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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.
Oncol Rep ; 44(4): 1758-1770, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32700745

RESUMO

Breast cancer is the leading cause of cancer­-associated deaths in women. Combination immunotherapy attracts great interest as a treatment for breast cancer. However, there are no studies on the use of cytotoxic T­lymphocyte antigen 4 (CTLA­4) monoclonal antibody in combination with the melanoma­associated antigen A family (MAGE­As) co­antigen peptide (p248V9) for treating breast cancer, which should be explored. To this aim, in the present study, the samples of 115 patients with breast cancer were collected, and MAGE­As and CTLA­4 levels in breast cancer and adjacent normal tissues were assessed by immunohistochemical staining. The effect of 5­aza­2'­deoxycytidine (5DC) on the expression of MAGE­As in breast cancer cell lines was assessed by reverse transcription­quantitative PCR and western blot assay. Cytotoxic T cells (CTLs) were induced by MAGE­As co­antigen peptide. The specific lytic rate and IFN­Î³ level were examined by CCK­8 assay and ELISA, respectively. It was found that MAGE­As were highly expressed in breast cancer tissues. 5DC treatment promoted the expression of MAGE­As in breast cancer cells. The upregulation of the expression of MAGE­As specifically enhanced the ability of CTLs to kill breast cancer cells. CTLA­4 was highly expressed in breast cancer tissues and cells, and patients with breast cancer exhibiting high expression of CTLA­4 had low overall survival. CTLA­4 promoted the lytic efficiency of CTLs in breast cancer cells, and the combination of an anti­CTLA­4 antibody and 10 µM 5DC exhibited the highest cell lysis ability of CTLs. The present study demonstrated that MAGE­As co­antigen peptide­specific CTLs in combination with an anti­CTLA­4 monoclonal antibody and 5DC, have potent tumor cell­killing effects. It provides a novel theory for the development of breast cancer therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma Ductal de Mama/tratamento farmacológico , Antígenos Específicos de Melanoma/metabolismo , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Antígeno CTLA-4/imunologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Linhagem Celular Tumoral , Decitabina/administração & dosagem , Feminino , Seguimentos , Humanos , Metástase Linfática , Células MCF-7 , Antígenos Específicos de Melanoma/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida , Linfócitos T Citotóxicos/efeitos dos fármacos
3.
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
4.
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
5.
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
6.
Breast Cancer Res Treat ; 181(2): 331-338, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32253685

RESUMO

BACKGROUND: High F18-fluorodeoxyglucose (FDG) uptake has been reported to be a predictor of poor prognosis in patients with breast cancer. We investigated the relationship between FDG uptake and immunological factors, including the data of programmed cell death-ligand 1 (PD-L1), CD8, and tumor-infiltrating lymphocytes (TILs). METHODS: Breast cancer tissues of 97 patients who underwent surgery without preoperative therapy were examined. The grade of stromal TILs was immunohistochemically evaluated using the criteria of the International TILs Working Group in breast cancer. PD-L1 positivity and CD8 positivity were immunohistochemically evaluated. The FDG uptakes were evaluated based on the standardized uptake value max (SUVmax). The relationships between SUVmax and TIL grade and expression of PD-L1 and CD8 were investigated. RESULTS: Among the 97 patients, 41 (42.3%) had a high SUVmax in their primary tumor, based on the SUVmax cut-off value 3 yielded by receiver operating characteristic curves. PD-L1 was positive in 17 patients (17.5%). Our analyses revealed that large tumor size, high nuclear grade, high degree of TILs and positive expression of PD-L1 were significantly associated with high SUVmax in the primary tumor. There were significant associations between SUVmax and the degree of TILs (r = 0.428, p < 0.001) and between SUVmax and the PD-L1 positivity (r = 0.413, p < 0.001). All cases with a high degree of TILs showed high CD8 expression. CONCLUSION: Our results indicate that the FDG uptake may be predictive of immunological features including TILs and PD-L1 expression in breast cancer patients. Additional research is necessary to further evaluate FDG-PET as a biomarker of immune checkpoint therapy in breast cancer.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Fluordesoxiglucose F18/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Tomografia por Emissão de Pósitrons , Prognóstico , Compostos Radiofarmacêuticos/metabolismo , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos
7.
Cancer Immunol Immunother ; 69(7): 1315-1326, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32198536

RESUMO

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


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Ductal de Mama/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
8.
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
9.
World J Surg Oncol ; 18(1): 11, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937323

