Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 79
Filtrar
1.
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 Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Microambiente Tumoral/imunologia
2.
Breast Cancer Res ; 22(1): 69, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576238

RESUMO

BACKGROUND: In the evaluation of PD-L1 expression to select patients for anti-PD-1/PD-L1 treatment, uniform guidelines that account for different immunohistochemistry assays, different cell types and different cutoff values across tumor types are lacking. Data on how different scoring methods compare in breast cancer are scant. METHODS: Using FDA-approved 22C3 diagnostic immunohistochemistry assay, we retrospectively evaluated PD-L1 expression in 496 primary invasive breast tumors that were not exposed to anti-PD-1/PD-L1 treatment and compared three scoring methods (TC: invasive tumor cells; IC: tumor-infiltrating immune cells; TCIC: a combination of tumor cells and immune cells) in expression frequency and association with clinicopathologic factors. RESULTS: In the entire cohort, positive PD-L1 expression was observed in 20% of patients by TCIC, 16% by IC, and 10% by TC, with a concordance of 87% between the three methods. In the triple-negative breast cancer patients, positive PD-L1 expression was observed in 35% by TCIC, 31% by IC, and 16% by TC, with a concordance of 76%. Associations between PD-L1 and clinicopathologic factors were investigated according to receptor groups and whether the patients had received neoadjuvant chemotherapy. The three scoring methods showed differences in their associations with clinicopathologic factors in all subgroups studied. Positive PD-L1 expression by IC was significantly associated with worse overall survival in patients with neoadjuvant chemotherapy and showed a trend for worse overall survival and distant metastasis-free survival in triple-negative patients with neoadjuvant chemotherapy. Positive PD-L1 expression by TCIC and TC also showed trends for worse survival in different subgroups. CONCLUSIONS: Our findings indicate that the three scoring methods with a 1% cutoff are different in their sensitivity for PD-L1 expression and their associations with clinicopathologic factors. Scoring by TCIC is the most sensitive way to identify PD-L1-positive breast cancer by immunohistochemistry. As a prognostic marker, our study suggests that PD-L1 is associated with worse clinical outcome, most often shown by the IC score; however, the other scores may also have clinical implications in some subgroups. Large clinical trials are needed to test the similarities and differences of these scoring methods for their predictive values in anti-PD-1/PD-L1 therapy.


Assuntos
Antígeno B7-H1/biossíntese , Neoplasias da Mama/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , 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 , Terapia Combinada , Aprovação de Drogas , Feminino , Seguimentos , Humanos , Imuno-Histoquímica/métodos , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Estados Unidos , United States Food and Drug Administration
3.
Breast Cancer Res ; 22(1): 46, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32410705

RESUMO

BACKGROUND: The presence of tumour-infiltrating lymphocytes (TILs) is associated with response to neoadjuvant chemotherapy among patients with triple-negative and HER2-positive breast cancer. However, the significance of TILs is less clear in luminal breast cancer. Here, we in postmenopausal patients with primary oestrogen receptor-positive (ER+), HER2 normal, operable breast cancer assessed the importance of inducing TILs during 4 months of letrozole on response in a neoadjuvant phase II study. METHODS: Participants were postmenopausal women with ER+, HER2 normal operable breast cancer assigned to 4 months of neoadjuvant letrozole. Pretreatment core biopsies and surgical specimens were assessed centrally for the percentage of TILs on haematoxylin and eosin-stained slides according to the International Immuno-Oncology Biomarker Working Group on Breast Cancer guidelines. Pathological response was assessed by the Residual Cancer Burden (RCB) index and a modified Miller-Payne grading system and was analysed according to change in TILs. RESULTS: Tumour specimens were available from 106 of the 112 patients treated per protocol. TIL concentration increased with mean 6.8 percentage point (p < 0.0001) during treatment (range - 39 to 60). An increase in TILs was significantly associated with pathological response with OR = 0.71 (95% CI 0.53-0.96; p = 0.02) per 10% absolute increase for pathological response and correspondingly OR = 0.56 (95% CI 0.40-0.78; p = 0.0007) for lower RCB index per 10% increase. CONCLUSION: Increasing TILs during letrozole was significantly associated with a poor treatment response. An increase in TILs during endocrine therapy might imply immunogenicity, and these patients could be targetable by immunotherapy. TRIAL REGISTRATION: ClinicalTrials.govNCT00908531, registered 27 May 2009.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Letrozol/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/imunologia , Carcinoma Lobular/patologia , Carcinoma Lobular/cirurgia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
4.
Breast Cancer Res Treat ; 181(2): 391-401, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32323103

