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1.
Anticancer Res ; 41(9): 4619-4627, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475090

RESUMO

BACKGROUND: The real-world outcomes of patients with advanced invasive lobular carcinoma (ILC) of the breast are unclear because of its rarity. PATIENTS AND METHODS: We identified 435 patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer treated at our Institute between 2002 and 2019, and analyzed their outcomes retrospectively. RESULTS: We identified 29 patients with advanced ILC. At presentation, they had a lower rate of lung metastasis (p=0.0053) but a higher rate of stomach metastasis (p=0.0379) compared with other patients with advanced breast cancer. Median overall survival did not differ; however, multivariate analyses showed that ILC histopathology was a risk factor for poorer overall survival (hazard ratio=3.43, p=0.0038) in patients with de novo stage IV ER+ HER2- breast cancer. Patients with ILC showed a markedly different patten of subsequent metastasis, such as less in the lung and more in the stomach, leptomeninges, and bone marrow. CONCLUSION: According to our retrospective study, in patients with de novo stage IV ER+ HER2- breast cancer, ILC histopathology was associated with increased risk of death.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidade , Carcinoma Lobular/metabolismo , Carcinoma Lobular/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
2.
Exp Mol Pathol ; 121: 104654, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34087231

RESUMO

Breast cancer (BC) is the most common cancer in females. In this regard, the identification of molecular alterations driving BC is an immediate need for developing effective immunotherapeutic tools. Here we investigated the expression of a placenta-specific protein, Retrotransposon-like 1 (RTL1) in a series of BC tissues and cell lines. RTL1-specific polyclonal antibody was generated and characterized. Using tissue microarray immunohistochemistry, expression of RTL1 in a total of 147 BC and 36 non-malignant breast tissues was investigated and the association of patient's clinicopathological parameters with RTL1 expression was then examined. Expression of RTL1 in four BC cells was assessed by flow cytometry, immunofluorescent staining and Western blotting. We observed a mixture pattern of nuclear and cytoplasmic RTL1 expression in most tissues examined, however nuclear expression was found to be dominant pattern of expression. The level of nuclear RTL1 expression was significantly higher in BC tissues (P < 0.001). A statistically significant association between nuclear RTL1 expression and histological grade and vascular invasion was found (P < 0.001 and P < 0.05). All cell lines expressed RTL1 with varying degrees at their surface. The most invasive BC cell line MDA-MB-231, compared to T-47D, SKBR3 and MCF7 expressed higher levels of RTL1 at their surface. Cells with a low level of surface expression, expressed high levels of intracellular RTL1 expression. Our antibody reacted with a specific band of about 125 KD in normal human placenta and all cell lines examined. In contrast to placenta, two additional bands were also observed in cancer cell lines. Our results showed for the first time that RTL1 is differentially expressed in BC compared to non-malignant breast tissues and is associated with a higher grade and vascular invasion. In BC cells with high metastatic and invasive potential, this antigen is mostly confined to cell surface compartment indicating the possibility of using antibody-based immunotherapy for advanced metastatic BC patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Proteínas da Gravidez/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas da Gravidez/genética , Prognóstico , Células Tumorais Cultivadas
3.
J Cancer Res Clin Oncol ; 147(9): 2535-2544, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34085098

RESUMO

PURPOSE: The aim of this study was to investigate the expression of liver X receptors α/ß (LXR) in primary breast cancer (BC) tissues and to analyze its correlations with clinicopathological parameters including patient survival. METHODS: In a well-characterized cohort of 305 primary BC, subcellular distribution of LXR was evaluated by immunohistochemistry. Correlations with clinicopathological characteristics as well as with patient outcome were analyzed. RESULTS: LXR was frequently localized in both nuclei and cytoplasms of BC cells, with stronger staining in nuclei. Total and nuclear LXR expression was positively correlated with ER and PR status. Overall survival analysis demonstrated that cytoplasmic LXR was significantly correlated with poor survival and appeared as an independent marker of poor prognosis, in stage I but not in stage II-III tumors CONCLUSION: Altogether, these data suggest that cytoplasmic LXR could be defined as a prognostic marker in early stage primary BC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Citoplasma/metabolismo , Receptores X do Fígado/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
4.
Sci Rep ; 11(1): 12128, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108561

