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1.
Rev. venez. oncol ; 33(1): 46-59, mar. 2021. tab
Article in Spanish | LILACS, LIVECS | ID: biblio-1147479

ABSTRACT

El cáncer de mama Triple Negativo es un subtipo molecular que se caracteriza por ausencia de expresión de receptores de estrógeno, progesterona y proteína HER2. Representa el 10 % a 15 % de todos los subtipos de cáncer de mama con impacto en el pronóstico y en las líneas de tratamiento; siendo negativo para receptores hormonales y HER2, la terapéutica hormonal y anti-HER2 no cuentan para su manejo. Aún no se dispone de productos dirigidos a blancos específicos para esta categoría.(AU)


The Triple Negative breast cancer is a molecular subtype characterized by no expression of the estrogen, the progesterone and the HER2 protein receptors. They represents 10 % to 15 % of all the breast cancer subtypes with an impact on the prognosis and in the treatment lines; is negative for the hormone receptors and for the HER2, hormonal and the anti-HER2 therapeutics do not count for the management of them. The products targeting specific to this category are not yet available(AU)


Subject(s)
Humans , Female , Biomarkers, Tumor , Anthracyclines/therapeutic use , Taxoids/therapeutic use , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/epidemiology , Mammography , Drug Therapy , Medical Oncology
2.
Electron. j. biotechnol ; 50: 59-67, Mar. 2021. ilus, graf, tab
Article in English | LILACS | ID: biblio-1292412

ABSTRACT

BACKGROUND: Cross talk of tumor­immune cells at the gene expression level has been an area of intense research. However, it is largely unknown at the alternative splicing level which has been found to play important roles in the tumor­immune microenvironment. RESULTS: Here, we re-exploited one transcriptomic dataset to gain insight into tumor­immune interactions from the point of AS level. Our results showed that the AS profiles of triple-negative breast cancer cells co-cultured with activated T cells were significantly changed but not Estrogen receptor positive cells. We further suggested that the alteration in AS profiles in triple-negative breast cancer cells was largely caused by activated T cells rather than paracrine factors from activated T cells. Biological pathway analyses showed that translation initiation and tRNA aminoacylation pathways were most disturbed with T cell treatment. We also established an approach largely based on the AS factor­AS events associations and identified LSM7, an alternative splicing factor, may be responsible for the major altered events. CONCLUSIONS: Our study reveals the notable differences of response to T cells among breast cancer types which may facilitate the development or improvement of tumor immunotherapy.


Subject(s)
T-Lymphocytes , Triple Negative Breast Neoplasms , Peptide Chain Initiation, Translational , Gene Expression , Alternative Splicing , Cell Culture Techniques , Receptor Cross-Talk , Transfer RNA Aminoacylation , Transcriptome , Immunotherapy
3.
Rev. bras. cancerol ; 67(2): e-061014, 2021.
Article in Portuguese | LILACS | ID: biblio-1223914

ABSTRACT

Introdução: O câncer de mama é o mais comumente diagnosticado em mulheres e uma das principais causas de morte por câncer em mulheres em todo o mundo. Apesar, ou talvez por causa, de sua natureza agressiva e da falta de tratamentos direcionados atuais, pesquisas clínicas e laboratoriais significativas estão fornecendo opções de tratamento diferenciadas. Historicamente, a quimioterapia tem sido a única opção viável de tratamento sistêmico para doenças precoces e avançadas. No entanto, ensaios clínicos publicados recentemente mostraram que a imunoterapia tem um papel importante no paradigma de tratamento dessa condição devastadora. Objetivo: Demonstrar o estado da arte da imunoterapia no tratamento do câncer de mama triplo-negativo. Método: Revisão integrativa de literatura, entre janeiro/2020 a março/2020, a partir das bases de dados PubMed, SciELO, InternationalClinical Trials Registry Platform e LILACS, por meio dos descritores "Imunoterapia", "Neoplasias da mama" e "Neoplasias de mama triplo negativas" e seus respectivos correspondentes em inglês. Resultados: Foram encontrados 465 artigos; destes, 457 foram excluídos após aplicação dos critérios metodológicos. Assim, restaram oito artigos que atendiam aos critérios de inclusão, demonstrando os principais agentes terapêuticos utilizados, mecanismos de ação e combinações terapêuticas. Encontraram-se 25 ensaios clínicos em andamento na plataforma de registro de ensaios clínicos InternationalClinical Trials Registry Platform. Conclusão: Embora a imunoterapia seja algo recente, seus resultados com agentes inibidores da PARP, PD-1 e PD-L1 demonstraram resultados satisfatórios. Novos ensaios com subgrupos estratificados de acordo com biomarcadores tumorais específicos são necessários, a fim de avaliar se algum subgrupo tem maior benefício ao tratamento.