RESUMO

PURPOSE: AE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis. METHODS: In this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated. RESULTS: 456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573 CI 0.275-1.193), HER2 under-expression (p = 0.181, HR 0.756 CI 0.499-1.145), and triple-negative breast cancer (p = 0.266, HR 0.443 CI 0.114-1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375 CI 0.142-0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG. CONCLUSIONS: This phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Receptor ErbB-2/imunologia , Vacinas de Subunidades/administração & dosagem , Adulto , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/imunologia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Fragmentos de Peptídeos , Prognóstico , Estudos Prospectivos , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Método Simples-Cego , Taxa de Sobrevida , Vacinas de Subunidades/imunologia
5.
Medicina (Kaunas) ; 56(2)2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033289

RESUMO

Plasma cell features are encountered in a variety of non-plasma cell neoplasias, especially carcinomas of a discohesive type, such as those occurring in the digestive tract and breast. Lobular carcinomas of the breast present themselves in a variety of architectural patterns and many cell morphologies, including plasmacytoid types. A matching plasma cell phenotype is sometimes an associated feature. We report a case of a moderate grade invasive lobular carcinoma with focal plasmacytoid morphology and aberrant expression of plasma cell markers in a patient previously diagnosed with multiple myeloma. Paradoxical plasma cell immunoprofiles can be encountered in many malignancies, causing serious diagnostic problems, even more so with those occurring in discohesive carcinomas in multiple myeloma patients.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Lobular/patologia , Mieloma Múltiplo/patologia , Plasmócitos/patologia , Doenças Raras/patologia , Tecido Adiposo/patologia , Idoso , Anticorpos Antineoplásicos , Neoplasias da Mama/imunologia , Carcinoma Lobular/imunologia , Feminino , Humanos , Cadeias kappa de Imunoglobulina/análise , Imuno-Histoquímica , Mieloma Múltiplo/imunologia , Inclusão em Parafina/métodos , Fenótipo , Plasmócitos/imunologia , Doenças Raras/imunologia , Sindecana-1/análise
6.
Eur J Cancer ; 127: 240-250, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31956037

RESUMO

BACKGROUND: The prognostic value of tumour-infiltrating lymphocytes (TILs) differs by breast cancer (BC) subtype. The aim of this study was to evaluate TILs in stage III BC in the context of BRCA1/2-like phenotypes and association with outcome and benefit of intensified platinum-based chemotherapy. PATIENTS AND METHODS: Patients participated in a randomised controlled trial of adjuvant intensified platinum-based chemotherapy versus conventional anthracycline-based chemotherapy carried out between 1993 and 1999 in stage III BC. Stromal TILs were scored according to International guidelines in these human epidermal growth factor receptor 2 (HER2)-negative tumours. BRCA-profiles were determined using Comparative Genomic Hybridization. RESULTS: TIL levels were evaluated in 248 BCs. High TILs were associated with Triple Negative BC (TNBC). BRCA-like tumours harboured higher TILs compared to non-BRCA-like tumours (median TILs of 20% versus 10%, p < 0.01). TIL levels in BRCA1-like tumours were higher compared to BRCA2-like tumours (median TILs of 20% versus 10%, p < 0.001). These correlations remained significant within the oestrogen (ER)-positive subgroup, however not within the TNBC subgroup. In this stage III BC cohort, high TIL level was associated with favourable outcome (TILs per 10% increment, recurrence-free survival (RFS): multivariate hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.71-0.94, p = 0.01; overall survival (OS): multivariate HR 0.80, 95% CI 0.68-0.94, p = 0.01). There was no significant interaction between TILs and benefit of intensified platinum-based chemotherapy. CONCLUSION: In this high-risk breast cancer cohort, high TILs were associated with TNBC and BRCA1-like status. Within the ER-positive subgroup, TIL levels were higher in BRCA1-like compared to BRCA2-like tumours. When adjusted for clinical characteristics, TILs were significantly associated with a more favourable outcome in stage III BC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Linfócitos do Interstício Tumoral/imunologia , Mutação , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carboplatina/administração & dosagem , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/genética , Carcinoma Lobular/imunologia , Carcinoma Lobular/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Tiotepa/administração & dosagem , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia
7.
Cancer Epidemiol Biomarkers Prev ; 28(12): 1977-1985, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31533938