RESUMO

Prognostic implications of therapeutic response of metastatic lymph nodes (LNs) to neoadjuvant chemotherapy (NAC) remain unclear in patients with breast cancer. We aimed to evaluate the prognostic value of axillary LN regression after NAC in locally-advanced breast cancer patients. Therapeutic response of the LNs was evaluated in 563 breast cancer patients and classified into four grades according to the regression pattern. Initial pathologic N stage was estimated from the sum of the metastatic LNs and those with complete regression. In survival analyses, LN regression grade, pathologic N stage after NAC, and presumed initial pathologic N stage stratified clinical outcome of the patients in the whole group, in both ER-positive and ER-negative subgroups, and in those with residual breast disease. On multivariate analysis, LN regression grade and presumed initial pathologic N stage were revealed as independent prognostic factors. The number of completely-responsive LNs and the ratio of non-responsive LNs also revealed a prognostic value. In conclusion, regression grade of axillary LNs and presumed initial pathologic N stage have prognostic values in breast cancer patients who receive NAC. Thus, regression of axillary LNs should be evaluated and included in pathologic reporting of post-NAC resection specimens.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Quimioterapia Adjuvante/mortalidade , Linfonodos/patologia , Terapia Neoadjuvante/mortalidade , Axila , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/metabolismo , Feminino , Seguimentos , Humanos , Linfonodos/efeitos dos fármacos , Metástase Linfática , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida
5.
Oncology ; 99(5): 280-291, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33652435

RESUMO

INTRODUCTION: The aim of this study was to assess for clinicopathologic and socioeconomic features that predict improved survival for patients with advanced breast cancer with synchronous brain metastases at diagnosis. METHODS: We utilized the National Cancer Database (NCDB) to identify all patients with brain metastases present at diagnosis, with adequate information on receptor status (ER, PR, Her2), clinical T stage of cT1-4, clinical M1, with 3,943 patients available for analysis. The association between brain metastases patterns and patient/disease variables was examined by robust Poisson regression model. Cox proportional hazards model was used to quantify the associations between overall survival (OS) and these variables. RESULTS: In univariable analysis, OS was significantly associated with the number of sites of metastases (p < 0.0001). Patients with 2 or more additional extracranial sites of metastases had significantly worse OS (median 8.8 months, 95% confidence interval [CI] 7.8, 9.9) than patients with brain metastases only (median OS 10.6 months, 95% CI 9.4, 12.9) or brain metastases plus one other extracranial site of metastases (median OS 13.1 months, 95% CI 11.8, 14.4). Risk factors which predicted poor prognosis included triple-negative disease, high comorbidity score, poorly differentiated tumors, invasive lobular histology, multi-organ involvement of metastases, and government or lack of insurance. Factors which improve survival include younger age and Hispanic race. DISCUSSION/CONCLUSION: Using a large NCDB, we identified various factors associated with prognosis for patients with brain metastases at the time of breast cancer diagnosis. Insurance status and related socioeconomic challenges provide potential areas for improvement in care for these patients. This information may help stratify patients into prognostic categories at the time of diagnosis to improve treatment plans.


Assuntos
Neoplasias Encefálicas/mortalidade , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/mortalidade , Carcinoma Lobular/mortalidade , Bases de Dados Factuais , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Carcinoma Lobular/terapia , Estudos de Casos e Controles , Terapia Combinada , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
6.
Asian Pac J Cancer Prev ; 22(3): 757-766, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33773539

RESUMO

OBJECTIVE: Investigate the effect of SDF1a, nuclear, and cytoplasmic CXCR4 breast cancer tissue on metastasis and overall survival in patients with complete-chemotherapy and no-chemotherapy. METHODS: Cohort ambidirectional design was employed with survival analysis that followed the patient's diagnosis until obtaining the outcome, distant metastasis, or death. We analyzed samples in three groups (all-patient, no-chemotherapy, and complete-chemotherapy groups).  Breast cancer cell nuclear and cytoplasm expressions of CXCR4 protein were examined using immunohistochemistry. Amplification of mRNA SDF1a of breast cancer tissue was examined using rtPCR on 131 samples from the same initial paraffin block. RESULTS: In the distant metastasis and Overall Survival (OS) analysis, there was no correlation between cytoplasmic and nuclear CXCR4 in all-patient, no-chemotherapy, and complete-chemotherapy groups. SDF1a was significantly correlated to shorter distant metastasis and poor OS in the all-patient (p=0.004 and p=0.04, respectively) and no-chemotherapy group (p=0.008 and p=0.026, respectively). However, in the complete-chemotherapy group, SDF1a was not correlated to either metastasis (p=0.527) or OS (p=0.993), advanced stage demonstrated a strong association on shorter distant metastatic in no-chemotherapy (p=0.021) and complete-chemotherapy group (p=0.004) and also poor OS in both groups (p=0.006 and p=0.002, respectively). The hormone receptor showed a protective effect on the no-chemotherapy group's OS (p= 0.019). Meanwhile, not undergoing chemotherapy was associated with poor OS in the all-patient group (p= 0.011). CONCLUSION: SDF1a mRNA amplification has a significant correlation with the occurrence of metastasis and OS in all-patient and no-chemotherapy group. Undergoing chemotherapy negates the effect of SDF1a for distant metastasis and OS.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Quimiocina CXCL12/genética , Quimioterapia Adjuvante , Mastectomia , RNA Mensageiro/metabolismo , Receptores CXCR4/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Carcinoma Medular/tratamento farmacológico , Carcinoma Medular/genética , Carcinoma Medular/metabolismo , Carcinoma Medular/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Taxa de Sobrevida
7.
Int J Cancer ; 149(1): 200-213, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33634878

