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Introduction: The presence of tumor-infiltrating lymphocytes (TILs) is correlated with good prognosis and outcome after (immuno)therapy in triple-negative and HER2-positive breast cancer. However, the role of TILs in luminal breast cancer is less clear. Emerging evidence has now demonstrated that genetic aberrations in malignant cells influence the immune landscape of tumors. Phosphatidylinositol 3-kinase (PI3K) is the most common altered pathway in ER-positive breast cancer. It is unknown whether changes in the PI3K pathway result in a different composition of the breast tumor microenvironment. Here we present the retrospective analysis of a prospective randomized trial in ER-positive breast cancer on the prognostic and predictive value of specific tumor-associated lymphocytes in the context of PI3K alterations.Methods: We included 563 ER-positive tumors from a multicenter trial for stage I to III postmenopausal breast cancer patients, who were randomized to tamoxifen or no adjuvant therapy. The amount of CD8-, CD4-, and FOXP3-positive cells was evaluated by immunohistochemistry and quantified by imaging-analysis software. We analyzed the associations between PIK3CA hotspot mutations, PTEN expression, phosphorylated proteins of the PI3K and MAPK pathway (p-AKT, p-ERK1/2, p-4EBP1, p-p70S6K), and recurrence-free interval after adjuvant tamoxifen or no adjuvant treatment.Results: CD8-positive lymphocytes were significantly more abundant in PIK3CA-mutated tumors (OR = 1.65; 95% CI 1.03-2.68). While CD4 and FOXP3 were not significantly associated with prognosis, patients with tumors classified as CD8-high had increased risk of recurrence (HR = 1.98; 95% CI 1.14-3.41; multivariable model including PIK3CA status, treatment arm, and other standard clinicopathological variables). Lymphocytes were more often present in tumors with increased PI3K downstream phosphorylation. This was most pronounced for FOXP3-positive cells.Conclusion: These exploratory analyses of a prospective trial in luminal breast cancer suggest high CD8 infiltration is associated with unfavorable outcome and that PI3K pathway alterations might be associated with the composition of the tumor microenvironment. [ABSTRACT FROM AUTHOR]

To classify as breast cancer with neuroendocrine differentiation a growth pattern as encountered in well differentiated (G1, G2) neuroendocrine tumors (NET) of the gastrointestinal tract and the lung must be present in addition to the immunohistochemical expression of neuroendocrine markers (chromogranin, synaptophysin). The majority of breast cancers fulfilling these criteria show hormone receptor positivity and with regard to prognosis resemble luminal type of breast cancer from which they are not fundamentally different. Despite lacking clinical relevance the up-coming WHO classification of breast cancer will nevertheless introduce the new category of NET luminal type. Immunohistochemical detection of neuroendocrine marker alone cannot be considered as sufficient for classification because it can frequently be encountered in other types of breast cancer (e.g. mucinous, solid papillary). From low grade NET with good differentiation those with poor differentiation and most frequently small cell appearance have to be differentiated. Poorly differentiated NET can primarily originate in the breast, which may be indicated by intraductal growth and co-expression of GATA3 but in these cases metastasis of extra mammary cancers has to be considered and correlation with the clinical findings is required for correct classification.