RESUMO

BACKGROUND: The impact of the immune landscape of the microenvironment on cancer progression is not well understood for triple-negative breast cancer (TNBC). We, therefore, aimed to examine the association of immune cell enrichment scores as a proxy for immune profiles of tumor microenvironment with TNBC prognosis. METHODS: We included 76 patients with TNBC diagnosed between 2008 to 2016 in West China Hospital and 158 patients with TNBC from The Cancer Genome Atlas. On the basis of transcriptome data, we calculated the overall ImmuneScore and type-specific enrichment scores for 34 types of immune cells, using xCell, a gene signature-based method. HRs of recurrence-free survival (RFS) and overall survival (OS) were calculated by Cox proportional hazards models. RESULTS: During the median follow-up time of 2.8 (0.1-9.8) years, 42 patients had a recurrence, and 34 patients died. The overall ImmuneScore and most immune cell enrichment scores were relatively higher in tumors than normal tissues. A higher enrichment score of plasma cells was associated with favorable RFS [HR 0.45; 95% confidence interval (CI), 0.27-0.73] and OS (HR 0.32; 95% CI, 0.17-0.61). The score of CD4+ central memory T cell (Tcm) was negatively associated with RFS (HR 1.52; 95% CI, 1.17-1.97). Besides, CD4+ Tcm enrichment score was higher in invasive tumors that were not ductal/lobular carcinoma (OR 1.59; 95% CI, 1.06-2.37). CONCLUSIONS: Our findings suggest that plasma cells and CD4+ Tcm in the tumor microenvironment may play a role in the subsequent progression of TNBC. IMPACT: This study provides evidence of the role of immune cells in TNBC progression that may have clinical utility.


Assuntos
Biomarcadores/análise , Carcinoma Ductal de Mama/imunologia , Carcinoma Lobular/imunologia , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Neoplasias de Mama Triplo Negativas/imunologia , Microambiente Tumoral/imunologia , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/patologia , China , Estudos de Coortes , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Prognóstico , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/patologia
8.
Breast J ; 25(5): 813-822, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31165568

RESUMO

Rabbit monoclonal antibody (RabMAb) demonstrates higher sensitivity without sacrificing specificity than mouse monoclonal antibody (MMAb). MMAb against E-cadherin stain is heavily utilized in distinguishing ductal carcinoma in situ (DCIS) from lobular carcinoma in situ (LCIS). We aimed to compare the E-cadherin stain using RabMAb vs MMAb in distinguishing DCIS from LCIS. One hundred and seventeen in situ breast carcinomas (55 DCIS, 58 LCIS, and 4 DCIS and LCIS) were studied. Sections from a representative block of each were stained with RabMAb [EP700Y] and MMAb [36B5]. Scanned images of stained slides were compared in tandem. All DCIS cases (59/59) showed comparable staining by RabMAb and MMAb. Comparable staining was also observed in all but one case of LCIS (61/62; 98%). One case of pleomorphic LCIS showed mostly complete, weak to moderately intense membranous staining with RabMAb and fragmented, weak membranous staining with MMAb. Consistently better staining quality was observed in slides stained by RabMAb vs MMAb. RabMAb and MMAb against E-cadherin were diagnostically equivalent with the exception of one case where RabMAb may have led to diagnostic misinterpretation. However, the not insignificant cost savings and easier interpretation using RabMAb may justify the risk of misinterpretation of increased staining in rare cases, largely avertable with proper training.


Assuntos
Anticorpos Monoclonais/imunologia , Neoplasias da Mama/diagnóstico , Caderinas/imunologia , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Lobular/diagnóstico , Animais , Anticorpos Monoclonais/economia , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Caderinas/economia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/imunologia , Carcinoma Lobular/patologia , Feminino , Humanos , Camundongos , Coelhos , Sensibilidade e Especificidade
9.
Breast Cancer Res Treat ; 175(2): 459-472, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30778902

