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Human epidermal growth factor receptor 2 (HER2)-enriched breast cancer benefits significantly from anti-HER2 targeted therapies. This highlights the critical need for precise HER2 immunohistochemistry (IHC) interpretation serving as a triage tool for selecting patients for anti-HER2 regimens. Recently, the emerging eligibility of patients with HER2-low breast cancers for a novel HER2-targeted antibody-drug conjugate (T-DXd) adds challenges to HER2 IHC scoring interpretation, notably in the 0-1+ range, which shows high interobserver and interlaboratory staining platform variability. In this review, we navigate evolving challenges and suggest practical recommendations for HER2 IHC interpretation.
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Biomarcadores de Tumor , Neoplasias de la Mama , Inmunohistoquímica , Receptor ErbB-2 , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/diagnóstico , Receptor ErbB-2/metabolismo , Receptor ErbB-2/análisis , Femenino , Inmunohistoquímica/métodos , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismoRESUMEN
BACKGROUND: Although considered a favorable subtype, pure mucinous breast cancer (PMBC) can recur, and evidence for adjuvant therapy is limited. We aimed to compare outcomes of nonmetastatic PMBC with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) to address these uncertainties. METHODS: Individual patient-level data from 6 centers on stage I-III hormone receptor-positive and HER2-negative PMBC, IDC, and ILC were used to analyze recurrence-free interval (RFI), recurrence-free survival (RFS), and overall survival (OS), and to identify prognostic factors for PMBC. RESULTS: Data from 20,684 IDC cases, 1,475 ILC cases, and 943 PMBC cases were used. Median follow-up was 6.6 years. Five-year RFI, RFS, and OS for PMBC were 96.1%, 94.9%, and 98.1%, respectively. On multivariable Cox regression, PMBC demonstrated superior RFI (hazard ratio [HR], 0.59; 95% CI, 0.43-0.80), RFS (HR, 0.70; 95% CI, 0.56-0.89), and OS (HR, 0.71; 95% CI, 0.53-0.96) compared with IDC. ILC showed comparable outcomes to IDC. Fewer than half (48.7%) of recurrences in PMBC were distant, which was a lower rate than for IDC (67.3%) and ILC (80.6%). In contrast to RFI, RFS events were driven more by non-breast cancer deaths in older patients. Significant prognostic factors for RFI among PMBC included positive lymph node(s) (HR, 2.42; 95% CI, 1.08-5.40), radiotherapy (HR, 0.44; 95% CI, 0.23-0.85), and endocrine therapy (HR, 0.25; 95% CI, 0.09-0.70). No differential chemotherapy associations with outcomes were detected across PMBC subgroups by nodal stage, tumor size, and age. A separate SEER database analysis also did not find any association of improved survival with adjuvant chemotherapy in these subgroups. CONCLUSIONS: Compared with IDC, PMBC demonstrated superior RFI, RFS, and OS. Lymph node negativity, adjuvant radiotherapy, and endocrine therapy were associated with superior RFI. Adjuvant chemotherapy was not associated with better outcomes.
