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1.
J Photochem Photobiol B ; 222: 112280, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34375907

RESUMO

Confocal Raman microspectral imaging (CRMI) has been used to detect the spectra-pathological features of ductal carcinoma in situ (DCIS) and lobular hyperplasia (LH) compared with the heathy (H) breast tissue. A total of 15-20 spectra were measured from healthy tissue, LH tissue, and DCIS tissue. One-way ANOVA and Tukey's honest significant difference (HSD) post hoc multiple tests were used to evaluate the peak intensity variations in all three tissue types. Besides that, linear discrimination analysis (LDA) algorithm was adopted in combination with principal component analysis (PCA) to classify the spectral features from tissues at different stages along the continuum to breast cancer. Moreover, by using the point-by-point scanning methodology, spectral datasets were obtained and reconstructed for further pathologic visualization by multivariate imaging methods, including K-mean clustering analysis (KCA) and PCA. Univariate imaging of individual Raman bands was also used to describe the differences in the distribution of specific molecular components in the scanning area. After a detailed spectral feature analysis from 800 to 1800 cm-1 and 2800 to 3000 cm-1 for all the three tissue types, the histopathological features were visualized based on the content and structural variations of lipids, proteins, phenylalanine, carotenoids and collagen, as well as the calcification phenomena. The results obtained not only allowed a detailed Raman spectroscopy-based understanding of the malignant transformation process of breast cancer, but also provided a solid spectral data support for developing Raman based breast cancer clinical diagnostic techniques.


Assuntos
Neoplasias da Mama/patologia , Microscopia Confocal/métodos , Análise Espectral Raman , Neoplasias da Mama/química , Neoplasias da Mama/metabolismo , Análise por Conglomerados , Análise Discriminante , Progressão da Doença , Feminino , Humanos , Análise de Componente Principal
2.
Biochem Biophys Res Commun ; 559: 129-134, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-33940383

RESUMO

Tumor brain metastasis is a severe threat to patients' neurological function, in which microglia may be involved in the process of tumor cell metastasis among nerve cells. Our study focused on the interaction between microglia and breast and lung cancer cells. Changes in the proliferation and migration ability of cocultured tumor cells were examined; synchrotron radiation-based fourier transform infrared microspectroscopy (SR-FTIR) was used to detect changes in the structures and contents of biomolecules within the tumor cells. The experimental results showed that the proliferation and migration ability of tumor cells increased after coculture, and the structures and contents of biological macromolecules in tumor cells changed. The absorption peak positions of the amide Ⅱ and amide Ⅰ bands observed for the four kinds of tumor cells changed, and the absorption intensities were significantly enhanced, indicating changes in the secondary structures and contents of proteins in tumor cells, which may be the root cause of the change in tumor cell characteristics. Therefore, the metabolites of microglia may be involved in the progression of tumor cells in the nervous system. In this study, we focused on the interaction between microglia and tumor cells by using SR-FTIR and provided a new understanding of the mechanism of brain metastasis.


Assuntos
Neoplasias da Mama/patologia , Neoplasias Pulmonares/patologia , Microglia/patologia , Células A549 , Neoplasias da Mama/química , Linhagem Celular , Movimento Celular , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/química , Células MCF-7 , Microglia/química , Estrutura Secundária de Proteína , Espectroscopia de Infravermelho com Transformada de Fourier
3.
Ultrasound Med Biol ; 47(8): 2193-2201, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33994231

RESUMO

This purpose of this study is to correlate a new shear-wave elastography (SWE) parameter, mass characteristic frequency (fmass) and other elasticity measure with the prognostic histological factors and immunohistochemical (IHC) biomarkers for the evaluation of heterogeneous breast carcinomas. The new parameter, fmass, first introduced in this paper, is defined as the ratio of the averaged minimum shear wave speed taken spatially within regions of interest to the largest mass dimension. 264 biopsy-proven breast cancerous masses were included in this study. Mean (Emean), maximum (Emax), minimum (Emin) shear wave elasticity and standard deviation (Esd) of shear wave elasticity were found significantly correlated with tumor size, axillary lymph node (ALN) status, histological subtypes and IHC subtypes. The areas under the curve for the ALN prediction are 0.73 (95% confidence interval [CI]: 0.67-0.80) and 0.75 (95% CI: 0.69-0.81) for the combination of Emean with Breast Imaging Reporting and Data System (BI-RADS) score and Emax with BI-RADS score, respectively. fmass was significantly correlated with the presence of calcifications, ALN status, histological grade, the expressions of IHC biomarkers and IHC subtypes. To conclude, poor prognostic factors were associated with high shear wave elasticity values and low mass characteristic frequency value. Therefore, SWE provides valuable information that may help with prediction of breast cancer invasiveness.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Técnicas de Imagem por Elasticidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Correlação de Dados , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Ultrassonografia Mamária
4.
BMC Cancer ; 21(1): 487, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933027

RESUMO

BACKGROUND: Socioeconomic differences in receipt of adjuvant treatment contribute to persistent disparities in breast cancer (BCA) outcomes, including survival. Adjuvant endocrine therapy (AET) substantially reduces recurrence risk and is recommended by clinical guidelines for nearly all women with hormone receptor-positive non-metastatic BCA. However, AET use among uninsured or underinsured populations has been understudied. The health reform implemented by the US state of Massachusetts in 2006 expanded health insurance coverage and increased the scope of benefits for many with coverage. This study examines changes in the initiation of AET among BCA patients in Massachusetts after the health reform. METHODS: We used Massachusetts Cancer Registry data from 2004 to 2013 for a sample of estrogen receptor (ER)-positive BCA surgical patients aged 20-64 years. We estimated multivariable regression models to assess differential changes in the likelihood initiating AET after Massachusetts health reform by area-level income, comparing women from lower- and higher-income ZIP codes in Massachusetts. RESULTS: There was a 5-percentage point (p-value< 0.001) relative increase in the likelihood of initiating AET among BCA patients aged 20-64 years in low-income areas, compared to higher-income areas, after the reform. The increase was more pronounced among younger patients aged 20-49 years (7.1-percentage point increase). CONCLUSIONS: The expansion of health insurance in Massachusetts was associated with a significant relative increase in the likelihood of AET initiation among women in low-income areas compared with those in high-income areas. Our results suggest that expansions of health insurance coverage and improved access to care can increase the number of eligible patients initiating AET and may ameliorate socioeconomic disparities in BCA outcomes.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Reforma dos Serviços de Saúde , Fatores Socioeconômicos , Adulto , Fatores Etários , Neoplasias da Mama/química , Feminino , Humanos , Renda , Cobertura do Seguro , Funções Verossimilhança , Massachusetts , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Receptores de Estrogênio , Análise de Regressão , Adulto Jovem
5.
Cochrane Database Syst Rev ; 5: CD011220, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34037241

