor as well as old age (>60) and HER-2 expression ( P = 0.039; P = 0.003; P = 0.005; respectively). This study provides new insights and evidences that NOCA5 over-expression was significantly correlated with progression and prognosis in luminal breast cancer. However, the precise cellular mechanisms for NOCA5 in luminal breast cancer need to be further explored. [ABSTRACT FROM AUTHOR]

There is a paucity of models for hormone receptor-positive ( HR+) breast cancer because of the difficulty of establishing xenografts from these tumours. We show that this obstacle can be overcome by injecting human tumour cells directly into the mammary ducts of immunodeficient mice. Tumours from 31 patients were infected overnight with a lentiviral vector expressing tdTomato and injected through the nipple into the mammary ducts of NOD-SCID-IL2RG−/− mice. Tumours formed in the mice in 77% of cases after the first injection (6/8 luminal A, 15/20 luminal B, and 3/3 molecular apocrine). Four luminal A and one molecular apocrine graft were tested in secondary and tertiary grafts: all were successfully passaged in secondary and 4/5 in tertiary grafts. None of the samples engrafted when injected subcutaneously. The morphology, oestrogen receptor ( ER), progesterone receptor ( PR), androgen receptor ( AR), and Ki-67 profiles of the clinical samples were maintained in the tertiary grafts. We also show that the intraductal approach can be used to test the response to targeted therapy with fulvestrant and palbociclib, using a genetically defined ER+ model. We conclude that the mammary ducts create a microenvironment that is uniquely favourable to the survival and growth of tumours derived from mammary hormone-sensing cells. This approach opens the door to testing genomically targeted treatment of HR+ tumours in precision medicine programmes. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Dysregulation of Forkhead-box (FOX) transcription factors is linked to cancers of numerous tissue types. Here, we report that FOXF2 is frequently silenced in luminal-type and HER2-positive breast cancers, but is overexpressed in basal-like breast cancers; thus, FOXF2 appears to play distinct roles in different breast cancer subtypes. Inactivation of FOXF2 in luminal-type and HER2-positive breast cancers is attributable to epigenetic silencing. Silencing of FOXF2 is associated with poor prognosis in luminal-type breast cancer. Ectopic expression of FOXF2 in luminal and HER2-positive breast cancer cells suppresses their tumorigenic properties in vitro and in vivo via inhibition of the CDK2-RB-E2F cascade. The in vivo function of FOXF2 is to maintain the stringency of DNA replication, and its loss triggers dysregulation of DNA replication, which in turn activates the p53 checkpoint pathway. Besides its role in cell cycle regulation, FOXF2 is functionally required for mobility and epithelial-to-mesenchymal transition (EMT) of normal breast epithelial cells. In basal-like breast cancer cells, the cell–cycle function of FOXF2 is impaired. However, the EMT function of FOXF2 is still required for mobility, invasiveness and anchorage-independent growth of basal-like breast cancer cells. Our gene expression profiling studies demonstrate that FOXF2 regulates the expression of genes implicated in cell cycle and EMT regulation. Moreover, FOXF2 is highly co-expressed with basal- and metastasis-related genes in breast cancer. These findings suggest that FOXF2 has a dual role in breast tumorigenesis and functions as either a tumor suppressor or an oncogene depending on the breast tumor subtype. [ABSTRACT FROM AUTHOR]

Myeloid leukemia factor 1-interacting protein (MLF1IP) has been found to be involved in the progression of several malignancies. The potential correlation between MLF1IP and clinical outcome in patients with luminal breast cancer, however, remains unknown. In the present study, we demonstrated that MLF1IP was significantly upregulated in luminal breast cancer tissue compared with adjacent normal tissue both in validated cohort and TCGA cohort. Upregulated expression of MLF1IP was correlated with more often lymph node metastasis and negative progesterone receptor expression in TCGA cohorts. Kaplan-Meier analysis indicated that patients with high MLF1IP expression had significantly lower overall survival. Moreover, multivariate analysis revealed that high MLF1IP expression was independent high risk factor as well as old age (>60) and distant metastasis. This study provides new insights and evidences that MLF1IP over-expression plays important roles in progression of luminal breast cancer. However, the precise cellular mechanisms for MLF1IP in luminal breast cancer need to be further explored. [ABSTRACT FROM AUTHOR]

Background: Occasionally, breast cancer relapses more than 5 years after initial treatment, sometimes with highly aggressive disease in such late-recurring patients. This study investigated predictors of recurrence after more than 5 years in operable breast cancer. Methods: We retrospectively analyzed data from patients with recurrent breast cancer treated at Siriraj Hospital. Patients were divided into those whose relapse times were longer or shorter than 5 years. Factors that predicted late recurrence were analyzed in both the overall population and the luminal subgroup. Patterns of relapse, changes in biomarkers, and time to disease progression after first relapse were also recorded. Results: We included 300 women whose breast cancers recurred between 2005 and 2013, of whom 180 had recurrence within 5 years of diagnosis and 120 later than 5 years (median time to recurrence: 45.43 months; range: 4.4-250.3 months). Tumors larger than 2 cm, lymph node metastasis, and high nuclear grade were related with early recurrence. Estrogen receptor-positive, progesterone receptor-positive, and HER2- disease predicted late recurrence. Almost all late-relapsing patients with luminal tumors had high estrogen receptor (ER+) titers (≥50%) and HER2- disease. Liver and brain were the most common early recurrence sites. Biomarkers did not significantly change by time of recurrence. Conclusions: ER+/PR+ and HER2- patients have higher risk of recurrence later than 5 years, especially in patients with high ER titer and low nuclear grade. Larger and node-positive tumors had higher risk of early recurrence. [ABSTRACT FROM AUTHOR]

