RESUMEN
BACKGROUND: Genomic profiling can identify targetable mutations; however, the impact of tissue-based genomic profiling on clinical decision making for patients with metastatic breast cancer has not been well characterized. METHODS: Patients with stage IV breast cancer who had undergone genomic profiling between 7/2013 and 3/2015 were identified at three academic cancer centers. Genomic analysis was determined to have impacted clinical decision if (A) a patient was enrolled onto a genotype-matched clinical trial or (B) prescribed off-label an FDA-approved therapy targeting an identified mutation. The frequency of mutated genes was determined. RESULTS: A total of 117 patients with stage IV breast cancer were identified. Median age was 46 (25-75). Fifty-three patients (45%) had ER-positive/HER2-negative disease, 50 (43%) had ER-negative/HER2-negative disease, and 14 (12%) had ER-any/HER2-positive disease. Median number of previous therapies received prior to genomic profiling was 2 (range 0-15), and median follow-up after testing was obtained after 5.8 months (range 0-24.4 months). Commercial reports indicated that 85 (73%) patients had at least one mutation targetable by an FDA-approved medication, and 112 (96%) patients had at least one clinical trial available; however, clinical management was only affected in 11 patients (9%). The most frequent mutations observed were those in TP53, FGF, PI3KCA, MYC, ZNF, FGFR, CCND, ARID1A, GATA3, and MAP; frequencies of these mutations varied by clinical subtype. CONCLUSIONS: Tumor genomic profiling affected clinical management in a minority of patients with metastatic breast cancer, thus these data do not support the routine use of genomic profiling outside of a clinical trial.
Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama/genética , Toma de Decisiones Clínicas , Perfilación de la Expresión Génica , Genómica , Centros Médicos Académicos , Adulto , Anciano , Alelos , Biopsia , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Manejo de la Enfermedad , Femenino , Perfilación de la Expresión Génica/métodos , Frecuencia de los Genes , Genómica/métodos , Humanos , Persona de Mediana Edad , Mutación , Estadificación de NeoplasiasRESUMEN
Human epidermal growth factor receptor 2 (HER2)/neu-positive breast cancer has changed from being an aggressive disease with a poor prognosis to a disease that is highly treatable, with prolonged survival possible even in patients with metastatic disease. A better understanding of HER2 biology has led to the development of powerful targeted therapies, and four drugs are already approved by the US Food and Drug Administration for treatment in the metastatic setting (trastuzumab, pertuzumab, lapatinib, and trastuzumab emtansine). Optimizing how these drugs are delivered and in what sequence is an important part of modern management of HER2-positive breast cancer. However, while the prognosis has improved, metastatic disease is still not curable; newer, better drugs are needed. This review will summarize the current standard of care; key issues that arise when treating patients with HER2-positive disease; and developments in novel therapeutics, including small-molecule inhibitors, nanoparticles, immunotherapy, and agents targeting resistance pathways.
Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Neoplasias de la Mama/terapia , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Animales , Antineoplásicos/efectos adversos , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos , Femenino , Humanos , Inhibidores de Proteínas Quinasas/efectos adversos , Receptor ErbB-2/metabolismo , Transducción de Señal , Resultado del TratamientoRESUMEN
Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients.
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Inhibidores Enzimáticos/farmacología , Leucemia Mieloide Aguda/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Adolescente , Adulto , Apoptosis/efectos de los fármacos , Western Blotting , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la Polimerasa , Transfección , Adulto JovenRESUMEN
Current methods of cell processing for gene and cell therapies use several separate procedures for gene transfer and cell separation or elimination, because no current technology can offer simultaneous multifunctional processing of specific cell subsets in highly heterogeneous cell systems. Using the cell-specific generation of plasmonic nanobubbles of different sizes around cell-targeted gold nanoshells and nanospheres, we achieved simultaneous multifunctional cell-specific processing in a rapid single 70 ps laser pulse bulk treatment of heterogeneous cell suspension. This method supported the detection of cells, delivery of external molecular cargo to one type of cells and the concomitant destruction of another type of cells without damaging other cells in suspension, and real-time guidance of the above two cellular effects.