Patients with early estrogen receptor-positive breast cancer are at continuous risk of relapse even after more than 10 years of follow up. Currently, no biomarker that identifies patients for early versus late recurrence, or one that selects patients or tumors for longer versus shorter durations of endocrine therapy (ET) is available and a crucial question is how to properly select patients who could be spared extended ET or those who require it. In the last 20 years more than 40,000 women were enrolled in randomized trials to answer the question of optimal duration of ET. According to the results of these studies extended adjuvant ET is more effective than standard 5 years of adjuvant ET. Extended ET in patients who remain premenopausal after 5 years of adjuvant tamoxifen is still tamoxifen for another 5 years. Extended ET with aromatase inhibitors (AIs) should be offered to postmenopausal women with substantial residual risk of relapse after completing 5 years of tamoxifen therapy. Extension of AI treatment to 10 years resulted in significantly better 5-year disease-free survival including disease recurrence local/distant or the occurrence of contralateral breast cancer events. Currently, new therapeutic targets are under investigation, but the beneficial effect of prolonged treatment for high-risk patients, identified by using multigenomic tests, remains unclear. Thus, further studies need to be performed to confirm the advantage of extended adjuvant ET in selected patients. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) is more prevalent in African and African American (AA) women compared to European American (EA) women. African and AA women diagnosed with TNBC experience high frequencies of metastases and less favorable outcomes. Emerging evidence indicates that this disparity may in fact be the result of the uniquely aggressive biology of African and AA disease., Purpose: To understand the reasons for TNBC in AA aggressive biology, we designed the present study to examine the proteomic profiles of TNBC and luminal A (LA) breast cancer within and across patients' racial demographic groups in order to identify proteins or molecular pathways altered in TNBC that offer some explanation for its aggressiveness and potential targets for treatment., Materials and Methods: Proteomic profiles of TNBC, LA tumors, and their adjacent normal tissues from AA and EA women were obtained using 2-dimensional gel electrophoresis and bioinformatics, and differentially expressed proteins were validated by Western blot and immunohistochemistry. Our data showed that a number of proteins have significantly altered in expression in LA tumors compared to TNBC, both within and across patients' racial demographic groups. The differentially overexpressed proteins in TNBC (compared to LA) of AA samples were distinct from those in TNBC (compared to LA) of EA women samples. Among the signaling pathways altered in AA TNBC compared to EA TNBC are innate immune signaling, calpain protease, and pyrimidine de novo synthesis pathways. Furthermore, liver LXR/RXR signaling pathway was altered between LA and TNBC in AA women and may be due to the deficiency of the CYP7B1 enzyme responsible for cholesterol degradation., Conclusion: These findings suggest that TNBC in AA women enriched in signaling pathways that are different from TNBC in EA women. Our study draws a link between LXR/RXR expression, cholesterol, obesity, and the TNBC in AA women., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background/aim: Genomic signatures are needed for the determination of prognosis in patients with early stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers. EndoPredict test is a RNA-based multigene assay that assesses the risk of 10-year relapse in this context. Quality assessment is a mandatory requirement for a laboratory to address the analytical quality of these molecular analyses. The aim of the study was to demonstrate the robustness of this prognostic test, its usefulness for the patient's treatment strategy, at the national level., Materials and Methods: This study presents a pilot quality assessment (QA) of the EndoPredict test using composite design, including the follow-up of internal control values (qREF) of the 12 genes of the assay for 151 independent tests and one formalin-fixed paraffin embedded (FFPE) breast cancer sample. The evaluation of the test was performed by comparing the results of six independent medical laboratories., Results: All measures were highly reproducible and quantification of the qREF showed a standard deviation of less than 0.50 and a coefficient of variation always of <2%. All laboratories found concordant results for the breast cancer samples. The mean EndoPredict (EP) score for the breast cancer sample was 4.97±0.24. The mean of EPclin score was 3.07±0.05., Conclusion: This first French independent reported QA assessed the robustness and reproducibility of the EndoPredict test. Such a simple composite design could represent an adapted QA for an expensive diagnostic test., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Distal metastasis of luminal breast cancer is frequent and incurable, yet the metastasis mechanisms are poorly understood. Estrogen, even at postmenopausal concentrations, suppresses invasiveness of luminal breast cancer cells through the estrogen receptor (ER). Invasive tumors overexpress the short progesterone receptor A (PR-A) isoform. Even at postmenopausal concentrations, progesterone activates PR-A, inducing invasiveness by counteracting estrogen's effects, particularly when cells are hypersensitized to progesterone by PR-A overexpression. To interrogate the role of this cross-talk in metastasis, we investigated selective