RESUMEN
The US National Cancer Institute (NCI), in collaboration with scientists representing multiple areas of expertise relevant to 'omics'-based test development, has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. The checklist criteria cover issues relating to specimens, assays, mathematical modelling, clinical trial design, and ethical, legal and regulatory aspects. Funding bodies and journals are encouraged to consider the checklist, which they may find useful for assessing study quality and evidence strength. The checklist will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests will be used to guide therapy.
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Ensayos Clínicos como Asunto/métodos , Genómica , Proyectos de Investigación , Lista de Verificación , Ensayos Clínicos como Asunto/economía , Ensayos Clínicos como Asunto/ética , Ensayos Clínicos como Asunto/normas , Estudios de Evaluación como Asunto , Genómica/ética , Humanos , Modelos Biológicos , National Cancer Institute (U.S.)/economía , Medicina de Precisión/ética , Medicina de Precisión/métodos , Medicina de Precisión/normas , Proyectos de Investigación/normas , Manejo de Especímenes , Estados UnidosRESUMEN
BACKGROUND: Using next-generation sequencing (NGS) to guide cancer therapy has created challenges in analyzing and reporting large volumes of genomic data to patients and caregivers. Specifically, providing current, accurate information on newly approved therapies and open clinical trials requires considerable manual curation performed mainly by human "molecular tumor boards" (MTBs). The purpose of this study was to determine the utility of cognitive computing as performed by Watson for Genomics (WfG) compared with a human MTB. MATERIALS AND METHODS: One thousand eighteen patient cases that previously underwent targeted exon sequencing at the University of North Carolina (UNC) and subsequent analysis by the UNCseq informatics pipeline and the UNC MTB between November 7, 2011, and May 12, 2015, were analyzed with WfG, a cognitive computing technology for genomic analysis. RESULTS: Using a WfG-curated actionable gene list, we identified additional genomic events of potential significance (not discovered by traditional MTB curation) in 323 (32%) patients. The majority of these additional genomic events were considered actionable based upon their ability to qualify patients for biomarker-selected clinical trials. Indeed, the opening of a relevant clinical trial within 1 month prior to WfG analysis provided the rationale for identification of a new actionable event in nearly a quarter of the 323 patients. This automated analysis took <3 minutes per case. CONCLUSION: These results demonstrate that the interpretation and actionability of somatic NGS results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing could potentially improve patient care by providing a rapid, comprehensive approach for data analysis and consideration of up-to-date availability of clinical trials. IMPLICATIONS FOR PRACTICE: The results of this study demonstrate that the interpretation and actionability of somatic next-generation sequencing results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing can significantly improve patient care by providing a fast, cost-effective, and comprehensive approach for data analysis in the delivery of precision medicine. Patients and physicians who are considering enrollment in clinical trials may benefit from the support of such tools applied to genomic data.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Biomarcadores de Tumor , Estudios de Casos y Controles , Terapia Combinada , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Metástasis Linfática , Invasividad Neoplásica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Neoplasias/patología , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Metastases play a role in about 90% of cancer deaths. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells might provide diagnostic information about the likelihood that cancer cells have detached from the primary tumor. Used together with established diagnostic tests of detachment-lymph node evaluation and radiologic imaging-EMT marker measurements might improve the ability of clinicians to assess the patient's risk of metastatic disease. Translation of EMT markers to clinical use has been hampered by a lack of valid analyses of clinically-informative parameters. Here, we demonstrate a rigorous approach to estimating the sensitivity, specificity, and prediction increment of an EMT marker to assess cancer cell detachment from primary tumors. METHODS: We illustrate the approach using immunohistochemical measurements of the EMT marker E-cadherin in a set of colorectal primary tumors from a population-based prospective cohort in North Carolina. Bayesian latent class analysis was used to estimate sensitivity and specificity in a setting of multiple imperfect diagnostic tests and no gold standard. Risk reclassification analysis was used to assess the extent to which addition of the marker to the panel of established diagnostic tests would improve mortality prediction. We explored how changing the latent class conditional dependence assumptions and definition of marker positivity would impact the results. RESULTS: All diagnostic accuracy and prediction increment statistics varied with the choice of cut point to define marker positivity. When comparing different definitions of marker positivity to each other, numerous trade-offs were observed in terms of sensitivity, specificity, predictive discrimination, and prediction model calibration. We then discussed several implementation considerations and the plausibility of analytic assumptions. CONCLUSIONS: The approaches presented here can be extended to any EMT marker, to most forms of cancer, and to different kinds of EMT marker measurements, such as RNA or gene methylation data. These methods provide valid, clinically-informative assessment of whether and how to use a given EMT marker to refine tumor staging and consequent treatment decisions.
