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lncRNAs are noncoding transcripts with tissue and cancer specificity. Particularly, in breast cancer, lncRNAs exhibit subtype-specific expression; they are particularly upregulated in luminal tumors. However, no gene signature-based laboratory tests have been developed for luminal breast cancer identification or the differential diagnosis of luminal tumors, since no luminal A- or B-specific genes have been identified. Particularly, luminal B patients are of clinical interest, since they have the most variable response to neoadjuvant treatment; thus, it is necessary to develop diagnostic and predictive biomarkers for these patients to optimize treatment decision-making and improve treatment quality. In this study, we analyzed the lncRNA expression profiles of breast cancer cell lines and patient tumor samples from RNA-Seq data to identify an lncRNA signature specific for luminal phenotypes. We identified an lncRNA signature consisting of LINC01016, GATA3-AS1, MAPT-IT1, and DSCAM-AS1 that exhibits luminal subtype-specific expression; among these lncRNAs, GATA3-AS1 is associated with the presence of residual disease (Wilcoxon test, p < 0.05), which is related to neoadjuvant chemotherapy resistance in luminal B breast cancer patients. Furthermore, analysis of GATA3-AS1 expression using RNA in situ hybridization (RNA ISH) demonstrated that this lncRNA is detectable in histological slides. Similar to estrogen receptors and Ki67, both commonly detected biomarkers, GATA3-AS1 proves to be a suitable predictive biomarker for clinical application in breast cancer laboratory tests.

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Chromosomal instability (CIN), defined by variations in the number or structure of chromosomes from cell to cell, is recognized as a distinctive characteristic of cancer associated with the ability of tumors to adapt to challenging environments. CIN has been recognized as a source of genetic variation that leads to clonal heterogeneity (CH). Recent findings suggest a potential association between CIN and CH with the prognosis of BC patients, particularly in tumors expressing the epidermal growth factor receptor 2 (HER2+). In fact, information on the role of CIN in other BC subtypes, including luminal B BC, is limited. Additionally, it remains unknown whether CIN in luminal B BC tumors, above a specific threshold, could have a detrimental effect on the growth of human tumors or whether low or intermediate CIN levels could be linked to a more favorable BC patient prognosis when contrasted with elevated levels. Clarifying these relationships could have a substantial impact on risk stratification and the development of future therapeutic strategies aimed at targeting CIN in BC. This study aimed to assess CIN and CH in tumor tissue samples from ten patients with luminal B BC and compare them with established clinicopathological parameters. The results of this study reveal that luminal B BC patients exhibit intermediate CIN and stable aneuploidy, both of which correlate with lymphovascular invasion. Our results also provide valuable preliminary data that could contribute to the understanding of the implications of CIN and CH in risk stratification and the development of future therapeutic strategies in BC.

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PURPOSE: Invasive ductal breast cancer (IDC) is heterogeneous. Staging and immunohistochemistry (IH) allow for effective therapy but are not yet ideal. Women with Luminal B tumors show an erratic response to treatment. This prospective study with 81 women with breast cancer aims to improve the prognostic stratification of Luminal B patients. METHODS: This is a prospective translational study with 81 women with infiltrating ductal carcinoma, grouped by TNM staging and immunohistochemistry, for survival analysis, and their correlations with the chemokines. Serum measurements of 13 chemokines were performed, including 7 CC chemokines [CCL2(MCP1), CCL3(MIP1α), CCL4(MIP1ß), CCL5(Rantes), CCL11(Eotaxin), CCL17(TARC), CCL20(MIP3α)], 6 CXC chemokines [CXCL1(GroAlpha), CXCL5(ENA78), CCXCL8(IL-8), CXCL9(MIG), CXCL10(IP10), CXCL11(ITAC)]. RESULTS: Overall survival was significantly dependent on tumor staging and subtypes by immunohistochemistry, with a median follow-up time the 32.87 months (3.67-65.63 months). There were age correlations with IP10/CXCL10 chemokines (r = 0.4360; p = 0.0079) and TARC/CCL17 (Spearman + 0.2648; p = 0.0360). An inverse correlation was found between body weight and the chemokines Rantes/CCL5 (r = - 0.3098; p = 0.0169) and Eotaxin/CCL11 (r = - 0.2575; p = 0.0470). Smokers had a higher concentration of MIP3α/CCL20 (Spearman + 0.3344; p = 0.0267). Luminal B subtype patients who expressed lower concentrations of ENA78/CXCL5 (≤ 254.83 pg/ml) (Log-Rank p = 0.016) and higher expression of MIP1ß/CCL4 (> 34.84 pg/ml) (Log-Rank p = 0.014) had a higher risk of metastases. CONCLUSION: Patients with Luminal B breast tumors can be better stratified by serum chemokine expression, suggesting that prognosis is dependent on biomarkers other than TNM and IH.