cross-talk mechanisms of PR-A with ER. We developed a quantitative PCR-based lymph node infiltration assay to address the slowness of metastasis of tumor xenografts. We found that 15 microRNAs (miRNAs) are regulated by progesterone via PR-A, but not the longer PR-B isoform, with increased progesterone sensitivity when PR-A was overexpressed. Two of these miRNAs whose induction (miR-92a-3p) or repression (miR-26b-5p) by estrogen was suppressed by progesterone plus PR-A were critical for the PR-A-ER cross-talk causing a gene-regulatory pattern of invasiveness and metastasis and complete rescue of invasiveness in vitro Constitutive expression of miR-92a-3p or inhibition of miR-26b-5p profoundly suppressed metastasis. Finally, in primary breast tumors, PR-A expression was correlated negatively with miR-92a-3p expression and positively with miR-26b-5p expression. Therefore, hormonal cross-talk of PR-A with ER is probably a fundamental mechanism that enables metastasis of luminal breast cancer. Moreover, miRNA biomarkers of hyperactive PR-A may help predict metastatic potential of luminal breast tumors. Further, miR-92a-3p and miR-26b-5p may reveal target pathways for selective intervention to suppress hormone-regulated metastasis, both pre- and postmenopause., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Triple negative breast cancer (TNBC) is characterized by poor prognosis and a DNA hypomethylation profile. Withaferin A (WA) is a plant derived steroidal lactone which holds promise as a therapeutic agent for treatment of breast cancer (BC). We determined genome-wide DNA methylation changes in weakly-metastatic and aggressive, metastatic BC cell lines, following 72h treatment to a sub-cytotoxic concentration of WA. In contrast to the DNA demethylating agent 5-aza-2'-deoxycytidine (DAC), WA treatment of MDA-MB-231 cells rather tackles an epigenetic cancer network through gene-specific DNA hypermethylation of tumor promoting genes including ADAM metallopeptidase domain 8 (ADAM8), urokinase-type plasminogen activator (PLAU), tumor necrosis factor (ligand) superfamily, member 12 (TNFSF12), and genes related to detoxification (glutathione S-transferase mu 1, GSTM1), or mitochondrial metabolism (malic enzyme 3, ME3). Gene expression and pathway enrichment analysis further reveals epigenetic suppression of multiple cancer hallmarks associated with cell cycle regulation, cell death, cancer cell metabolism, cell motility and metastasis. Remarkably, DNA hypermethylation of corresponding CpG sites in PLAU, ADAM8, TNSF12, GSTM1 and ME3 genes correlates with receptor tyrosine-protein kinase erbB-2 amplification (HER2)/estrogen receptor (ESR)/progesterone receptor (PR) status in primary BC tumors. Moreover, upon comparing differentially methylated WA responsive target genes with DNA methylation changes in different clinical subtypes of breast cancer patients in the cancer genome atlas (TCGA), we found that WA silences HER2/PR/ESR-dependent gene expression programs to suppress aggressive TNBC characteristics in favor of luminal BC hallmarks, with an improved therapeutic sensitivity. In this respect, WA may represent a novel and attractive phyto-pharmaceutical for TNBC treatment.

BET bromodomain inhibitors, which have an antitumoral effect against various solid cancer tumor types, have not been studied in detail in luminal breast cancer, despite the prevalence of this subtype of mammary malignancy. Here we demonstrate that the BET bromodomain inhibitor JQ1 exerts growth-inhibitory activity in human luminal breast cancer cell lines associated with a depletion of the C-MYC oncogene, but does not alter the expression levels of the BRD4 bromodomain protein. Interestingly, expression microarray analyses indicate that, upon JQ1 administration, the antitumoral phenotype also involves downregulation of relevant breast cancer oncogenes such as the Breast Carcinoma-Amplified Sequence 1 (BCAS1) and the PDZ Domain-Containing 1 (PDZK1). We have also applied these in vitro findings in an in vivo model by studying a transgenic mouse model representing the luminal B subtype of breast cancer, the MMTV-PyMT, in which the mouse mammary tumor virus promoter is used to drive the expression of the polyoma virus middle T-antigen to the mammary gland. We have observed that the use of the BET bromodomain inhibitor for the treatment of established breast neoplasms developed in the MMTV-PyMT model shows antitumor potential. Most importantly, if JQ1 is given before the expected time of tumor detection in the MMTV-PyMT mice, it retards the onset of the disease and increases the survival of these animals. Thus, our findings indicate that the use of bromodomain inhibitors is of great potential in the treatment of luminal breast cancer and merits further investigation., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Drugs that target the Renin-Angiotensin System (RAS) have recently come into focus for their potential utility as cancer treatments. The use of Angiotensin Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme (ACE) Inhibitors (ACEIs) to manage hypertension in cancer patients is correlated with improved survival outcomes for renal, prostate, breast and small cell lung cancer. Previous studies demonstrate that the Angiotensin Receptor Type I (AT1R) is linked to breast cancer pathogenesis, with unbiased analysis of gene-expression studies identifying significant up-regulation of AGTR1, the gene encoding AT1R in ER+ve/HER2-ve tumors correlating with poor prognosis. However, there is no evidence, so far, of the functional contribution of AT1R to breast tumorigenesis. We explored the potential therapeutic benefit of ARB in a carcinogen-induced mouse model of breast cancer and clarified the