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1.
Medicine (Baltimore) ; 99(18): e19986, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32358373

RESUMO

BACKGROUND: The incidence of triple negative breast cancer (TNBC) is at a relatively high level, and our study aimed to identify differentially expressed genes (DEGs) in TNBC and explore the key pathways and genes of TNBC. METHODS: The gene expression profiling (GSE86945, GSE86946 and GSE102088) data were obtained from Gene Expression Omnibus Datasets, DEGs were identified by using R software, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs were performed by the Database for Annotation, Visualization and Integrated Discovery (DAVID) tools, and the protein-protein interaction (PPI) network of the DEGs was constructed by the STRING database and visualized by Cytoscape software. Finally, the survival value of hub DEGs in breast cancer patients were performed by the Kaplan-Meier plotter online tool. RESULTS: A total of 2998 DEGs were identified between TNBC and health breast tissue, including 411 up-regulated DEGs and 2587 down-regulated DEGs. GO analysis results showed that down-regulated DEGs were enriched in gene expression (BP), extracellular exosome (CC), and nucleic acid binding, and up-regulated were enriched in chromatin assembly (BP), nucleosome (CC), and DNA binding (MF). KEGG pathway results showed that DEGs were mainly enriched in Pathways in cancer and Systemic lupus erythematosus and so on. Top 10 hub genes were picked out from PPI network by connective degree, and 7 of top 10 hub genes were significantly related with adverse overall survival in breast cancer patients (P < .05). Further analysis found that only EGFR had a significant association with the prognosis of triple-negative breast cancer (P < .05). CONCLUSIONS: Our study showed that DEGs were enriched in pathways in cancer, top 10 DEGs belong to up-regulated DEGs, and 7 gene connected with poor prognosis in breast cancer, including HSP90AA1, SRC, HSPA8, ESR1, ACTB, PPP2CA, and RPL4. These can provide some guidance for our research on the diagnosis and prognosis of TNBC, and further research is needed to evaluate their value in the targeted therapy of TNBC.


Assuntos
Mineração de Dados/métodos , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias de Mama Triplo Negativas/genética , Bases de Dados Genéticas , Regulação para Baixo , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/mortalidade , Regulação para Cima
2.
BMC Bioinformatics ; 21(Suppl 2): 89, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32164540

RESUMO

BACKGROUND: Phenotype prediction problems are usually considered ill-posed, as the amount of samples is very limited with respect to the scrutinized genetic probes. This fact complicates the sampling of the defective genetic pathways due to the high number of possible discriminatory genetic networks involved. In this research, we outline three novel sampling algorithms utilized to identify, classify and characterize the defective pathways in phenotype prediction problems, such as the Fisher's ratio sampler, the Holdout sampler and the Random sampler, and apply each one to the analysis of genetic pathways involved in tumor behavior and outcomes of triple negative breast cancers (TNBC). Altered biological pathways are identified using the most frequently sampled genes and are compared to those obtained via Bayesian Networks (BNs). RESULTS: Random, Fisher's ratio and Holdout samplers were more accurate and robust than BNs, while providing comparable insights about disease genomics. CONCLUSIONS: The three samplers tested are good alternatives to Bayesian Networks since they are less computationally demanding algorithms. Importantly, this analysis confirms the concept of "biological invariance" since the altered pathways should be independent of the sampling methodology and the classifier used for their inference. Nevertheless, still some modifications are needed in the Bayesian networks to be able to sample correctly the uncertainty space in phenotype prediction problems, since the probabilistic parameterization of the uncertainty space is not unique and the use of the optimum network might falsify the pathways analysis.


Assuntos
Algoritmos , Neoplasias de Mama Triplo Negativas/patologia , Teorema de Bayes , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Metástase Neoplásica , Fenótipo , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade
3.
Cancer Immunol Immunother ; 69(7): 1315-1326, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32198536

