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1.
Breast Cancer Res Treat ; 148(2): 315-25, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25338319

RESUMO

Breast cancers are categorized into three subtypes based on protein expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2/ERBB2). Patients enroll onto experimental clinical trials based on ER, PR, and HER2 status and, as receptor status is prognostic and defines treatment regimens, central receptor confirmation is critical for interpreting results from these trials. Patients enrolling onto experimental clinical trials in the metastatic setting often have limited available archival tissue that might better be used for comprehensive molecular profiling rather than slide-intensive reconfirmation of receptor status. We developed a Random Forests-based algorithm using a training set of 158 samples with centrally confirmed IHC status, and subsequently validated this algorithm on multiple test sets with known, locally determined IHC status. We observed a strong correlation between target mRNA expression and IHC assays for HER2 and ER, achieving an overall accuracy of 97 and 96%, respectively. For determining PR status, which had the highest discordance between central and local IHC, incorporation of expression of co-regulated genes in a multivariate approach added predictive value, outperforming the single, target gene approach by a 10% margin in overall accuracy. Our results suggest that multiplexed qRT-PCR profiling of ESR1, PGR, and ERBB2 mRNA, along with several other subtype associated genes, can effectively confirm breast cancer subtype, thereby conserving tumor sections and enabling additional biomarker data to be obtained from patients enrolled onto experimental clinical trials.


Assuntos
Algoritmos , Biomarcadores Tumorais/genética , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/metabolismo , RNA Neoplásico/genética , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Ensaios Clínicos Fase III como Assunto , Feminino , Seguimentos , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Limite de Detecção , Estudos Multicêntricos como Assunto , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Curva ROC , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida
2.
PLoS One ; 9(2): e88401, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24520381

RESUMO

Patients with newly diagnosed, early stage estrogen receptor positive (ER+) breast cancer often show disease free survival in excess of five years following surgery and systemic adjuvant therapy. An important question is whether diagnostic tumor tissue from the primary lesion offers an accurate molecular portrait of the cancer post recurrence and thus may be used for predictive diagnostic purposes for patients with relapsed, metastatic disease. As the class I phosphatidylinositol 3' kinase (PI3K) pathway is frequently activated in ER+ breast cancer and has been linked to acquired resistance to hormonal therapy, we hypothesized pathway status could evolve over time and treatment. Biomarker analyses were conducted on matched, asynchronous primary and metastatic tumors from 77 patients with ER+ breast cancer. We examined whether PIK3CA and AKT1 alterations or PTEN and Ki67 levels showed differences between primary and metastatic samples. We also sought to look more broadly at gene expression markers reflective of proliferation, molecular subtype, and key receptors and signaling pathways using an mRNA analysis platform developed on the Fluidigm BioMark™ microfluidics system to measure the relative expression of 90 breast cancer related genes in formalin-fixed paraffin-embedded (FFPE) tissue. Application of this panel of biomarker assays to matched tumor pairs showed a high concordance between primary and metastatic tissue, with generally few changes in mutation status, proliferative markers, or gene expression between matched samples. The collection of assays described here has been optimized for FFPE tissue and may have utility in exploratory analyses to identify patient subsets responsive to targeted therapies.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Metaboloma , Receptores de Estrogênio/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Microfluídica , Mutação/genética , Metástase Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais , Células Tumorais Cultivadas
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