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Adenocarcinoma Mucinoso , Neoplasias de la Mama , Receptor ErbB-2 , Receptores de Estrógenos , Humanos , Femenino , Receptor ErbB-2/metabolismo , Neoplasias de la Mama/terapia , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Persona de Mediana Edad , Anciano , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/mortalidad , Pronóstico , Receptores de Estrógenos/metabolismo , Adulto , Receptores de Progesterona/metabolismo , Estadificación de Neoplasias , Carcinoma Ductal de Mama/terapia , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/metabolismo , Estudios de Cohortes , Carcinoma Lobular/terapia , Carcinoma Lobular/patología , Carcinoma Lobular/metabolismo , Carcinoma Lobular/mortalidad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/epidemiologíaRESUMEN
Triple-negative breast cancer (TNBC) has a poor prognosis with limited therapeutic options available for affected patients. Efforts are ongoing to identify surrogate markers for tumor-specific CD8+ T cells that can predict the response to immune checkpoint inhibitor (ICI) therapies, such as programmed cell death protein 1 or programmed cell death ligand-1 blockade. We have previously identified tumor-specific CD39+CD8+ T cells in non-small cell lung cancer that might help predict patient responses to programmed cell death protein 1 or programmed cell death ligand-1 blockade. Based on this finding, we conducted a comparative interrogation of TNBC in an Asian cohort to evaluate the potential of CD39 as a surrogate marker of tumor-specific CD8+ T cells. Using ICI-treated TNBC mouse models (n = 24), flow cytometric analyses of peripheral blood mononuclear cells and tumor-infiltrating lymphocytes revealed that >99% of tumor-specific CD8+ T cells also expressed CD39. To investigate the relationship between CD39+CD8+ T-cell density and CD39 expression with disease prognosis, we performed multiplex immunohistochemistry staining on treatment-naive human TNBC tissues (n = 315). We saw that the proportion of CD39+CD8+ T cells in human TNBC tumors correlated with improved overall survival, as did the densities of other CD39+ immune cell infiltrates, such as CD39+CD68+ macrophages. Finally, increased CD39 expression on CD8+ T cells was also found to predict the response to ICI therapy (pembrolizumab) in a separate cohort of 11 TNBC patients. These findings support the potential of CD39+CD8+ T-cell density as a prognostic factor in Asian TNBC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Animales , Ratones , Linfocitos T CD8-positivos , Pronóstico , Neoplasias de la Mama Triple Negativas/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Leucocitos Mononucleares/metabolismo , Ligandos , Neoplasias Pulmonares/metabolismo , Biomarcadores/metabolismo , Linfocitos Infiltrantes de Tumor , Antígeno B7-H1/metabolismoRESUMEN
Tumor evolution to evade immune surveillance is a hallmark of carcinogenesis, and the modulation of tumor immunogenicity has been a challenge to present therapeutic responses in immunotherapies alone for numerous cancers. By altering the cell phenotype and reshaping the tumor microenvironment, epigenetic modifications enable tumor cells to overcome immune surveillance as a mechanism of cancer progression and immunotherapy resistance. Demethylase enzymatic activity of lysine-specific demethylase 1 (LSD1), a histone demethylase first identified in 2004, plays a pivotal role in the vast cellular processes of cancer. While FDA-approved indications for epigenetic therapies are limited to hematological malignancies, it is imperative to understand how epigenetic machinery can be targeted to prime immunotherapy responses in breast cancers. In this review, we discuss the potential roles of epigenetics and demethylating agent LSD1 as a potent new cancer management strategy to combat the current challenges of breast cancers, which have presented modest efficacy to immune checkpoint inhibitors till date. Additionally, we describe the combined use of LSD1-specific inhibitors and immune checkpoint inhibitors in existing breast cancer preclinical and clinical trials that elicits a robust immune response and benefit. Overall, the promising results observed in LSD1-targeting therapies signify the central role of epigenetics as a potential novel strategy to overcome resistance commonly seen in immunotherapies.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Lisina/genética , Inhibidores de Puntos de Control Inmunológico , Epigénesis Genética , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Inmunidad , Microambiente TumoralRESUMEN
Mutations in the PI3K pathway, particularly PIK3CA, were reported to be intimately associated with triple-negative breast cancer (TNBC) progression and the development of treatment resistance. We profiled PIK3CA and other genes on 166 early-stage TNBC tumors from Singapore for comparison to publicly available TNBC cohorts. These tumors were profiled transcriptionally using a NanoString panel of immune genes and multiplex immunohistochemistry, then manually scored for PD-L1-positivity using 2 clinically relevant clones, SP142 and 22C3. We discovered a higher rate of PIK3CA mutations in our TNBC cohort than in non-Asian cohorts, along with TP53, BRCA1, PTPN11, and MAP3K1 alterations. PIK3CA mutations did not affect overall or recurrence-free survival, and when compared with PIK3CAWT tumors, there were no differences in immune infiltration. Using 2 clinically approved antibodies, PIK3CAmut tumors were associated with PD-L1 negativity. Analysis of comutation frequencies further revealed that PIK3CA mutations tended to be accompanied by MAP kinase pathway mutation. The mechanism and impact of PIK3CA alterations on the TNBC tumor immune microenvironment and PD-L1 positivity warrant further study.