RESUMO

BACKGROUND: Metaplastic breast cancer remains poorly characterized given its rarity and heterogeneity. The majority of metaplastic breast cancers demonstrate a phenotype of triple-negative breast cancer; however, differences in clinical outcomes between metaplastic breast cancer and triple-negative breast cancer in the era of third-generation chemotherapy remain unclear. METHODS: We compared the clinical outcomes between women with metaplastic breast cancer and women with triple-negative breast cancer diagnosed between 1994 and 2014. Metaplastic breast cancer patients were matched 1:3 to triple-negative breast cancer patients by stage and age at diagnosis. Distant disease-free survival (DDFS) and overall survival (OS) were estimated using Kaplan Meier methods and Cox proportional hazard regression models. Immune checkpoint markers were characterized by immunohistochemistry in a subset of samples. RESULTS: Forty-four metaplastic breast cancer patients (stage I 14%; stage II 73%; stage III 11%; stage IV 2%) with an average age of 55.4 (± 13.9) years at diagnosis. Median follow-up for the included metaplastic breast cancer and triple-negative breast cancer patients (n = 174) was 2.8 (0.1-19.0) years. The DDFS and OS between matched metaplastic breast cancer and triple-negative breast cancer patients were similar, even when adjusting for clinical covariates (DDFS: HR = 1.64, p = 0.22; OS: HR = 1.64, p = 0.26). Metaplastic breast cancer samples (n = 27) demonstrated greater amount of CD163 in the stroma (p = 0.05) and PD-L1 in the tumor (p = 0.01) than triple-negative breast cancer samples (n = 119), although more triple-negative breast cancer samples were positive for CD8 in the tumor than metaplastic breast cancer samples (p = 0.02). CONCLUSIONS: Patients with metaplastic breast cancer had similar outcomes to those with triple-negative breast cancer based on DDFS and OS. The immune checkpoint marker profile of metaplastic breast cancers in this study may prove useful in future studies attempting to demonstrate an association between immune profile and survival.


Assuntos
Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Metaplasia/patologia , Metaplasia/terapia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/patologia
10.
Histopathology ; 76(4): 560-571, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31554015

RESUMO

AIMS: HER2-positive (HER2+) breast carcinoma (BC) cases are often treated similarly; however, they can be classified as either luminal B (LH) or non-luminal type (NLH) BC, which have different prognoses. In this study, we investigated the clinicohistomorphological features of each HER2+ BC subgroup. METHODS AND RESULTS: We classified 166 patients with HER2+ invasive BC into LH (n = 110, 66.3%) and NLH groups (n = 56, 33.7%). We further subclassified LH into patients with carcinomas expressing high levels of hormone receptors [LH-high; Allred score, oestrogen receptor (ER) and/or progesterone receptor (PgR) 4-8, n = 89, 53.6%] or low levels (LH-low; Allred score, ER and/or PgR 2 or 3, n = 21, 12.7%) for clinicohistomorphological characterisation. Morphological review showed that NLH included a percentage of patients with comedo necrosis, while LH patients had significantly more central scarring. In terms of immune responsiveness, NLH showed significantly higher rates of tumour-infiltrating lymphocytes and healing. The LH-high and NLH groups showed distinct characteristics (by both models, P < 0.05) and the LH-low group appeared to demonstrate intermediate characteristics according to multinomial analyses using covariates reflecting tumour morphology and immune response outcomes. CONCLUSIONS: These results support the classification of HER2+ BC into two major subgroups, LH-high and NLH, based on tumour morphology and immune response; LH-high proliferates via scirrhous and/or spiculated growth with a central scar, while the primary proliferation pattern of NLH is based on in-situ carcinomas containing comedo necrosis with noticeable TILs and healing.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Receptores Estrogênicos/biossíntese , Adulto , Idoso , Neoplasias da Mama/imunologia , Carcinoma Ductal de Mama/classificação , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Feminino , Humanos , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Receptores de Progesterona/biossíntese , Estudos Retrospectivos
11.
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
12.
Proteomics ; 19(21-22): e1800446, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31318138

RESUMO

Human olfactomedin-4 (OLFM4) is a secreted protein involved in a variety of cellular functions including proliferation, differentiation, apoptosis, and cell adhesion. OLFM4 expression has been studied in several tumor types including gastric, colorectal, lung, and endometrioid cancers where it has been suggested to be an independent favorable or unfavorable prognostic marker. For breast cancer, the clinical significance of OLFM4 is still unclear. In the present study, SWATH-MS is used as a tool for the robust identification and quantification of breast tissue proteins. SWATH-MS data show that OLFM4 expression is higher in DCIS than in invasive breast cancer. In-depth analysis of the breast tumor proteome show that OLFM4 is a favorable pronostic marker. Serum OLFM4 levels in peripheral blood are also analyzed by ELISA in 825 cases, including 94 cases of healthy individuals, 61 cases of non-invasive breast tumor (DCIS) and 670 cases of breast cancer (BC). It is found that serum OLFM4 levels are significantly higher in the DCIS cohort and in the breast cancer cohort compared with the healthy controls. This result suggests that circulating OLFM4 could be an interesting biomarker of early breast cancer. Data are available via ProteomeXchange with identifier PXD014194.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Fator Estimulador de Colônias de Granulócitos/metabolismo , Proteômica , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Carcinoma Ductal de Mama/sangue , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/imunologia , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos/sangue , Fator Estimulador de Colônias de Granulócitos/genética , Humanos , Invasividade Neoplásica , Lesões Pré-Cancerosas/patologia , Prognóstico
13.
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
14.
Ann Surg Oncol ; 26(10): 3337-3343, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31240590