Although Ki67 index suffers from poor reproducibility, it is one of the most important prognostic markers used by oncologists to select the treatment of estrogen receptor (ER) positive breast cancer patients. In this study, we aim to establish the optimal Ki67 cut-offs for stratifying patient prognosis and to create a comprehensive prognostic index for clinical applications. A mono-institutional cohort of 1.577 human epidermal growth factor receptor 2 negative/ER+ breast cancer patients having complete clinical, histological, and follow-up data was collected. The 14 and 20 % Ki67 cut-offs were correlated to disease-free interval (DFI) and disease-specific survival (DSS). To create a comprehensive prognostic index, we used independent variables selected by uni/multivariate analyses. In terms of DFI and DSS, patients bearing tumors with Ki67 < 14 % proliferation index did not differ from those with Ki67 values between 14 and 20 %. Patients with tumor with Ki67 > 20 % showed the poorest prognosis. Moreover, to tumor size, the number of metastatic lymph nodes and Ki67 > 20 % was given a score value, varying depending on definite cut-offs and used to create a prognostic index, which was applied to the population. Patients with a prognostic index ≥3 were characterized by significant risk of relapse [DFI: Hazard Ratio (HR) = 4.74, p < 0.001] and death (DSS: HR = 5.03, p < 0.001). We confirm that the 20 % Ki67 cut-off is the best to stratify high-risk patients in luminal breast cancers, and we suggest to integrate it with other prognostic factors, to better stratify patients at risk of adverse outcome. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most common cancers and the second leading cause of cancer death in the United States. Estrogen receptor (ER)-positive cancer is the most frequent subtype representing more than 70% of breast cancers. These tumors respond to endocrine therapy targeting the ER pathway including selective ER modulators (SERMs), selective ER downregulators (SERDs) and aromatase inhibitors (AIs). However, resistance to endocrine therapy associated with disease progression remains a significant therapeutic challenge. The precise mechanisms of endocrine resistance remain unclear. This is partly due to the complexity of the signaling pathways that influence the estrogen-mediated regulation in breast cancer. Mechanisms include ER modifications, alteration of coregulatory function and modification of growth factor signaling pathways. In this review, we provide an overview of epigenetic mechanisms of tamoxifen resistance in ER-positive luminal breast cancer. We highlight the effect of epigenetic changes on some of the key mechanisms involved in tamoxifen resistance, such as tumor-cell heterogeneity, ER signaling pathway and cancer stem cells (CSCs). It became increasingly recognized that CSCs are playing an important role in driving metastasis and tamoxifen resistance. Understanding the mechanism of tamoxifen resistance will provide insight into the design of novel strategies to overcome the resistance and make further improvements in breast cancer therapeutics.

Recurrent deletion of 16q12.2 is observed in luminal breast cancer, yet the causal genomic alterations in this region are largely unknown. In this study, we identify that loss of AKTIP , which is located on 16q12.2, drives tumorigenesis of estrogen receptor alpha (ERα)-positive, but not ERα-negative, breast cancer cells and is associated with poor prognosis of patients with ERα-positive breast cancer. Intriguingly, AKTIP -depleted tumors have increased ERα protein level and activity. Cullin-associated and neddylation-dissociated protein 1 (CAND1), which regulates the cullin-RING E3 ubiquitin ligases, protects ERα from cullin 2-dependent proteasomal degradation. Apart from ERα signaling, AKTIP loss triggers JAK2-STAT3 activation, which provides an alternative survival signal when ERα is inhibited. AKTIP -depleted MCF7 cells and ERα-positive patient-derived organoids are more resistant to ERα antagonists. Importantly, the resistance can be overcome by co-inhibition of JAK2/STAT3. Together, our results highlight the subtype-specific functional consequences of AKTIP loss and provide a mechanistic explanation for the enriched AKTIP copy-number loss in ERα-positive breast cancer. [Display omitted] • AKTIP loss selectively promotes tumorigenesis of ERα-positive breast cancer cells • AKTIP loss leads to ERα protein stabilization and JAK2/STAT3 activation • Cullin 2-mediated ERα degradation is inhibited in AKTIP -depleted cells via CAND1 • AKTIP loss-induced endocrine resistance can be overcome by inhibiting JAK2/STAT3 Ng et al. report AKTIP loss at 16q12.2 as a functional aberration of ERα-positive breast cancer and the therapeutic approach to target such aberration. They show that ERα stabilization and JAK2/STAT3 activation are the mechanisms underlying the enhanced tumorigenesis and endocrine resistance. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the second most cause of central nervous system (CNS) metastases. Studies report that almost one third of patients (pts) with triple-negative, one-third with human epidermal growth factor receptor 2 (HER2)-positive and 15% of those with hormone receptor-positive, HER2-negative metastatic breast cancer will develop brain metastases. It is known that the development of symptomatic brain metastases in women with advanced breast cancer is associated with poor prognosis, irrespective of local and systemic treatments. In the present study, we aim to determine the association between BC subtypes and CNS metastases occurrence and prognosis. Retrospective analysis of 309 BC patients with CNS metastases, confirmed by pathological and/or radiological methods, treated in a Cancer Center between 2003 and 2021, was obtained to identify clinicopathologic factors associated with early onset of brain metastases and survival outcomes. For analysis purposes, 3 BC subtypes were considered according to hormone receptor status and HER-2 expression: ER and/or PR positive, HER-2 positive and triple negative. The median time between diagnosis of BC and detection of CNS metastases was 43 months, and it was significantly shorter in triple negative group (8 months). Twenty-one patients (6,8%) had CNS metastases at BC diagnosis, with CNS being the first site of recurrence in 35,3%, mainly in HER2 positive. Most of the patients had parenchymal metastases (n = 245) and 37 (12%) had leptomeningeal (LM) disease, with predominance in ER and/or PR positive subtype (70,3%). In patients submitted to CNS surgery, the concordance between primary tumor and metastases subtype was higher in triple negative (76,9%) compared to 63,2% in HER-2 positive and 38,9% in ER and/or PR positive group (P < 0.05). After CNS involvement, 25,4% (n = 34) of patients with triple negative disease did not receive any systemic therapy, compared to 30,6% (n = 41) in HER-2 positive and 44% (n = 59) in ER and/or PR positive groups (P = 0.05). Median survival after CNS metastases was 9 months, but significantly longer in HER-2 positive group (16 months) and in patients submitted to surgical resection of CNS metastases, irrespectively of subtype (22 months vs 5 months in other treatment modalities). In multivariate Cox regression analysis, having HER-2 positive tumor was an independent prognostic factor for increasing survival after CNS metastases (HR 0.60, 95% CI: 0.41-0.87, P = 0.007), regardless the therapeutic strategy. Clinical behavior and prognosis of CNS metastases varies according to BC subtype. The association between LM disease and ER and/or PR positive tumors should be explored in upcoming studies. Also, these patients' prognosis depends on the availability of specific treatment options, therefore, innovative and effective therapeutic approaches are needed, in order to improve survival and quality of life of these patients. [ABSTRACT FROM AUTHOR]