RESUMO

Determining the status of steroid hormone receptors [oestrogen (ER) and progesterone receptors (PR)] is a crucial part of the breast cancer workup. Thereby, breast cancers can be classified into four subtypes. However, the existence of ER-/PR+ tumours, often reported to be ill-classified due to technical errors, remains controversial. In order to address this controversy, we reviewed the hormone receptor status of 49 breast tumours previously classified as ER-/PR+ by immunohistochemistry, and compared clinical, pathological and molecular characteristics of confirmed ER-/PR+ tumours with those of ER+ and triple-negative tumours. We unequivocally confirmed the ER-/PR+ status in 27 of 49 tumours (0.3% of all breast cancers diagnosed in our institution between 2000 and 2014). We found that ER-/PR+ were morphologically and histologically similar to triple-negative tumours, but very distinct from ER+ tumours, with more aggressive phenotypes and more frequent basal marker expression than the latter. On the molecular level, RNA sequencing revealed different gene expression profiles between the three groups. Of particular interest, several genes controlled by the suppressor of zest 12 (SUZ12) were upregulated in ER-/PR+ tumours. Overall, our results confirm that ER-/PR+ breast cancers are an extremely rare but 'real' tumour subtype that requires careful diagnosis and has distinct features warranting different responsiveness to therapies and different clinical outcomes. Studies on larger cohorts are needed to further characterise these tumours. The likely involvement of SUZ12 in their biology is an interesting finding which may - in a long run - give rise to the development of new therapeutic alternatives.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Idoso , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Neoplasias de Mama Triplo Negativas/classificação , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
8.
Eur J Surg Oncol ; 47(4): 796-803, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33097334

RESUMO

INTRODUCTION: Risk of breast cancer increases with age and very few data are available in patients older than 89. METHODS: A retrospective analysis on patients aged 89 and older treated between 2008 and 2019 at our certified breast center. The aim was to analyze clinical characteristics, decision-making, treatment, outcomes and open questions regarding this subpopulation for which there is a lack of guidelines. RESULTS: 58 patients included. Tumor characteristics were analyzed, 85% patients underwent surgery of which 44% had a mastectomy. The median follow-up and overall survival were 20 and 76 months, respectively.The median survival of metastatic and non-metastatic patients were 14 and 50 months, respectively. Most patients did not receive any adjuvant treatment and among these 14% had a relapse. CONCLUSIONS: Elderly patients should not be under or over-treated because of their age; they represent a large heterogeneous group deserving a sub-stratification for a better tailored treatment.


Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma in Situ/terapia , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/terapia , Recidiva Local de Neoplasia/patologia , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias da Mama Masculina/diagnóstico , Neoplasias da Mama Masculina/patologia , Neoplasias da Mama Masculina/cirurgia , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/diagnóstico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/secundário , Quimioterapia Adjuvante , Tomada de Decisão Clínica , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Mastectomia , Gradação de Tumores , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Radioterapia Adjuvante , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia
9.
Cancer Med ; 10(2): 586-594, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33280268

RESUMO

BACKGROUND: Human epidermal growth factor receptor 2-in situ hybridization (HER2-ISH) is widely approved for diagnostic, prognostic biomarker testing of formalin-fixed paraffin-embedded tissue blocks. However, cytologic ISH analysis has a potential advantage in tumor samples such as pleural effusion and ascites that are difficult to obtain the histological specimens. Our aim was to evaluate the clinical reliability of a novel rapid cytologic HER2 fluorescence ISH protocol (rapid-CytoFISH). MATERIALS AND METHODS: Using a new device, we applied a high-voltage/frequency, noncontact alternating current electric field to tissue imprints and needle rinses, which mixed the probe within microdroplets as the voltage was switched on and off (AC mixing). Cytologic samples (n = 143) were collected from patients with immunohistochemically identified HER2 breast cancers. The specimens were then tested using standard dual-color ISH using formalin-fixed paraffin-embedded tissue (FFPE-tissue DISH) for HER2-targeted therapies, CytoFISH, and rapid-CytoFISH (completed within 4 h). RESULTS: All 143 collected cytologic specimens (50 imprinted cytology specimens from resected tumors and 93 liquid-based cytology specimens from needle rinses) were suitable for FISH analysis. The HER2/chromosome enumeration probe (CEP) 17 ratios did not significantly differ between FFPE-tissue DISH and either CytoFISH protocol. Based on HER2 scoring criteria, we found 95.1% agreement between FFPE-tissue DISH and CytoFISH (Cohen's kappa coefficient = 0.771 and 95% confidence interval (CI): 0.614-0.927). CONCLUSION: CytoFISH could potentially serve as a clinical tool for prompt determination of HER2 status in breast cancer cytology. Rapid-CytoFISH with AC mixing will enable cancer diagnoses and HER2 status to be determined on the same day a patient comes to a clinic or hospital.