RESUMO

BACKGROUND: Growing evidence suggests that the tumor immune microenvironment influences breast cancer development and prognosis. Density of tumor-infiltrating lymphocytes (TILs) within invasive breast cancer is correlated with response to therapy, especially in triple-negative disease. The clinical relevance and outcomes of TILs within ductal carcinoma in situ (DCIS) are less understood. METHODS: Our institutional database of 668 patients with pure DCIS from 2010 to 2018 was queried. TILs were evaluated by International TILs Working Group guidelines. Percentage of TILs was assessed from the densest focus (hotspot) in one high-power field of stroma touching the basement membrane. Statistical methods included cluster analyses (to define sparse versus dense TILs), logistic, and Cox regression models. RESULTS: Sixty-nine patients with DCIS and TILs were evaluated, of whom 54 (78%) were treated by breast-conserving surgery. Thirteen (19%) patients had ipsilateral recurrence. Each recurrence (n = 13) was matched to four controls (n = 56) based on date of surgery. Median follow-up was 6.7 years. TILs were defined as sparse (< 45%) or dense (≥ 45%). Dense TILs were associated with younger age (p = 0.045), larger tumor size (p < 0.001), high nuclear grade (p = 0.010), comedo histology (p = 0.033), necrosis (p = 0.027), estrogen receptor (ER) negativity (p = 0.037), and ipsilateral recurrence (p = 0.001). Nine patients with dense TILs had mean time to recurrence of 73.5 months compared with four patients with sparse TILs with mean time to recurrence of 97.9 months (p = 0.003). CONCLUSIONS: Dense TILs were significantly associated with age, tumor size, nuclear grade, comedo histology, necrosis, and ER status and was a significant predictor of recurrence in patients with pure DCIS.


Assuntos
Neoplasias da Mama/imunologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Intraductal não Infiltrante/imunologia , Linfócitos do Interstício Tumoral/imunologia , Mastectomia Segmentar/métodos , Recidiva Local de Neoplasia/imunologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Intraductal não Infiltrante/cirurgia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico
15.
J Immunol Res ; 2019: 8505021, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049361

RESUMO

Objective: This study is aimed at investigating the association of exhausted CD8+ tumor-infiltrating lymphocytes with clinic-pathological factors. Methods: 133 patients diagnosed with primary invasive ductal breast cancer were recruited into the cross-sectional study consecutively. Immunohistochemistry was used to detect biomarker expression on formalin-fixed and paraffin-embedded sections. Double staining of CD8 and PD-1 was conducted on lymphocytes. Results: The proportion of CD8+/PD-1- TILs was 16% among patients with axillary lymph node metastasis, significantly lower than those without metastasis (24%). The expression of CK7, CK20, or Ki-67 was not related with the proportion of phenotypes of CD8/PD-1 TILs. Younger patients had more cell counts of CD8+/PD-1- TILs than elderly patients (18/HPF vs. 9/HPF, p < 0.05). Patients with axillary lymph node metastasis had less CD8+/PD-1- TILs than those without metastasis (11/HPF vs. 27/HPF, p < 0.05). Median counts of CD8+/PD-1- TILs among patients with CK20 and E-Cad expression were 33/HPF and 14/HPF, significantly higher than those among patients with negative CK20 (16/HPF) and E-Cad expression (6/HPF). Ki-67 index had a significant correlation with cell counts of CD8+/PD-1+ TILs and CD8+/PD-1- TILs, and the correlation coefficients were 0.19 and 0.21 (p < 0.05), respectively. Conclusion: The proportion of CD8+/PD-1- TILs was related with metastatic status of the axillary lymph node but cell counts of CD8+/PD-1- TILs were related with metastatic status of the axillary lymph node and expression of CK7, CK20, E-Cad, and Ki-67. Absolute cell counts, not proportion of CD8/PD-1 TILs, were more likely to distinguish clinic and pathologic characteristics of breast cancer.