mechanisms associated with its success.Mammary tumors were induced with 7,12-dimethylbenz[α]antracene (DMBA) and medroxyprogesterone acetate (MPA) in female wild type mice and the effects of the ARB, Losartan treatment assessed in a preventative setting (n = 15 per group). Tumor histopathology was characterised by immunohistochemistry, real-time qPCR to detect gene expression signatures, and tumor cytokine levels measured with quantitative bioplex assays. AT1R was detected with radiolabelled ligand binding assays in fresh frozen tumor samples.We showed that therapeutic inhibition of AT1R, with Losartan, resulted in a significant reduction in tumor burden; and no mammary tumor incidence in 20% of animals. We observed a significant reduction in tumor progression from DCIS to invasive cancer with Losartan treatment. This was associated with reduced tumor cell proliferation and a significant reduction in IL-6, pSTAT3 and TNFα levels. Analysis of tumor immune cell infiltrates, however, demonstrated no significant differences in the recruitment of lymphocytes or tumour-associated macrophages in Losartan or vehicle-treated mammary tumors.Analysis of AT1R expression with radiolabelled ligand binding assays in human breast cancer biopsies showed high AT1R levels in 30% of invasive ductal carcinomas analysed. Furthermore, analysis of the TCGA database identified that high AT1R expression to be associated with luminal breast cancer subtype.Our in vivo data and analysis of human invasive ductal carcinoma samples identify the AT1R is a potential therapeutic target in breast cancer, with the availability of a range of well-tolerated inhibitors currently used in clinics. We describe a novel signalling pathway critical in breast tumorigenesis, that may provide new therapeutic avenues to complement current treatments.

Aim: Luminal A breast cancers (BC) represent low-risk tumors conferring better outcome than luminal B and human epidermal growth factor 2 (HER2)-positive or triple-negative tumors. One reason for the heterogeneous outcome among patients with luminal BC is the variation in cell proliferation. As chemokine receptors and tumor suppressors show potential for estimation of infiltration to regional lymph nodes, we aimed to compare differently sized sentinel node metastases with their primary tumors (PT)., Materials and Methods: We compared 29 BCs of luminal subtype A and 23 of subtype B (Ki-67 cut off at 14%) by immunohistochemistry for the chemokine receptors C-X-C chemokine receptor 4 (CXCR4), C-C-chemokine receptor 7 (CCR7), the tumor suppressor Maspin and the regulatory T-cell immunosuppressor forkhead box protein 3 (FOXP3) between PTs and their metastases of different size., Results: Expression of CXCR4 was low in luminal A type tumors, and CCR7 and FOXP3 expression were high in luminal B type cancer. CXCR4 expression significantly positively correlated with CCR7 both in PTs and metastases. Most Maspin-positive PTs became negative in the metastases. The PTs for all Maspin-positive metastases were luminal B type., Conclusion: High CXCR4 expression in PTs was found to be associated with luminal A type tumor, suggesting more favorable outcome. In contrast, CCR7 and FOXP3 expressions in PTs represented luminal B tumors, pointing to more aggressive tumor behavior. Maspin expression did not differ between luminal types., (Copyright© 2017 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Neoadjuvant systemic therapies have been extensively evaluated in luminal breast cancer. Conventional cytotoxic chemotherapy increases breast conservation rate, albeit with a low level of complete pathological response of uncertain clinical significance. Endocrine therapies allow similar clinical results with much less side effects. Biological criteria of response to endocrine therapies are still being defined. The neoadjuvant setting must be used for early development of new compounds and to further document biological mechanisms of sensitivity and resistance to treatments., (Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Luminal breast cancer constitutes a group of highly heterogeneous diseases with a sustained high risk of late recurrence. We aimed to develop comprehensive and practical nomograms to better estimate the long-term survival of luminal breast cancer.Patients with luminal breast cancer diagnosed between 1990 and 2006 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into the training (n = 87,867) and validation (n = 88,215) cohorts. The cumulative incidence function (CIF) and a competing-risks model were used to estimate the probability of breast cancer-specific survival (BCSS) and death from other causes. We integrated significant prognostic factors to build nomograms and subjected the nomograms to bootstrap internal validation and to external validation.We screened 176,082 luminal breast cancer cases. The 5- and 10-year probabilities of overall death were 0.089 and 0.202, respectively. The 5- and 10-year probabilities of breast cancer-specific mortality (BCSM) were 0.053 and 0.112, respectively. Nine independent prognostic factors for both OS and BCSS were integrated to construct the nomograms. The calibration curves for the probabilities of 5- and 10-year OS and BCSS showed excellent agreement between the nomogram prediction and actual observation. The C-indexes of the nomograms were high in both internal validation (0.732 for OS and 0.800 for BCSS) and external validation (0.731 for OS and 0.794 for BCSS).We established nomograms that accurately predict OS and BCSS for patients with luminal breast cancer. The nomograms can identify patients with higher risk of late overall mortality and BCSM, helping physicians in facilitating individualized treatment.