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Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/patología , Antígeno B7-H1/genética , Singapur , Fosfatidilinositol 3-Quinasas/genética , Mutación , Fosfatidilinositol 3-Quinasa Clase I/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Microambiente TumoralRESUMEN
BACKGROUND: The effect of extracellular microenvironment (hypoxia and pH) has been regarded as a key hallmark in cancer progression. The study aims to investigate the effects of carbonic anhydrase IX (CAIX), a key hypoxia-inducible marker, in triple-negative breast cancer (TNBC) in correlation with clinicopathological parameters and predicting survival outcomes. METHODS: A total of 323 TNBC cases diagnosed at the Department of Anatomical Pathology, Singapore General Hospital from 2003 to 2013 were used. Immunohistochemical staining (IHC) was performed using CAIX antibody and digital mRNA quantification was performed using NanoString assays. CAIX membranous expression was correlated with clinicopathological parameters using Chi-squared test or Fisher's exact tests. Disease-free survival (DFS) and overall-survival (OS) were estimated using Kaplan-Meier analysis and compared between groups with the log-rank test. RESULTS: Forty percent of TNBCs were observed to express CAIX protein and demonstrated significant association with larger tumour size (P = 0.002), higher histological grade (P < 0.001), and significantly worse disease-free survival (DFS) and overall survival (OS) (after adjustment: HR = 2.99, 95% CI = 1.78-5.02, P < 0.001 and HR = 2.56, 95% CI = 1.41-4.65, P = 0.002, respectively). Gene ontology enrichment analysis revealed six significantly enriched cellular functions (secretion, cellular component disassembly, regulation of protein complex assembly, glycolytic process, cellular macromolecular complex assembly, positive regulation of cellular component biogenesis) associated with genes differentially expressed (CAIX, SETX, WAS, HK2, DDIT4, TUBA4α, ARL1). Three genes (WAS, SETX and DDIT4) were related to DNA repair, indicating that DNA stability may be influenced by hypoxia in TNBC. CONCLUSIONS: Our results demonstrate that CAIX appears to be a significant hypoxia-inducible molecular marker and increased CAIX protein levels are independently associated with poor survival in TNBC. Identification of CAIX-linked seven gene-signature and its relationship with enriched cellular functions further support the implication and influence of hypoxia-mediated CAIX expression in TNBC tumour microenvironment.
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Neoplasias de la Mama , Anhidrasas Carbónicas , Neoplasias de la Mama Triple Negativas , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/metabolismo , Anhidrasa Carbónica IX/genética , Anhidrasa Carbónica IX/metabolismo , Anhidrasas Carbónicas/genética , Anhidrasas Carbónicas/metabolismo , ADN Helicasas , Femenino , Humanos , Hipoxia/genética , Enzimas Multifuncionales , Pronóstico , ARN Helicasas , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Microambiente Tumoral/genéticaRESUMEN
[This corrects the article DOI: 10.3389/fmolb.2021.658932.].
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AIM: Phyllodes tumours (PTs) categorised as benign, borderline and malignant, account for 1% of all breast tumours. Histological assessment does not always predict tumour behaviour, hindering determination of the clinical course and management.Epithelial-mesenchymal transition (EMT) is an important process during embryogenesis. Dysregulation of EMT causes loss of cell polarity, decreased intercellular adhesion, increased motility and invasiveness, promoting tumour progression. Similarly, cancer stem cells (CSCs) promote tumour growth, resistance and recurrence. The aim of this study is to evaluate expression of CSC markers; enhancer of zeste homolog 2 (EZH2), CD24 and CD44 and EMT associated proteins; ezrin (EZR) and high-mobility group AT-hook 2 (HMGA2) in PTs. METHOD: Uing tissue microarray sections, immunohistochemistry was performed on 360 PTs. Epithelial and stromal expressions of EZH2, EZR, HMGA2, CD24 and CD44 were evaluated to assess their impact on disease progression and behaviour in correlation with clinicopathological parameters. RESULTS: Stromal expression of EZH2, EZR and HMGA2 was observed in 73 (20.3%), 53 (14.7%) and 28 (7.8%) of tumours, epithelial expression in 121 (35.9%), 3 (0.8%) and 351 (97.5%) tumours, respectively. CD24 and CD44 staining was absent in both components. CONCLUSION: Expression of biomarkers correlated significantly with aggressive tumour traits such as stromal hypercellularity, atypia, mitoses and permeative tumour borders.Stromal expression of EZH2 and EZR shortened disease-free survival and overall survival; HMGA2 expression did not alter patient survival. EZH2 and EZR may thus be useful in predicting PT behaviour.