Introduction: Breast cancer is the most commonly diagnosed cancer in women and is one of the leading causes of death from cancer in women worldwide. Despite, or perhaps because of its aggressive nature and current lack of targeted treatments, significant basic research and clinical trials are being conducted to provide new treatment options. Historically, chemotherapy has been the only viable systemic treatment option for early and advanced diseases. However, recently published clinical trials have shown that immunotherapy plays an important role in the treatment paradigm of this devastating clinical condition. Objective: To demonstrate the state-of-the-art results of immunotherapy in the treatment of triple-negative breast cancer. Method:An integrative literature review was carried out between January/2020 and March/2020, in PubMed, SciELO, International Clinical Trials Registry Platform and LILACS databases, using the keywords "Immunotherapy", "Breast Cancer", and "Triple Negative Breast Cancer" and its respective correspondents in Portuguese. Results: 465 articles were found; of those, 457 were excluded after applying the methodological criteria. Thus, 8 articles that met the inclusion criteria, showing the main therapeutic agents used, mechanisms of action and therapeutic combinations, remained. 25 clinical trials were found in progress on the International Clinical Trials Registry Platform. Conclusion: Although immunotherapy is somewhat recent, its results with PARP, PD-1 and PD-L1 inhibitors have shown satisfactory results. New trials with subgroups stratified according to specific tumor biomarkers are needed in order to assess if some subgroups have greater benefit to treatment.


Introducción: El cáncer de mama es el más comúnmente diagnosticado en las mujeres y es una de las principales causas de muerte por cáncer en mujeres de todo el mundo. A pesar de, o quizás debido a su naturaleza agresiva y la falta de tratamientos dirigidos actuales, investigaciones clínicas y de laboratorio significativas están proporcionando opciones de tratamiento diferenciadas. Históricamente, la quimioterapia ha sido la única opción viable para el tratamiento sistémico de enfermedades tempranas y avanzadas. Sin embargo, los ensayos clínicos publicados recientemente han demostrado que la inmunoterapia desempeña un papel importante en el paradigma del tratamiento de esta condición devastadora. Objetivo: Demostrar el estado del arte de la inmunoterapia en el cáncer de mama triple negativo. Método: Revisión integradora entre enero/2020 y marzo/2020, utilizando las bases de datos PubMed, SciELO, InternationalClinical Trials Registry Platform y LILACS, empleando las palabras clave "Inmunoterapia", "Cáncer de mama" y "Cáncer de mama triple negativo" y los respectivos términos en inglés. Resultados: Se encontraron 465 artículos; de estos, 457 fueron excluidos después de aplicar los criterios metodológicos. Así, quedaron 8 artículos que cumplían los criterios, que mostraban los principales agentes terapéuticos utilizados, mecanismos de acción y combinaciones terapéuticas. Se encontraron 25 ensayos clínicos en progreso en la plataforma InternationalClinical Trials Registry Platform. Conclusión: Aunque la inmunoterapia es algo reciente, sus resultados con inhibidores de PARP, PD-1 y PD-L1 han mostrado resultados satisfactorios. Se necesitan nuevos ensayos con subgrupos estratificados según biomarcadores tumorales específicos para evaluar si algún subgrupo tiene un mayor beneficio.


Subject(s)
Humans , Female , Breast Neoplasms/therapy , Triple Negative Breast Neoplasms , Immunotherapy , Biomarkers
4.
Frontiers of Medicine ; (4): 1-10, 2021.
Article in English | WPRIM | ID: wpr-880946

ABSTRACT

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a heterogeneous genetic profile. Chemotherapy exhibits substantial activity in a small subset of these patients. Drug resistance is inevitable. Major progress has been made in the genetic analysis of TNBC to identify novel targets and increase the precision of therapeutic intervention. Such progress has translated into major advances in treatment strategies, including modified chemotherapy approaches, immune checkpoint inhibitors, and targeted therapeutic drugs. All of these strategies have been evaluated in clinical trials. Nevertheless, patient selection remains a considerable challenge in clinical practice.


Subject(s)
Humans , Immunotherapy , Molecular Targeted Therapy , Triple Negative Breast Neoplasms/genetics
5.
J. bras. econ. saúde (Impr.) ; 12(2): 149-154, Agosto/2020.
Article in English | LILACS, ECOS | ID: biblio-1118325

ABSTRACT

Objective: The aim of the study was to demonstrate the economic impact of two PD-L1 immunohistochemistry (IHC) assays, SP142 versus 22C3, in the treatment with atezolizumab plus nab-paclitaxel in patients with advanced triple negative breast cancer (aTNBC) in the Brazilian private healthcare system (BPHS). Methods: The study performed two analyses: one per patient and other of the potential population projected for the BPHS (budget impact analysis). Data of progressionfree survival and overall survival were extracted from a post hoc analysis of the IMpassion130 trial to develop a partitioned-survival model to simulate the economic impact of the treatment with atezolizumab plus nab-paclitaxel guided by the SP142 and 22C3 assays on patients with aTNBC. The analyses included only direct costs that were based on CBHPM (Classificação Brasileira Hierarquizada de Procedimentos Médicos) and CMED (Câmara de Regulação do Mercado de Medicamentos) PF18% tables. A univariate sensitivity analysis was performed with the parameters varying ± 20%. Results: The study has demonstrated that the SP142 assay has the potential to save ­BRL 179,730 with the treatment of atezolizumab plus nab-paclitaxel per patient with aTNBC in five years. Conclusion: The SP142 assay can optimize the use of atezolizumab plus nab-paclitaxel avoiding its prescription in patients who will not have a significant clinical improvement.