RESUMO

PURPOSE: Breast cancer is a heterogeneous disease, and although advances in molecular subtyping have been achieved in recent years, most subtyping strategies target individual genes independent of one another and primarily concentrate on proliferative markers. The contributions of biological processes and immune patterns have been neglected in breast cancer subtype stratification. METHODS: We performed a gene set variation analysis to simplify the information on biological processes using hallmark terms and to decompose immune cell data using the immune cell gene terms on 985 breast invasive ductal/lobular carcinoma RNAseq samples in the TCGA database. RESULTS: The samples were gathered into three clusters following implementation of the t-SNE and DBSCAN algorithms and were categorized as 'hallmark-tsne' subtypes. Here, we identified a high-risk luminal A dominant breast cancer subtype (C3) that displayed increased motility, cancer stem cell-like features, a higher expression of hormone/luminal-related genes, a lower expression of proliferation-related genes and immune dysfunction. With regard to immune dysfunction, we observed that the motility-increased C3 subtype exhibited high granulocyte colony stimulating factor (G-CSF) expression accompanied by neutrophil aggregation. Cancer cells that produce high levels of G-CSF can stimulate neutrophils to form neutrophil extracellular traps, which promote cancer cell migration. This finding sheds light on one potential explanation for why the C3 subtype correlates with poor prognosis. CONCLUSIONS: The hallmark-tsne subtypes confirmed again that even the luminal A subtype is heterogeneous and can be further subdivided. The biological processes and immune heterogeneity of breast cancer must be understood to facilitate the improvement of clinical treatments.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Fator Estimulador de Colônias de Granulócitos/genética , Proteínas de Neoplasias/genética , Algoritmos , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/classificação , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/classificação , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/classificação , Carcinoma Lobular/genética , Carcinoma Lobular/imunologia , Carcinoma Lobular/patologia , Movimento Celular/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/imunologia , Fator Estimulador de Colônias de Granulócitos/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células MCF-7 , Proteínas de Neoplasias/imunologia , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Prognóstico , Receptores de Progesterona
10.
Pathol Oncol Res ; 25(3): 1233-1243, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30759303

RESUMO

Epidemiological evidence points to a link between insulin resistance (IR) and breast cancer (BrCA). Insulin plays a role in CD8+ T cells (CD8T) differentiation and function and affects adipocytokines levels. CD8T activity in BrCA is associated with favorable outcome; while PD1 and TIM3 are markers of CD8T exhaustion and play critical roles in the negative regulation of T cell responses. Patients with (BrCA) have high expression levels of PD1 on circulating. Therefore, we hypothesized that BrCA and IR could affect PD1 and/or TIM3 expression on circulating CD8T. We determine PD1 and TIM3 expression on CD8T and analyze the relationship of CD8T phenotype with serum insulin and plasma adipocytokines levels in the different groups. We enrolled four groups of treatment-naive patients: women without neoplasms (Neo-)/without IR (IR-), Neo-/with IR (IR+), BrCa/IR- and BrCa/IR+. We found interactions between BrCA and IR with respect to TIM3 on naïve and central memory (CM) CD8T subsets. Furthermore, BrCA had a greater PD1 + TIM3- CD8T frequency in CD8T subsets than Neo-. IR+ presented a significantly lower PD1 + TIM3- frequency in CD8T subsets compare to Non-IR. In addition, we found a negative correlation between insulin levels, HOMA and frequency of PD1 + TIM3- in CD8T and a positive correlation between adiponectin levels and the frequency PD1 + TIM3- in CD8T. The increased expression of PD1 on different subsets of CD8T from BrCa patients is consistent with immunological tolerance, whereas IR has a contrary effect. IR could have a deleterious role in the activation of CD8T that can be relevant to new BrCa immunotherapy.


Assuntos
Neoplasias da Mama/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Resistência à Insulina , Receptor de Morte Celular Programada 1/metabolismo , Adiponectina/metabolismo , Neoplasias da Mama/sangue , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Ductal de Mama/sangue , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/sangue , Carcinoma Lobular/imunologia , Carcinoma Lobular/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico
11.
Cell Rep ; 25(3): 702-714.e6, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30332649

RESUMO

CDH1 and PIK3CA are the two most frequently mutated genes in invasive lobular carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which, immune-related (IR), is associated with gene expression linked to lymphocyte and macrophage infiltration. Here, we report that deletion of Cdh1, together with activation of Pik3ca in mammary epithelium of genetically modified mice, leads to formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression linked to T-regulatory (Treg) cell signaling and activation of targetable immune checkpoint pathways. Interestingly, these tumors show enhanced Rac1- and Yap-dependent transcription and signaling, as well as sensitivity to PI3K, Rac1, and Yap inhibitors in culture. Finally, high-dimensional immunophenotyping in control mouse mammary gland and IR-ILC tumors by mass cytometry shows dramatic alterations in myeloid and lymphoid populations associated with immune suppression and exhaustion, highlighting the potential for therapeutic intervention via immune checkpoint regulators.