RESUMO

BACKGROUND: Retrospective analyses suggest that capecitabine may carry superior activity in hormone receptor-positive relative to hormone receptor-negative metastatic breast cancer. This review examined the veracity of that finding and explored whether this differential activity extends to early breast cancer. OBJECTIVES: To assess effects of chemotherapy regimens containing capecitabine compared with regimens not containing capecitabine for women with hormone receptor-positive versus hormone receptor-negative breast cancer across the three major treatment scenarios: neoadjuvant, adjuvant, metastatic. SEARCH METHODS: On 4 June 2019, we searched the Cochrane Breast Cancer Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 5) in the Cochrane Library; MEDLINE; Embase; the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials looking at chemotherapy regimens containing capecitabine alone or in combination with other agents versus a control or similar regimen without capecitabine for treatment of breast cancer at any stage. The primary outcome measure for metastatic and adjuvant trials was overall survival (OS), and for neoadjuvant studies pathological complete response (pCR). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. Hazard ratios (HRs) were derived for time-to-event outcomes, and odds ratios (ORs) for dichotomous outcomes, and meta-analysis was performed using a fixed-effect model. MAIN RESULTS: We included 26 studies with outcome data by hormone receptor: 12 metastatic studies (n = 4325), 6 neoadjuvant trials (n = 3152), and 8 adjuvant studies (n = 13,457). Capecitabine treatment was added in several different ways across studies. These could be classified as capecitabine alone compared to another treatment, capecitabine substituted for part of the control chemotherapy, and capecitabine added to control chemotherapy. In the metastatic setting, the effect of capecitabine was heterogenous between hormone receptor-positive and -negative tumours. For OS, no difference between capecitabine-containing and non-capecitabine-containing regimens was observed for all participants taken together (HR 1.01, 95% confidence interval (CI) 0.98 to 1.05; 12 studies, 4325 participants; high-certainty evidence), for those with hormone receptor-positive disease (HR 0.93, 95% CI 0.84 to 1.04; 7 studies, 1834 participants; high-certainty evidence), and for those with hormone receptor-negative disease (HR 1.00, 95% CI 0.88 to 1.13; 8 studies, 1577 participants; high-certainty evidence). For progression-free survival (PFS), a small improvement was seen for all people (HR 0.89, 95% CI 0.82 to 0.96; 12 studies, 4325 participants; moderate-certainty evidence). This was largely accounted for by a moderate improvement in PFS for inclusion of capecitabine in hormone receptor-positive cancers (HR 0.82, 95% CI 0.73 to 0.91; 7 studies, 1594 participants; moderate-certainty evidence) compared to no difference in PFS for hormone receptor-negative cancers (HR 0.96, 95% CI 0.83 to 1.10; 7 studies, 1122 participants; moderate-certainty evidence). Quality of life was assessed in five studies; in general there did not seem to be differences in global health scores between the two treatment groups at around two years' follow-up. Neoadjuvant studies were highly variable in design, having been undertaken to test various experimental regimens using pathological complete response (pCR) as a surrogate for disease-free survival (DFS) and OS. Across all patients, capecitabine-containing regimens resulted in little difference in pCR in comparison to non-capecitabine-containing regimens (odds ratio (OR) 1.12, 95% CI 0.94 to 1.33; 6 studies, 3152 participants; high-certainty evidence). By subtype, no difference in pCR was observed for either hormone receptor-positive (OR 1.22, 95% CI 0.76 to 1.95; 4 studies, 964 participants; moderate-certainty evidence) or hormone receptor-negative tumours (OR 1.28, 95% CI 0.61 to 2.66; 4 studies, 646 participants; moderate-certainty evidence). Four studies with 2460 people reported longer-term outcomes: these investigators detected no difference in either DFS (HR 1.02, 95% CI 0.86 to 1.21; high-certainty evidence) or OS (HR 0.97, 95% CI 0.77 to 1.23; high-certainty evidence). In the adjuvant setting, a modest improvement in OS was observed across all participants (HR 0.89, 95% CI 0.81 to 0.98; 8 studies, 13,547 participants; moderate-certainty evidence), and no difference in OS was seen in hormone receptor-positive cancers (HR 0.86, 95% CI 0.68 to 1.09; 3 studies, 3683 participants), whereas OS improved in hormone receptor-negative cancers (HR 0.72, 95% CI 0.59 to 0.89; 5 studies, 3432 participants). No difference in DFS or relapse-free survival (RFS) was observed across all participants (HR 0.93, 95% CI 0.86 to 1.01; 8 studies, 13,457 participants; moderate-certainty evidence). As was observed for OS, no difference in DFS/RFS was seen in hormone receptor-positive cancers (HR 1.03, 95% CI 0.91 to 1.17; 5 studies, 5604 participants; moderate-certainty evidence), and improvements in DFS/RFS with inclusion of capecitabine were observed for hormone receptor-negative cancers (HR 0.74, 95% CI 0.64 to 0.86; 7 studies, 3307 participants; moderate-certainty evidence). Adverse effects were reported across all three scenarios. When grade 3 or 4 febrile neutropenia was considered, no difference was seen for capecitabine compared to non-capecitabine regimens in neoadjuvant studies (OR 1.31, 95% CI 0.97 to 1.77; 4 studies, 2890 participants; moderate-certainty evidence), and a marked reduction was seen for capecitabine in adjuvant studies (OR 0.55, 95% CI 0.47 to 0.64; 5 studies, 8086 participants; moderate-certainty evidence). There was an increase in diarrhoea and hand-foot syndrome in neoadjuvant (diarrhoea: OR 1.95, 95% CI 1.32 to 2.89; 3 studies, 2686 participants; hand-foot syndrome: OR 6.77, 95% CI 4.89 to 9.38; 5 studies, 3021 participants; both moderate-certainty evidence) and adjuvant trials (diarrhoea: OR 2.46, 95% CI 2.01 to 3.01; hand-foot syndrome: OR 13.60, 95% CI 10.65 to 17.37; 8 studies, 11,207 participants; moderate-certainty evidence for both outcomes). AUTHORS' CONCLUSIONS: In summary, a moderate PFS benefit by including capecitabine was seen only in hormone receptor-positive cancers in metastatic studies. No benefit of capecitabine for pCR was noted overall or in hormone receptor subgroups when included in neoadjuvant therapy. In contrast, the addition of capecitabine in the adjuvant setting led to improved outcomes for OS and DFS in hormone receptor-negative cancer. Future studies should stratify by hormone receptor and triple-negative breast cancer (TNBC) status to clarify the differential effects of capecitabine in these subgroups across all treatment scenarios, to optimally guide capecitabine inclusion.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Capecitabina/uso terapêutico , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Viés , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Capecitabina/efeitos adversos , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Terapia Neoadjuvante , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
6.
Cochrane Database Syst Rev ; 4: CD011395, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33886122