RUNX1 encodes a RUNX family transcription factor (TF) and was recently identified as a novel mutated gene in human luminal breast cancers. We found that Runx1 is expressed in all subpopulations of murine mammary epithelial cells (MECs) except the secretory alveolar luminal cells. Conditional knockout of Runx1 in MECs by MMTV-Cre led to a decrease in luminal MECs, largely due to a profound reduction in the estrogen receptor (ER)-positive mature luminal subpopulation, a phenotype that could be rescued by the loss of either Trp53 or Rb1. Mechanistically RUNX1 represses Elf5, a master regulatory TF gene for alveolar cells, and regulates mature luminal TF/co-factor genes (e.g., Foxa1 and Cited1) involved in the ER program. Collectively, our data identified a key regulator of the ER+ luminal lineage whose disruption may contribute to the development of ER+ luminal breast cancer when under the background of either TP53 or RB1 loss.

Gene co-expression networks are a useful tool in the study of interactions that have allowed the visualization and quantification of diverse phenomena, including the loss of co-expression over long distances in cancerous samples. This characteristic, which could be considered fundamental to cancer, has been widely reported in various types of tumors. Since copy number variations (CNVs) have previously been identified as causing multiple genetic diseases, and gene expression is linked to them, they have often been mentioned as a probable cause of loss of co-expression in cancerous networks. In order to carry out a comparative study of the validity of this statement, we took 477 protein-coding genes from chromosome 8, and the CNVs of 101 genes, also protein-coding, belonging to the 8q24.3 region, a cytoband that is particularly active in the appearance of breast cancer. We created CNVS-conditioned co-expression networks of each of the 101 genes in the 8q24.3 region using conditional mutual information. The study was carried out using the four molecular subtypes of breast cancer (Luminal A, Luminal B, Her2, and Basal), as well as a case corresponding to healthy samples. We observed that in all cancer cases, the measurement of the Kolmogorov-Smirnov statistic shows that there are no significant differences between one and other values of the CNVs for any case. Furthermore, the co-expression interactions are stronger in all cancer subtypes than in the control networks. However, the control network presents a homogeneously distributed set of co-expression interactions, while for cancer networks, the highest interactions are more confined to specific cytobands, in particular 8q24.3 and 8p21.3. With this approach, we demonstrate that despite copy number alterations in the 8q24 region being a common trait in breast cancer, the loss of long-distance co-expression in breast cancer is not determined by CNVs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hernández-Gómez, Hernández-Lemus and Espinal-Enríquez.)

Introduction: Circular RNAs (circRNAs) regulatory network is important in human cancer. We, therefore, mapped the regulatory networks driven by circRNA in luminal-subtype breast cancer. Methods: Breast cancer-related microarray datasets from GEO database were analyzed for the differentially expressed circRNAs, miRNAs, and mRNAs. The potential downstream RNAs were collected using Circular RNA Interactome or Targetscan database. Protein-protein interaction (PPI) analysis was performed for the filtered genes to identify hub genes. The functions were annotated by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. CircRNA-miRNA-mRNA networks were mapped using Cytoscape software. Hsa&#95;circ&#95;0086735-miR-1296-5p-STAT1 axis was used for verification. The expression levels of hsa&#95;circ&#95;0086735, miR-1296-5p, and STAT1 mRNA were confirmed by qRT-PCR in luminal-subtype tissues and cell lines. The interactions among them were verified by Luciferase reporter assay and RNA pull-down assay. Cell proliferation and apoptosis were assayed. Overall and distant metastasis-free survival was analyzed. Results: A total of 70 genes were finally targeted and enriched in multi-process and multi-pathway. Networks containing 96 circRNA-miRNA-mRNA axes were constructed. Hsa&#95;circ&#95;0086735 and STAT1 mRNA was upregulated in luminal breast cancer, while miR-1296-5p was downregulated. Hsa&#95;circ&#95;0086735-miR-1296-5p-STAT1 axis promotes breast cancer progression and contributes to tamoxifen resistance. High hsa&#95;circ&#95;0086735 was associated with poor overall and distant metastasis-free survival. Discussion: This study identified the hsa&#95;circ&#95;0086735-miR-1296-5p-STAT1 as an important regulatory axis in luminal-subtype breast cancer, aiding to determine potential therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Qian, Chu, Chen, Jian and Wang.)

Estrogen receptor-positive (ER+)/HER2-negative (HER2-), the so-called luminal-type breast cancer, is the most frequent subset, accounting for around 70% of all breast cancer cases. Endocrine therapy (ET) combined with cyclin-dependent kinases (CDK) 4/6 inhibitors is the standard first option in the management of advanced luminal breast cancer independently of disease extension. Classically, patients undergo multiple lines of ET ± targeted treatments until endocrine resistance occurs and palliative chemotherapy is proposed. Understanding endocrine resistance mechanisms and development of novel ET options is one of the main challenges in current clinical research. Another area of utmost interest is the improvement of post-endocrine therapeutic approaches. Among others, the development of antibody-drug conjugates (ADCs) is very promising, and some of these drugs will probably soon become a part of the therapeutic arsenal against this incurable disease. This review paper provides an overview of currently available treatment options in ER+/HER2- metastatic breast cancer and extensively discusses new approaches in late clinical development., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cancer cell metabolism reprogramming is one of the hallmarks of cancer. Cancer cells preferentially utilize aerobic glycolysis, which is regulated by activated oncogenes and the tumor microenvironment. Extracellular matrix (ECM) in the tumor microenvironment, including the basement membranes (BMs), is dynamically remodeled. However, whether and how ECM regulates tumor glycolysis is largely unknown. We show that type IV collagens, components of BMs essential for the tissue integrity and proper function, are differentially expressed in breast cancer subtypes that α5 chain (α5(IV)) is preferentially expressed in the luminal-type breast cancer and is regulated by estrogen receptor-α. α5(IV) is indispensable for luminal breast cancer development. Ablation of α5(IV) significantly reduces the growth of luminal-type breast cancer cells and impedes the development of luminal-type breast cancer. Impaired cell growth and tumor development capability of α5(IV)-ablated luminal breast cancer cells is attributed to the reduced expression of glucose transporter and glycolytic enzymes and impaired glycolysis in luminal breast cancer cells. Non-integrin collagen receptor discoidin domain receptor-1 (DDR1) expression and p38 mitogen-activated protein kinase activation are attenuated in α5(IV)-ablated luminal breast cancer cells, resulting in reduced c-Myc oncogene expression and phosphorylation. Ectopic expression of constitutively active DDR1 or c-Myc restores the expression of glucose transporter and glycolytic enzymes, and thereafter restores aerobic glycolysis, cell proliferation, and tumor growth of luminal breast cancer. Thus, type IV collagen α5 chain is a luminal-type breast cancer-specific microenvironmental regulator modulating cancer cell metabolism., (© The Author(s) (2022). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)