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Neoplasias de la Mama , Tumor Filoide , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Antígeno CD24/metabolismo , Proteínas del Citoesqueleto , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Transición Epitelial-Mesenquimal , Femenino , Humanos , Receptores de Hialuranos/metabolismo , Células Madre Neoplásicas/patología , PronósticoRESUMEN
Coronavirus disease-19 (COVID-19) is caused by the newly discovered coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the lung remains the primary target site of COVID-19 injury, damage to myocardium, and other organs also contribute to the morbidity and mortality of this disease. There is also increasing demand to visualize viral components within tissue specimens. Here we discuss the cardiac autopsy findings of 12 intensive care unit (ICU) naïve and PCR-positive COVID-19 cases using a combination of histological, Immunohistochemical/immunofluorescent and molecular techniques. We performed SARS-CoV-2 qRT-PCR on fresh tissue from all cases; RNA-ISH and IHC for SARS-CoV-2 were performed on selected cases using FFPE tissue from heart. Eight of these patients also had positive post-mortem serology for SARS-CoV-2. Histopathologic changes in the coronary vessels and inflammation of the myocardium as well as in the endocardium were documented which support the reports of a cardiac component to the viral infection. As in the pulmonary reports, widespread platelet and fibrin thrombi were also identified in the cardiac tissue. In keeping with vaccine-induced activation of virus-specific CD4+ and CD8+ T cells, and release of cytokines such as interferon-gamma (IFNγ), we observed similar immune cellular distribution and cytokines in these patients. Immunohistochemical and immunofluorescent localisation for the viral Spike (S-protein) protein and the nucleocapsid protein (NP) were performed; presence of these aggregates may possibly contribute to cardiac ischemia and even remodelling.
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Breast cancer cells commonly express tumour-associated antigens that can induce immune responses to eradicate the tumour. Triple-negative breast cancer (TNBC) is a form of breast cancer lacking the expression of hormone receptors and cerbB2 (HER2) and tends to be more aggressive and associated with poorer prognoses due to the limited treatment options. Characterisation of biomarkers or treatment targets is thus of great significance in revealing additional therapeutic options. Cancer-testis antigens (CTAs) are tumour-associated antigens that have garnered strong attention as potential clinical biomarkers in targeted immunotherapy due to their cancer-restricted expressions and robust immunogenicity. Previous clinical studies reported that CTAs correlated with negative hormonal status, advanced tumour behaviour and a poor prognosis in a variety of cancers. Various studies also demonstrated the oncogenic potential of CTAs in cell proliferation by inhibiting cell death and inducing metastasis. Multiple clinical trials are in progress to evaluate the role of CTAs as treatment targets in various cancers. CTAs hold great promise as potential treatment targets and biomarkers in cancer, and further research could be conducted on elucidating the mechanism of actions of CTAs in breast cancer or combination therapy with other immune modulators. In the current review, we summarise the current understandings of CTAs in TNBC, addressing the role and utility of CTAs in TNBC, as well as discussing the potential applications and advantage of incorporating CTAs in clinical practise.
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Signaling between cancer and nonmalignant (stromal) cells in the tumor microenvironment (TME) is a key to tumor progression. Here, we deconvoluted bulk tumor transcriptomes to infer cross-talk between ligands and receptors on cancer and stromal cells in the TME of 20 solid tumor types. This approach recovered known transcriptional hallmarks of cancer and stromal cells and was concordant with single-cell, in situ hybridization and IHC data. Inferred autocrine cancer cell interactions varied between tissues but often converged on Ephrin, BMP, and FGFR-signaling pathways. Analysis of immune checkpoints nominated interactions with high levels of cancer-to-immune cross-talk across distinct tumor types. Strikingly, PD-L1 was found to be highly expressed in stromal rather than cancer cells. Overall, our study presents a new resource for hypothesis generation and exploration of cross-talk in the TME. SIGNIFICANCE: This study provides deconvoluted bulk tumor transcriptomes across multiple cancer types to infer cross-talk in the tumor microenvironment.