Assuntos
Neoplasias da Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Lobular/diagnóstico , Citodiagnóstico/métodos , Eletricidade , Hibridização in Situ Fluorescente/métodos , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Testes Diagnósticos de Rotina , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico
10.
Clin Transl Oncol ; 23(3): 620-627, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32683540

RESUMO

PURPOSE: To study the imaging parameters of 18F-fluorodeoxy glucose (18F-FDG) in breast cancer on positron emission tomography/computed tomography (PET/CT)-the correlation of clinical pathological factors and prognosis among the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of lesions for patients. METHODS: From January 2012 to December 2014, a total of 125 female patients were treated in our hospital for the first time and were diagnosed as breast cancer by histopathology. They were selected as the research subjects. All of them had complete 18F-FDG PET/CT examination data before surgery, the postoperative clinicopathological information, and follow-up data. They were divided into the event group (38 cases) and the event-free group (87 cases) according to whether local recurrence or distant metastasis occurred after the follow-up, with the follow-up time 4-60 months. The correlation on 18F-FDG PET/CT metabolic parameters of breast cancer with clinicopathological factors and prognosis was retrospectively evaluated. RESULTS: The primary lesions of 125 cases with breast cancers all had higher 18F-FDG uptake, and the SUVmax, MTV, and TLG of the primary tumors in the event group were significantly higher than those in the event-free group (t = 2.645, 2.782, 15.263, p = 0.011, 0.008, 0.000), p < 0.05; SUVmax, MTV, and TLG of primary breast cancer have no correlation with age and tumor site of patient (p > 0.05); there were statistically significant differences in the SUVmax, MTV, and TLG of primary tumor in the comparison of different tumor size, T stage, N stage, and histological grades (p < 0.05); all of SUVmax, MTV, and TLG in the estrogen receptor (ER) and/or progesterone receptor (PR) positive groups were lower than those in the negative group, with statistically significant difference (p < 0.05); the SUVmax, MTV, and TLG of human epidermal growth factor receptor 2 (HER2) positive group, proliferating cell nuclear antigen (Ki-67) high expression group were higher than those in the negative group and low expression group, with statistically significant difference (p < 0.05). There were 38 recurrence and metastasis cases within 125 cases with breast cancer in 5 years after operation, with the total recurrence and metastasis rate as 30.40% (38/125). The event-free survival rate in the SUVmax ≥ 8.64 group was significantly lower than that in the SUVmax < 8.64 group (p < 0.01). CONCLUSIONS: The metabolic parameters of 18F-FDG PET/CT in breast cancer can reflect the biological behavior of the tumor indirectly; therefore, it was studied on the related correlation to provide the guidance of clinical individualized comprehensive treatment and prognostic judgment.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Fluordesoxiglucose F18/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/metabolismo , Adulto , Idoso , Área Sob a Curva , Carcinoma de Mama in situ/diagnóstico por imagem , Carcinoma de Mama in situ/metabolismo , Carcinoma de Mama in situ/mortalidade , Carcinoma de Mama in situ/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/diagnóstico por imagem , Carcinoma Lobular/metabolismo , Carcinoma Lobular/mortalidade , Carcinoma Lobular/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Glicólise , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Curva ROC , Análise de Regressão , Carga Tumoral
11.
BMC Cancer ; 20(1): 1102, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33187507