RESUMO

BACKGROUND: Locally advanced and metastatic breast cancer remains a challenge to treat. With emerging study results, it is important to interpret the available clinical data and apply the evidence offering the most effective treatment to the right patient. Poly(ADP Ribose) Polymerase (PARP) inhibitors are a new class of drug and their role in the treatment of locally advanced and metastatic breast cancer is being established. OBJECTIVES: To determine the efficacy, safety profile, and potential harms of Poly(ADP-Ribose) Polymerase (PARP) inhibitors in the treatment of patients with locally advanced or metastatic breast cancer. The primary outcome of interest was overall survival; secondary outcomes included progression-free survival, tumour response rate, quality of life, and adverse events. SEARCH METHODS: On 8 June 2020, we searched the Cochrane Breast Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via OvidSP, Embase via OvidSP, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) search portal and ClinicalTrials.gov. We also searched proceedings from the major oncology conferences as well as scanned reference lists from eligible publications and contacted corresponding authors of trials for further information, where needed. SELECTION CRITERIA: We included randomised controlled trials on participants with locally advanced or metastatic breast cancer comparing 1) chemotherapy in combination with PARP inhibitors, compared to the same chemotherapy without PARP inhibitors or 2) treatment with PARP inhibitors, compared to treatment with other chemotherapy. We included studies that reported on our primary outcome of overall survival and secondary outcomes including progression-free survival, tumour response rate, quality of life, and adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity. MAIN RESULTS: We identified 49 articles for qualitative synthesis, describing five randomised controlled trials that were included in the quantitative synthesis (meta-analysis). A sixth trial was assessed as eligible but had ended prematurely and no data were available for inclusion in our meta-analysis. Risk of bias was predominately low to unclear across all studies except in regards to performance bias (3/5 high risk) and detection bias for the outcomes of quality of life (2/2 high risk) and reporting of adverse events (3/5 high risk). High-certainty evidence shows there may be a small advantage in overall survival (HR 0.87, 95% CI 0.76 to 1.00; 4 studies; 1435 patients). High-certainty evidence shows that PARP inhibitors offer an improvement in PFS in locally advanced/metastatic HER2-negative, BRCA germline mutated breast cancer patients (HR 0.63, 95% CI 0.56 to 0.71; 5 studies; 1474 patients). There was no statistical heterogeneity for these outcomes. Subgroup analyses for PFS outcomes based on trial level data were performed for triple-negative breast cancer, hormone-positive and/or HER2-positive breast cancer, BRCA1 and BRCA2 germline mutations, and patients who had received prior chemotherapy for advanced breast cancer or not. The subgroup analyses showed a persistent PFS benefit regardless of the subgroup chosen. Pooled analysis shows PARP inhibitors likely result in a moderate improvement in tumour response rate compared to other treatment arms (66.9% vs 48.9%; RR 1.39, 95% CI 1.24 to 1.54; 5 studies; 1185 participants; moderate-certainty evidence). The most common adverse events reported across all five studies included neutropenia, anaemia and fatigue. Grade 3 or higher adverse events probably occur no less frequently in patients receiving PARP inhibitors (59.4% for PARP arm versus 64.5% for non-PARP arm, RR 0.98, 95% CI 0.91 to 1.04; 5 studies; 1443 participants; moderate-certainty evidence). Only two studies reported quality of life outcomes so this was not amenable to meta-analysis. However, both studies that did assess quality of life showed PARP inhibitors were superior compared to physician's choice of chemotherapy in terms of participant-reported outcomes. AUTHORS' CONCLUSIONS: In people with locally advanced or metastatic HER2-negative, BRCA germline mutated breast cancer, PARP inhibitors offer an improvement in progression-free survival, and likely improve overall survival and tumour response rates. This systematic review provides evidence supporting the use of PARP inhibitors as part of the therapeutic strategy for breast cancer patients in this subgroup. The toxicity profile for PARP inhibitors is probably no worse than chemotherapy but more information is required regarding quality of life outcomes, highlighting the importance of collecting such data in future studies. Future studies should also be powered to detect clinically important differences in overall survival and could focus on the role of PARP inhibitors in other relevant breast cancer populations, including HER2-positive, BRCA-negative/homologous recombination repair-deficient and Programmed Death-Ligand 1 (PDL1) positive.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Viés , Neoplasias da Mama/química , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
7.
BMC Cancer ; 21(1): 463, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33902516