Background: Given the low chance of response to neoadjuvant chemotherapy (NACT) in luminal breast cancer (LBC), the identification of predictive factors of pathological complete response (pCR) represents a challenge. A multicenter retrospective analysis was performed to develop and validate a predictive nomogram for pCR, based on pre-treatment clinicopathological features., Methods: Clinicopathological data from stage I-III LBC patients undergone NACT and surgery were retrospectively collected. Descriptive statistics was adopted. A multivariate model was used to identify independent predictors of pCR. The obtained log-odds ratios (ORs) were adopted to derive weighting factors for the predictive nomogram. The receiver operating characteristic analysis was applied to determine the nomogram accuracy. The model was internally and externally validated., Results: In the training set, data from 539 patients were gathered: pCR rate was 11.3% [95% confidence interval (CI): 8.6-13.9] (luminal A-like: 5.3%, 95% CI: 1.5-9.1, and luminal B-like: 13.1%, 95% CI: 9.8-13.4). The optimal Ki67 cutoff to predict pCR was 44% (area under the curve (AUC): 0.69; p < 0.001). Clinical stage I-II (OR: 3.67, 95% CI: 1.75-7.71, p = 0.001), Ki67 ⩾44% (OR: 3.00, 95% CI: 1.59-5.65, p = 0.001), and progesterone receptor (PR) <1% (OR: 2.49, 95% CI: 1.15-5.38, p = 0.019) were independent predictors of pCR, with high replication rates at internal validation (100%, 98%, and 87%, respectively). According to the nomogram, the probability of pCR ranged from 3.4% for clinical stage III, PR > 1%, and Ki67 <44% to 53.3% for clinical stage I-II, PR < 1%, and Ki67 ⩾44% (accuracy: AUC, 0.73; p < 0.0001). In the validation set (248 patients), the predictive performance of the model was confirmed (AUC: 0.7; p < 0.0001)., Conclusion: The combination of commonly available clinicopathological pre-NACT factors allows to develop a nomogram which appears to reliably predict pCR in LBC., Competing Interests: E.B. received speakers’ and travels’ fee from MSD, Astra-Zeneca, Celgene, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis, and Roche. E.B. received institutional research grants from Astra-Zeneca, Roche., (© The Author(s), 2023.)

Ki67 index is considered to be a reliable indicator of the proliferative activity of breast cancer. Additionally, the Ki67 proliferative marker may play a role in assessing response to systemic therapeutic strategies and can act as a prognostic biomarker. But its limited reproducibility which stems from a lack of standardization of procedures, inter-observer variability, and preanalytical and analytical variabilities all have hampered the use of the Ki67 index in clinical practice. Currently, clinical trials have been evaluating Ki67 as a predictive marker for needing adjuvant chemotherapy in luminal early breast cancer patients receiving neoadjuvant endocrine therapy. But the inconsistencies existing in the estimation of the Ki67 index limit the utility of Ki67 in standard clinical practice. The purpose of this review is to evaluate the benefits and drawbacks of utilizing Ki-67 in early-stage breast cancer to prognosticate the disease and predict the risk of recurrence., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Indian Association of Surgical Oncology 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Luminal breast cancer, as defined by oestrogen and/or progesterone expression by immunohistochemistry, accounts for up to 75% of all breast cancers. In this population, endocrine therapy is likely to account for most of the gains obtained with the administration of adjuvant systemic treatment. The role of adjuvant chemotherapy in these patients remains debatable since it is known that only a small fraction of patients will derive meaningful benefit from this treatment whilst the majority will be exposed to significant and unnecessary chemotherapy-related toxicities, in particular the elderly and frail. Therefore, neoadjuvant endocrine therapy (NET) becomes an attractive option for selected patients with hormonal-receptor positive locally advanced breast cancer. In this review, we discuss the current role of NET and future perspectives in the field. [ABSTRACT FROM AUTHOR]

The epithelium of the lactiferous ducts in the breast is comprised of luminal epithelial cells and underlying basal myoepithelial cells. The regulation of cell fate and transit of cells between these two cell types remains poorly understood. This relationship becomes of greater importance when studying the subtypes of epithelial breast carcinoma, which are categorized according to their expression of luminal or basal markers. The epithelial mesenchymal transition (EMT) is a pivotal event in tumor invasion. It is important to understand mechanisms that regulate this process, which bears relation to the normal dynamic of epithelial/basal phenotype regulation in the mammary gland. Understanding this process could provide answers for the regulation of EMT in breast cancer, and thereby identify potential targets for therapy. Evidence points towards a role for hedgehog signaling in breast tissue homeostasis and also in mammary neoplasia. This review examines our current understanding of role of the hedgehog-signaling (Hh) pathway in breast epithelial cells both during breast development and homeostasis and to assess the potential misappropriation of Hh signals in breast neoplasia, cancer stem cells and tumor metastasis via EMT. [ABSTRACT FROM AUTHOR]