RESUMO

BACKGROUND: Tumour subtype has a significant effect on bone metastasis in breast cancer, but population-based estimates of the prognosis of patients with bone metastases at breast cancer diagnosis are lacking. The aim of this study was to analyse the influence of tumour subtype and other factors on the prognosis and survival of patients with bone metastases of breast cancer. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) Program data from 2012 to 2016, a retrospective cohort study was conducted to investigate stage IV breast cancer patients with bone metastases. Stage IV patient characteristics according to subtype were compared using chi-square tests. Overall survival (OS) and prognostic factors were compared using the Kaplan-Meier method and the Cox proportional hazards model, respectively. RESULTS: A total of 3384 stage IV patients were included in this study; 63.42% were HR+/HER2-, 19.86% were HR+/HER2+, 9.34% were HR-/HER2-, and 7.39% were HR-/HER2+. The median OS for the whole population was 38 months, and 33.9% of the patients were alive at 5 years. The median OS and five-year survival rate were significantly different among stage IV breast cancer patients with different molecular subtypes (p < 0.05). Multivariate Cox regression analysis showed that age of 55-59 (HR = 1.270), black race (HR = 1.317), grade III or IV (HR = 1.960), HR-/HER2- (HR = 2.808), lung metastases (HR = 1.378), liver metastases (HR = 2.085), and brain metastases (HR = 1.903) were independent risk factors for prognosis; married status (HR = 0.819), HR+/HER2+ (HR = 0.631), HR-/HER2+ (HR = 0.716), insurance (HR = 0.587) and surgery (HR = 0.504) were independent protection factors of prognosis. There was an interaction between the HR+/HER2+ subtype and other metastases (except bone metastases, HR = 0.694, 95% CI: 0.485-0.992), but the interaction between race and subtype did not reach significance for prognosis. CONCLUSIONS: There were substantial differences in OS according to tumour subtype. In addition to tumour subtype, other independent predictors of OS were age at diagnosis, race, marital status, insurance, grade, surgery and visceral metastases. There was an interaction between the HR+/HER2+ subtype and other metastases (except bone metastases) for prognosis. Tumour subtype, as a significant prognostic factor, warrants further investigation.


Assuntos
Neoplasias Ósseas/mortalidade , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/mortalidade , Carcinoma Lobular/mortalidade , Programa de SEER , Adulto , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/metabolismo , Carcinoma Lobular/secundário , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
12.
Sci Rep ; 10(1): 20100, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208857

RESUMO

Triple negative breast cancer (TNBC), usually presenting with a very aggressive phenotype, is a heterogeneous entity. We aim to discuss new biomarkers, suitable for prognostic and predictive purposes. We retrospectively collected clinical variables and immunohistochemical characteristics of early TNBCs, specifically focusing on the prognostic and predictive significance of tumor infiltrating lymphocytes (TILs) and androgen receptor (AR) expression, assessing their correlation with clinical variables. Among 159 patients, TILs were significantly higher in younger patients and with lower BMI, and in tumors with higher ki-67 and greater nodal involvement; conversely, AR was significantly higher in older patients and in tumors with lower ki-67. Interestingly and in line with literature, both TILs level and ARs expression were lower within metastatic sites, in patients who developed distant metastases, compared to those found in the primary site. Small (pT1) and node negative tumors were highly represented and no correlation of either TILs or AR with prognosis could be observed. Our findings support the use of stromal TILs to identify a more aggressive, but chemo-sensitive phenotype, mostly represented in younger women, while AR may identify a less aggressive, slow-growing luminal TNBC subtype, more common among older patients. TILs and AR are worth implementing in routine clinical practice to refine prognosis even if, in our case series, we couldn't identify a significant correlation of the two variables with either disease-free and overall survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Linfócitos do Interstício Tumoral/imunologia , Receptores Androgênicos/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/imunologia , Carcinoma Lobular/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo
13.
BMC Cancer ; 20(1): 1150, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33238978

RESUMO

BACKGROUND: Whether tumour-infiltrating lymphocytes (TILs) play different roles in different molecular subtypes of breast cancer remains unknown. Additionally, their prognostic and predictive value in different molecular subtypes of breast cancer is still controversial. The aim of our meta-analysis was to assess the prognostic and predictive value of TILs in different molecular subtypes of breast cancer by summarizing all relevant studies performing multivariate analysis. METHODS: PubMed, Embase, EBSCO, ScienceDirect, the Cochrane Database and Web of Science were comprehensively searched (until March 2020). Hazard ratios (HRs), odds ratios (ORs) and their 95% confidence intervals (CIs) were used as effect measures to perform our meta-analysis. A random effect model was used. Stata software, version 15 (2017) (StataCorp, College Station, TX, USA) was used to perform the statistical analysis. RESULTS: Thirty-three studies including 18,170 eligible breast cancer patients were analysed. The meta-analysis showed that high TIL expression was significantly associated with increased pathological complete response (pCR) rates after neoadjuvant chemotherapy in patients with the HER2-enriched molecular subtype (OR = 1.137, 95% CI [1.061 ~ 1.218], p < 0.001) and triple-negative breast cancer (TNBC) subtype (OR = 1.120, 95% CI [1.061 ~ 1.182], p < 0.001). However, high TIL expression was not significantly associated with high pCR rates after neoadjuvant chemotherapy in patients with the luminal molecular subtype of breast cancer (OR = 1.154, 95% CI [0.789 ~ 1.690], p = 0.460). We carried out a meta-analysis on the HRs of overall survival (OS) and disease-free survival (DFS) to assess the prognostic value of TILs in breast cancer with different molecular subtypes more deeply. Our meta-analysis confirmed that high TILs were associated with significantly improved DFS in patients with the HER2-enriched molecular subtype [HR = 0.940, 95% CI (0.903 ~ 0.979), p = 0.003] and TNBC molecular subtype [HR = 0.907, 95% CI (0.862 ~ 0.954), p < 0.001]. However, high TILs were not associated with significantly better DFS in patients with the luminal molecular subtype of breast cancer [HR = 0.998, 95% CI (0.977 ~ 1.019), p = 0.840]. Furthermore, the results confirmed that high TILs were significantly related to better OS in patients with the HER2-enriched molecular subtype [HR = 0.910, 95% CI (0.866 ~ 0.957), p < 0.001] and TNBC molecular subtype [HR = 0.869, 95% CI (0.836 ~ 0.904), p < 0.001]. Conversely, the summarized results indicated that high TILs were significantly associated with poor OS in patients with the luminal molecular subtype of breast cancer [HR = 1.077, 95% CI (1.016 ~ 1.141), p = 0.012]. CONCLUSIONS: Our meta-analysis confirms that high TILs are associated with favourable survival and predicts pCR in breast cancer patients with the TNBC and HER2-enriched molecular subtypes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/imunologia , Carcinoma Lobular/metabolismo , Feminino , Humanos , Terapia Neoadjuvante , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
14.
BMC Cancer ; 20(1): 1106, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33198673

