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1.
Mod Pathol ; 29(8): 799-809, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27125355

RESUMO

Breast cancers are routinely assessed for estrogen receptor status using immunohistochemical assays to assist in patient prognosis and clinical management. Specific assays vary between laboratories, and several antibodies have been validated and recommended for clinical use. As numerous factors can influence assay performance, many laboratories have opted for ready-to-use assays using automated stainers to improve reproducibility and consistency. Three commonly used autostainer vendors-Dako, Leica, and Ventana-all offer such estrogen receptor assays; however, they have never been directly compared. Here, we present a systematic comparison of three platform-specific estrogen receptor ready-to-use assays using a retrospective, tamoxifen-treated, breast cancer cohort from patients who were treated in Calgary, Alberta, Canada from 1985 to 2000. We found all assays showed good intra-observer agreement. Inter-observer pathological scoring showed some variability: Ventana had the strongest agreement followed closely by Dako, whereas Leica only showed substantial agreement. We also analyzed each estrogen receptor assay with respect to 5-year disease-free survival, and found that all performed similarly in univariate and multivariate models. Determination of measures of test performance found that the Leica assay had a lower negative predictive value than Dako or Ventana, compared with the original ligand-binding assay, while other measures-sensitivity, specificity, positive predictive value, and accuracy-were comparable between the three ready-to-use assays. When comparing against disease-free survival, the difference in negative predictive value between the vendor assays were not as extreme, but Dako and Ventana still performed slightly better than Leica. Despite some discordance, we found that all ready-to-use assays were comparable with or superior to the ligand-binding assay, endorsing their continued use. Our analysis also allowed for exploration of estrogen receptor-negative, progesterone receptor-positive cases, and we discovered that this phenotype was not consistent across the assays, suggesting this might be an artifact.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Imuno-Histoquímica , Kit de Reagentes para Diagnóstico , Receptores de Estrogênio/análise , Alberta , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Intervalo Livre de Doença , Antagonistas de Estrogênios/uso terapêutico , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Análise Multivariada , Variações Dependentes do Observador , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Tamoxifeno/uso terapêutico , Resultado do Tratamento
2.
Mod Pathol ; 29(12): 1492-1500, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27562489

RESUMO

Estrogen receptor and progesterone receptor status are routinely assessed using immunohistochemistry assays to assist in patient prognosis and clinical management. Three commonly utilized autostainer vendors-Dako, Leica and Ventana-provide ready-to-use progesterone receptor assays; however, they have never been directly compared in a single breast cancer cohort. We looked at three immunohistochemical progesterone receptor assays, in addition to original ligand-binding assay results, in a single retrospective, tamoxifen-treated breast cancer cohort to investigate inter- and intra-observer agreement, concordance, prognostic ability and measures of test performance. All immunohistochemical assays utilized the manufacturer's specified protocols. Five-year disease-free survival was the endpoint of interest, and multivariate models were adjusted for lymph node status, tumor grade, tumor size and human epidermal growth factor 2 status. All assays showed substantial to almost perfect agreement between the three observers (Dako κ=0.69-0.90; Leica κ=0.70-0.89; and Ventana κ=0.78-0.94) and concordance (Dako/Leica κ=0.81; Dako/Ventana κ=0.78; and Leica/Ventana κ=0.82). Univariate survival analyses showed that only the ligand-binding assay, Dako and Ventana assays achieved statistical significance. No statistically significant results were seen in multivariate models, although a strong trend was seen with the Ventana progesterone receptor assay. All assays performed similarly with regards to measures of test performance with ligand-binding assay set as the reference, and all immunohistochemical assays outperformed the ligand-binding assay in regards to 5-year disease-free survival. Despite similar agreement and concordance with the progesterone receptor assays, clear differences were noted with regards to 5-year disease-free survival. Additional survival analyses suggest that clinical utility of estrogen receptor assays vary when investigated in combination with progesterone receptor.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/metabolismo , Kit de Reagentes para Diagnóstico , Receptores de Progesterona/análise , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica/métodos , Estimativa de Kaplan-Meier , Variações Dependentes do Observador , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico
3.
Breast Cancer Res Treat ; 128(1): 69-78, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20669046