RESUMO

In view of the relatively limited efficacy of immunotherapies targeting the PD-1-PD-L1 axis in triple-negative breast cancer (TNBC) and of published reports on tumor-promoting roles of TNFR2+ tumor-infiltrating lymphocytes (TNFR2+ TILs), we determined the incidence of TNFR2+ TILs in TNBC patient tumors, their association with disease outcome and relations with PD-1+ TILs. Using a cohort of treatment-naïve TNBC patients with long follow-up (n = 70), we determined the presence of TNFR2+ TILs and PD-1+ TILs by immunohistochemistry. TILs (≥ 1% of cellular mass) and TNFR2+ TILs (≥ 1% of total TILs) were detected in 96% and 74% of tumors, respectively. The presence of TILs at > 5% of tumor cell mass ("Positive TILs"), as well as of positive TNFR2+ TILs (> 5%), was independently associated with good prognosis, and combination of both parameters demonstrated superior outcome relative to their lower levels. PD1+ TILs (> 5/hot spot) were detected in 63% of patients. High levels of PD-1+ TILs (> 20/hot spot) showed an unfavorable disease outcome, and in their presence, the favorable outcome of positive TNFR2+ TILs was ablated. Thus, TNFR2+ TILs are strongly connected to improved prognosis in TNBC; these findings suggest that TNFR2+ TILs have favorable effects in TNBC patients, unlike the tumor-promoting roles attributed to them in other cancer systems. Overall, our observations propose that the TNFR2+ TIL subset should not be targeted in the course of TNBC therapy; rather, its beneficial impacts may become into power when anti-PD-1 regimens-that may potentiate immune activities-are administered to TNBC patients.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Ductal de Mama/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
4.
N Engl J Med ; 382(9): 810-821, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32101663

RESUMO

BACKGROUND: Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab-chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo-chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population. RESULTS: At the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab-chemotherapy group and 46 of 390 patients (11.8%) in the placebo-chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab-chemotherapy group and 73.0% in the placebo-chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively. CONCLUSIONS: Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme [a subsidiary of Merck]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
5.
Medicine (Baltimore) ; 99(7): e19091, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32049813

RESUMO

Triple negative breast cancer (TNBC) account for 12% to 17% of all breast cancers. It is a heterogeneous group of tumors associated with aggressive clinical course. Insulin-like growth factor II mRNA binding protein 3 (IMP3) belongs to a family of insulin-like growth factor type II (IGF2), which plays a key role in the transmission and stabilization of mRNA, cell growth, and migration during embryogenesis. Increased expression of IMP3 is associated with aggressive behavior of different tumor types, advanced clinical stage, distant metastasis, and shorter overall survival (OS).The study included 118 patients with breast carcinoma diagnosed as TNBC and immunohistochemical staining for estrogen receptors (ER), progesterone receptors (PR), epidermal growth factor receptor 2 (HER2/neu), Ki-67, and IMP3 was performed. Correlations between categorical variables were studied using the chi-square and the Mann-Whitney U test. For survival analysis, the Kaplan-Meier method, log-rank test and the Cox proportional hazard regression model were used.Positive expression of IMP3 protein was present in 35.6% of TNBC. The presence of basal morphology was observed in 46.6% of TNBC. Positive IMP3 expression was connected with larger size of tumor, higher clinical stage, and basal morphology (P = .039, P = .034, P < .001). Disease-free survival and OS were significantly shorter in IMP3 positive TNBC.According to results of our study IMP3 expression can be used as negative prognostic factor for triple negative breast carcinomas. Targeting IMP3 molecule could be an effective approach to the management of a triple negative breast cancer with new immunological therapies, which does not yet exist for this group of tumors.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a RNA/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Carga Tumoral
6.
BMC Cancer ; 20(1): 18, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906874

RESUMO

BACKGROUND: We retrospectively compared the prognostic value between the AJCC 8th edition anatomic (AS) and prognostic staging (PS) system for triple negative breast cancer (TNBC) in a cohort from two involved institutions and a large population database. METHODS: Clinicopathological data of TNBCs were identified in two involved institutions (SYSUCC-PWH cohort). Data from SEER database during 2010-2015 was also accessed. We restaged all cases into AS and PS group according to the AJCC 8th staging system. RESULTS: A total of 611 and 31,941 TNBCs were identified in two cohorts, with a median follow-up of 53.5 and 27 months respectively. PS upstaged 46.1% of patients in SYSUCC-PWH cohort, and 62.4% in SEER cohort. No significant difference was observed in C index between AS and PS models for disease-specific survival (DSS), progression-free survival (PFS) or overall survival (OS) in either cohort. χ2 statistic and Hazard Ratio for PFS, DSS and OS showed better discrimination between IA and IB, IIB and IIIA, IIIA and IIIB in AS model than PS model. Besides, patients with IIIC unchanged stage showed worse PFS compared to those with AS IIIA or IIIB upstaged to PS IIIC in both cohorts(p = 0.049, p < 0.001). CONCLUSIONS: Our findings demonstrated that prognostic staging system did not provide better discriminatory ability in predicting TNBCs prognosis than anatomic staging system.