Assuntos
Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/citologia , Carcinoma Ductal de Mama/patologia , Linfócitos do Interstício Tumoral/citologia , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral , Idoso , Grupo com Ancestrais do Continente Asiático , Neoplasias da Mama/imunologia , Carcinoma Ductal de Mama/imunologia , Contagem de Células , China , Estudos Transversais , Feminino , Humanos , Antígeno Ki-67/análise , Pessoa de Meia-Idade , Estudos Retrospectivos
16.
Breast Cancer Res Treat ; 177(1): 17-27, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31134489

RESUMO

PURPOSE: Ductal carcinoma in situ (DCIS) of the breast is often regarded as a non-obligate precursor to invasive breast carcinoma but current diagnostic tools are unable to accurately predict the invasive potential of DCIS. Infiltration of immune cells into the tumour and its microenvironment is often an early event at the site of tumourigenesis. These immune infiltrates may be potential predictive and/or prognostic biomarkers for DCIS. This review aims to discuss recent findings pertaining to the potential prognostic significance of immune infiltrates as well as their evaluation in DCIS. METHODS: A literature search on PubMed was conducted up to 28th January 2019. Search terms used were "DCIS", "ductal carcinoma in situ", "immune", "immunology", "TIL", "TIL assessment", and "tumour-infiltrating lymphocyte". Search filters for "Most Recent" and "English" were applied. Information from published papers related to the research topic were synthesised and summarised for this review. RESULTS: Studies have revealed that immune infiltrates play a role in the biology and microenvironment of DCIS, as well as treatment response. There is currently no consensus on the evaluation of TILs in DCIS for clinical application. CONCLUSIONS: This review highlights the recent findings on the potential influence and prognostic value of immunological processes on DCIS progression, as well as the evaluation of TILs in DCIS. Further characterisation of the immune milieu of DCIS is recommended to better understand the immune response in DCIS progression and recurrence.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/mortalidade , Carcinoma Intraductal não Infiltrante/imunologia , Carcinoma Intraductal não Infiltrante/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral/imunologia , Animais , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Biomarcadores , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Citotoxicidade Imunológica , Progressão da Doença , Estrogênios/metabolismo , Feminino , Humanos , Imunofenotipagem , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Prognóstico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia
17.
Nat Commun ; 10(1): 1600, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30962452

RESUMO

In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Mapas de Interação de Proteínas , Proteoma/metabolismo , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/imunologia , Variações do Número de Cópias de DNA , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Proteogenômica/métodos , Proteoma/genética , Proteoma/imunologia , RNA Mensageiro/metabolismo
18.
Neurol Sci ; 40(7): 1461-1463, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30843116

RESUMO

INTRODUCTION: Motor neuron disease (MND) can occur in patients with cancer, but there is minimal evidence that this is more than by chance. We contrast two cases of motor neuronopathies occurring in the context of systemic malignancy and argue that in one case the cause was most likely paraneoplastic, while in the other it was not. CASE 1: A 61-year-old woman developed progressive walking difficulties over 9 months with weakness and stiffness in her legs. EMG showed fibrillations and positive sharp waves in multiple lower limb muscles bilaterally, with neurogenic units and a reduced recruitment pattern. An invasive ductal carcinoma of the breast was identified and she continued to deteriorate neurologically with worsening mobility, upper limb spasticity and fasciculations. She died approximately 26 months after symptom onset. CASE 2: A 57-year-old woman developed weight loss and weakness of her right arm without any sensory symptoms. At presentation, she had wasting and fasciculations in her right upper limb muscles, with normal reflexes, normal left upper limb and lower limb examination. Over the following week, she developed left upper limb weakness and fasciculations, brisk knee reflexes, and flexor plantar responses. Her EMG showed upper and lower limb denervation. She was found to have anti-Hu and anti-CV2 antibodies present in serum. A PET-CT showed active uptake in lymph nodes in the right hilum. Biopsy confirmed a small cell lung cancer. She had chemoradiation therapy and the tumour went into remission. She has remained well on follow-up 24 months later, regaining weight and strength after her chemotherapy. She continues to be monitored for cancer recurrence, but thus far appears to be in remission. CONCLUSION: In cases with rapidly progressive MND, particularly of upper limb onset, consideration should be given to testing anti-neuronal antibodies and searching for an occult tumour.


Assuntos
Neoplasias da Mama/complicações , Carcinoma Ductal de Mama/complicações , Neoplasias Pulmonares/complicações , Doença dos Neurônios Motores/complicações , Síndromes Paraneoplásicas do Sistema Nervoso , Carcinoma de Pequenas Células do Pulmão/complicações , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Evolução Fatal , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Pessoa de Meia-Idade , Doença dos Neurônios Motores/etiologia , Doença dos Neurônios Motores/imunologia , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/terapia
19.
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
20.
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
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