RESUMO

Antiestrogen therapies arrest susceptible estrogen receptor (ER)-positive breast cancers by increasing p27. Since Src phosphorylates p27 to promote p27 proteolysis, Src activation observed in up to 40% of ER-positive cancers may contribute to antiestrogen resistance. In this article, we show that treatment with the Src-inhibitor saracatinib (AZD0530) together with ER-blocking drugs increased breast cancer cell cycle arrest via p27. Saracatinib and fulvestrant together more effectively increased p27, reduced Ki67, and impaired MDA-MB-361 xenograft tumor growth in vivo than either of the drugs alone. In contrast, saracatinib monotherapy rapidly gave rise to drug resistance. Since combined ER and Src inhibition delays development of resistance in vivo, these data support further clinical investigation of saracatinib in combination with fulvestrant for women with ER-positive breast cancer. Proteomic analysis revealed striking bypass activation of the mTOR pathway in saracatinib-resistant tumors. mTORC1 activation also arose following long-term culture of ER-positive breast cancer lines in the presence of saracatinib. These data indicate the utility of proteomic analysis of drug-resistant tumors to identify potential means of drug resistance. The use of mTOR kinase inhibitors with saracatinib may subvert drug resistance and prove to be more effective than saracatinib alone.


Assuntos
Antineoplásicos/farmacologia , Benzodioxóis/farmacologia , Estradiol/análogos & derivados , Receptor alfa de Estrogênio/antagonistas & inibidores , Quinazolinas/farmacologia , Tamoxifeno/farmacologia , Quinases da Família src/antagonistas & inibidores , Animais , Neoplasias da Mama , Linhagem Celular Tumoral , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Fulvestranto , Fase G1/efeitos dos fármacos , Humanos , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Nus , Neoplasias Hormônio-Dependentes , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Clin Cancer Res ; 15(10): 3396-405, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19451593

RESUMO

PURPOSE: Antiestrogens are used to treat estrogen receptor (ER)-alpha-positive breast cancers and cause a p27-dependent G(1) arrest. Estrogen-bound ER recruits Src to mediate proteolysis of p27 and drive cell proliferation. Here, we tested the antitumor efficacy of combined Src and aromatase inhibition for ER-positive breast cancer. EXPERIMENTAL DESIGN: Antiproliferative effects of the aromatase inhibitor, anastrozole, and Src inhibitor, AZD0530, alone or in combination were tested in vitro and in vivo on aromatase-transfected MCF-7Arom5 xenografts. Xenografts were analyzed by immunohistochemistry and proteomic analysis to identify potential biomarkers of drug response and resistance. RESULTS: AZD0530 and anastrozole together increased p27 and caused greater G(1) cell cycle arrest than either drug alone. AZD0530 monotherapy initially retarded xenograft growth in vivo, but drug resistance rapidly emerged. Combined anastrozole/AZD0530 reduced drug resistance and showed greater antitumor efficacy in vivo with greater Src and epidermal growth factor receptor inhibition and a greater increase in p27 and reduction of Ki-67 than either drug alone, supporting further evaluation of these putative predictors of response to combined Src/aromatase inhibition in vivo. Anastrozole alone stimulated Src activity both in vitro and in vivo. AZD0530-resistant tumors showed activation of bypass pathways including MEK and phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin, raising the possibility that MEK, mammalian target of rapamycin (mTOR), or PI3K inhibitors may augment Src inhibitor efficacy. CONCLUSIONS: These data support clinical investigation of anastrozole-AZD0530 therapy for postmenopausal ER-positive breast cancer. Loss of p27 and increased Ki-67 may predict response and further clinical studies should evaluate for activation of bypass pathways including MEK and PI3K pathways during Src inhibitor therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Anastrozol , Animais , Inibidores da Aromatase/administração & dosagem , Benzodioxóis/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteína Tirosina Quinase CSK , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Nitrilas/administração & dosagem , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinas/administração & dosagem , Triazóis/administração & dosagem , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src
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