Assuntos
Estadiamento de Neoplasias , Neoplasias de Mama Triplo Negativas/mortalidade , Estudos de Coortes , Humanos , Estimativa de Kaplan-Meier , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Programa de SEER , Neoplasias de Mama Triplo Negativas/patologia
7.
Br J Radiol ; 93(1106): 20190712, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31821036

RESUMO

OBJECTIVE: To evaluate the associations between computer-aided diagnosis (CAD)-generated kinetic volume parameters and survival in triple-negative breast cancer (TNBC) patients. METHODS: 40 patients with TNBC who underwent pre-operative MRI between March 2008 and March 2014 were included. We analyzed CAD-generated parameters on dynamic contrast-enhanced MRI, visual MRI assessment, and histopathological data. Cox proportional hazards models were used to determine associations with survival outcomes. RESULTS: 12 of the 40 (30.0%) patients experienced recurrence and 7 died of breast cancer after a median follow-up of 73.6 months. In multivariate analysis, higher percentage volume (%V) with more than 200% initial enhancement rate correlated with worse disease-specific survival (hazard ratio, 1.12; 95% confidence interval, 1.02-1.22; p-value, 0.014) and higher %V with more than 100% initial enhancement rate followed by persistent curve type at 30% threshold correlated with worse disease-specific survival (hazard ratio, 1.33; 95% confidence interval, 1.10-1.61; p-value, 0.004) and disease-free survival (hazard ratio, 1.27; 95% confidence interval, 1.12-1.43; p-value, 0.000). CONCLUSION: CAD-generated kinetic volume parameters may correlate with survival in TNBC patients. Further study would be necessary to validate our results on larger cohorts. ADVANCES IN KNOWLEDGE: CAD generated kinetic volume parameters on breast MRI can predict recurrence and survival outcome of patients in TNBC. Varying the enhancement threshold improved the predictive performance of CAD generated kinetic volume parameter.


Assuntos
Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Meios de Contraste , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Mastectomia/estatística & dados numéricos , Pessoa de Meia-Idade , Cuidados Pré-Operatórios/métodos , Cuidados Pré-Operatórios/mortalidade , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/cirurgia , Carga Tumoral
8.
J Clin Pathol ; 73(3): 147-153, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31563883

RESUMO

AIMS: Characterising the factors responsible for metastatic triple-negative breast cancer (TNBC) is of significant importance, considering its high mortality rate and scant data. In this study, we evaluated the characteristics, clinical behaviour and role of biomarkers (androgen receptor (AR), oestrogen receptor beta (ERß) and p53) in metastatic TNBC. METHODS: Immunohistochemistry was performed for AR, ERß and p53 on 125 primary TNBCs with known metastasis and correlated with clinicopathological parameters and outcome. AR and p53 mRNA profiling was also carried out on 34 tumours from the same series and correlated with outcomes. RESULTS: In this cohort, grade 3 and pT2 tumours predominated. The most common site for metastasis was the lung and pleura (41, 32.8%), and 15 (12.0%) cases demonstrated metastasis in multiple sites. Among these, 92% of tumours metastasised without preceding local recurrences. Five- and ten-year overall survival (OS) rates were 27% and 7.2%, while 5- and 10- year survival rates after metastasis were 9.6% and 3.2% respectively. AR, ERß and p53 protein expressions were observed in 16%, 96.8% and 58.1% of tumours, respectively. A combinational phenotype of AR-ERß+p53+ tumours was associated with poorer OS (HR 1.543, 95%CI 1.030 to 2.310, p=0.035). Higher AR mRNA levels were significantly associated with favourable OS (p=0.015) and survival after metastasis (p=0.027). CONCLUSIONS: Metastatic TNBC harboured aggressive behaviour and displayed predominantly visceral metastasis with most metastatic events occurring without intervening local recurrences. A combinational phenotype of AR-ERß+p53+ was significantly associated with poorer OS.


Assuntos
Biomarcadores Tumorais/análise , Receptor beta de Estrogênio/análise , Receptores Androgênicos/análise , Neoplasias de Mama Triplo Negativas/química , Proteína Supressora de Tumor p53/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Prognóstico , Receptores Androgênicos/genética , Fatores de Tempo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Proteína Supressora de Tumor p53/genética
9.
Cell Physiol Biochem ; 53(6): 999-1014, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31838790