Objetivo: O objetivo do estudo foi demonstrar o impacto econômico de dois testes de imuno-histoquímica, SP142 versus 22C3, no tratamento com atezolizumabe + nab-paclitaxel em pacientes com câncer de mama triplo-negativo avançado (CMTNa) no sistema de saúde suplementar (SSS) no Brasil. Métodos: O estudo realizou duas análises: uma por paciente e outra na população potencial projetada para o SSS (análise de impacto no orçamento). Dados de sobrevida livre de progressão e de sobrevida global foram extraídos da análise post hoc do estudo IMpassion130 para o desenvolvimento de um modelo de sobrevida particionado que simulasse o impacto econômico do tratamento com atezolizumabe + nab-paclitaxel direcionado pelos testes SP142 e 22C3 em pacientes com CMTNa. A análise considerou somente os custos diretos baseados nas tabelas CBHPM (Classificação Brasileira Hierarquizada de Procedimentos Médicos) e CMED (Câmara de Regulação do Mercado de Medicamentos) PF18%. Uma análise de sensibilidade univariada foi realizada variando os parâmetros em ± 20%. Resultados: O estudo demonstrou que o teste SP142 apresenta um potencial de economia de -179.730 reais (BRL) no tratamento de atezolizumabe + nab-paclitaxel por paciente com CMTNa em cinco anos. Conclusão: O uso do teste SP142 possibilita otimizar o uso de atezolizumabe + nab-paclitaxel evitando a sua prescrição em pacientes que não irão se beneficiar de forma significativa.


Subject(s)
Immunohistochemistry , Supplemental Health , Triple Negative Breast Neoplasms
6.
Article in English | WPRIM | ID: wpr-811198

ABSTRACT

PURPOSE: We investigated the expression of the N-myc and STAT interactor (NMI) protein in invasive ductal carcinoma tissue and estimated its clinicopathologic significance as a prognostic factor. The expression levels and prognostic significance of NMI were also analyzed according to the molecular subgroup of breast cancers.METHODS: Human NMI detection by immunohistochemistry was performed using tissue microarrays of 382 invasive ductal carcinomas. The correlation of NMI expression with patient clinicopathological parameters and prognostic significance was analyzed and further assessed according to the molecular subgroup of breast cancers. Moreover, in vitro experiments with 13 breast cancer cell lines were carried out. We also validated NMI expression significance in The Cancer Genome Atlas cohort using the Human Protein Atlas (HPA) database.RESULTS: Low NMI expression was observed in 190 cases (49.7%). Low NMI expression was significantly associated with the “triple-negative” molecular subtype (p < 0.001), high nuclear grade (p < 0.001), high histologic grade (p < 0.001), and advanced anatomic stage (p = 0.041). Patients with low NMI expression had poorer progression-free survival (p = 0.038) than patients with high NMI expression. Low NMI expression was not significantly associated with patient prognosis in the molecular subgroup analysis. In vitro, a reduction of NMI expression was observed in 8 breast cancer cell lines, especially in the estrogen receptor-positive and basal B type of triple-negative breast cancer molecular subgroups. The HPA database showed that low NMI expression levels were associated with a lower survival probability compared with that associated with high NMI expression (p = 0.053).CONCLUSION: NMI expression could be a useful prognostic biomarker and a potential novel therapeutic target in invasive ductal carcinoma.


Subject(s)
Biomarkers, Tumor , Breast , Breast Neoplasms , Carcinoma, Ductal , Cell Line , Cohort Studies , Databases, Genetic , Disease-Free Survival , Down-Regulation , Estrogens , Genome , Humans , Immunohistochemistry , In Vitro Techniques , Prognosis , Triple Negative Breast Neoplasms
7.
Article in English | WPRIM | ID: wpr-811197

ABSTRACT

PURPOSE: Tau is a microtubule-associated protein that can be found in both normal and abnormal breast cells. Whether the expression of Tau protein can predict the response to neoadjuvant chemotherapy (NACT) is still unclear. In this study, we assessed the role of Tau protein expression in predicting a pathological complete response (pCR) to NACT for different subtypes of breast cancer.METHODS: Four hundred and sixty-eight eligible patients were retrospectively recruited in our study. The relationship between clinicopathologic factors, including Tau protein expression, and pCR in different subtypes was evaluated using logistic regression analysis. Correlation between Tau and disease-free survival (DFS) and overall survival (OS) was performed using Kaplan–Meier analysis.RESULTS: The expression of Tau protein was negatively correlated with pCR, especially in triple-negative breast cancer (TNBC). No significant difference was observed in the luminal human epidermal growth factor receptor-2 (HER2)-negative subtype and HER2-positive subtype. Patients with pCR were associated with better DFS and OS (p < 0.05). However, Tau protein expression had no association with either DFS or OS (p > 0.05).CONCLUSION: Tau protein expression can predict pCR before NACT in TNBC, but there was no correlation between Tau expression and DFS or OS.