RESUMO

BACKGROUND: Over than one third (28-58%) of pregnancy-associated breast cancer (PABC) cases are characterized by positive epidermal growth factor receptor 2-positive (HER2) expression. Trastuzumab anti-HER2 monoclonal antibody is still the benchmark treatment of HER2-positive breast tumors. However, FDA has categorized Trastuzumab as a category D drug for pregnant patients with breast cancer. This systemic review aims to synthesize all currently available data of trastuzumab administration during pregnancy and provide an updated view of the effect of trastuzumab on fetal and maternal outcome. METHODS: Eligible articles were identified by a search of MEDLINE bibliographic database and ClinicalTrials.gov for the period up to 01/09/2020; The algorithm consisted of a predefined combination of the words "breast", "cancer", "trastuzumab" and "pregnancy". This study was performed in accordance with the PRISMA guidelines. RESULTS: A total of 28 eligible studies were identified (30 patients, 32 fetuses). In more than half of cases, trastuzumab was administered in the metastatic setting. The mean duration of trastuzumab administration during gestation was 15.7 weeks (SD: 10.8; median: 17.5; range: 1-32). Oligohydramnios or anhydramnios was the most common (58.1%) adverse event reported in all cases. There was a statistically significant decrease in oligohydramnios/anhydramnios incidence in patients receiving trastuzumab only during the first trimester (P = 0.026, Fisher's exact test). In 43.3% of cases a completely healthy neonate was born. 41.7% of fetuses exposed to trastuzumab during the second and/or third trimester were born completely healthy versus 75.0% of fetuses exposed exclusively in the first trimester. All mothers were alive at a median follow-up of 47.0 months (ranging between 9 and 100 months). Of note, there were three cases (10%) of cardiotoxicity and decreased ejection fraction during pregnancy. CONCLUSIONS: Overall, treatment with trastuzumab should be postponed until after delivery, otherwise pregnancy should be closely monitored.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Trastuzumab/administração & dosagem , Adulto , Líquido Amniótico/efeitos dos fármacos , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/química , Cardiotoxicidade/etiologia , Feminino , Feto/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Oligo-Hidrâmnio/induzido quimicamente , Oligo-Hidrâmnio/epidemiologia , Gravidez , Trimestres da Gravidez , Receptor ErbB-2 , Fatores de Tempo , Trastuzumab/efeitos adversos , Trastuzumab/farmacologia , Adulto Jovem
8.
BMC Cancer ; 21(1): 473, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33910530

RESUMO

INTRODUCTION: Disruption of cellular processes in the breast by abnormally expressed miRNA is characterized to develop cancer. We aimed to identify the differential expression of small RNAs (sRNAs) and mRNAs in formalin-fixed paraffin-embedded (FFPE) tissue of the breast cancer (BC) and normal adjacent tissue (NAT). Another aim is to determine the differential expression of miR-1275 as a novel biomarker for BC and also identify its target genes. METHODS: TrueQuant method for analysis of sRNA expression and MACE-sequencing method for analysis of gene expression were used analyzing. The RT-qPCR technique was used to confirm miR-1275 down expression. Target genes of miR-1275 were computationally identified using target prediction sites and also the expression level of them was experimentally determined among the expressed genes. RESULTS: TrueQuant findings showed that 1400 sRNAs were differentially expressed in the FFPE tissue of two Kurdish cases with BC, as compared to NAT. Among the sRNAs, 29 small RNAs were shown to be significantly downregulated in BC cells. The RT-qPCR results confirmed that miR-1275 was significantly down-expressed in 20 Kurdish cases with BC compared to NAT. However, Overall survival (OS) analysis revealed that the correlation between the expression level of miR-1275 and clinical significance was highly corrected in cases with BC (OS rate: P = 0.0401). The MACE-seq results revealed that 26,843 genes were differentially expressed in the BC tissue compared to NAT, but 7041 genes were displayed in a scatter plot. Furthermore, putative target genes (DVL3, PPP2R2D, THSD4, CREB1, SYT7, and PRKACA) were computationally identified as direct targets of miR-1275 in several target predicted sites. The MACE-seq results revealed that the expression level of these targets was increased in BC tissue compared to NAT. The level of these targets was negatively associated with miR-1275 expression. Finally, the role of down-regulated miR-1275 on its targets in biological mechanisms of BC cells was identified; including cell growth, proliferation, movement, invasion, metastasis, and apoptosis. CONCLUSION: Down-expressed miR-1275, a tumor suppressor, is a novel biomarker for early detection of BC. DVL3, PPP2R2D, THSD4, CREB1, SYT7, and PRKACA are newly identified to be targeted by miR-1275.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/química , MicroRNAs/análise , RNA Neoplásico/análise , Proteínas ADAM/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Mama/química , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Proteínas Desgrenhadas/genética , Regulação para Baixo , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Biblioteca Gênica , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , Proteína Fosfatase 2/genética , RNA Neoplásico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de RNA/métodos , Sinaptotagminas/genética , Proteínas Supressoras de Tumor/análise , Proteínas Supressoras de Tumor/genética , Turquia , Adulto Jovem
9.
BMC Cancer ; 21(1): 476, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33926418

RESUMO

BACKGROUND: The initial therapeutic strategy for hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer is based on the first metastatic site; however, little evidence is available regarding the influence of metastatic distribution patterns of first metastatic sites on prognosis. In this study, we aimed to identify the metastatic distribution patterns of first metastatic sites that significantly correlate with survival after recurrence. METHODS: We performed a retrospective review of records from 271 patients with recurrent metastatic HR+/HER2- breast cancer diagnosed between January 2000 and December 2015. We assessed survival after recurrence according to the metastatic distribution patterns of the first metastatic sites and identified significant prognostic factors among patients with single and multiple metastases. RESULTS: Prognosis was significantly better in patients with a single metastasis than in those with multiple metastases (median overall survival after recurrence: 5.86 years vs. 2.50 years, respectively, p < 0.001). No metastatic organ site with single metastasis was significantly associated with prognostic outcome, although single metastasis with diffuse lesions was an independent risk factor for worse prognosis (HR: 3.641; 95% CI: 1.856-7.141) and more easily progressing to multiple metastases (p = 0.002). Multiple metastases, including liver metastasis (HR: 3.145; 95% CI: 1.802-5.495) or brain metastasis (HR: 3.289; 95% CI: 1.355-7.937), were regarded as significant independent poor prognostic factors; however, multiple metastases not involving liver or brain metastasis were not significantly related to prognosis after recurrence. CONCLUSIONS: Single metastases with diffuse lesions could more easily disseminate systemically and progress to multiple metastases, leading to a poor prognosis similar to multiple metastases. Our findings indicate that the reconsideration of the determinant factors of therapeutic strategies for first recurrence in HR+/HER2- breast cancer may be needed.


Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Recidiva Local de Neoplasia/mortalidade , Receptores de Estrogênio , Receptores de Progesterona , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Neoplasias da Mama/química , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Metástase Linfática , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/química , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/secundário , Prognóstico , Receptor ErbB-2 , Estudos Retrospectivos
10.
Bull Cancer ; 108(5): 544-552, 2021 May.
Artigo em Francês | MEDLINE | ID: mdl-33820647

RESUMO

INTRODUCTION: The addition of palbociclib to endocrine therapy has been shown to improve progression free survival in hormone receptor positive metastatic breast cancer patients. This cyclin CDK4/6 inhibitor could expose patients to a grade 3-4 hematological toxicity, leading to treatment discontinuation or treatment interruption that is potentially associated with a lack of efficiency. The aim of this study was to identify predictive factors of severe early hematotoxicity (ESHT). METHODS: This retrospective cohort study included patients who started palbociclib in the Institut Sainte Catherine between December 1, 2016 and January 1, 2019 for the treatment of metastatic breast cancer. Individual data and hematological toxicity were collected from electronic medical records. ESHT was defined as the occurrence, during the first 3 cycles, of grade 4 or grade 3 hematological toxicity requiring palbociclib dose reduction. RESULTS: In total, 181 patients (180 females) were included; median age was 67 years. Forty-six patients (25.4%) experienced an ESHT. Predictive factors of ESHT in multivariate analysis were a performance status (PS) of 2 or more (P=0.024) and an history of radiotherapy of bone metastasis in the previous year (P=0.003). Before palbociclib initiation, a neutrophil count below 3.37g/L was predictive of ESHT with a sensibility of 76% and a specificity of 71%. CONCLUSIONS: ECOG PS, bone radiotherapy within the year and low baseline neutrophils count are associated with ESHT in palbociclib-treated metastatic breast cancer patients. These elements could be useful for a careful monitoring leading to adapted therapy.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Piperazinas/efeitos adversos , Piridinas/efeitos adversos , Trombocitopenia/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Fulvestranto/efeitos adversos , Fulvestranto/uso terapêutico , Humanos , Letrozol/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neutropenia/induzido quimicamente , Piperazinas/uso terapêutico , Intervalo Livre de Progressão , Piridinas/uso terapêutico , Estudos Retrospectivos
11.
Clin Exp Metastasis ; 38(2): 175-185, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33655422

RESUMO

No reliable, non-invasive biomarker of metastatic breast cancer (mBC) exists: circulating CA15-3 (cCA15-3) is the marker mostly used to monitor mBC. Circulating collagen IV (cCOLIV) has been evaluated in other metastatic cancers and has been found to be a promising biomarker. The overarching aim of this study was to evaluate cCOLIV as a potential biomarker in patients with mBC. The first aim was to determine the levels of cCOL IV and cCA15-3 in patients with healthy controls, primary breast cancer (pBC) and mBC. The second aim was to compare levels of cCOLIV and cCA15-3 in patients with different metastatic sites of BC. The third aim was to investigate the prognostic value of cCOLIV and cCA15-3 for mBC patients. The fourth aim was to analyse whether a combination of the two biomarkers was more accurate in detecting mBC than a single marker. Lastly, we investigated the tissue expression levels of COLIV in BC bone metastases (BM) and liver metastases (LM). Plasma levels of cCOLIV and cCA15-3 from healthy controls and patients with pBC and mBC were measured. COLIV expression in tissue from patients with LM and BM was analysed using immunohistochemistry. Clinical and survival data were collected from medical charts. The levels of cCOLIV and cCA15-3 were significantly elevated in mBC patients compared with healthy controls and pBC patients. No differences in cCOLIV and cCA15-3 levels were found based on the metastatic site. High levels of cCOLIV, but not cCA15-3, correlated with poorer survival. cCOLIV alone and the combination of cCA15-3 and cCOLIV were superior to cCA15-3 at detecting mBC. COL IV was highly expressed in the tissue of LM and BM. Our study suggests that cCOLIV is a potential marker to monitor patients with BC.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Colágeno Tipo IV/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mucina-1/análise
12.
JAMA Netw Open ; 4(3): e211785, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33710293

RESUMO

Importance: Although neoadjuvant endocrine therapy (NET) is an alternative to chemotherapy for strongly hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (ERBB2)-negative breast cancer, evidence is currently lacking regarding the probable survival outcomes of NET in comparison with those of neoadjuvant chemotherapy (NACT) for this cancer. Objective: To evaluate all-cause mortality among patients with strongly HR-positive and ERBB2-negative breast cancer treated with NET vs NACT. Design, Setting, and Participants: This cohort study included patients with a diagnosis of invasive ductal carcinoma (IDC) with strong HR positivity and ERBB2 negativity, treated between January 1, 2009, and December 31, 2016, with follow-up from the index date (ie, date of IDC diagnosis) to December 31, 2018. The data came from the Taiwan Cancer Registry Database. Data were analyzed from January to November 2020. Exposures: NET vs NACT for IDC with strong HR positivity and ERBB2 negativity. Main Outcomes and Measures: The primary end point was all-cause mortality. Propensity score matching was performed, and Cox proportional hazard models were used to analyze all-cause mortality among patients undergoing different neoadjuvant treatments. Results: A total of 640 patients (297 [46.4%] aged 20-49 years) undergoing NET (145 patients [22.7%]) or NACT (495 patients [77.3%]) were eligible for further analysis. In the multivariate Cox regression analyses, the adjusted hazard ratio (aHR) for all-cause mortality among the NET cohort compared with the NACT cohort was 2.67 (95% CI, 1.95-3.51; P < .001). The aHRs for age were 1.13 (95% CI, 1.03-2.24), 1.25 (95% CI, 1.13-2.45), and 1.37 (95% CI, 1.17-3.49) for all-cause mortality among patients aged 50 to 59, 60 to 69, and 70 years or older, respectively, compared with those aged 20 to 49 years (P = .002); the aHR for all-cause mortality among premenopausal women was 1.35 (95% CI, 1.13-1.56) compared with postmenopausal women (P < .001); and that of patients with a Charlson Comorbidity Index score of 2 or greater was 1.77 (1.37-2.26) compared with those with a score of 0 (P < .001). The aHRs of all-cause mortality for clinical tumor stage 2, 3, and 4 compared with 1 were 1.84 (95% CI, 1.07-3.40), 1.97 (95% CI, 1.03-3.77), and 2.49 (95% CI, 1.29-4.81), respectively (P = .009). The aHRs for all-cause mortality by clinical nodal (cN) stages were 1.49 (95% CI, 1.13-1.99) and 1.84 (95% CI, 1.31-2.61) for cN stage 1 and cN stages 2 or 3, respectively, compared with cN stage 0 (P = .005); those for differentiation were 1.77 (95% CI, 1.24-2.54) and 2.31 (95% CI, 1.61-3.34) for differentiation grade 2 and differentiation grade 3, respectively, compared with differentiation grade 1 (P < .001). Conclusions and Relevance: The findings of this study suggest that for patients with strongly HR-positive and ERBB2-negative IDC, NACT may be considered the first choice for neoadjuvant treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Carcinoma Ductal/tratamento farmacológico , Carcinoma Ductal/mortalidade , Adulto , Idoso , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Carcinoma Ductal/química , Carcinoma Ductal/patologia , Causas de Morte , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica , Receptor ErbB-2/análise , Adulto Jovem
13.
BMC Cancer ; 21(1): 303, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33757458