RESUMO

BACKGROUND/AIMS: Schlafen12 (SLFN12) promotes human intestinal and prostatic epithelial differentiation. We sought to determine whether SLFN12 reduces triple-negative breast cancer (TNBC) aggressiveness. METHODS: We validated bioinformatics analyses of publicly available databases by staining human TNBC. After virally overexpressing or siRNA-reducing SLFN12 in TNBC cell lines, we measured proliferation by CCK-8 assay, invasion into basement-membrane-coated pores, mRNA by q-RT-PCR and protein by Western blotting. Flow cytometry assessed proliferation and stem cell marker expression, and sorted CD44+/CD24- cells. Stemness was also assessed by mammosphere formation, and translation by click-it-AHA chemistry. RESULTS: SLFN12 expression was lower in TNBC tumors and correlated with survival. SLFN12 overexpression reduced TNBC MDA-MB-231, BT549, and Hs578T proliferation. In MDA-MB-231 cells, AdSLFN12 reduced invasion, promoted cell cycle arrest, increased E-cadherin promoter activity, mRNA, and protein, and reduced vimentin expression and protein. SLFN12 knockdown increased vimentin. AdSLFN12 reduced the proportion of MDA-MB-231 CD44+CD24- cells, with parallel differentiation changes. SLFN12 overexpression reduced MDA-MB-231 mammosphere formation. SLFN12 overexpression decreased ZEB1 and Slug protein despite increased ZEB1 and Slug mRNA in all three lines. SLFN12 overexpression accelerated MDA-MB-231 ZEB1 proteasomal degradation and slowed ZEB1 translation. SLFN12 knockdown increased ZEB1 protein. Coexpressing ZEB1 attenuated the SLFN12 effect on E-cadherin mRNA and proliferation in all three lines. CONCLUSION: SLFN12 may reduce TNBC aggressiveness and improve survival in part by a post-transcriptional decrease in ZEB1 that promotes TNBC cancer stem cell differentiation.


Assuntos
Diferenciação Celular , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Neoplasias de Mama Triplo Negativas/patologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
10.
Nat Commun ; 10(1): 5805, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31862882

RESUMO

The development of triple-negative breast cancer (TNBC) negatively impacts both quality of life and survival in a high percentage of patients. Here, we show that RING finger protein 208 (RNF208) decreases the stability of soluble Vimentin protein through a polyubiquitin-mediated proteasomal degradation pathway, thereby suppressing metastasis of TNBC cells. RNF208 was significantly lower in TNBC than the luminal type, and low expression of RNF208 was strongly associated with poor clinical outcomes. Furthermore, RNF208 was induced by 17ß-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner. Overexpression of RNF208 suppresses tumor formation and lung metastasis of TNBC cells. Mechanistically, RNF208 specifically polyubiquitinated the Lys97 residue within the head domain of Vimentin through interaction with the Ser39 residue of phosphorylated Vimentin, which exists as a soluble form, eventually facilitating proteasomal degradation of Vimentin. Collectively, our findings define RNF208 as a negative regulator of soluble Vimentin and a prognostic biomarker for TNBC cells.


Assuntos
Estradiol/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias de Mama Triplo Negativas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Vimentina/metabolismo , Animais , Mama/patologia , Linhagem Celular Tumoral , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Pulmão/patologia , Camundongos , Prognóstico , Estabilidade Proteica , Proteólise , Análise de Sobrevida , Análise Serial de Tecidos , Neoplasias de Mama Triplo Negativas/mortalidade , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Breast Cancer Res ; 21(1): 143, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842957

RESUMO

BACKGROUND: Metastatic triple-negative breast cancer (mTNBC), an aggressive histological subtype, has poor prognosis. Chemotherapy remains standard of care for mTNBC, although no agent has been specifically approved for this breast cancer subtype. Instead, chemotherapies approved for metastatic breast cancer (MBC) are used for mTNBC (National Comprehensive Cancer Network Guidelines [NCCN] v1.2019). Atezolizumab in combination with nab-paclitaxel was recently approved for programmed death-ligand 1 (PD-L1)-positive locally advanced or metastatic TNBC. Published historical data were reviewed to characterize the efficacy of NCCN-recommended (v1.2016) agents as first-line (1L) and second-line or later (2L+) treatment for patients with locally recurrent inoperable or metastatic TNBC (collectively termed mTNBC herein). METHODS: A systematic literature review was performed, examining clinical efficacy of therapies for mTNBC based on NCCN v1.2016 guideline recommendations. Data from 13 studies, either published retrospective mTNBC subgroup analyses based on phase III trials in MBC or phase II trials in mTNBC, were included. RESULTS: A meta-analysis of mTNBC subgroups from three phase III trials in 1L MBC reported pooled objective response rate (ORR) of 23%, median overall survival (OS) of 17.5 months, and median progression-free survival (PFS) of 5.4 months with single-agent chemotherapy. In two subgroup analyses from a phase III study and a phase II trial (n = 40 each), median duration of response (DOR) to 1L chemotherapy for mTNBC was 4.4-6.6 months; therefore, responses were not durable. A meta-analysis of seven cohorts showed the pooled ORR for 2L+ chemotherapy was 11% (95% CI, 9-14%). Median DOR to 2L+ chemotherapy in mTNBC was also limited (4.2-5.9 months) per two subgroup analyses from a phase III study. No combination chemotherapy regimens recommended by NCCN v1.2016 for treatment of MBC showed superior OS to single agents. CONCLUSIONS: Chemotherapies have limited effectiveness and are associated with unfavorable toxicity profiles, highlighting a considerable unmet medical need for improved therapeutic options in mTNBC. In addition to the recently approved combination of atezolizumab and nab-paclitaxel for PD-L1-positive mTNBC, new treatments resulting in durable clinical responses, prolonged survival, and manageable safety profile would greatly benefit patients with mTNBC.