Triple-negative (TN) breast cancer accounts for ∼ 15% of breast cancers and is characterized by a high likelihood of relapse and a lack of targeted therapies. In contrast, luminal-type tumors that express the estrogen and progesterone receptors (ER+/PR+) and lack expression of human epidermal growth factor receptor 2 (Her2-) are treated with targeted hormonal therapy and carry a better prognosis. To identify potential targets for the development of future therapeutics aimed specifically at TN breast cancers, we have used a hydrazide-based glycoproteomic workflow to compare protein expression in clinical tumors from nine TN (Her2-/ER-/PR-) and nine luminal (Her2-/ER+/PR+) patients. Using a label-free LC-MS based approach, we identified and quantified 2264 proteins. Of these, 90 proteins were more highly expressed and 86 proteins were underexpressed in the TN tumors relative to the luminal tumors. The expression level of four of these potential targets was verified in the original set of tumors by Western blot and correlated well with our mass-spectrometry-based quantification. Furthermore, 30% of the proteins differentially expressed between luminal and TN tumors were validated in a larger cohort of 406 TN and 469 luminal tumors through corresponding differences in their mRNA expression in publically available microarray data. A group of 29 of these differentially expressed proteins was shown to correctly classify 88% of TN and luminal tumors using microarray data of their associated mRNA levels. Interestingly, even within a group of TN breast cancer patients, the expression levels of these same mRNAs were able to significantly predict patient survival, suggesting that these proteins play a role in the aggressiveness seen in TN tumors. This study provides a comprehensive list of potential targets for the development of diagnostic and therapeutic agents specifically aimed at treating TN breast cancer and demonstrates the utility of using publicly available microarray data to further prioritize potential targets.

Summary: Luminal breast cancers are traditionally considered to comprise of tumors expressing estrogen receptor (ER) and represent the majority of breast cancers. These tumors are characterized by significant heterogeneity in phenotype, molecular signature, relapse patterns and therapeutic response to endocrine and chemotherapy. Whilst adjuvant endocrine therapy is standard of care in patients with tumors that express either ER and/or progesterone receptor (PR), the indication for adjuvant chemotherapy is less clear-cut. On average, ER-positive breast tumors derive less benefit from chemotherapy compared to ER-negative tumors, however there is still clearly a subset of patients with ER-positive tumors that are chemosensitive. The basis for the addition of chemotherapy to adjuvant endocrine therapy is usually guided by the clinician''s estimation of prognosis and assessment of the endocrine sensitivity of the tumor. The use of chemotherapy in this setting, however, is highly variable. There is tremendous value in identifying subgroups of patients who can expect favorable outcomes with endocrine therapy and who may not require any additional therapy. Similarly, it is equally important, if not more important, to characterize patients with ER-positive disease who will derive a substantial benefit from cytotoxic chemotherapy. In this article, we aim to discuss the utility of current biomarkers used to guide decisions regarding chemotherapy in ER-positive, HER2-negative breast cancers. [Copyright &y& Elsevier]

The WHO classification of breast tumors distinguishes, besides invasive breast cancer 'of no special type' (former invasive ductal carcinoma, representing 60-70% of all breast cancers), 30 special types, of which invasive lobular carcinoma (ILC) is the most common (5-15%). We review the literature on (i) the specificity and heterogeneity of ILC biology as documented by various analytical techniques, including the results of molecular testing for risk of recurrence; (ii) the impact of lobular histology on prediction of prognosis and effect of systemic therapies in patients. Though it is generally admitted that ILC has a better prognosis than IDC, is endocrine responsive, and responds poorly to chemotherapy, currently available data do not unanimously support