RESUMO

BACKGROUND: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) is a predictor of improved outcomes in breast cancer. In patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) -negative breast cancer, the response to NAC is variable and mostly limited. This study was an investigation of the predictive relevance of parameters of 18F-FDG PET/CT for the pCR to NAC in patients with HR-positive, HER2-negative breast cancer. METHODS: AH total of 109 consecutive HR-positive and HER2-negative breast cancer patients who were treated with NAC were enrolled in this prospective cohort study. The relationships between pretreatment 18F-FDG PET/CT and clinical outcomes including pathologic response to NAC were evaluated. RESULTS: All patients finished their planned NAC cycles and eight patients (7.3%) achieved pCR. In the receiver operating characteristic (ROC) curve analysis, pSUVmax exhibited high sensitivity and specificity for predicting pCR. Furthermore, multivariate logistic regression analysis revealed pSUVmax as a predictive factor for pCR (hazard ratio = 17.452; 95% CI = 1.847-164.892; p = 0.013). CONCLUSION: The results of this study suggest that 18F-FDG PET/CT pSUVmax is a predictive factor for pCR of HR-positive, HER2-negative breast cancer to NAC.


Assuntos
Neoplasias da Mama/patologia , Fluordesoxiglucose F18/metabolismo , Terapia Neoadjuvante/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/diagnóstico por imagem , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Compostos Radiofarmacêuticos/metabolismo , Taxa de Sobrevida
15.
Asian Pac J Cancer Prev ; 21(10): 3027-3032, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33112563

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer (BC), and its diagnosis is associated with negative expression of hormone receptors and HER2/neu. It consists of 10-20% of all BCs diagnosed. METHODS AND MATERIALS: This study focuses on three groups with different pathology: group one showed complete triple-negative HER2 expression with IHC of BC; groups two and three included patients with ER-, PR-, and HER21+, and ER-, PR-, and HER22+ with a negative FISH test. These three groups were compared from the point of prognosis, which consisted of tumor size, patients' age, lymphatic, vascular and perineural invasion, organ metastasis, number of lymph nodes involvement, and the survival rate. RESULTS: A total of 459 TNBC patients were enrolled, of which 268 were placed in the HER20 group, 146 in the HER21+ group, and 45 in the HER22+ group. Distant metastasis and recurrence rate were more common in HER20 patients, but bone metastasis was more common in patients with low HER2 expression. All patients with HER20 had a smaller tumor size at the time of BC diagnosis in comparison to patients in the low HER2 expression group. Patients with HER22+ had less lymphatic and vascular invasion as well as axillary lymph nodes involvement, but larger tumor size at presentation, resulting in a lower rate of recurrence and higher overall survival. CONCLUSION: The findings revealed that patients with HER22+ had better outcome in comparison to the patients with HER20 and HER21+. Furthermore, the results showed that many patients with HER22+ expression were not basal-like and had good prognosis amongst TNBC patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/secundário , Recidiva Local de Neoplasia/patologia , Receptor ErbB-2/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/cirurgia , Estudos Transversais , Feminino , Seguimentos , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/cirurgia , Adulto Jovem
16.
Int J Mol Sci ; 21(17)2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32899175