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Neoplasias , Receptor Cross-Talk/fisiología , Microambiente Tumoral , Comunicación Autocrina/fisiología , Comunicación Celular/genética , Biología Computacional , Conjuntos de Datos como Asunto , Femenino , Genómica/métodos , Humanos , Ligandos , Masculino , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Receptores Citoplasmáticos y Nucleares/fisiología , Microambiente Tumoral/genética , Secuenciación del ExomaAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Células Asesinas Naturales/efectos de los fármacos , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Secuenciación Completa del Genoma/métodosRESUMEN
Xenogeneic extracellular matrix (ECM) based tissue engineering graft is one of the most promising products for transplantation therapies, which could alleviate the pain of patients and reduce surgery cost. However, in order to put ECM based xenografts into clinical use, the induced inflammatory and immune responses have yet to be resolved. Cell membrane is embedded with membrane proteins for regulation of cell interactions including self-recognition and potent in reducing foreign body rejections. In this study, a novel and facile method for evasion from immune system was developed by coating autologous red blood cell membrane as a disguise on xenogeneic ECM based tissue engineering graft surface. Porcine source Living Hyaline Cartilage Graft (LhCG) and decellularized LhCG (dLhCG) established by our group for cartilage tissue engineering were chosen as model grafts. The cell membrane coating was quite stable on xenografts with no obvious decrease in amount for 4 weeks. The autologous cell membrane coated xenograft has been proved to be recognized as "self" by immune system on cell, protein and gene levels according to the 14-day lasting in vivo study on rats with less inflammatory cells infiltrated and low inflammation-related cytokines gene expression, showing alleviated acute immune and inflammatory responses.
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Matriz Extracelular , Ingeniería de Tejidos , Animales , Membrana Celular , Xenoinjertos , Humanos , Inmunidad , Ratas , Porcinos , Andamios del Tejido , Trasplante HeterólogoRESUMEN
BACKGROUND: Burnout is a serious issue plaguing the medical profession with potential negative consequences on patient care. Burnout symptoms are observed as early as medical school. Based on a Job Demands-Resources model, this study aims to assess associations between specific job resources measured at the beginning of the first year of medical school with burnout symptoms occurring later in the first year. METHODS: The specific job resources of grit, tolerance for ambiguity, social support and gender were measured in Duke-NUS Medical School students at the start of Year 1. Students were then surveyed for burnout symptoms at approximately quarterly intervals throughout the year. Using high ratings of cynicism and exhaustion as the definition of burnout, we investigated the associations of the occurrence of burnout with student job resources using multivariable logistic regression analysis. RESULTS: Out of 59 students, 19 (32.2%) indicated evidence of burnout at some point across the first year of medical school. Stepwise multivariable logistic regression analysis identified grit as having a significant protective effect against experiencing burnout (Odds Ratio, 0.84; 95%CI 0.74 to 0.96). Using grit as a single predictor of burnout, area under the ROC curve was 0.76 (95%CI: 0.62 to 0.89). CONCLUSIONS: Grit was identified as a protective factor against later burnout, suggesting that less gritty students are more susceptible to burnout. The results indicate that grit is a robust character trait which can prognosticate burnout in medical students. These students would potentially benefit from enhanced efforts to develop grit as a personal job resource.
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Agotamiento Profesional , Estudiantes de Medicina , Agotamiento Profesional/epidemiología , Agotamiento Profesional/prevención & control , Agotamiento Psicológico/epidemiología , Agotamiento Psicológico/prevención & control , Humanos , Estudios Longitudinales , Encuestas y CuestionariosRESUMEN
Xenogeneic grafts are promising candidates for transplantation therapy due to their easily accessible sources. Nevertheless, the immune and inflammatory responses induced by xenografts need to be addressed for clinical use. A novel and facile method was introduced for the attenuation of immune and inflammatory responses by extending the immune evasion potential of albumin to the tissue engineering field and coating albumin, which could passivate biomaterial surfaces, onto xenografts. Albumin was first modified by dopamine to enhance its adhesion on graft surfaces. Porcine chondrocytes derived living hyaline cartilage graft (LhCG) and decellularized LhCG (dLhCG) were applied as xenograft models implanted in the omentum of rats. Both LhCG which contained porcine chondrocytes as well as secreted ECM and dLhCG which was mainly composed of the porcine source ECM showed alleviated immune and inflammatory responses after being coated with albumin at cell, protein and gene levels, respectively. Significantly less inflammatory cells including neutrophils, macrophages and lymphocytes were recruited according to pathological analysis and immunohistochemistry staining with lower gene expression encoding inflammation-related cytokines including MCP-1, IL-6 and IL-1ß after employing LhCG and dLhCG with albumin passivation coating.