these assumptions. This review demonstrates some lack of specific data and a need for improving clinical research design to allow oncologists to make informed systemic therapy decisions in patients with ILC. Importantly, future studies should compare various endpoints in ILC breast cancer patients among the group of hormonosensitive breast cancer., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The secreted cellular sub-proteome (secretome) is a rich source of biologically active glycoproteins. N-Glycan profiling of secretomes of cultured cancer cells provides an opportunity to investigate the link between protein N-glycosylation and tumorigenesis. Utilizing carbon-LC-ESI-CID-MS/MS of protein released native N-glycans, we accurately profiled the secretome N-glycosylation of six human epithelial breast cells including normal mammary epithelial cells (HMEC) and breast cancer cells belonging to luminal A subtype (MCF7), HER2-overexpressing subtype (SKBR3), and basal B subtype (MDA-MB157, MDA-MB231, HS578T). On the basis of intact molecular mass, LC retention time, and MS/MS fragmentation, a total of 74 N-glycans were confidently identified and quantified. The secretomes comprised significant levels of highly sialylated and fucosylated complex type N-glycans, which were elevated in all cancer cells relative to HMEC (57.7-87.2% vs 24.9%, p < 0.0001 and 57.1-78.0% vs 38.4%, p < 0.0001-0.001, respectively). Similarly, other glycan features were found to be altered in breast cancer secretomes including paucimannose and complex type N-glycans containing bisecting β1,4-GlcNAc and LacdiNAc determinants. Subtype-specific glycosylation were observed, including the preferential expression of α2,3-sialylation in the basal B breast cancer cells. Pathway analysis indicated that the regulated N-glycans were biosynthetically related. Tight clustering of the breast cancer subtypes based on N-glycome signatures supported the involvement of N-glycosylation in cancer. In conclusion, we are the first to report on the secretome N-glycosylation of a panel of breast epithelial cell lines representing different subtypes. Complementing proteome and lipid profiling, N-glycome mapping yields important pieces of structural information to help understand the biomolecular deregulation in breast cancer development and progression, knowledge that may facilitate the discovery of candidate cancer markers and potential drug targets.

The multi cellular tumor spheroid (MCTS) model has been used for decades with proven superiority over monolayer cell culture models at recapitulating in vivo tumor growth. Yet its use in high-throughput drug discovery has been limited, particularly with image based screening, due to practical and technical hurdles. Here we report a significant advance in utilizing live MCTS models for high-content image based drug discovery. Using a validated GFP reporter (CK5Pro-GFP) of luminal breast cancer stem cells (CSC), we developed an algorithm to quantify changes in CK5Pro-GFP expression levels for individual Z-stack planes (local) or as maximal projections of the summed Z-stacks (global) of MCTS. From these image sets, we can quantify the cross-sectional area of GFP positive cells, the fluorescence intensity of the GFP positive cells, and the percent of spheroid cross-sectional area that expresses CK5Pro-GFP.We demonstrate that acquiring data in this manner can be done in real time and is statistically robust (Z'=0.85) for use in primary high-content screening cancer drug discovery.

The developments in gene expression analysis have made it possible to sub-classify hormone receptor-positive (luminal) breast cancer in different prognostic subgroups. This sub-classification is currently used in clinical routine as prognostic signature (e.g. 21-gene Onoctype DX®, 70-gene Mammaprint®). As yet, the optimal method for sub-classification has not been defined. Moreover, there is no evidence from prospective trials. This review explores widely used genomic signatures in luminal breast cancer, making a critical appraisal of evidence from retrospective/prospective trials. It is based on systematic literature search performed using Medline (accessed September 2013) and abstracts presented at the Annual Meeting of American Society of Clinical Oncology and San Antonio Breast Cancer Symposium.