Subject(s)
Breast Neoplasms , Breast , Disease-Free Survival , Drug Therapy , Epidermal Growth Factor , Humans , Logistic Models , Neoadjuvant Therapy , Phenobarbital , Polymerase Chain Reaction , Retrospective Studies , tau Proteins , Triple Negative Breast Neoplasms
8.
São Paulo; s.n; 2020. 87 p. ilust, tabelas, quadros.
Thesis in Portuguese | LILACS, Inca | ID: biblio-1179672

ABSTRACT

Introdução: O câncer de mama triplo negativo (CMTN) corresponde de 10 a 20% dos carcinomas invasivos de mama, é altamente agressivo e na maioria das vezes tem apenas a quimioterapia padrão como tratamento. As citocinas inflamatórias são um grupo heterogêneo de proteínas solúveis produzidas por diferentes tipos de células, que medeiam e regulam o sistema imune. A resposta imune celular é regulada por proteínas acessórias denominadas receptores co-estimuladores e co-inibidores, como 4-1BB e TIM-3, respectivamente. A procura por biomarcadores que possam predizer resposta à quimioterapia neoadjuvante (QT neo) ainda é um desafio na medicina. Objetivo: Avaliar os níveis solúveis de sTIM-3 e s4-1BB, e de citocinas inflamatórias no sangue de mulheres com câncer de mama triplo negativo localmente avançado e associá-los à sobrevida livre de doença e com o tipo de resposta patológica à QT neo. Métodos: O estudo foi realizado entre os anos de 2015 e 2017 no Hospital de Câncer de Pernambuco (HCP) e Laboratório de Pesquisa Translacional do Instituto de Medicina Integral Prof. Fernando Figueira (IMIP). Foram incluídas 29 mulheres, entre 18 e 60 anos de idade, com diagnóstico de CMTN localmente avançado e submetidas à QT neo, e um grupo de 30 mulheres saudáveis. Coletas de sangue periférico foram realizadas antes e após a QT neo. A dosagem dos níveis solúveis de s4-1BB e sTIM-3 foi realizada por enzyme linked immunonoSorbent assay (ELISA). As dosagens de IL-1ß, IL-6, IL-8, TNF-α e IL-10 foram realizadas pela técnica de Cytometric Bead Array por citometria de fluxo. O nível de significância estatística foi de p<0,05. Resultados: Níveis mais elevados de IL-6 e de IL-10 foram observados no grupo de pacientes com tumor T4 com relação as grupo T2-T3 (p<0.05). Níveis elevados de IL-6, IL-8, IL-10 e TNF-α no grupo CMTN com status linfonodal N2 versus N0 e N1 (p<0,05). Os níveis de IL-1ß, IL-6, IL-10 e TNF-α foram elevados no grupo com resposta patológica parcial (RP) quando comparado aos grupos com resposta patológica completa (RC) e controles (p<0,05). Com relação aos níveis de IL-8, os grupos de pacientes RC e RP apresentaram níveis elevados quando comparados aos controles (p<0,05). Não foi observada diferença significativa de IL-8 entre os grupos RC e RP. Não foram observadas diferenças significativas em níveis de s4-1BB E sTIM-3 de acordo com o tumor primário e status linfonodal. Elevados níveis de s4-1BB foram observados no grupo RC comparado aos grupos RP e de controles (p<0,0004 e p<0,0001, respectivamente). Da mesma forma, os níveis de sTIM-3 foram mais elevados nas pacientes com RC e RP em relação aos controles (p<0,0001 e p<0,0003, respectivamente). Para análise da sobrevida livre de doença (SLD) em 24 meses de seguimento, utilizamos como ponto de corte o valor da mediana (< ou ≥ percentil 50) dos níveis solúveis de sTIM-3 e s4-1BB. Não houve diferenças significativas na SLD entre os grupos com níveis de s4-1BB ≥ 122 e < 122 pg/mL. A SLD foi de 93,33% no grupo com níveis de sTIM-3 < 2874 pg/mL e de 60% no grupo com níveis ≥ 2874 pg/mL (p=0,03). Conclusão: O s4-1BB foi um bom indicador preditivo de resposta à QT neo, enquanto elevação de sTIM-3 mostrou estar associado ao risco de recidiva loco-regional e metástases à distância. Ambos, TIM-3 e 4-1BB, parecem ser potenciais alvos terapêuticos no CMTN localmente avançado por estarem associadas ao desfecho clínico da doença


Introduction: Triple negative breast cancer (TNBC) corresponds to 10 to 20% of invasive breast carcinoma with high aggressiveness and in most cases has only standard chemotherapy as treatment. Inflammatory cytokines are heterogeneous group of soluble proteins produced by different types of cell, that mediate and regulate the immune system. The cellular immune response is regulated by accessory proteins called co-stimulatory and co-inhibitory receptors, such as 4-1BB and TIM-3, respectively. The search for biomarkers that can predict response to neoadjuvant chemotherapy (NAC) is still a challenge to medicine. Objective: To evaluate the soluble levels of sTIM-3 and s4-1BB, and inflammatory cytokines in the blood of women with locally advanced triple negative breast cancer, and to associate them with disease-free survival and the type of pathological response to NAC. Methods: The study was carried out between the years 2015 and 2017 at the Hospital de Cancer de Pernanbuco (HCP) and Translational Research Laboratory of the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP). Twenty-nine women, between 18 and 60 years old, diagnosed with locally advanced TNBC, and submitted to NAC, and 30 healthy women were included. Peripheral blood samples were taken before and after neo QT. The determination of the soluble levels of s4-1BB and sTIM-3 was performed by enzyme linked immunonosorbent assay (ELISA). The measurements of IL-1ß, IL-6, IL-8, TNF-α and IL-10 were performed using the Cytometric Bead Array by flow cytometry. The level of statistical significance was p <0.05. Results: There were higher levels of IL-6 and IL-10 in the group of patients with tumor size T4 compared to groups T2-T3 (p <0.05). High levels of IL-6, IL8, IL-10 and TNF-α were found in the TNBC group with lymph node status in N2 in relation to N0 and N1 (p <0.05). High levels of IL1ß, IL-6, IL-10 and TNF-α were observed in the group with partial pathological response (PR) when compared to groups with complete pathologial response (RC) and controls (p <0.05). With regard to IL-8 levels, the groups of CR and RP patients showed high levels when compared to controls (p <0.05). There was no significant difference in IL-8 between the CR and PR groups. No significant differences were observed in the levels of s4-1BB and sTIM-3 in accordance with primary tumor and lymph node status. High levels of s4-1BB were observed in the RC group compared to the PR and control groups (p <0.0004 and p <0.0001, respectively). As well, the levels of sTIM-3 were higher in patients with CR and PR compared to controls (p <0.0001 and p <0.0003, respectively). In the analyses of disease-free survival (DFS) with 24 months of follow-up, we used as a cut-off point the median value (< or ≥ 50th percentile) of the soluble levels of sTIM-3 and s4-1BB. There were no significant differences in DFS at 24 months between groups with levels of s4-1BB ≥ 122 and <122 pg/mL. The DFS was 93.33% in the group with sTIM-3 levels <2874 pg/mL and 60% in the group with levels ≥ 2874 pg/mL (p = 0.03). Conclusion: s4-1BB was a good predictive indicator of response to NAC, while elevation of sTIM-3 levels was shown to be associated with the risk of locoregional recurrence and distant metastases. Both TIM-3 and 4-1BB appear to be potential therapeutic targets in locally advanced TNBC because they were associated with the clinical outcome of the disease