Background: Previous studies have established that levels of the Inhibitor of Growth 1(ING1) tumor suppressor are reduced in a significant proportion of different cancer types. Here we analyzed levels of ING1 in breast cancer patients to determine its prognostic significance as a biomarker for breast cancer prognosis. Methods: We used automated quantitative analysis (AQUA) to determine the levels of ING1 in the tumor associated stromal cells of 462 breast cancer samples. To better understand how high ING1 levels affect nearby epithelium, we measured the levels of cytokines and secreted matrix metalloproteases (MMPs), using an ELISA based assay in mammary fibroblasts overexpressing ING1. These cells were also used in a 3-dimensional co-culture with MCF7 cells to determine the effect of released MMPs and other cytokines on growing colonies. Results: We find that high levels of ING1 in stroma are associated with tumor grade (p = 0.001) and size (p = 0.02), and inversely associated with patient survival (p = 0.0001) in luminal, but not in non-luminal cancers, suggesting that high stromal ING1 promotes cancer development. In this group of patients ING1 could also predict patient survival and act as a biomarker (HR = 2.125). While ING1 increased or decreased the expression of different cytokines, ING1 also increased the levels of MMP1, MMP3 and MMP10 by 5-8 fold, and concomitantly decreased levels of the tissue inhibitors of metalloproteases TIMP2, TIMP3 and TIMP4 by 1.5-3.3 fold, resulting in significant increases in MMP activity as determined by zymography. Co-culturing of MCF7 cells with stromal cells expressing ING1 in 3-dimensional organoid cultures suggested that MCF7 colonies were less well defined, suggesting that secreted MMPs might promote migration. Conclusion: These data indicate that stromal ING1 expression can predict the survival of patients with luminal breast cancer. High levels of ING1 in stromal cells can promote the development of breast cancer through increased expression and release of MMPs and down regulation of TIMPs, which may be an underlying mechanism of reduced patient survival. [ABSTRACT FROM AUTHOR]

We assessed whether progesterone receptor (PgR) and Ki67 in primary tumors and/or matched metastases are predictors of clinical benefit from first-line endocrine therapy (ET) in advanced breast cancer. We evaluated patients treated at our institute with first-line ET (2002-2011), excluding those receiving concomitant chemotherapy or trastuzumab or pretreated with >2 lines of chemotherapy. A cut-off of 20 % immunostained cells was used for PgR and Ki67. The main endpoint was time-to-progression (TTP). Groups were compared by the log-rank test and Cox multivariate analysis. In the 135 assessable patients (93 % were receiving an aromatase inhibitor; biomarker assessment had been performed on primary tumors in 77 cases, on metastases in 23 and on both in 35), median TTP was 16 months (median follow-up 43 months). The overall discordance rate between primary tumors and metastases was 23 % for Ki67 and 31 % for PgR. A longer median TTP (24 vs. 12 months, P = 0.012) was seen for PgR >20 % in metastases. Ki67 showed a trend for TTP prediction in the entire case series ( P = 0.062). Patients with high Ki67 and low PgR in metastases had a median TTP of only 5 months. High Ki67 in primary tumors ( P = 0.026) or metastases ( P = 0.01) predicted disease progression at the first evaluation. PgR in metastases remained a significant independent predictor of TTP at multivariate analysis (HR 2.45). In an ER-high population, PgR >20 % in metastases identified patients with a long TTP on endocrine treatment, while Ki67 >20 % was associated with an increased risk of non-response. [ABSTRACT FROM AUTHOR]

Luminal A and B breast cancers are the most prevalent forms of breast cancer diagnosed in women. Compared to luminal A breast cancer patients, patients with luminal B breast cancers experience increased disease recurrence and lower overall survival. The mechanisms that regulate the luminal B subtype remain poorly understood. The chemokine CCL2 is overexpressed in breast cancer, correlating with poor patient prognosis. The purpose of this study was to determine the role of CCL2 expression in luminal B breast cancer cells. Breast tissues, MMTV-PyVmT and MMTV-Neu transgenic mammary tumors forming luminal B-like lesions, were immunostained for CCL2 expression. To determine the role of CCL2 in breast cancer cells, CCL2 gene expression was silenced in mammary tumor tissues and cells using TAT cell-penetrating peptides non-covalently cross linked to siRNAs (Ca-TAT/siRNA). CCL2 expression was examined by ELISA and flow cytometry. Cell growth and survival were analyzed by flow cytometry, immunocytochemistry, and fluorescence microscopy. CCL2 expression was significantly increased in luminal B breast tumors, MMTV- PyVmT and MMTV-Neu mammary tumors, compared or normal breast tissue or luminal A breast tumors. Ca-TAT delivery of CCL2 siRNAs significantly reduced CCL2 expression in PyVmT mammary tumors, and decreased cell proliferation and survival. CCL2 gene silencing in PyVmT carcinoma cells or BT474 luminal B breast cancer cells decreased cell growth and viability associated with increased necrosis and autophagy. CCL2 expression is overexpressed in luminal B breast cancer cells and is important for regulating cell growth and survival by inhibiting necrosis and autophagy. [ABSTRACT FROM AUTHOR]

Luminal breast cancer subtypes respond poorly to endocrine and trastuzumab treatments due to cellular heterogeneity arising from the phenotype transitions, accounted for mainly by the loss of receptor expression. The origins of basal-like and human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer subtypes have been attributed to genetic and protein modifications in stem-like cells and luminal progenitor cell populations, respectively. The post-transcriptional regulation of protein expression is known to be influenced by microRNAs (miRNAs) that are deemed to be master regulators of several biological processes in breast tumorigenesis and progression. Our objective was to identify the fractions of luminal breast cancer cells that share stemness potentials and marker profiles and to elucidate the molecular regulatory mechanism that drives transitions between fractions, leading to receptor discordances. Established breast cancer cell lines of all prominent subtypes were screened for the expression of putative cancer stem cell (CSC) markers and drug transporter proteins using a side population (SP) assay. Flow-cytometry-sorted fractions of luminal cancer cells implanted in immunocompromised mice generated a pre-clinical estrogen receptor alpha (ERα+) animal model with multiple tumorigenic fractions displaying differential expression of drug transporters and hormone receptors. Despite an abundance of estrogen receptor 1 (ESR1) gene transcripts, few fractions transitioned to the triple-negative breast cancer (TNBC) phenotype with a visible loss of ER protein expression and a distinct microRNA expression profile that is reportedly enriched in breast CSCs. The translation of this study has the potential to provide novel therapeutic miRNA-based targets to counter the dreaded subtype transitions and the failure of antihormonal therapies in the luminal breast cancer subtype.