Assuntos
Caderinas/fisiologia , Carcinoma Lobular/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Mamárias Animais/patologia , Mutação , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Lobular/imunologia , Carcinoma Lobular/metabolismo , Proteínas de Ciclo Celular/metabolismo , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Neoplasias Mamárias Animais/imunologia , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Knockout , Células Mieloides/imunologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Invasividade Neoplásica , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Transcriptoma , Proteínas rac de Ligação ao GTP/metabolismo
12.
Clin Breast Cancer ; 18(6): 451-458.e1, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29866579

RESUMO

BACKGROUND: CD8+ tumor-infiltrating lymphocytes (TILs) have emerged as a prognostic indicator in triple-negative breast cancer (TNBC). There is debate surrounding the prognostic value of hot spots for CD8+ TIL enumeration. METHODS: We compared hot spot versus whole-tumor CD8+ TIL enumeration in prognosticating TNBC using immunohistochemistry on whole tissue sections and quantification by digital image analysis (Halo imaging analysis software; Indica Labs, Corrales, NM). A wide range of clinically relevant hot spot sizes was evaluated. RESULTS: CD8+ TIL enumeration was independently statistically significant for all hot spot sizes and whole-tumor annotations for disease-free survival by multivariate analysis. A 10× objective (2.2 mm diameter) hot spot was found to correlate significantly with overall survival (P = .04), while the remaining hot spots and whole-tumor CD8+ TIL enumeration did not (P > .05). Statistical significance was not demonstrated when comparing between hot spots and whole-tumor annotations, as the groups had overlapping confidence intervals. CONCLUSION: CD8+ TIL hot spot enumeration is equivalent to whole-tumor enumeration for prognostication in TNBC and may serve as a good alternative methodology in future studies and clinical practice.


Assuntos
Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Processamento de Imagem Assistida por Computador/métodos , Linfócitos do Interstício Tumoral/patologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/imunologia , Carcinoma Lobular/terapia , Estudos de Coortes , Terapia Combinada , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/terapia
13.
Nat Commun ; 9(1): 1725, 2018 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-29713003

RESUMO

Breast cancer (BC) in the Asia Pacific regions is enriched in younger patients and rapidly rising in incidence yet its molecular bases remain poorly characterized. Here we analyze the whole exomes and transcriptomes of 187 primary tumors from a Korean BC cohort (SMC) enriched in pre-menopausal patients and perform systematic comparison with a primarily Caucasian and post-menopausal BC cohort (TCGA). SMC harbors higher proportions of HER2+ and Luminal B subtypes, lower proportion of Luminal A with decreased ESR1 expression compared to TCGA. We also observe increased mutation prevalence affecting BRCA1, BRCA2, and TP53 in SMC with an enrichment of a mutation signature linked to homologous recombination repair deficiency in TNBC. Finally, virtual microdissection and multivariate analyses reveal that Korean BC status is independently associated with increased TIL and decreased TGF-ß signaling expression signatures, suggesting that younger Asian BCs harbor more immune-active microenvironment than western BCs.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Carcinoma Ductal/genética , Carcinoma Lobular/genética , Transcriptoma , Adulto , Grupo com Ancestrais do Continente Asiático , Proteína BRCA1/genética , Proteína BRCA1/imunologia , Proteína BRCA2/genética , Proteína BRCA2/imunologia , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/etnologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Carcinoma Ductal/etnologia , Carcinoma Ductal/imunologia , Carcinoma Ductal/patologia , Carcinoma Lobular/etnologia , Carcinoma Lobular/imunologia , Carcinoma Lobular/patologia , Estudos de Coortes , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/imunologia , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pós-Menopausa , Pré-Menopausa , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia , Sequenciamento Completo do Exoma
14.
Sci Rep ; 8(1): 7205, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29739984

RESUMO

Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer following invasive ductal carcinoma (IDC). ILC differs from IDC in a number of histological and clinical features, such as single strand growth, difficulty in detection, and frequent late recurrences. To understand the molecular pathways involved in the clinical characteristics of ILC, we compared the gene expression profiles of luminal A ILC and luminal A IDC using data from TCGA and utilized samples from METABRIC as a validation data set. Top pathways that were significantly enriched in ILC were related to immune response. ILC exhibited a higher activity of almost all types of immune cells based on cell type-specific signatures compared to IDC. Conversely, pathways that were less enriched in ILC were related to protein translation and metabolism, which we functionally validated in cell lines. The higher immune activity uncovered in our study highlights the currently unexplored potential of a response to immunotherapy in a subset of patients with ILC. Furthermore, the lower rates of protein translation and metabolism - known features of tumor dormancy - may play a role in the late recurrences of ILC and lower detection rate in mammography and PET scanning.