Subject(s)
Humans , Female , Adult , Middle Aged , T-Lymphocytes , Neoadjuvant Therapy , Cytosine , Triple Negative Breast Neoplasms , Immune System
9.
Biol. Res ; 53: 42, 2020. tab, graf
Article in English | LILACS | ID: biblio-1131886

ABSTRACT

BACKGROUND: Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. METHODS: We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. RESULTS: MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. CONCLUSIONS: Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.


Subject(s)
Humans , Female , Genes, Tumor Suppressor , RNA-Binding Proteins/genetics , Nuclear Matrix-Associated Proteins/genetics , Triple Negative Breast Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Cell Movement , Apoptosis , Cell Line, Tumor , Cell Proliferation , Epithelial-Mesenchymal Transition
10.
Rev. argent. mastología ; 38(140): 34-47, dic. 2019. graf
Article in Spanish | LILACS | ID: biblio-1116266

ABSTRACT

Introducción Los cánceres de mama Triple Negativo representan entre el 12 y el 17% de todos los carcinomas mamarios. Son un grupo heterogéneo con diferentes subgrupos. La reacción inflamatoria que produce el huésped como respuesta a la enfermedad puede cuantificarse a través de la infiltración linfocitaria intratumoral (tils). Objetivos Evaluar la infiltración linfocitaria intratumoral (tils) como factor pronóstico independiente en las core biopsias de las pacientes con cáncer de mama Triple Negativo que fueron sometidas a quimioterapias neoadyuvantes. Relacionarla con la respuesta patológica obtenida luego de la cirugía. Material y método Se seleccionaron retrospectivamente pacientes con carcinoma de mama Triple Negativo que realizaron quimioterapia neoadyuvante en la Unidadde Mastología de la Clínica Breast y en el Hospital Italiano de la Ciudad de La Plata entre los años 2014 y 2017. Se obtuvo una muestra de 36 pacientes. Resultados Sobre un total de 36 pacientes, 24 mostraron tils estromales menores al 50% y 12 mayores o iguales al 50%. El 16,7% de los tumores con tils menores al 50% y la mitad de los tumores con tils mayores o iguales al 50% presentaron una Respuesta Patológica Completa (rpc) post tratamiento quimioterápico neoadyuvante. En relación con los tils intratumorales, 6 tumores de 32 con tils menores al 50% (18,8%) y 4 de 4 (100%) con tils > o iguales al 50% presentaron una Respuesta Patológica Completa (rpc) post tratamiento quimioterápico neoadyuvante. Conclusiones En nuestra serie de casos, observamos que existe relación entre el porcentaje de tils y la respuesta patológica obtenida luego de la realización del tratamiento con quimioterapia neoadyuvante, siendo un factor pronóstico en las pacientes con cáncer de mama Triple Negativo


Introduction Triple Negative breast cancers account for between 12 and 17% of all breast carcinomas. They are a heterogeneous group with different subgroups. The inflammatory reaction produced by the host in response to the disease can be quantified through intratumoral lymphocyte infiltration (tils). Objectives To evaluate intratumoral lymphocyte infiltration (tils), as an independent prognostic factor, in the core biopsies of patients with Triple Negative breast cancer who underwent neoadjuvant chemotherapies. To relate it to the pathological response obtained after surgery. Materials and method Patients with Triple Negative breast carcinoma who underwent neoadjuvant chemotherapy in the Mastology Unit of the Breast Clinic and the Italian Hospital of La Plata were retrospectively selected between the years 2014 and 2017. A sample of 36 patients was obtained. Results Out of a total of 36 patients, 24 showed stromal tils less than 50% and 12 greater than or equal to 50%. 16.7% of tumours with tils less than 50% and half of tumours with tils greater than or equal to 50% presented a complete pathological response after neoadjuvant chemotherapy treatment. In relation to intratumoral tils, 6 tumors of 32 with tils less than 50% (18.8%) and 4 of 4 (100%) with tils > or equal to 50% presented a complete pathological response after neoadjuvant chemotherapy treatment. Conclusions In our series of cases, we observe that there is a relationship between the percentage of tils and the pathological response obtained after treatment with neoadjuvant chemotherapy, being a prognostic factor in patients with triple negative breast cancer