Breast cancer is the most common cancer in women around the world. Emerging evidence has indicated the important roles that non-coding RNAs play in regulating tumor development and progression in breast cancer. Herein, we found a dual function of long non-coding RNA (LncRNA) CCAT2 in the luminal subtype of breast cancer, depending on its subcellular distribution. CCAT2 showed an overall downregulation in the tumor tissues from luminal breast cancer patients. Transient overexpression of CCAT2 in the luminal subtype of breast cancer cell MCF-7 or T47D significantly suppressed cell proliferation in vitro and inhibited tumor growth in vivo. Gene expression analysis of cancer stem cell markers including OCT4, NANOG, h-TERT, SOX2 and KLF4; flow cytometry analysis of breast cancer stem cell population, and mammosphere formation assay demonstrated inhibition of cancer cell stemness with transient transfection of CCAT2 in which exogenous CCAT2 mainly distributed in the cytoplasm and regulated miR-221-p27 signaling via RNA sequence interaction. However, overexpression of CCAT2 in MCF-7 cells through pMX retroviral nuclear expression vector accumulated CCAT2 in the nucleus, leading to upregulation of OCT4-PG1, a pseudogene of stem gene OCT4, thereby promoting the cancer cell stemness. In conclusion, the current study, for the first time, revealed a dual function of lncRNA CCAT2 as a tumor suppressor or oncogene depending upon its subcellular distribution. It also demonstrated the regulatory mechanism of cytoplasmic CCAT2 in suppressing tumorigenesis in the luminal subtype of breast cancer.

Combined B-cell lymphoma 2 (Bcl2) and Ki67 expression for breast cancer prognostication has been proposed recently. However, the combinatorial relationship with patient outcome, clinico-pathologic features, and various biomarkers has not been fully explored. Bcl2 and Ki67 expression were examined in a large cohort of breast cancers. Differential Bcl2 and Ki67 combinatorial analysis, particularly in luminal cancers, were evaluated with respect to the clinico-pathologic features, biomarkers profile and outcome. Combined Bcl2/Ki67 phenotypes classified by Bcl2 and Ki67 cutoffs showed a better correlation with outcome. Multivariate analysis revealed this to be an independent prognostic factor in luminal cancers. Both Ki67 and Bcl2 contributed to the prognostic implications of different subgroups defined by Bcl2/Ki67 combination phenotypes with clinico-pathologic features and biomarkers profile. Ki67low/Bcl2high cases showed better DFS (HR = 2.17, P = 0.015) and OS (HR = 3.217, P = 0.015) compared to Ki67high/Bcl2low cases. Interestingly, Ki67low/Bcl2high cases also showed better outcome than other phenotypes in grade 2 cancers (log-rank = 4.844, P = 0.028) and TNM stage 2 cancers (log-rank = 8.161, P = 0.004). This classification by Bcl2/Ki67 combination phenotypes, together with PR expression, can also refine luminal A cancers prognostication. Not all PR low luminal A cases had poorer outcome compared to the PR high luminal A cases; poor prognosis was only limited to those with also low Bcl2 (log-rank = 23.568, P < 0.001 compared to PR high Bcl2 high cases). The combined Ki67/Bcl2 phenotyping was useful in luminal cancers prognostication. It also refined prognostication in intermediate groups (grade 2 and stage 2 cancers) of luminal cancers; and aided in further classification of luminal A cancers. [ABSTRACT FROM AUTHOR]

Background: Patients with luminal HER2-negative tumours have a favourable prognosis. However, there is a subpopulation in which poorer outcomes are obtained with endocrine therapy alone. This subpopulation is considered to benefit from chemotherapy. However, the significance of chemotherapy for those with luminal tumours has decreased due to recent changes in treatment strategies. Thus, it is often difficult to determine whether we should recommend chemotherapy to such patients in clinical practice. We investigated Ki67 expression, as a means of predicting the responses of luminal HER2-negative breast cancer patients to neo-adjuvant chemotherapy (NAC), in order to identify a subpopulation that would benefit from these treatments. Methods: We enrolled 114 luminal HER2-negative breast cancer patients undergoing surgery after NAC. Biomarkers were examined using biopsy specimens obtained prior to treatment, to avoid any chemotherapy-related effects. Chemotherapy effects were determined employing operative specimens and we defined pathological complete response (pCR) as invasive nest disappearance, based only on the primary breast tumour. We applied receiver operating characteristic curve analysis to data from our 114 patients, to investigate Ki67 expression as a predictor of pCR. Results: The pCR rate was significantly higher for tumours with high Ki67 expression (p < 0.01) and all patients who obtained pCR remained recurrence-free during the median 58-month observation period. We identified 35% as the Ki67 cut-off value which distinguishes those with a pCR from other cases. Another dataset, comprised of 196 patients with a median 29-month observation period, was recruited for validation. Disease-free survival was found to be significantly (p < 0.01) lower in the patients with tumours in which Ki67 expression was higher than 35%. Conclusion: Our results raise the possibility of the luminal HER2-negative subpopulation with Ki67 expression higher than 35% benefiting from chemotherapy, as evidenced by improved survival. [ABSTRACT FROM AUTHOR]

The classification of luminal breast cancer has been a popular topic regarding its heterogeneity with distinct biological features and clinical outcomes. This study aimed to assess the power of proliferative indices (Ki67 and histological grade) to determine various clinicopathological characteristics and survival in luminal disease. A total of 541 patients with stage I-III luminal breast cancer were enrolled. Subtypes were determined using proliferative indices and were compared with clinicopathological variables and short-term survival. The significance of various treatments was evaluated in a subgroup of pN0 (lymph node negative) patients. Histological grade, independent of other variables, was a better predictor in the ER/PR+, human epidermal growth factor receptor 2 (Her-2) subgroup ( p = 0.011) and the pN0 subgroup ( p = 0.044) compared with Ki67, which only showed significance in the ER/PR+, Her-2 subgroup ( p = 0.008). Neither grade nor Ki67 was associated with outcomes in the luminal Her-2 class. In pN0 patients, various treatments did not show significance in short-term survival. Histological grade outperformed Ki67 as a determinant for the stratification of luminal class regarding short-term survival. Chemotherapy most likely did not provide additional benefit to pN0 patients with luminal breast cancer compared with endocrine therapy. [ABSTRACT FROM AUTHOR]