RESUMO

BACKGROUND: The enhanced knowledge of cancer biology has led to considerable advancement in systemic therapy for advanced breast cancer. Recently, studies showed that cyclin-dependent kinase (CDK) 4/6 inhibitor, when added to endocrine therapy, had improved the outcomes of patients with advanced ER-positive HER2-negative breast cancer. However, the disease often progresses following a period of treatment response. In a subset of patients, disease progression may occur at limited sites, i.e., oligoprogressive disease (OPD). In the past few years, stereotactic radiotherapy (SRT) has emerged as a safe and effective treatment for advanced cancer when delivered to limited metastatic sites. Hence, it is worth investigating the role of SRT in the setting of oligoprogressive breast cancer. METHOD: AVATAR is a multicentre phase II registry trial of SRT with endocrine therapy and CDK 4/6 inhibitor for the management of advanced ER-positive HER2-negative breast cancer. The study aims to enrol 32 patients with OPD limited to 5 lesions. The primary endpoint of the study is time to change systemic therapy measured from the commencement of SRT to change in systemic therapy. Secondary objectives include overall survival, progression free survival and treatment related toxicity. The exploratory objective is to describe the time to change in systemic therapy by the site (bone only vs. non-bone lesions) and number (1 vs. > 1) of OPD. DISCUSSION: This study aims to explore the effect of SRT in maximising the benefit of systemic therapy in patients with oligoprogressive ER-positive HER2-negative breast cancer. This approach might help reduce the burden of disease and improve the life quality in these patients. TRIAL REGISTRATION: ACTRN, ACTRN12620001212943 . Date of registration 16 November 2020- Retrospectively registered.


Assuntos
Neoplasias da Mama/radioterapia , Radiocirurgia/métodos , Receptores de Estrogênio/análise , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Feminino , Humanos , Radiocirurgia/efeitos adversos , Receptor ErbB-2/análise
14.
BMC Cancer ; 21(1): 223, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663447

RESUMO

BACKGROUND: Due to recent concerns about the toxicity of trastuzumab emtansine (T-DM1) with stereotactic radiation, we assessed our institutional outcomes treating HER2-positive breast cancer brain metastases (BCBM) with T-DM1 and stereotactic radiation. METHODS: This is a single institution series of 16 patients with HER2-positive breast cancer who underwent 18 stereotactic sessions to 40 BCBM from 2013 to 2019 with T-DM1 delivered within 6 months. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), distant intracranial control (DIC), and systemic progression-free survival (sPFS) from the date of SRS. A neuro-radiologist independently reviewed follow-up imaging. RESULTS: One patient had invasive lobular carcinoma, and 15 patients had invasive ductal carcinoma. All cases were HER2-positive, while 10 were hormone receptor (HR) positive. Twenty-four lesions were treated with stereotactic radiosurgery (SRS) to a median dose of 21 Gy (14-24 Gy). Sixteen lesions were treated with fractionated stereotactic radiation (FSRT) with a median dose of 25 Gy (20-30Gy) delivered in 3 to 5 fractions. Stereotactic radiation was delivered concurrently with T-DM1 in 19 lesions (48%). Median follow up time was 13.2 months from stereotactic radiation. The 1-year LC, DIC, sPFS, and OS were 75, 50, 30, and 67%, respectively. There was 1 case of leptomeningeal progression and 1 case (3%) of symptomatic radionecrosis. CONCLUSIONS: We demonstrate that stereotactic radiation and T-DM1 is well-tolerated and effective for patients with HER2-positive BCBM. An increased risk for symptomatic radiation necrosis was not noted in our series.


Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/terapia , Radiocirurgia , Receptor ErbB-2/análise , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Necrose , Radiocirurgia/efeitos adversos , Dosagem Radioterapêutica
15.
Cancer Chemother Pharmacol ; 87(5): 673-679, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33585999