Subject(s)
Breast Neoplasms , Infiltration-Percolation , Triple Negative Breast Neoplasms
11.
Rev. argent. mastología ; 38(138): 55-78, jul 2019. graf
Article in Spanish | LILACS | ID: biblio-1116812

ABSTRACT

El cáncer de mama Triple Negativo ha sido estudiado a lo largo de los años principalmente por ser uno de los de peor pronóstico y, además, por carecer de terapia blanco. El debut de esta patología se puede dar de diversas formas, y es en función de esto que el especialista optará entre distintas medidas: ya sea instaurará tratamiento adyuvante o neoadyuvante o enfrentará directamente la enfermedad metastásica. Si bien muchas veces las terapias a utilizar no se encuentran bien establecidas, las drogas quimioterápicas no difieren de las de los otros subtipos. Pero, al ser tumores que se asocian con mayor frecuencia a mutaciones en el brca, se han investigado tratamientos que apuntan más hacia el defecto de reparación del adn mediante la recombinación homóloga, como son los platinos y los inhibidores del parp. Por otro lado, no se debe dejar de mencionar las terapias dirigidas hacia los distintos subtipos tumorales como, por ejemplo, los antagonistas androgénicos que aún se encuentran en estudio. Sabemos que el cáncer de mama Triple Negativo es una patología extremadamente difícil de tratar, pero todavía quedan en el tintero investigaciones para esclarecer y enfocar las terapias blanco según cada subtipo dentro de estos tumores


Over the years, Triple Negative breast cancers have been studied, mainly because of its poor prognosis but also because it lacks a target therapy. Its debut may occur in different ways, therefore specialists can choose between different measures for treatment. The choices lay between adjuvant or neoadjuvant therapies or to directly face metastatic disease. Although these therapies are not fully established, chemotherapeutic drugs do not differ from other breast cancer subtypes. The association between these tumors and brca mutations is so high, target treatments have been focusing in dna defect repair, through homologous recombination, such as platinum-based chemotherapy and parp inhibitors. Other target therapies should be taken into account, such as androgenic antagonists, which are still being studied. Considering the nature of such an heterogeneous disease, which is extremely difficult to treat, we should acknowledge research in this subject is yet to be clarified to be able to provide new target therapies for each subtype within the triple negative tumors


Subject(s)
Therapeutics , Breast Neoplasms , Neoadjuvant Therapy , Drug Therapy , Triple Negative Breast Neoplasms
12.
Biol. Res ; 52: 38, 2019. graf
Article in English | LILACS | ID: biblio-1019502

ABSTRACT

BACKGROUND: Breast cancer is the second common malignant cancer among females worldwide. Accumulating studies have indicated that deregulation of miRNA expression in breast cancer will contribute to tumorigenesis and form different cancer subtypes. However, the reported studies on miR-29b-3p-regulated breast cancer are limited so far. Herein, we investigated the role and mechanism of miR-29b-3p in the triple negative breast cancer cell line MDA-MB-231. METHODS: The relative miR-29b-3p expression in different breast cancer cell lines were determined by qRT-PCR. CCK8 and colony formation assay were used to determine the influence of miR-29b-3p on cell proliferation. Migration assay and invasion assay were performed for cell migration and invasion respectively. To study the cell integrity immunofluorescence was performed. TUNEL assay, flow cytometry assay, hoechst staining and western blot were conducted to determine the influence of miR-29b-3p inhibitor on cell apoptosis. TRAF3 was found to be the target gene of miR-29b-3p using bioinformatics predictions. Dual-luciferase assay was performed to determine the relative luciferase activity in NC, miR-29b-3p mimic, miR-29b-3p inhibitor with TRAF3 3'-UTR wt or TRAF3 3'-UTR mt reporter plasmids. The proteins expression of NF-κB signaling pathway in MDA-MB-231 after transfection with NC, miR-29b-3p mimic, miR-29b-3p inhibitor were determined by western blot. RESULTS: The miR-29b-3p expression was significantly increased in MDA-MB-231 compare with MCF-10A. miR-29b-3p inhibitor reduced the cell viability of MDA-MB-231 and inhibited cell migration and invasion. Cell cytoskeleton integrity destroyed after miR-29b-3p inhibitor treatment. Furthermore, we identified the mechanism and found miR-29b-3p targets the TRAF3 and activates NF-κB signaling pathway. CONCLUSIONS: From the above studies, our results indicated that miR-29b-3p acts as a promoter for the development of MDA-MB-231.