Background: Luminal advanced breast cancer (ABC) patients eventually progress on endocrine therapy. REVERT aimed to explore whether eribulin could restore endocrine sensitivity in a randomized, non-comparative phase II trial., Methods: Aromatase inhibitor (AI)-resistant patients with luminal ABC were randomized 1:1 to receive eribulin +/- AI. Patients were stratified by prior cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) treatment. The primary endpoint was an investigator-assessed overall response rate (ORR) according to RECIST version 1.1 in the eribulin + AI arm. An interim analysis was planned with 11 evaluable patients according to a two-stage Simon design., Results: Twenty-two patients were enrolled (15 eribulin + AI arm; 7 eribulin arm). The trial was terminated early in March 2021, with eight (36.4%) patients still on treatment. ORR was 26.7% in the eribulin + AI arm (95% CI, 7.8-55.1%; p = 0.0541). In the eribulin arm, two (28.6%) patients had an objective response (95% CI, 3.7-71.0%). The difference between the study arms was not significant ( p = 0.918). The addition of AI to eribulin also failed to show improvement in other efficacy endpoints. A significant interaction between the treatment arm and previous CDK4/6i treatment was observed for ORR ( p = 0.018) and progression-free survival ( p = 0.084). Overall, the toxicity profile was consistent with the known safety profile of eribulin. No treatment-related deaths were reported., Conclusion: Eribulin + AI does not seem to improve outcomes compared with eribulin monotherapy in patients with AI-resistant luminal ABC. This chemo-endocrine approach deserves further investigation after progression to CDK4/6i-based therapy.

The interactions between aromatase inhibitors (AI) in breast cancer (BC) and gut microbiota (GM) have not been completely established yet. The aim of the study is to evaluate the bio-diversity of GM and the relationship between GM, inflammation and tumor-infiltrating lymphocytes (TILs) in postmenopausal women with BC during adjuvant AI treatment compared to women with disease relapse during or after one year of AI therapy ("endocrine-resistant"). We conducted a monocenter observational case-control study. Eighty-four women with BC (8 cases, 76 controls) were enrolled from 2019 to 2021. We observed a significant difference in the mean microbial abundance between the two groups for the taxonomic rank of order ( p 0.035) and family ( p 0.029); specifically, the case group showed higher diversity than the control group. Veillonella reached its maximum abundance in cases ( p 0.022). Cytokine levels were compared among the groups created considering the TILs levels. We obtained a statistically significant difference ( p 0.045) in IL-17 levels among the groups, with patients with low TILs levels showing a higher median value for IL-17 (0.15 vs. 0.08 pg/mL). Further studies about the bio-diversity in women with BC may lead to the development of new biomarkers and targeted interventions.

Luminal breast cancer (BC) accounts for a large proportion of patients in BC, with high heterogeneity. Determining the precise subtype and optimal selection of treatment options for luminal BC is a challenge. In this study, we proposed an MSBR framework that integrate DNA methylation profiles and transcriptomes to identify immune subgroups of luminal BC. MSBR was implemented both on a key module scoring algorithm and "Boruta" feature selection method by DNA methylation. Luminal A was divided into two subgroups and luminal B was divided into three subgroups using the MSBR. Furthermore, these subgroups were defined as different immune subgroups in luminal A and B respectively. The subgroups showed significant differences in DNA methylation levels, immune microenvironment (immune cell infiltration, immune checkpoint PD1/PD-L1 expression, immune cell cracking activity (CYT)) and pathology features (texture, eccentricity, intensity and tumor-infiltrating lymphocytes (TILs)). The results also showed that there is a subgroup in both luminal A and B that has the benefit from immunotherapy. This study proposed a classification of luminal BC from the perspective of epigenetics and immune characteristics, which provided individualized treatment decisions.

Genomic platforms have proven to be more accurate as a prognostic tool than immunohistochemistry studies in patients with early, hormone receptor positive, HER 2 negative breast cancer and, in some cases, have also demonstrated predictive ability for chemotherapy benefit. They are now widely applied in node-negative disease, but their use in node-positive disease is more recent and more controversial, especially in premenopausal patients. In this article, we review the use of these tests in node-positive disease., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: The gene BRCA1 plays a key role in DNA repair in breast and ovarian cell lines and this is considered one of target tumor suppressor genes in same line of cancers. The 5382insC mutation is among the most frequently detected in patients (Eastern Europe) with triple-negative breast cancer (TNBC). In Ukraine, there is not enough awareness of necessity to test patients with TNBC for BRCA1 mutations. That is why this group of patients is not well-studied, even through is known the mutation may affect the course of disease., Methods: The biological samples of 408 female patients were analyzed of the 5382insC mutation in BRCA1. We compared the frequency of the 5382insC mutation in BRCA1 gene observed in Ukraine with known frequencies in other countries., Results: For patients with TNBC, BRCA1 mutations frequency was 11.3%, while in patients with luminal types of breast cancers, the frequency was 2.8%. Prevalence of 5382insC among TNBC patients reported in this study was not different from those in Tunisia, Poland, Russia, and Bulgaria, but was higher than in Australia and Germany., Conclusion: The BRCA1 c.5382 mutation rate was recorded for the first time for TNBC patients in a Ukrainian population. The results presented in this study underscore the importance of this genetic testing of mutations in patients with TNBC. Our study supports BRCA1/2 genetic testing for all women diagnosed with TNBC, regardless of the age of onset or family history of cancer and not only for women diagnosed with TNBC at <60y.o., as guidelines recommend., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background Luminal breast cancer is a highly endocrine responsive disease. However, the therapeutic benefit of chemotherapy (CT) in this population is not fully characterized. This study investigates the value of CT and hormone therapy (HT) in luminal breast cancer patients in the neoadjuvant setting. Patients and Methods Patients with operable breast cancer and immunophenotypically defined luminal disease (ER+/PR+/HER2−/cytokeratin 8/18+) were recruited. Patients were randomized to CT (epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 × 4 cycles followed by docetaxel 100 mg/m2 × 4 cycles [EC-T]) or HT (exemestane 25 mg daily × 24 weeks [combined with goserelin in premenopausal patients]). The primary end point was the clinical response measured by magnetic resonance imaging. Results Ninety-five patients were randomized (47 CT, 48 HT). The clinical response rate was 66% for CT and 48% for HT (P = 0.075). We performed an unplanned analysis based on Ki67 levels (cut-off of 10%). Similar clinical response was seen between arms in patients with low Ki67 (CT: 63%, HT: 58%; P = 0.74); patients with high Ki67 had a better response with CT (67 versus 42%; P = 0.075). Grade 3/4 toxicity was more frequent with CT. Conclusions Luminal immunophenotype is not enough to identify patients who do not benefit from neoadjuvant CT. Luminal patients with low proliferation index could potentially avoid CT. [ABSTRACT FROM AUTHOR]