RESUMO

PURPOSE: Preclinical studies support the JAK2-STAT3 signaling pathway as a key driver in CD44+ CD24- "stem-cell-like" breast cancer cells. Ruxolitinib is an orally bioavailable JAK1/2 inhibitor. We aimed to identify the recommended phase 2 dose (RP2D) of ruxolitinib in combination with paclitaxel in patients with HER2-negative metastatic breast cancer (MBC). METHODS: Eligible patients had HER2-negative MBC and had received ≤ 3 chemotherapy regimens for advanced disease. Patients received oral ruxolitinib (10-25 mg bid) in a 3 + 3 dose escalation design in combination with weekly paclitaxel 80 mg/m2 in a 3-week cycle. The primary objective was to determine the maximum tolerated dose (MTD) and the RP2D. RESULTS: Nineteen patients received protocol therapy (mean age 52 years). Eight (42%) had triple-negative breast cancer and 11 (58%) had hormone receptor-positive disease; 12 (63%) had visceral disease. Ten (53%) patients had not received prior treatment for advanced disease. Patients received a median number of 5 cycles of combination therapy (range 1-12) and five patients continued single-agent ruxolitinib. The MTD of ruxolitinib was 25 mg bid when combined with paclitaxel, and the RP2D for the combination was 15 mg bid. Thirteen (68%) patients required dose reductions or holds. Most frequent toxicities reported of any grade were neutropenia (50%) and anemia (33%). There were no grade 4/5 toxicities attributed to study drug. Four (21%) patients had PR, 12 (63%) had SD and three (16%) had PD as their best response. CONCLUSION: The combination of ruxolitinib and weekly paclitaxel was well tolerated with evidence of clinical activity. Further analysis of this combination is ongoing (NCT02041429). TRIAL REGISTRATION: NCT02041429. Date of registration: January 22, 2014.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Inibidores de Janus Quinases/administração & dosagem , Paclitaxel/administração & dosagem , Pirazóis/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Paclitaxel/efeitos adversos , Pirazóis/efeitos adversos , Receptor ErbB-2/análise
16.
Cancer Med ; 10(6): 1955-1963, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33620160

RESUMO

PURPOSE: To date there has not been an extensive analysis of the outcomes of biomarker use in oncology. METHODS: Data were pooled across four indications in oncology drawing upon trial outcomes from www.clinicaltrials.gov: breast cancer, non-small cell lung cancer (NSCLC), melanoma and colorectal cancer from 1998 to 2017. We compared the likelihood drugs would progress through the stages of clinical trial testing to approval based on biomarker status. This was done with multi-state Markov models, tools that describe the stochastic process in which subjects move among a finite number of states. RESULTS: Over 10000 trials were screened, which yielded 745 drugs. The inclusion of biomarker status as a covariate significantly improved the fit of the Markov model in describing the drug trajectories through clinical trial testing stages. Hazard ratios based on the Markov models revealed the likelihood of drug approval with biomarkers having nearly a fivefold increase for all indications combined. A 12, 8 and 7-fold hazard ratio was observed for breast cancer, melanoma and NSCLC, respectively. Markov models with exploratory biomarkers outperformed Markov models with no biomarkers. CONCLUSION: This is the first systematic statistical evidence that biomarkers clearly increase clinical trial success rates in three different indications in oncology. Also, exploratory biomarkers, long before they are properly validated, appear to improve success rates in oncology. This supports early and aggressive adoption of biomarkers in oncology clinical trials.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Aprovação de Drogas , Cadeias de Markov , Neoplasias/tratamento farmacológico , Biomarcadores Tumorais/classificação , Biomarcadores Tumorais/genética , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinoma Pulmonar de Células não Pequenas/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Ensaios Clínicos como Assunto/classificação , Ensaios Clínicos como Assunto/estatística & dados numéricos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/química , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Bases de Dados Factuais/estatística & dados numéricos , Aprovação de Drogas/métodos , Aprovação de Drogas/estatística & dados numéricos , Feminino , Marcadores Genéticos , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Oncologia , Melanoma/química , Melanoma/tratamento farmacológico , Melanoma/genética , Neoplasias/química , Neoplasias/genética , Risco , Neoplasias Cutâneas/química , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Processos Estocásticos , Fatores de Tempo , Falha de Tratamento
17.
Am J Surg Pathol ; 45(4): 439-449, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33538422

RESUMO

Salivary duct carcinoma is a relatively uncommon malignancy of the salivary glands; however, it frequently occurs as a carcinomatous component of carcinoma ex pleomorphic adenoma. We previously reported salivary duct carcinoma with rhabdoid features (SDCRF) as an extremely rare subtype of salivary duct carcinoma, and that it occurred as a salivary counterpart of pleomorphic lobular carcinoma of the breast (PLCB). We collected new cases of SDCRF for this study, in which we examined a total of 17 cases immunohistochemically and genetically. As it is known that PLCB exhibits loss of or aberrant E-cadherin expression and carries nonsense/missense mutations in or deletion of the CDH1 gene, we examined the CDH1 gene status of our SDCRF cases. All of the examined SDCRF cases involved the diffuse proliferation of large ovoid cells with eosinophilic cytoplasm and eccentric nuclei, which displayed reduced cell-cell adhesion. Most cases were positive for pan-cytokeratin, androgen receptor, gross cystic disease fluid protein-15, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1, and WI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4, whereas they were negative for vimentin. No and decreased/cytoplasmic E-cadherin expression was observed in 11 and 4 of 17 cases, respectively, whereas no and decreased/cytoplasmic ß-catenin expression were observed in 10 and 5 of 17 cases, respectively. Among the 11 cases that could be genetically analyzed, a nonsense mutation (1 case), missense mutations (6 cases), and insertions (1 case) were detected in the CDH1 gene. In conclusion, we propose that SDCRF is the salivary counterpart of PLCB due to its morphology and immunophenotype, and the genetic status of CDH1.


Assuntos
Adenoma Pleomorfo , Antígenos CD , Biomarcadores Tumorais , Caderinas , Carcinoma , Mutação , Neoplasias das Glândulas Salivares , Adenoma Pleomorfo/química , Adenoma Pleomorfo/genética , Adenoma Pleomorfo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Antígenos CD/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias da Mama/química , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/análise , Caderinas/genética , Carcinoma/química , Carcinoma/genética , Carcinoma/patologia , Carcinoma Lobular/química , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Neoplasias das Glândulas Salivares/química , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia
18.
Eur J Cancer ; 145: 19-28, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33418233