Subject(s)
Humans , Female , Down-Regulation/genetics , Apoptosis/drug effects , MicroRNAs/metabolism , TNF Receptor-Associated Factor 3/metabolism , Triple Negative Breast Neoplasms/genetics , Blotting, Western , Cell Line, Tumor , TNF Receptor-Associated Factor 3/genetics , Cell Proliferation , Triple Negative Breast Neoplasms/pathology , Luciferases/metabolism
13.
Article in English | WPRIM | ID: wpr-719720

ABSTRACT

PURPOSE: We investigated whether irinotecan plus capecitabine improved progression-free survival (PFS) compared with capecitabine alone in patients with human epidermal growth factor 2 (HER2) negative and anthracycline and taxane pretreated metastatic breast cancer (MBC). MATERIALS AND METHODS: A total of 221 patients were randomly assigned to irinotecan (80 mg/m2, days 1 and 8) and capecitabine (1,000 mg/m2 twice a day, days 1-14) or capecitabine alone (1,250 mg/m2 twice a day, days 1-14) every 3 weeks. The primary endpoint was PFS. RESULTS: There was no significant difference in PFS between the combination and monotherapy arm (median, 6.4 months vs. 4.7 months; hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63 to 1.11; p=0.84). In patients with triple-negative breast cancer (TNBC, n=90), the combination significantly improved PFS (median, 4.7 months vs. 2.5 months; HR, 0.58; 95% CI, 0.37 to 0.91; p=0.02). Objective response rate was numerically higher in the combination arm, though it failed to reach statistical significance (44.4% vs. 33.3%, p=0.30). Overall survival did not differ between arms (median, 20.4 months vs. 24.0 months; p=0.63). While grade 3 or 4 neutropenia was more common in the combination arm (39.6% vs. 9.0%), hand-foot syndrome was more often observed in capecitabine arm. Quality of life measurements in global health status was similar. However, patients in the combination arm showed significantly worse symptom scales especially in nausea/vomiting and diarrhea. CONCLUSION: Irinotecan plus capecitabine did not prove clinically superior to single-agent capecitabine in anthracycline- and taxane-pretreated HER2 negative MBC patients. Toxicity profiles of the two groups differed but were manageable. The role of added irinotecan in patients with TNBC remains to be elucidated.


Subject(s)
Arm , Breast Neoplasms , Breast , Capecitabine , Diarrhea , Disease-Free Survival , Epidermal Growth Factor , Global Health , Hand-Foot Syndrome , Humans , Neutropenia , Quality of Life , Triple Negative Breast Neoplasms , Weights and Measures
14.
Article in English | WPRIM | ID: wpr-719716

ABSTRACT

PURPOSE: In the presence of interferon, proteasome subunits are replaced by their inducible counterparts to form an immunoproteasome (IP) plays a key role in generation of antigenic peptides presented by MHC class I molecules, leading to elicitation of a T cell‒mediated immune response. Although the roles of IP in other cancers, and inflammatory diseases have been extensively studied, its significance in breast cancer is unclear. MATERIALS AND METHODS: We investigated the expression of LMP7, an IP subunit, and its relationship with immune system components in two breast cancer cohorts. RESULTS: In 668 consecutive breast cancer cohort, 40% of tumors showed high level of LMP7 expression, and tumors with high expression of LMP7 had more tumor-infiltrating lymphocytes (TILs) in each subtype of breast cancer. In another cohort of 681 triple-negative breast cancer patients cohort, the expression of LMP7 in tumor cells was significantly correlated with the amount of TILs and the expression of interferon-associated molecules (MxA [p < 0.001] and PKR [p < 0.001]), endoplasmic reticulum stress-associated molecules (PERK [p=0.012], p-eIF2a [p=0.001], and XBP1 [p < 0.001]), and damage-associated molecular patterns (HMGN1 [p < 0.001] and HMGB1 [p < 0.001]). Patients with higher LMP7 expression had better disease-free survival outcomes than those with no or low expression in the positive lymph node metastasis group (p=0.041). CONCLUSION: Close association between the TIL levels and LMP7 expression in breast cancer indicates that better antigen presentation through greater LMP7 expression might be associated with more TILs.


Subject(s)
Antigen Presentation , Breast Neoplasms , Breast , Cohort Studies , Disease-Free Survival , Endoplasmic Reticulum , HLA Antigens , HMGB1 Protein , Humans , Immune System , Interferons , Lymph Nodes , Lymphocytes, Tumor-Infiltrating , Neoplasm Metastasis , Peptides , Proteasome Endopeptidase Complex , Triple Negative Breast Neoplasms
15.
Journal of Breast Cancer ; : 141-148, 2019.
Article in English | WPRIM | ID: wpr-738408

ABSTRACT

The luteinizing hormone-releasing hormone/androgen receptor (LHRH/AR) pathway is a promising treatment target in a subgroup of female patients with triple-negative breast cancer (TNBC). However, very little is known about the efficacy of this strategy in male patients with TNBC. In this report, we describe a male patient with AR-positive TNBC who was successfully treated using an LHRH agonist after pretreatment with several lines of chemotherapy and achieved a durable response. We also review the existing evidence supporting LHRH- and AR-targeted therapy for this rare disease.