Primary breast invasive ductal carcinoma coexisting with ductal carcinoma in situ (IDC-DCIS) is characterized by lower proliferation rate and metastatic propensity than size-matched pure IDC. IDC-DCIS is also more often ER-positive, PR-positive and/or HER2-positive. This analysis aims to clarify whether the presence of coexisting DCIS in IDC affects tumor aggressiveness in various biological subtypes of breast cancer, respectively. Tumor data obtained from 1,355 consecutive female patients undergoing upfront surgery for primary breast cancer were analyzed retrospectively; 196 patients with pure DCIS were excluded. Based on evidence that immunohistochemistry (IHC) provides a reasonable approximation of molecular phenotypes, the tumor samples were divided into 4 groups: (1) luminal A (ER and/or PR-positive, HER2-negative, Ki67 ≤ 12), (2) luminal B (ER and/or PR-positive, HER2-negative, Ki67 > 12), (3) HER2 (HER2-positive) and (4) basal-like (triple-negative) disease. Ki67 expression and nodal involvement of IDC with or without DCIS in these groups were compared. The number of patients with luminal A, luminal B, HER2 and basal-like breast cancer were 396, 265, 258 and 117, respectively. Ki-67 was lower in IDC-DCIS than in size-adjusted pure IDC of both luminal A and luminal B subtypes ( P = 0.15 and <0.005, respectively). In HER2 or basal-like tumors, there were no significant difference between pure IDC and IDC-DCIS. The presence of coexisting DCIS in IDC predicts lower biological aggressiveness in luminal cancers but not in the conventionally more aggressive HER2-positive and triple-negative subtypes. [ABSTRACT FROM AUTHOR]

Luminal breast cancer is the most frequently encountered type of human breast cancer and accounts for half of all breast cancer deaths due to metastatic disease. We have developed new in vivo models of disseminated human luminal breast cancer that closely mimic the human disease. From initial lesions in the tibia, locoregional metastases develop predictably along the iliac and retroperitoneal lymph node chains. Tumors cells retain their epithelioid phenotype throughout the process of dissemination. In addition, systemically injected metastatic MCF-7 cells consistently give rise to metastases in the skeleton, floor of mouth, adrenal glands, as well as in the lungs, liver, brain and mammary fat pad. We show that growth of luminal breast cancer metastases is highly dependent on estrogen in a dose-dependent manner and that estrogen withdrawal induces rapid growth arrest of metastatic disease. On the other hand, even though micrometastases at secondary sites remain viable in the absence of estrogen, they are dormant and do not progress to macrometastases. Thus, homing to and seeding of secondary sites do not require estrogen. Moreover, in sharp contrast to basal-like breast cancer metastasis in which transforming growth factor-β signaling plays a key role, luminal breast cancer metastasis is independent of this cytokine. These findings have important implications for the development of targeted anti-metastatic therapy for luminal breast cancer. [ABSTRACT FROM AUTHOR]

Patients with resectable, nonmetastatic (stage I-IIIA) breast cancer usually receive adjuvant (postoperative) systemic therapy to control micrometastasis and prevent recurrence. Neoadjuvant (preoperative) chemotherapy is a standard treatment for resectable breast cancer, potentially enabling patients to undergo partial dissection. However, it has been reported that neoadjuvant chemotherapy has a limited effect in patients with hormone receptor-positive disease in terms of pathologic complete response rate, and in elderly patients there may be safety concerns. Furthermore, the appropriateness of chemotherapy for luminal early breast cancer [defined as hormone receptor-positive and human epidermal growth factor receptor-2 (HER2)-negative tumors] is an important clinical issue. We determine the need for chemotherapy in postmenopausal patients with hormone receptor-positive, HER2-negative, lymph node-negative early breast cancer according to clinicopathologic factors, including multigene signature. The National Surgical Adjuvant Study of Breast Cancer (N-SAS-BC06) New primary Endocrine-therapy Origination Study (NEOS) is a randomized phase III trial conducted in Japanese centers. It is evaluating adjuvant endocrine therapy, with or without chemotherapy, in patients with postmenopausal breast cancer that has responded to neoadjuvant letrozole. The aims of this trial are to: define patients who might not require chemotherapy by using their response to neoadjuvant endocrine therapy; analyze the relationship between neoadjuvant endocrine therapy and long-term prognosis; and analyze the correlation between clinical and pathologic response to neoadjuvant hormonal therapy with additional postoperative chemotherapy. We hope that the results of this trial will lead to the development of a new clinical strategy of pre- and postsurgical treatment for luminal breast cancer. [ABSTRACT FROM AUTHOR]

Novel breast tumor antigens are needed to develop T cell and antibody-based vaccine immunotherapy approach against breast cancer. To this purpose, we have previously shown that PDEF is frequently over expressed in human breast tumors and exhibits highly restricted expression in normal human tissues that is primarily limited to normal prostate. Moreover, PDEF expression correlates with poor overall survival for breast cancer patients. Additionally, Pse (prostate-specific Ets, mouse homologue of PDEF) is immunogenic in female mice and PDEF sequence contains HLA-A2 binding potentially immunogenic peptides. Together, these observations support PDEF as a novel candidate breast tumor antigen. Further, we have identified certain PDEF-induced proteins including CEACAM6, B7-H4, and S100A7 as additional candidate breast tumor antigens. [ABSTRACT FROM AUTHOR]