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Background: Breast cancer (BRCA) represents the most frequent diagnosed malignancy in women worldwide. Despite treatment advances, BRCAs eventually develop resistance to targeted therapies, resulting in poor prognosis. The identification of new biomarkers, like immune-related long non-coding RNAs (lncRNAs), could contribute to the clinical management of BRCA patients. In this report, we evaluated the LINC00426 expression in PAM50 BRCA subtypes from two clinical independent cohorts (BRCA-TCGA and GEO-GSE96058 datasets). Methods and results: Using Cox regression models and Kaplan-Meier survival analyses, we identified that LINC00426 expression was a consistent overall survival (OS) predictor in luminal B (LB) BRCA patients. Subsequently, differential gene expression and gene set enrichment analyses identified that LINC00426 expression was associated with different immune-related and cancer-related pathways and processes in LB BRCA. Additionally, the LINC00426 expression was correlated with the infiltration level of diverse immune cell populations, alongside immune checkpoint and cytolytic activity-related gene expression. Conclusion: This evidence suggests that LINC00426 is a potential biomarker of immune phenotype and an OS predictor in PAM50 LB BRCA.

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Gene co-expression networks have become a usual approach to integrate the vast amounts of information coming from gene expression studies in cancer cohorts. The reprogramming of the gene regulatory control and the molecular pathways depending on such control are central to the characterization of the disease, aiming to unveil the consequences for cancer prognosis and therapeutics. There is, however, a multitude of factors which have been associated with anomalous control of gene expression in cancer. In the particular case of co-expression patterns, we have previously documented a phenomenon of loss of long distance co-expression in several cancer types, including breast cancer. Of the many potential factors that may contribute to this phenomenology, copy number variants (CNVs) have been often discussed. However, no systematic assessment of the role that CNVs may play in shaping gene co-expression patterns in breast cancer has been performed to date. For this reason we have decided to develop such analysis. In this study, we focus on using probabilistic modeling techniques to evaluate to what extent CNVs affect the phenomenon of long/short range co-expression in Luminal B breast tumors. We analyzed the co-expression patterns in chromosome 8, since it is known to be affected by amplifications/deletions during cancer development. We found that the CNVs pattern in chromosome 8 of Luminal B network does not alter the co-expression patterns significantly, which means that the co-expression program in this cancer phenotype is not determined by CNV structure. Additionally, we found that region 8q24.3 is highly dense in interactions, as well as region p21.3. The most connected genes in this network belong to those cytobands and are associated with several manifestations of cancer in different tissues. Interestingly, among the most connected genes, we found MAF1 and POLR3D, which may constitute an axis of regulation of gene transcription, in particular for non-coding RNA species. We believe that by advancing on our knowledge of the molecular mechanisms behind gene regulation in cancer, we will be better equipped, not only to understand tumor biology, but also to broaden the scope of diagnostic, prognostic and therapeutic interventions to ultimately benefit oncologic patients.