Assuntos
Neoplasias da Mama/imunologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Lobular/imunologia , Regulação Neoplásica da Expressão Gênica , Redes e Vias Metabólicas/imunologia , Proteínas de Neoplasias/imunologia , Recidiva Local de Neoplasia/imunologia , Idoso , Atlas como Assunto , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/diagnóstico , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Genoma Humano , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Sistema Imunitário/patologia , Imunoterapia/métodos , Metástase Linfática , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/classificação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Biossíntese de Proteínas , Evasão Tumoral/genética
15.
J Natl Cancer Inst ; 110(7): 768-776, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29471435

RESUMO

Background: Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer after invasive ductal cancer (IDC). Here, we aimed at evaluating the prevalence, levels, and composition of tumor-infiltrating lymphocytes (TILs) and their association with clinico-pathological and outcome variables in ILC, and to compare them with IDC. Methods: We considered two patient series with TIL data: a multicentric retrospective series (n = 614) and the BIG 02-98 study (n = 149 ILC and 807 IDC). We compared immune subsets identified by immuno-histochemistry in the ILC (n = 159) and IDC (n = 468) patients from the Nottingham series, as well as the CIBERSORT immune profiling of the ILC (n = 98) and IDC (n = 388) METABRIC and The Cancer Genome Atlas patients. All ILC/IDC comparisons were done in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors. All statistical tests were two-sided. Results: TIL levels were statistically significantly lower in ILC compared with IDC (fold-change = 0.79, 95% confidence interval = 0.70 to 0.88, P < .001). In ILC, high TIL levels were associated with young age, lymph node involvement, and high proliferative tumors. In the univariate analysis, high TIL levels were associated with worse prognosis in the retrospective and BIG 02-98 lobular series, although they did not reach statistical significance in the latter. The Nottingham series revealed that the levels of intratumoral but not total CD8+ were statistically significantly lower in ILC compared with IDC. Comparison of the CIBERSORT profiles highlighted statistically significant differences in terms of immune composition. Conclusions: This study shows differences between the immune infiltrates of ER-positive/HER2-negative ILC and IDC in terms of prevalence, levels, localization, composition, and clinical associations.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Carcinoma Lobular/imunologia , Carcinoma Lobular/patologia , Linfócitos do Interstício Tumoral/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Carcinoma Lobular/diagnóstico , Carcinoma Lobular/metabolismo , Feminino , Humanos , Metástase Linfática , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/metabolismo , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos
16.
Acta Oncol ; 57(1): 90-94, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29168428

RESUMO

INTRODUCTION: In breast cancer, there is a growing body of evidence that tumor-infiltrating lymphocytes (TILs) may have clinical utility and may be able to direct clinical decisions for subgroups of patients. Clinical utility is, however, not sufficient for warranting the implementation of a new biomarker in the routine practice, and evaluation of the analytical validity is needed, including testing the reproducibility of decentralized assessment of TILs. The aim of this study was to evaluate the inter-observer agreement of TILs assessment using a standardized method, as proposed by the International TILs Working Group 2014, applied to a cohort of breast cancers reflecting an average breast cancer population. MATERIAL AND METHODS: Stromal TILs were assessed using full slide sections from 124 breast cancers with varying histology, malignancy grade and ER- and HER2 status. TILs were estimated by nine dedicated breast pathologists using scanned hematoxylin-eosin stainings. TILs results were categorized using various cutoffs, and the inter-observer agreement was evaluated using the intraclass coefficient (ICC), Kappa statistics as well as individual overall agreements with the median value of TILs. RESULTS: Evaluation of TILs led to an ICC of 0.71 (95% CI: 0.65-0.77) corresponding to an acceptable agreement. Kappa values were in the range of 0.38-0.46 corresponding to a fair to moderate agreement. The individual agreements increased, when using only two categories ('high' vs. 'low' TILs) and a cutoff of 50-60%. DISCUSSION: The results of the present study are in accordance with previous studies, and shows that the proposed methodology for standardized evaluation of TILs renders an acceptable inter-observer agreement. The findings, however, indicate that assessment of TILs needs further refinement, and is in support of the latest St. Gallen Consensus, that routine reporting of TILs for early breast cancer is not ready for implementation in a clinical setting.