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Albúminas/química , Materiales Biocompatibles Revestidos/química , Inmunidad/efectos de los fármacos , Andamios del Tejido/química , Trasplante Heterólogo/métodos , Albúminas/metabolismo , Animales , Células Cultivadas , Condrocitos/citología , Condrocitos/metabolismo , Materiales Biocompatibles Revestidos/metabolismo , Humanos , Cartílago Hialino/trasplante , Ratas , PorcinosRESUMEN
BACKGROUND: Stromal and collagen biology has a significant impact on tumorigenesis and metastasis. Collagen is a major structural extracellular matrix component in breast cancer, but its role in cancer progression is the subject of historical debate. Collagen may represent a protective layer that prevents cancer cell migration, while increased stromal collagen has been demonstrated to facilitate breast cancer metastasis. METHODS: Stromal remodeling is characterized by collagen fiber restructuring and realignment in stromal and tumoral areas. The patients in our study were diagnosed with triple-negative breast cancer in Singapore General Hospital from 2003 to 2015. We designed novel image processing and quantification pipelines to profile collagen structures using numerical imaging parameters. Our solution differentiated the collagen into two distinct modes: aggregated thick collagen (ATC) and dispersed thin collagen (DTC). RESULTS: Extracted parameters were significantly associated with bigger tumor size and DCIS association. Of numerical parameters, ATC collagen fiber density (CFD) and DTC collagen fiber length (CFL) were of significant prognostic value for disease-free survival and overall survival for the TNBC patient cohort. Using these two parameters, we built a predictive model to stratify the patients into four groups. CONCLUSIONS: Our study provides a novel insight for the quantitation of collagen in the tumor microenvironment and will help predict clinical outcomes for TNBC patients. The identified collagen parameters, ATC CFD and DTC CFL, represent a new direction for clinical prognosis and precision medicine. We also compared our result with benign samples and DICS samples to get novel insight about the TNBC heterogeneity. The improved understanding of collagen compartment of TNBC may provide insights into novel targets for better patient stratification and treatment.
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Colágeno/ultraestructura , Matriz Extracelular/ultraestructura , Procesamiento de Imagen Asistido por Computador/métodos , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Neoplasias de la Mama Triple Negativas/mortalidad , Neoplasias de la Mama Triple Negativas/patología , Microambiente Tumoral , Colágeno/metabolismo , Supervivencia sin Enfermedad , Matriz Extracelular/metabolismo , Femenino , Humanos , Clasificación del Tumor , Estadificación de Neoplasias , Tasa de Supervivencia , Análisis de Matrices Tisulares/métodosRESUMEN
PURPOSE: Triple-negative breast cancers (TNBC) are aggressive tumours that exhibit abundant lymphoid infiltrates which modulate tumour behaviour. Recent findings suggest that TNBC with higher densities of plasma cells are associated with a favourable prognosis, and tertiary lymphoid structures (TLS) have prognostic significance. Here, we studied the phenotype and function of plasma cells in TNBCs by assessing their association with IgG Kappa light chain expression, B cells, and TLS. METHODS: A retrospective analysis of 269 TNBC cases was performed. Tumour-infiltrating CD38+ plasma cells, CD20+ B cells, and TLS were evaluated on conventional haematoxylin-eosin-stained and immunohistochemical-stained sections of TNBC. We then selected TNBC cases demonstrating the highest and lowest densities of plasma cells, and examined their association with TLS, B cells, as well as immunoglobulin expression using Opal-Vectra multiplex immunofluorescence (IF). RESULTS: TNBC with high density of plasma cells showed significantly higher numbers of IgG Kappa+ CD38+ cells (p = 0.0089, p < 0.0001), and higher numbers of TLS (p < 0.0001), compared to TNBC with low density of plasma cells. TNBC with high density of plasma cells also showed higher numbers of CD20+ B cells in the tumour core (p < 0.0001), invasive margin (p < 0.0001), as well as stromal (p = 0.015) compartments. CONCLUSION: TNBC with high density of plasma cells are associated with higher numbers of IgG Kappa+ CD38+ cells, CD20+ B cells, and TLS. Further studies to characterize the function of plasma cell infiltrates and how they may interact with other tumour-infiltrating lymphocytes and TLS in TNBC may help improve existing immunotherapy strategies.