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OBJECTIVE: Breast cancer is a disease of great concern. The prognosis of this tumor is related to its staging. Opioids are widely used to minimize pain in oncology clinics; however, the relationship between the administration of opioids and their effects on tumor cells has yet to be elucidated. Therefore, this study aimed to evaluate the immunoexpression of mu- (µ) and kappa- (κ) opioid receptors and their correlation with markers of angiogenesis, cell proliferation, and apoptosis in biopsies of breast tumors. METHODS: Demographic data, tumor characteristics, opioid use, and prognostic factors were collected from medical records. After the selection of the excisional biopsies, immunohistochemistry was performed for µ- and κ-opioid receptors, vascular endothelial growth factor (VEGF), Ki-67, and TUNEL. RESULTS: A significant predominance of Ki-67 and µ-opioid receptor immunoexpression in the lymph nodes was observed in patients administered opioid medications. The luminal A subtype showed higher apoptosis levels (TUNEL) compared to the luminal B subtype. Patients with T4 tumor who had recurrence demonstrated a reduced expression of κ-opioid receptors at the lymph node location. Correlation analyses between the µ and κ opioid markers, VEGF, Ki-67, and TUNEL showed that these findings are likely involved in the same mechanisms the cancer of T4 stage breast cancer. CONCLUSION: The κ-opioid receptor has a lower immunoexpression in nodal tumor metastasis with recurrence, whereas the µ-opioid receptor is directly related to expression of TUNEL-positive cells  in tumors and indirectly to Ki-67 in nodal metastasis. Neither of the two receptors was expressed in the primary tumor or nodal metastasis in relation to VEGF.

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The hormone receptor-positive (estrogen and/or progesterone receptor (PR)-positive) and HER2-negative breast cancer (BC) subtype is a biologically heterogeneous entity that includes luminal A-like (LumA-like) and luminal B-like (LumB-like) subtypes. Decreased PR levels is a distinctive biological feature of LumB-like tumors. These tumors also show reduced sensitivity to endocrine therapies and poorer prognosis than LumA-like tumors. Identification of biomarkers to accurately predict disease relapse in these subtypes is crucial in order to select effective therapies. We identified the tumor suppressor PDCD4 (programmed cell death 4), located in the nucleus (NPDCD4), as an independent prognostic factor of good clinical outcome in LumA-like and LumB-like subtypes. NPDCD4-positive LumB-like tumors presented overall and disease-free survival rates comparable to those of NPDCD4-positive LumA-like tumors, indicating that NPDCD4 improves the outcome of LumB-like patients. In contrast, NPDCD4 loss increased the risk of disease recurrence and death in LumB-like compared with LumA-like tumors. This, along with our results showing that LumB-like tumors present lower NPDCD4 positivity than LumA-like tumors, suggests that NPDCD4 loss contributes to endocrine therapy resistance in LumB-like BCs. We also revealed that PR induces PDCD4 transcription in LumB-like BC, providing a mechanistic explanation to the low PDCD4 levels in LumB-like BCs lacking PR. Finally, PDCD4 silencing enhanced BC cell survival in a patient-derived explant model of LumB-like disease. Our discoveries highlight NPDCD4 as a novel biomarker in LumA- and LumB-like subtypes, which could be included in the panel of immunohistochemical markers used in the clinic to accurately predict the prognosis of LumB-like tumors.

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Microsatellite instability (MSI) and POLD1 mutations are usually described in colorectal tumours in patients with polyposis syndrome but rarely found in breast tumours. This case describes a metastatic luminal B breast tumour in a young patient with an important family history of cancer. Mutational studies found a Variant of Uncertain Significance (VUS)-type alteration in POLD1 that motivated the study for MSI, which was found positive. Recent data point towards the use of pembrolizumab as a treatment option for tumour presenting with MSI instead of chemotherapy.

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PURPOSE: Expression of estrogen receptor alpha (ER) and/or progesterone receptor (PR) defines luminal breast cancer. Even though androgen (AR) and glucocorticoid receptors (GR) are highly expressed in luminal breast cancers, prognostic value remains uncertain and concomitant expression of these four hormone receptors is still unexplored. METHODS: Here, we evaluated ER, PR, AR, and GR expression, using immunohistochemistry, in a cohort of 169 breast cancer patients and correlated these findings with clinical and pathological parameters. RESULTS: We found that AR is more frequently expressed and at higher levels in the ER+PR- subset compared to ER+PR+ tumors. There were no significant differences in GR expression between tumor subsets. Moreover, most luminal tumors also expressed either AR or GR and most basal tumors were also negative for AR and GR. CONCLUSION: These data suggest that targeting AR in ER+PR- tumors may represent a promising therapeutic alternative in hormonal refractory tumors.