Assuntos
Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Ensaios Clínicos Fase III como Assunto , Gerenciamento Clínico , Humanos , Terapia de Alvo Molecular , Recidiva Local de Neoplasia , Razão de Chances , Prognóstico , Retratamento , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/mortalidade
12.
Breast Cancer Res ; 21(1): 127, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779659

RESUMO

BACKGROUND: Nuclear receptor subfamily 1, group D, member 1 (NR1D1) is a ligand-regulated nuclear receptor and transcriptional factor. Although recent studies have implicated NR1D1 as a regulator of DNA repair and proliferation in breast cancers, its potential as a therapeutic target for breast cancer has not been assessed in terms of clinical outcomes. Thus, this study aims to analyze NR1D1 expression in breast cancer patients and to evaluate its potential prognostic value. METHODS: NR1D1 expression was analyzed by immunohistochemistry using an anti-NR1D1 antibody in 694 breast cancer samples. Survival analyses were performed using the Kaplan-Meier method with the log-rank test to investigate the association of NR1D1 expression with clinical outcome. RESULTS: One hundred thirty-nine of these samples exhibited high NR1D1 expression, mostly in the nucleus of breast cancer cells. NR1D1 expression correlated significantly with histological grade and estrogen receptor status. Overall survival (OS) and disease-free survival (DFS) did not correlate significantly with NR1D1 expression in breast cancer patients regardless of whether they had received chemotherapy. Subgroup analysis performed according to molecular subtype of breast cancer showed a significant influence of high NR1D1 expression on OS (P = 0.002) and DFS (P = 0.007) in patients with triple-negative breast cancer (TNBC) treated with chemotherapy. CONCLUSIONS: High NR1D1 expression level had a favorable impact on OS and DFS in patients with TNBC treated with chemotherapy. NR1D1 should be investigated further as a possible prognostic marker in TNBC patients receiving chemotherapeutic treatment and as a target in the development of chemotherapeutic approaches to treating TNBC.


Assuntos
Biomarcadores Tumorais , Expressão Gênica , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Prognóstico , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
13.
Int J Mol Sci ; 20(22)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731733

RESUMO

The aim of this study was to evaluate the prognostic impact that hormone receptor (HR) expressions have on the two different breast cancer (BC) entities-multifocal versus unifocal BC. As the prognosis determining aspects, we investigated the overall survival (OS) and disease-free survival (DFS) by univariate and multivariate analysis. To underline the study's conclusions, we additionally considered the histopathological grading and the tumor node metastasis (TNM) staging. A retrospective analysis was performed on survival-related events in a series of 320 breast cancer patients treated at the Department of Gynecology and Obstetrics at the Ludwig Maximillian University in Munich between 2000 and 2002. All three steroid receptors analyzed by immunohistochemistry, namely, the estrogen receptor (ER), the progesterone receptor (PR), and the vitamin D receptor (VDR), showed a significantly positive influence on the course of the disease, but only for the unifocal breast tumor patients. The prognosis of patients with multifocal breast cancer was either not affected by estrogen and/or progesterone receptor expression or even involved a worse etiopathology for the vitamin D receptor-positive patients. The estrogen receptor in unifocal breast cancer and the vitamin D receptor in multifocal breast cancer were especially identified as an independent prognostic marker for overall survival, when adjusted for age, grading, and staging. Altogether, our results strengthen the need to further investigate the behavior of the hormone receptors in breast cancer and understand why they have different effects on each focality type. Moreover, the studies for an adopted vitamin D supplementation due to breast cancer focality type must be enlarged to fully comprehend the remarkable and interesting role played by the vitamin D receptor.