RESUMO

BACKGROUND: SRY-related HMG-box 10 (SOX-10) is commonly expressed in triple negative breast cancer (TNBC). However, data on the biological significance of SOX-10 expression is limited. Therefore, we investigated immunhistological SOX-10 expression in TNBC and correlated the results with genetic alterations and clinical data. METHODS: A tissue microarray including 113 TNBC cases was stained by SOX-10. Immunohistological data of AR, BCL2, CD117, p53 and Vimentin was available from a previous study. Semiconductor-based panel sequencing data including commonly altered breast cancer genes was also available from a previous investigation. SOX-10 expression was correlated with clinicopathological, immunohistochemical and genetic data. RESULTS: SOX-10 was significantly associated with CD117 and Vimentin, but not with AR expression. An association of SOX-10 with BCL2, EGFR or p53 staining was not observed. SOX-10-positive tumors harbored more often TP53 mutations but less frequent mutations of PIK3CA or alterations of the PIK3K pathway. SOX-10 expression had no prognostic impact either on disease-free, distant disease-free, or overall survival. CONCLUSIONS: While there might be a value of SOX-10 as a differential diagnostic marker to identify metastases of TNBC, its biological role remains to be investigated.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Lobular/patologia , Fatores de Transcrição SOXE/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/metabolismo , Estudos de Coortes , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo
17.
Biomolecules ; 10(9)2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32957504

RESUMO

The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). TrkA was expressed in cancer epithelial and myoepithelial cells, with higher levels of TrkA positively associated with IDC (39% of cases) (p < 0.0001). Interestingly, TrkA was significantly increased in tumours expressing the human epidermal growth factor receptor-2 (HER2), with expression in 49% of HER2-positive compared to 25% of HER2-negative tumours (p = 0.0027). A panel of breast cancer cells were used to confirm TrkA protein expression, demonstrating higher levels of TrkA (total and phosphorylated) in HER2-positive cell lines. Functional investigations using four different HER2-positive breast cancer cell lines indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability, through decreased phospho-TrkA (Tyr490) and downstream AKT (Ser473) activation, but did not display synergy with Herceptin. Overall, these data highlight a relationship between the tyrosine kinase receptors TrkA and HER2 and suggest the potential of TrkA as a novel or adjunct target for HER2-positive breast tumours.


Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptor trkA/biossíntese , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptor trkA/antagonistas & inibidores , Receptor trkA/genética , Análise de Sobrevida
18.
Breast Cancer Res ; 22(1): 85, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782013

RESUMO

BACKGROUND: Invasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancers and is typically estrogen receptor alpha positive (ER+) and ERBB2 non-amplified. Somatic mutations in ERBB2/3 are emerging as a tractable mechanism underlying enhanced human epidermal growth factor 2 (HER2) activity. We tested the hypothesis that therapeutically targetable ERBB2/3 mutations in primary ILC of the breast associate with poor survival outcome in large public datasets. METHODS: We performed in silico comparison of ERBB2 non-amplified cases of ER+ stage I-III primary ILC (N = 279) and invasive ductal carcinoma (IDC, N = 1301) using METABRIC, TCGA, and MSK-IMPACT information. Activating mutations amenable to HER2-directed therapy with neratinib were identified using existing functional data from in vitro cell line and xenograft experiments. Multivariate analysis of 10-year overall survival (OS) with tumor size, grade, and lymph node status was performed using a Cox regression model. Differential gene expression analyses by ERBB2 mutation and amplification status was performed using weighted average differences and an in silico model of response to neratinib derived from breast cancer cell lines. RESULTS: ILC tumors comprised 17.7% of all cases in the dataset but accounted for 47.1% of ERBB2-mutated cases. Mutations in ERBB2 were enriched in ILC vs. IDC cases (5.7%, N = 16 vs. 1.4%, N = 18, p < 0.0001) and clustered in the tyrosine kinase domain of HER2. ERBB3 mutations were not enriched in ILC (1.1%, N = 3 vs. 1.8%, N = 23; p = 0.604). Median OS for patients with ERBB2-mutant ILC tumors was 66 months vs. 211 months for ERBB2 wild-type (p = 0.0001), and 159 vs. 166 months (p = 0.733) for IDC tumors. Targetable ERBB2 mutational status was an independent prognostic marker of 10-year OS-but only in ILC (hazard ratio, HR = 3.7, 95% CI 1.2-11.0; p = 0.021). Findings were validated using a novel ERBB2 mutation gene enrichment score (HR for 10-year OS in ILC = 2.3, 95% CI 1.04-5.05; p = 0.040). CONCLUSIONS: Targetable ERBB2 mutations are enriched in primary ILC and their detection represents an actionable strategy with the potential to improve patient outcomes. Biomarker-led clinical trials of adjuvant HER-targeted therapy are warranted for patients with ERBB2-mutated primary ILC.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Mutação , Receptor ErbB-2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Simulação por Computador , Bases de Dados Genéticas/estatística & dados numéricos , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
19.
J Exp Clin Cancer Res ; 39(1): 161, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807212