Subject(s)
Breast Neoplasms, Male , Drug Therapy , Female , Gonadotropin-Releasing Hormone , Goserelin , Humans , Lutein , Male , Male , Rare Diseases , Receptors, Androgen , Triple Negative Breast Neoplasms
16.
Article in English | WPRIM | ID: wpr-785918

ABSTRACT

BACKGROUND: BRCA1 mutated breast cancer cells exhibit the elevated cell proliferation and the higher metastatic potential. G protein-coupled receptor 30 (GPR30) has been shown to regulate growth of hormonally responsive cancers, such as ovarian and breast cancers, and high expression of GPR30 is found in estrogen receptor (ER)-negative breast cancer cells. ER-negative breast cancer patients often have a mutation in the tumor suppressor gene, BRCA1. This study explored antiproliferative effects of genistein, a chemopreventive isoflavone present in legumes, and underlying molecular mechanisms in triple negative breast cancer cells with or without functionally active BRCA1.METHODS: Expression of BRCA1, GPR30 and Nrf2 was measured by Western blot analysis. Reactive oxygen species (ROS) accumulation was monitored by using the fluorescence-generating probe, 2’,7’-dichlorofluorescein diacetate. The effects of genistein on breast cancer cell viability and proliferation were assessed by the MTT, migration and clonogenic assays.RESULTS: The expression of GPR30 was dramatically elevated at both transcriptional and translational levels in BRCA1 mutated breast cancer cells compared to cells with wild-type BRCA1. Notably, there was diminished Akt phosporylation in GPR30 silenced cells. Treatment of BRCA1 silenced breast cancer cells with genistein resulted in the down-regulation of GPR30 expression and the inhibition of Akt phosphorylation as well as the reduced cell viability, migration and colony formation. Genistein caused cell cycle arrest at the G₂/M phase in BRCA1-mutant cells through down-regulation of cyclin B1 expression. Furthermore, BRCA1-mutant breast cancer cells exhibited higher levels of intracellular ROS than those in the wild-type cells. Genistein treatment lowered the ROS levels through up-regulation of Nrf2 expression.CONCLUSIONS: Lack of functional BRCA1 activates GPR30 signaling, thereby stimulating Akt phosphorylation and cell proliferation. Genistein induces G2/M phase arrest by down-regulating cyclin B1 expression, which is attributable to its suppression of GPR30 activation and Akt phosphorylation in BRCA1 impaired breast cancer cells.


Subject(s)
Blotting, Western , Breast Neoplasms , Breast , Cell Cycle Checkpoints , Cell Proliferation , Cell Survival , Cyclin B1 , Down-Regulation , Estrogens , Fabaceae , Genes, Tumor Suppressor , Genistein , Humans , Phosphorylation , Reactive Oxygen Species , Triple Negative Breast Neoplasms , Up-Regulation
19.
Article in English | WPRIM | ID: wpr-766018

ABSTRACT

BACKGROUND: Most triple-negative breast cancers (TNBCs) have a high histologic grade, are associated with high endoplasmic stress, and possess a high frequency of TP53 mutations. TP53 missense mutations lead to the production of mutant p53 protein and usually show high levels of p53 protein expression. Tumor-infiltrating lymphocytes (TILs) accumulate as part of the anti-tumor immune response and have a strong prognostic and predictive significance in TNBC. We aimed to elucidate the association between p53 expression and the amount of TILs in TNBC. METHODS: In 678 TNBC patients, we evaluated TIL levels and expression of endoplasmic stress molecules. Immunohistochemical examination of p53 protein expression was categorized into three groups: no, low, and high expression. RESULTS: No, low, and high p53 expression was identified in 44.1% (n = 299), 20.1% (n = 136), and 35.8% (n = 243) of patients, respectively. Patients with high p53 expression showed high histologic grade (p < .001), high TIL levels (p = .009), and high expression of endoplasmic reticulum stress-associated molecules (p-eIF2a, p = .013; XBP1, p = .007), compared to patients with low p53 expression. There was no significant difference in disease-free (p = .406) or overall survival rates (p = .444) among the three p53 expression groups. CONCLUSIONS: High p53 expression is associated with increased expression of endoplasmic reticulum stress molecules and TIL influx.


Subject(s)
Breast Neoplasms , Endoplasmic Reticulum , Endoplasmic Reticulum Stress , Humans , Lymphocytes, Tumor-Infiltrating , Mutation, Missense , Survival Rate , Triple Negative Breast Neoplasms
20.
Journal of Breast Disease ; (2): 1-8, 2019.
Article in Korean | WPRIM | ID: wpr-764290

ABSTRACT

PURPOSE: In breast cancer, response to endocrine therapy depends on estrogen receptor and progesterone receptor status. However, poor prognosis is conferred on patients with hormone receptor (HR)-positive breast cancer. We aimed to examine weakly positive HR breast cancer by comparing weakly positive HR to strongly positive HR and negative HR breast cancer. METHODS: We examined the clinical and biological features of 1,496 women with breast cancer, and these patients were categorized according to HR status as weakly positive, strongly positive, and negative HR breast cancer. RESULTS: In this study, among 1,496 patients with breast cancer, negative HR breast cancer was found in 374, weakly positive HR breast cancer in 90 and strongly positive HR breast cancer in 1,032 patients. Our multivariate analysis showed that there were differences in T stage, tumor-node-metastasis stage, vascular invasion, histologic grade and type, and Ki-67 index. Patients with weakly positive HR breast cancer had an increased risk of death and recurrence compared with those with strongly positive HR breast cancer and had similar prognosis as patients with negative HR breast cancer. CONCLUSION: Patients with weakly positive HR breast cancer received endocrine therapy because they were regarded as having positive HR breast cancer. However, their prognosis of overall survival and relapse-free survival was similar to that in patients with negative HR breast cancer. Therefore, we need to closely observe and consider active treatment for patients with weakly positive breast cancer.


Subject(s)
Breast Neoplasms , Breast , Estrogens , Female , Humans , Multivariate Analysis , Prognosis , Receptors, Estrogen , Receptors, Progesterone , Recurrence , Triple Negative Breast Neoplasms
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