Assuntos
Neoplasias da Mama/metabolismo , Receptores de Calcitriol/metabolismo , Neoplasias da Mama/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade
14.
Technol Cancer Res Treat ; 18: 1533033819882949, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31672084

RESUMO

MiR-146a-5p plays different roles in different types of cancers. We showed that miR-146a-5p and long noncoding RNA HOTAIR were both upregulated in triple-negative breast cancer. Follow-up study showed that high levels of miR-146a-5p and HOTAIR in tumor tissues were closely correlated with poor survival. MiR-146a-5p and HOTAIR were positively correlated in tumor tissues. MiR-146a-5p positively regulated HOTAIR triple-negative breast cancer cells, while HOTAIR showed no regulatory effects on miR-146a-5p expression. MiR-146a-5p and HOTAIR positively regulated the migration and invasion of triple-negative breast cancer cells. In addition, HOTAIR silencing attenuated the effects of miR-146a-5p. Therefore, overexpression of miR-146a-5p may promote triple-negative breast cancer cell invasion and migration by upregulating HOTAIR.


Assuntos
MicroRNAs/genética , Interferência de RNA , RNA Longo não Codificante/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Adulto , Idoso , Apoptose , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/patologia
15.
Medicine (Baltimore) ; 98(40): e17370, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577739

RESUMO

The aims of this study were to explore the expression of hypoxia inducible factor-1α (HIF-1α) and c-myc protein in triple-negative breast cancer (TNBC) and its clinical prognostic significance, and to establish a prediction model for postoperative survival of TNBC based on nomogram.A total of 87 patients with TNBC at the Department of Breast Surgery, Beijing Chaoyang Hospital, Capital Medical University from January 2012 to December 2015 were enrolled in this study. Immunohistochemistry was performed to detect the expression of HIF-1α and c-myc protein in breast cancer tissues. Cox regression analyses were performed to explore the correlation between HIF-1α/c-myc expression and clinical pathological parameters as well as prognosis. Receiver-operating characteristic curve was generated for cox multivariate analysis. A nomogram was generated based on the cox multivariate analysis, and a calibration curve was prepared for the nomogram to evaluate the consistency between the predicted probability of the nomogram and the actual observed probability. The stability of nomogram model was validated with an external cohort including 39 TNBC patients.The positive expression rates of HIF-1α and c-myc protein in breast cancer tissues were 41.4% (36/87) and 55.2% (48/87), respectively. HIF-1α expression was significantly correlated with age, tumor diameter, histological grade, lymph node status, and tumor TNM stage; c-myc expression was significantly associated with tumor diameter, histological grade, lymph node status, and tumor TNM stage. Cox univariate and multivariate analyses showed that HIF-1α and c-myc protein expression, histological grade, lymph node status, and tumor TNM stage were the independent risk factors for postoperative survival in TNBC patients. The AUC of prediction model was 0.843 (0.809-0.887). The nomogram could predict the probability of 3-year disease-free survival according to each patient's condition. The calibration curve displayed good agreement of the predicted probability with the actual observed probability, indicating that the nomogram model had great value of prediction. The external validation indicated the prediction model had good stability.HIF-1α-positive expression, c-myc positive expression, histological grade III, lymph node positive, and TNM stage III tumors suggested that TNBC patients had a poor prognosis. This prediction model can be used to predict postoperative survival of TNBC.


Assuntos
Genes myc/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Fatores Etários , Biomarcadores Tumorais , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Neoplasias de Mama Triplo Negativas/cirurgia , Carga Tumoral
16.
Hepatobiliary Pancreat Dis Int ; 18(5): 452-457, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31474444