RESUMO

BACKGROUND: Estrogen receptor α (ERα) signaling is a defining and driving event in most breast cancers; ERα is detected in malignant epithelial cells of 75% of all breast cancers (classified as ER-positive breast cancer) and, in these cases, ERα targeting is the main therapeutic strategy. However, the biological determinants of ERα heterogeneity and the mechanisms underlying therapeutic resistance are still elusive, hampered by the challenges in developing experimental models recapitulative of intra-tumoral heterogeneity and in which ERα signaling is sustained. Ex vivo cultures of human breast cancer tissue have been proposed to retain the original tissue architecture, epithelial and stromal cell components and ERα. However, loss of cellularity, viability and ERα expression are well-known culture-related phenomena. METHODS: BC samples were collected and brought to the laboratory. Then they were minced, enzymatically digested, entrapped in alginate and cultured for 1 month. The histological architecture, cellular composition and cell proliferation of tissue microstructures were assessed by immunohistochemistry. Cell viability was assessed by measurement of cell metabolic activity and histological evaluation. The presence of ERα was accessed by immunohistochemistry and RT-qPCR and its functionality evaluated by challenge with 17-ß-estradiol and fulvestrant. RESULTS: We describe a strategy based on entrapment of breast cancer tissue microstructures in alginate capsules and their long-term culture under agitation, successfully applied to tissue obtained from 63 breast cancer patients. After 1 month in culture, the architectural features of the encapsulated tissue microstructures were similar to the original patient tumors: epithelial, stromal and endothelial compartments were maintained, with an average of 97% of cell viability compared to day 0. In ERα-positive cases, fibers of collagen, the main extracellular matrix component in vivo, were preserved. ERα expression was at least partially retained at gene and protein levels and response to ERα stimulation and inhibition was observed at the level of downstream targets, demonstrating active ER signaling. CONCLUSIONS: The proposed model system is a new methodology to study ex vivo breast cancer biology, in particular ERα signaling. It is suitable for interrogating the long-term effects of anti-endocrine drugs in a set-up that closely resembles the original tumor microenvironment, with potential application in pre- and co-clinical assays of ERα-positive breast cancer.


Assuntos
Adenocarcinoma Mucinoso/patologia , Neoplasias da Mama/patologia , Carcinoma Lobular/patologia , Receptor alfa de Estrogênio/metabolismo , Adenocarcinoma Mucinoso/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Lobular/metabolismo , Técnicas de Cultura de Células , Proliferação de Células , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Microambiente Tumoral
20.
Breast Cancer Res ; 22(1): 76, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665033

RESUMO

BACKGROUND: Early luminal breast cancer (BC) represents 70% of newly diagnosed BC cases. Among them, small (under 2 cm) BC without lymph node metastasis (classified as T1N0) have been rarely studied, as their prognosis is generally favorable. Nevertheless, up to 5% of luminal T1N0 BC patients relapse with distant metastases that ultimately prove fatal. The aim of our work was to identify the mechanisms involved in metastatic recurrence in these patients. METHODS: Our study addresses the role that autonomous and non-autonomous tumor cell features play with regard to distant recurrence in early luminal BC patients. We created a cohort of T1N0 luminal BC patients (tumors between 0.5-2 cm without lymph node metastasis) with metastatic recurrence ("cases") and corresponding "controls" (without relapse) matched 1:1 on main prognostic factors: age, grade, and proliferation. We deciphered different characteristics of cancer cells and their tumor micro-environment (TME) by deep analyses using immunohistochemistry. We performed in vitro functional assays and highlighted a new mechanism of cooperation between cancer cells and one particular subset of cancer-associated fibroblasts (CAF). RESULTS: We found that specific TME features are indicative of relapse in early luminal BC. Indeed, quantitative histological analyses reveal that "cases" are characterized by significant accumulation of a particular CAF subset (CAF-S1) and decrease in CD4+ T lymphocytes, without any other association with immune cells. In multivariate analysis, TME features, in particular CAF-S1 enrichment, remain significantly associated with recurrence, thereby demonstrating their clinical relevance. Finally, by performing functional analyses, we demonstrated that CAF-S1 pro-metastatic activity is mediated by the CDH11/osteoblast cadherin, consistent with bones being a major site of metastases in luminal BC patients. CONCLUSIONS: This study shows that distant recurrence in T1N0 BC is strongly associated with the presence of CAF-S1 fibroblasts. Moreover, we identify CDH11 as a key player in CAF-S1-mediated pro-metastatic activity. This is independent of tumor cells and represents a new prognostic factor. These results could assist clinicians in identifying luminal BC patients with high risk of relapse. Targeted therapies against CAF-S1 using anti-FAP antibody or CDH11-targeting compounds might help in preventing relapse for such patients with activated stroma.


Assuntos
Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Fibroblastos Associados a Câncer/imunologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/imunologia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Carcinoma Lobular/terapia , Estudos de Casos e Controles , Terapia Combinada , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Microambiente Tumoral/imunologia
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