Assuntos
Neoplasias da Mama/patologia , Linfócitos do Interstício Tumoral/patologia , Neoplasias da Mama/imunologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/imunologia , Carcinoma Lobular/patologia , Feminino , Humanos , Patologia Clínica/normas , Reprodutibilidade dos Testes , Coloração e Rotulagem
17.
Lab Invest ; 98(1): 150-160, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29131161

RESUMO

Up to 40% of patients undergoing breast conserving surgery for breast cancer require repeat surgeries due to close to or positive margins. The lengthy processing required for evaluating surgical margins by standard paraffin-embedded histology precludes its use during surgery and therefore, technologies for rapid evaluation of surgical pathology could improve the treatment of breast cancer by reducing the number of surgeries required. We demonstrate real-time histological evaluation of breast cancer surgical specimens by staining specimens with acridine orange (AO) and sulforhodamine 101 (SR101) analogously to hematoxylin and eosin (H&E) and then imaging the specimens with fluorescence nonlinear microscopy (NLM) using a compact femtosecond fiber laser. A video-rate computational light absorption model was used to produce realistic virtual H&E images of tissue in real time and in three dimensions. NLM imaging could be performed to depths of 100 µm below the tissue surface, which is important since many surgical specimens require subsurface evaluation due to contamination artifacts on the tissue surface from electrocautery, surgical ink, or debris from specimen handling. We validate this method by expert review of NLM images compared to formalin-fixed, paraffin-embedded (FFPE) H&E histology. Diagnostically important features such as normal terminal ductal lobular units, fibrous and adipose stromal parenchyma, inflammation, invasive carcinoma, and in situ lobular and ductal carcinoma were present in NLM images associated with pathologies identified on standard FFPE H&E histology. We demonstrate that AO and SR101 were extracted to undetectable levels after FFPE processing and fluorescence in situ hybridization (FISH) HER2 amplification status was unaffected by the NLM imaging protocol. This method potentially enables cost-effective, real-time histological guidance of surgical resections.


Assuntos
Carcinoma de Mama in situ/patologia , Neoplasias da Mama/patologia , Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Margens de Excisão , Laranja de Acridina/química , Mama/citologia , Mama/imunologia , Mama/cirurgia , Carcinoma de Mama in situ/diagnóstico , Carcinoma de Mama in situ/imunologia , Carcinoma de Mama in situ/cirurgia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/imunologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/diagnóstico , Carcinoma Lobular/imunologia , Carcinoma Lobular/cirurgia , Corantes/química , Feminino , Corantes Fluorescentes/química , Humanos , Imageamento Tridimensional , Período Intraoperatório , Mastectomia , Mastectomia Segmentar , Microscopia de Fluorescência , Invasividade Neoplásica , Microscopia Óptica não Linear , Tratamentos com Preservação do Órgão , Rodaminas/química
18.
Mod Pathol ; 30(11): 1551-1560, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28731046

RESUMO

Tumor-infiltrating lymphocytes and immune checkpoint proteins such as PD-L1 are potential prognostic factors and therapeutic targets in breast cancer. Most studies characterizing the breast tumor immune microenvironment have focused on ductal carcinomas. Here we investigate the tumor microenvironment of primary invasive lobular carcinomas. Previously constructed tissue microarrays of 47 lobular carcinomas were labeled by immunohistochemistry for PD-L1, CD8, CD20, and FoxP3. The stromal immune infiltrate density was qualitatively scored as a percentage of tumor area: 1+ (<5%); 2+ (5-10%); 3+ (10-15%); or 4+ (>50%). The average immune cell subtype per high-power field was quantitatively scored. The percentage PD-L1 labeling on tumor-infiltrating lymphocytes was scored as none, focal (<5%), moderate (10-24%), or diffuse (50-100%). The percentage of membranous carcinoma cell PD-L1 labeling was also recorded, with <5% considered negative. All lobular carcinomas contained PD-L1+ tumor-infiltrating lymphocytes with the majority showing 1+ immune infiltrates with focal-moderate PD-L1 labeling. PD-L1 was expressed by tumor cells in 17% of lobular carcinomas. In contrast to ductal carcinomas, there was no correlation between the immune infiltrate density, the PD-L1 expression by lobular carcinoma cells, tumor grade, or the expression of estrogen receptor or human epidermal growth factor receptor-2. However, both the tumor-infiltrating lymphocyte density and the average CD8+ T-cell counts correlated with immune cell PD-L1 status (P=0.004 and 0.03, respectively). Similar to breast ductal carcinomas, PD-L1+ lobular breast carcinomas had higher numbers of PD-L1+ tumor-infiltrating lymphocytes (63%) than PD-L1- lobular carcinomas (23%; P=0.04). These data show that a subset of primary breast lobular carcinomas both express PD-L1 on tumor cells and contain PD-L1+ tumor-infiltrating lymphocytes, suggesting the possibility of both constitutive and adaptive PD-L1 expression. Together, these results support immunotherapy as a potential treatment for a subset of patients with primary invasive lobular breast carcinomas.