RESUMO

BACKGROUND: Survival of patients with breast cancer liver metastasis is very poor. This study aimed to analyze the survival outcome of hepatectomy for this patient population. METHODS: From January 1995 to December 2014, 2522 patients with liver cancer received hepatectomy at our hospital. Twenty-one of them, all female, received the operation for breast cancer liver metastasis. Performance was compared with patients with colorectal liver metastasis treated with hepatectomy after propensity score analysis in a ratio of 1:3. RESULTS: Twenty-one patients received hepatectomy for breast cancer. After propensity score matching, 63 patients who had hepatectomy for colorectal cancer were selected for comparison. There was no significant difference in immediate or short-term outcomes between the two groups of patients in terms of operative time, blood loss and surgical morbidities. All patients with breast cancer had R0 resection. No hospital death occurred. After hepatectomy, the 1-, 3- and 5-year overall survival rates were 100.0%, 58.9% and 58.9% respectively in patients with breast cancer. The 1-, 3- and 5-year overall survival rates were 95.0%, 57.2% and 39.7% respectively in patients with colorectal cancer (P = 0.572). On multivariate analysis, triple negative status was the only independent poor prognostic factor in breast cancer liver metastasis (OR = 6.411; 95% CI: 1.351-30.435; P = 0.019). CONCLUSIONS: Hepatectomy is a safe and effective way of treating breast cancer liver metastasis at experienced centers where multidisciplinary adjuvant treatments are available. It can be considered more frequently as part of the multidisciplinary care for this patient population.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , China/etnologia , Neoplasias Colorretais/mortalidade , Feminino , Hepatectomia , Hong Kong/epidemiologia , Humanos , Neoplasias Hepáticas/secundário , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/mortalidade
17.
PLoS One ; 14(9): e0222358, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31536530

RESUMO

PURPOSE: Triple negative breast cancer (TNBC) patients frequently receive neoadjuvant chemotherapy (NAC). Only 50% will achieve pathological complete response (pCR). In this retrospective study, we evaluated TNBC outcomes with NAC vs. AC. METHODS: Patients with stages II and III TNBC treated with NAC or AC between 2010 and 2013 were identified from the National Cancer Database. Baseline characteristics were compared with χ2 and two sample t tests. Kaplan-Meier survival analyses were computed in patients treated with NAC or AC, and log-rank tests used to examine differences. Unadjusted analyses of trends in proportions over time were performed using Cochran-Armitage tests. Log-binomial models were applied to estimate relative risks of non-pCR following NAC. RESULTS: Of 19,151 patients, 5,621 (29.4%) received NAC, 13,530 (70.6%) received AC. NAC treated patients had worse OS compared to AC treated patients (73.4% vs. 76.8%; p<0.0001). pCR rate following NAC was 47.4%, and was associated with improved 5 year OS compared to non-pCR (86.2% vs. 62.3%; p<0.0001). In patients who received NAC, age, black race, clinical stage, diagnosis year, and Charlson-Deyo comorbidity score predicted non-pCR status. Use of NAC increased over the study period from 2010 to 2013 (27.8% - 31.2%; p = 0.0002). CONCLUSIONS: NAC may be inferior to AC in TNBC, likely related to the high frequency of non-pCR following NAC. It is unclear if removing the primary tumor prior to chemotherapy will have a beneficial biologic impact on therapeutic efficacy. These data should be considered hypothesis-generating as it is possible that the findings are due to selection bias, as physicians may use NAC for TNBC patients with more advanced local disease. Although, NAC still has a role in TNBC, developing biomarkers to identify patients likely to achieve pCR and benefit from NAC is an urgent need.


Assuntos
Quimioterapia Adjuvante , Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/mortalidade , Adulto Jovem
18.
Breast Cancer Res Treat ; 178(2): 283-294, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31402409

RESUMO

PURPOSE: High-density tumor-infiltrating lymphocytes (TILs) are a prognostic marker for triple-negative breast cancer (TNBC). However, lymphocytic infiltration is heterogeneous in its pattern. We aimed to explore the utility of TIL distribution patterns against TIL density for predicting TNBC prognosis and chemotherapeutic effects. METHODS: Primary invasive TNBC cases were retrieved from a single institutional cohort, and archived samples were reviewed by two board-certificated pathologists. We used 154 consecutive surgical specimens from patients with standard adjuvant therapy, and 80 biopsies taken before primary systemic chemotherapy. The average density of stromal TILs was scored at 10% intervals, while the distribution pattern of TILs was evaluated as diffuse or non-diffuse. The association between TILs and prognosis or pathological complete response (pCR) was statistically analyzed. RESULTS: A diffuse pattern of TILs at primary surgery correlated with better prognosis (relapse-free survival [RFS], hazard ratio [HR] 3.71, 95% confidence interval [CI] 1.60-8.57; overall survival [OS], HR 3.87, 95% CI 1.46-10.27), as well as high TIL density (≥ 50%; RFS, HR 4.51, 95% CI 2.06-9.90; OS, HR 3.28, 95% CI 1.32-8.14). Diffuse TIL pattern and nodal status were independent prognostic factors in multivariate analysis. Diffuse TIL pattern upon biopsy was associated with higher pCR rate (diffuse, 46%; non-diffuse, 21%; P = 0.032). All high TIL cases had diffuse patterns and the best outcome. Interobserver concordance was moderate (k = 0.53-0.55; distribution pattern) to good (weighted k = 0.67-0.69; density), and it was faster to assess the distribution pattern than to assess the density of TIL. CONCLUSIONS: Showing similar clinical impacts to the TIL density, diffuse TILs could be a predictive marker for better prognosis and higher pCR. The assessment of TIL distribution pattern is simple, faster, and practical. Heterogeneous tumor immunity may contribute to further stratification of TNBC treatment.