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BACKGROUND: Several breast cancer (BC) trials have adopted pathological complete response (pCR) as a surrogate marker of long-term treatment efficacy. In patients with luminal subtype, pCR seems less important for outcome prediction. BC is a heterogeneous disease, which is evident in residual tumors after neoadjuvant-chemotherapy (NAC). This study evaluates changes in Ki67 in relation to disease-free survival (DFS) and overall survival (OS) in patients without pCR. SUBJECTS, MATERIALS, AND METHODS: Four hundred thirty-five patients with stage IIA-IIIC BC without pCR after standard NAC with anthracycline and paclitaxel were analyzed. We analyzed the decrease or lack of decrease in the percentage of Ki67-positive cells between core biopsy samples and surgical specimens and correlated this value with outcome. RESULTS: Twenty-five percent of patients presented with luminal A-like tumors, 45% had luminal B-like tumors, 14% had triple-negative BC, 5% had HER2-positive BC, and 11% had triple-positive BC. Patients were predominantly diagnosed with stage III disease (52%) and high-grade tumors (46%). Median Ki67 level was 20% before NAC, which decreased to a median of 10% after NAC. Fifty-seven percent of patients had a decrease in Ki67 percentage. Ki67 decrease significantly correlated with better DFS and OS compared with no decrease, particularly in the luminal B subgroup. Multivariate analysis showed that nonreduction of Ki67 significantly increased the hazard ratio of recurrence and death by 3.39 (95% confidence interval [CI] 1.8-6.37) and 7.03 (95% CI 2.6-18.7), respectively. CONCLUSION: Patients without a decrease in Ki67 in residual tumors after NAC have poor prognosis. This warrants the introduction of new therapeutic strategies in this setting. IMPLICATIONS FOR PRACTICE: This study evaluates the change in Ki67 percentage before and after neoadjuvant chemotherapy (NAC) and its relationship with survival outcomes in patients with breast cancer who did not achieve complete pathological response (pCR). These patients, a heterogeneous group with diverse prognoses that cannot be treated using a single algorithm, pose a challenge to clinicians. This study identified a subgroup of these patients with a poor prognosis, those with luminal B-like tumors without a Ki67 decrease after NAC, thus justifying the introduction of new therapeutic strategies for patients who already present a favorable prognosis (luminal B-like with Ki67 decrease).

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Introducción El cáncer de mama es una enfermedad heterogénea; tumores con factores pronósticos similares presentan diferente evolución, lo que hace suponer que la diferencia es molecular. El antígeno de proliferación celular Ki67 es un factor clave que representa la actividad mitótica celular. Objetivos Analizar el subtipo Luminal B y el valor del Ki67, evaluando su relación con los factores pronósticos y predictivos clásicos, y determinar su utilidad para subclasificar grupos moleculares en función del mismo. Material y métodos Estudio descriptivo, retrospectivo, analítico observacional. Se revisaron 520 fichas de patología mamaria pertenecientes al Hospital Churruca y al Sanatorio Corporación Médica General San Martín, en el período comprendido entre enero 2010-enero 2015. Fueron analizadas 82 pacientes subtipo Luminal B, con Ki67 elevado. Resultados La mediana de expresión del Ki67 fue de 25,9% y del 34% en las pacientes recaídas. Discusión Se observó relación proporcional del Ki67 con el tamaño tumoral y el grado histológico. Conclusiones El Ki67 debe ser analizado en la práctica diaria por patólogos expertos, a fin de predecir el comportamiento frente a tratamientos adyuvantes de una manera más certera, adecuando la terapéutica a cada paciente.

Introduction Breast cancer is a heterogeneous disease; tumors with similar prognostic factors have different evolution, which suggests that the difference is at the molecular level. The proliferation antigen Ki67 is a key factor that represents the cell mitotic activity. Objectives Analyze Luminal B subtype and the value of Ki67, evaluating its relationship with prognostic and predictive factors conventionally used. Determine its usefulness for subclassified different molecular groups. Matherials and method Observational analytical retrospective study. We reviewed 520 breast cancer files belonging to Churruca Hospital and Sanatorio Corporación Médica General San Martín in the period between January 2010- January 2015. We analyzed 82 patients Luminal B subtype with hight Ki67. Results The median expression of Ki67 was 25.9 % and 34% in patients with relapsed. Discussion We found proportional relationship between the value of Ki67 with tumor size and histologic hight grade. Conclusions The Ki67 must be analyzed in daily practice validated by expert pathologists in late predict behavior towards adjuvant treatments in a more accurate way available, adapting to each patient therapeutic methods.

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