RESUMO

BACKGROUND: Four randomised controlled trials (RCTs) in postmenopausal women with advanced breast cancer (ABC) comparing aromatase inhibitors (AIs) versus the selective estrogen receptor modulator tamoxifen, each individually reported significantly longer progression-free survival (PFS) but none showed a significant difference in overall survival (OS). In these trials between 6.8% and 55% of tumours were hormone receptor (HR) status unknown or negative. This meta-analysis restricted the comparison to HR-positive (HR+) tumours. METHODS: Anonymised individual patient data were obtained from three RCTs, EORTC (exemestane versus tamoxifen), Study 0027 and Study 0030 (both anastrozole versus tamoxifen). For the remaining RCT (Femara Study PO25; letrozole versus tamoxifen), odds ratio (OR) or hazard ratio (HzR), with confidence intervals were obtained from the clinical study report, for patients with HR+ tumours, in addition to published data. In total, data were obtained from 2296 patients; 1560 (68%) had HR+ ABC. FINDINGS: The OR for clinical benefit rate was 1.56, in favour of AIs (p < 0.001). The duration of clinical benefit was not significantly increased by AIs (HzR 0·88; p = 0.08). For PFS the HzR (0.82) was in favour of AIs (p = 0·007). However, for OS the HzR (1.05) was not significantly different between AIs and tamoxifen (p = 0.42). INTERPRETATION: Although third generation AIs put significantly more patients into 'clinical benefit', their tumours were not controlled for significantly longer. Overall, while this resulted in a significantly greater PFS in favour of the AIs, this did not translate into improvement in OS.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Pós-Menopausa , Receptores de Estrogênio/análise , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Idoso , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Tamoxifeno/efeitos adversos , Fatores de Tempo
19.
Cancer Res ; 81(8): 2195-2206, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33483370

RESUMO

Emerging evidence indicates that gut microbiota affect the response to anticancer therapies by modulating the host immune system. In this study, we investigated the impact of gut microbiota on immune-mediated trastuzumab antitumor efficacy in preclinical models of HER2-positive breast cancer and in 24 patients with primary HER2-positive breast cancer undergoing trastuzumab-containing neoadjuvant treatment. In mice, the antitumor activity of trastuzumab was impaired by antibiotic administration or fecal microbiota transplantation from antibiotic-treated donors. Modulation of the intestinal microbiota was reflected in tumors by impaired recruitment of CD4+ T cells and granzyme B-positive cells after trastuzumab treatment. Antibiotics caused reductions in dendritic cell (DC) activation and the release of IL12p70 upon trastuzumab treatment, a mechanism that was necessary for trastuzumab effectiveness in our model. In patients, lower α-diversity and lower abundance of Lachnospiraceae, Turicibacteraceae, Bifidobacteriaceae, and Prevotellaceae characterized nonresponsive patients (NR) compared with those who achieved pathologic complete response (R), similar to antibiotic-treated mice. The transfer of fecal microbiota from R and NR into mice bearing HER2-positive breast cancer recapitulated the response to trastuzumab observed in patients. Fecal microbiota ß-diversity segregated patients according to response and positively correlated with immune signature related to interferon (IFN) and NO2-IL12 as well as activated CD4+ T cells and activated DCs in tumors. Overall, our data reveal the direct involvement of the gut microbiota in trastuzumab efficacy, suggesting that manipulation of the gut microbiota is an optimal future strategy to achieve a therapeutic effect or to exploit its potential as a biomarker for treatment response. SIGNIFICANCE: Evidence of gut microbiota involvement in trastuzumab efficacy represents the foundation for new therapeutic strategies aimed at manipulating commensal bacteria to improve response in trastuzumab-resistant patients.See related commentary by Sharma, p. 1937 GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2195/F1.large.jpg.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Microbioma Gastrointestinal/fisiologia , Receptor ErbB-2 , Trastuzumab/uso terapêutico , Animais , Antibacterianos/farmacologia , Neoplasias da Mama/imunologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Linfócitos T CD4-Positivos , Ciclofosfamida/uso terapêutico , Citocinas/sangue , Células Dendríticas/efeitos dos fármacos , Doxorrubicina/uso terapêutico , Transplante de Microbiota Fecal , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Granzimas , Humanos , Sistema Imunitário , Imunidade nas Mucosas , Interferons/metabolismo , Interleucina-12/metabolismo , Camundongos , Terapia Neoadjuvante , Óxido Nítrico/metabolismo , Estreptomicina/farmacologia , Taxoides/uso terapêutico , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Vancomicina/farmacologia
20.
Sci Rep ; 11(1): 1032, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441811

RESUMO

The present study is to design an eco-friendly mode to rapidly synthesize selenium nanoparticles (SeNPs) through Ceropegia bulbosa tuber's aqueous extracts and confirming SeNPs synthesis by UV-Vis spectroscopy, FT-IR, XRD, FE-SEM-EDS mapping, HR-TEM, DLS and zeta potential analysis. In addition, to assess the anti-cancer efficacy of the SeNPs against the cultured MDA-MB-231, as studies have shown SeNPs biosynthesis downregulates the cancer cells when compared to normal HBL100 cell lines. The study observed the IC50 value of SeNPs against MDA-MB-231 cells was 34 µg/mL for 48 h. Furthermore, the SeNPs promotes growth inhibitory effects of certain clinical pathogens such as Bacillus subtilis and Escherichia coli. Apart, from this the SeNPs has shown larvicidal activity after 24 h exposure in Aedes albopitus mosquito's larvae with a maximum of 250 g/mL mortality concentration. This is confirmed by the histopathology results taken at the 4th larval stage. The histopathological studies revealed intense deterioration in the hindgut, epithelial cells, mid gut and cortex region of the larvae. Finally, tried to investigate the photocatalytic activity of SeNPs against the toxic dye, methylene blue using halogen lamp and obtained 96% degradation results. Withal computational study SeNPs was shown to exhibit consistent stability towards breast cancer protein BRCA2. Overall, our findings suggest SeNPs as a potent disruptive agent for MDA-MB-231 cells, few pathogens, mosquito larvae and boosts the photocatalytic dye degradation.


Assuntos
Anti-Infecciosos/química , Apocynaceae/química , Inseticidas/química , Nanopartículas/química , Selênio/química , Selênio/farmacologia , Aedes/efeitos dos fármacos , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Proteína BRCA2/química , Proteína BRCA2/efeitos dos fármacos , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Catálise , Linhagem Celular Tumoral , Feminino , Química Verde , Humanos , Inseticidas/síntese química , Inseticidas/farmacologia , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Nanopartículas/ultraestrutura , Processos Fotoquímicos , Extratos Vegetais/química , Espectrofotometria , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
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