Assuntos
Biomarcadores Tumorais , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/mortalidade , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Pessoa de Meia-Idade , Terapia Neoadjuvante , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
19.
EBioMedicine ; 47: 163-169, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31416721

RESUMO

BACKGROUND: Utilizing the linear quadratic model and the radiosensitivity index (RSI), we have derived an expression for the genomically adjusted radiation dose (GARD) to model radiation dose effect. We hypothesize GARD is associated with local recurrence and can be used to optimize individual triple negative breast cancer (TNBC) radiation dose. METHODS: TN patients from two independent datasets were assessed. The first cohort consisted of 58 patients treated at 5 European centers with breast conservation surgery followed by adjuvant radiotherapy (RT). The second dataset consisted of 55 patients treated with adjuvant radiation therapy. FINDINGS: In cohort 1, multivariable analysis revealed that as a dichotomous variable (HR: 2.5 95% CI 1-7.1; p = .05), GARD was associated with local control. This was confirmed in the second independent dataset where GARD was the only significant factor associated with local control (HR: 4.4 95% CI 1.1-29.5; p = .04). We utilized GARD to calculate an individualized radiation dose for each TN patient in cohort 2 by determining the physical dose required to achieve the GARD target value (GARD ≥ 21). While 7% of patients were optimized with a dose of 30 Gy, 91% of patients would be optimized with 70 Gy. INTERPRETATION: GARD is associated with local control following whole breast or post-mastectomy radiotherapy (RT) in TN patients. By modeling RT dose effect with GARD, we demonstrate that no single dose is optimal for all patients and propose the first dose range to optimize RT at an individual patient level in TNBC.


Assuntos
Doses de Radiação , Tolerância a Radiação/genética , Radioterapia Adjuvante , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Idoso , Biomarcadores Tumorais , Estudos de Coortes , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Radioterapia Adjuvante/métodos , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/mortalidade
20.
Breast Cancer Res Treat ; 178(2): 317-325, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31432366

RESUMO

PURPOSE: Disseminated tumor cells (DTCs) in the BM of breast cancer patients predict early disease relapse, but the molecular heterogeneity of these cells is less well characterized. Expression of a 46-gene panel was used to detect DTCs and classify patient BM samples to determine whether a composite set of biomarkers could better predict metastatic relapse. METHODS: Using a high-throughput qRT-PCR assay platform, BM specimens collected from 70 breast cancer patients prior to neoadjuvant therapy were analyzed for the expression of 46 gene transcripts. Gene expression was scored positive (detectable) relative to a reference pool of 16 healthy female control BM specimens. To validate findings from a subset of 28 triple-negative breast cancer (TNBC) patients in the initial 70 patient cohort, an independent set of pre-therapeutic BM specimens from 16 TNBC patients was analyzed. RESULTS: Expression of each of the 46 gene transcripts was highly variable between patients. Individual gene expression was detected in 0-84% of BM specimens analyzed and all but two patient BM specimens expressed at least one transcript. Among a subset of 28 patients with TNBC, positivity of one or more of eight transcripts correlated with time to distant relapse (p = 0.03). In an independent set of 16 triple-negative patient BM samples, detection of five of these same eight gene transcripts also correlated with time to distant relapse (p = 0.03) with a positive predictive value of 89%. CONCLUSIONS: We identified a set of gene transcripts whose detection in the BM of TNBC patients, prior to any treatment intervention, predicts time to first distant relapse, thus identifying a TNBC patient population which requires additional treatment intervention. Because these genes are presumably expressed in populations of DTCs and many encode proteins that are known therapeutic targets (e.g., ERBB2), these results also suggest a potential approach for targeted DTC therapy to mitigate distant metastases in TNBC.


Assuntos
Biomarcadores Tumorais , Medula Óssea/metabolismo , Medula Óssea/patologia , Transcriptoma , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Células Neoplásicas Circulantes , Prognóstico , Neoplasias de Mama Triplo Negativas/mortalidade , Carga Tumoral
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