Assuntos
Antígeno B7-H1/imunologia , Neoplasias da Mama/imunologia , Carcinoma Lobular/imunologia , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/imunologia , Feminino , Humanos , Pessoa de Meia-Idade
19.
Breast ; 35: 21-26, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28628772

RESUMO

INTRODUCTION: The intent of this analysis was to investigate and validate the prognostic potential of Ki67 in a multi-center series of patients affected by early stage 'pure' invasive lobular carcinoma (ILC). METHODS: Clinical-pathological data of patients affected by ILC were correlated with overall survival and disease-free survival (OS/DFS); data from a parallel invasive ductal carcinoma (IDC) patients' cohort were gathered as well. The maximally selected Log-Rank statistics analysis was applied to Ki67 continuous variable to estimate the appropriate cut-off. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed as well. RESULTS: Data from overall 1097 (457/222 ILC: training/validation set; 418 IDC) patients were gathered. The identified optimal Ki67 cut-offs were 4% and 14% for DFS in ILC and IDC cohort, respectively. In ILC patients, the Ki67 cut-off was an independent OS predictor. Ten-years OS and DFS were 89.9% and 77.2% (p = 0.007) and 79.4% and 69.2% (p = 0.03) for patients with Ki67 ≤ 4% and >4%, respectively. In IDC patients, 10-years OS was 93.8% and 71.7%, p = 0.02, DFS was 84.0% and 52.6%, p = 0.0003, for patients with Ki67 ≤ 14% and >14%, respectively. In the validation set, the optimal Ki67 OS cut-off was 5%. The STEPP analysis showed that in the presence of low Ki67 values, IDC patients have a better DFS than ILC patients, while with the increase of values the prognosis tends to overlap. CONCLUSIONS: Despite the retrospective design of the study, the prognostic relevance of Ki67 (as well as its optimal cut-off) seems to significantly differ according to breast cancer histology.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Carcinoma Lobular/imunologia , Carcinoma Lobular/patologia , Antígeno Ki-67/metabolismo , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
20.
Dis Markers ; 2016: 5128720, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27847402

RESUMO

Purpose. To investigate a frequency of antibody response to SEREX-identified medullary breast carcinoma autoantigens ZRF1 and KRR1 in sera of breast cancer patients taking into account clinical and molecular characteristics of tumors for opening of new perspectives in creation of minimally invasive immunological tests for cancer diagnostics. Methods. Enzyme-linked immunosorbent assay and bioinformatics analysis. Results. Increased frequency of antibody response was found in sera of breast cancer patients to ZRF and KRR1 antigens. The antibody response to these antigens was higher in sera of patients with invasive ductal carcinoma than in sera of patients with other histological types of breast tumors. Moreover, more frequent antibody response to ZRF antigen was found in sera of patients with less aggressive tumors. The sequence analysis of ZRF1 antigen SEREX clones obtained from cDNA libraries of different tumors demonstrates that they encode different protein isoforms. Conclusion. Tumor-associated antigens KRR1 and ZRF1 and their cognate autoantibodies could be considered as potential molecular markers of breast cancer which need to be further investigated.


Assuntos
Antígenos de Neoplasias/sangue , Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Neoplasias da Mama/imunologia , Proteínas de Ligação a DNA/sangue , Proteínas Oncogênicas/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Sequência de Bases , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/sangue , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/sangue , Carcinoma Lobular/imunologia , Carcinoma Lobular/patologia , Carcinoma Medular/sangue , Carcinoma Medular/imunologia , Carcinoma Medular/patologia , Estudos de Casos e Controles , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Biblioteca Gênica , Humanos , Pessoa de Meia-Idade , Chaperonas Moleculares , Gradação de Tumores , Estadiamento de Neoplasias , Complexo de Proteínas Formadoras de Poros Nucleares/sangue , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/imunologia , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/imunologia , Prognóstico , Proteínas de Ligação a RNA/sangue , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...