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Biomarcadores de Tumor/genética , Cadherinas/genética , Neoplasias Colorrectales/diagnóstico , Transición Epitelial-Mesenquimal/genética , Adulto , Anciano , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Factores de RiesgoRESUMEN
The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or reverse-phase protein assay subtype. Marked nuclear pleomorphism, necrosis, inflammation and a high mitotic count were associated with the basal-like subtype, and had a similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed by use of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of poorly differentiated epithelial tubules was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative breast cancer. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has the potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology, and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Bases de Datos Genéticas , Femenino , Perfilación de la Expresión Génica , Genómica , Humanos , Invasividad Neoplásica , Fenotipo , Receptores de Estrógenos/metabolismoRESUMEN
The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics. Here we report the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for galpha subunits in multiple cancer types. Furthermore, our experimental analyses demonstrate the functional roles of mutant GNAO1 (a Galpha subunit) and mutant MAP2K4 (a member of the JNK signalling pathway) in oncogenesis. Our study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.
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Genes Relacionados con las Neoplasias/genética , Mutación/genética , Neoplasias/genética , Neoplasias/metabolismo , Transducción de Señal/genética , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/genética , Variaciones en el Número de Copia de ADN/genética , Análisis Mutacional de ADN , Femenino , Subunidades alfa de la Proteína de Unión al GTP/genética , Humanos , Neoplasias Pulmonares/clasificación , Neoplasias Pulmonares/genética , MAP Quinasa Quinasa 4/genética , Masculino , Neoplasias/enzimología , Neoplasias/patología , Neoplasias Ováricas/clasificación , Neoplasias Ováricas/genética , Neoplasias de la Próstata/clasificación , Neoplasias de la Próstata/genética , Proteínas Quinasas/genética , Receptores Acoplados a Proteínas G/genéticaRESUMEN
High-throughput 'omics' technologies that generate molecular profiles for biospecimens have been extensively used in preclinical studies to reveal molecular subtypes and elucidate the biological mechanisms of disease, and in retrospective studies on clinical specimens to develop mathematical models to predict clinical endpoints. Nevertheless, the translation of these technologies into clinical tests that are useful for guiding management decisions for patients has been relatively slow. It can be difficult to determine when the body of evidence for an omics-based test is sufficiently comprehensive and reliable to support claims that it is ready for clinical use, or even that it is ready for definitive evaluation in a clinical trial in which it may be used to direct patient therapy. Reasons for this difficulty include the exploratory and retrospective nature of many of these studies, the complexity of these assays and their application to clinical specimens, and the many potential pitfalls inherent in the development of mathematical predictor models from the very high-dimensional data generated by these omics technologies. Here we present a checklist of criteria to consider when evaluating the body of evidence supporting the clinical use of a predictor to guide patient therapy. Included are issues pertaining to specimen and assay requirements, the soundness of the process for developing predictor models, expectations regarding clinical study design and conduct, and attention to regulatory, ethical, and legal issues. The proposed checklist should serve as a useful guide to investigators preparing proposals for studies involving the use of omics-based tests. The US National Cancer Institute plans to refer to these guidelines for review of proposals for studies involving omics tests, and it is hoped that other sponsors will adopt the checklist as well.
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Ensayos Clínicos como Asunto/métodos , Genómica/métodos , Investigación Biomédica , Ensayos Clínicos como Asunto/normas , Genómica/normas , Guías como Asunto , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Medicina de Precisión , Reproducibilidad de los Resultados , Proyectos de InvestigaciónRESUMEN
Quantitative clinical measurement of heterogeneity in immunohistochemistry staining would be useful in evaluating patient therapeutic response and in identifying underlying issues in histopathology laboratory quality control. A heterogeneity scoring approach (HetMap) was designed to visualize a individual patient's immunohistochemistry heterogeneity in the context of a patient population. HER2 semiquantitative analysis was combined with ecology diversity statistics to evaluate cell-level heterogeneity (consistency of protein expression within neighboring cells in a tumor nest) and tumor-level heterogeneity (differences of protein expression across a tumor as represented by a tissue section). This approach was evaluated on HER2 immunohistochemistry-stained breast cancer samples using 200 specimens across two different laboratories with three pathologists per laboratory, each outlining regions of tumor for scoring by automatic cell-based image analysis. HetMap was evaluated using three different scoring schemes: HER2 scoring according to American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) guidelines, H-score, and a new continuous HER2 score (HER2(cont)). Two definitions of heterogeneity, cell-level and tumor-level, provided useful independent measures of heterogeneity. Cases where pathologists had disagreement over reads in the area of clinical importance (+1 and +2) had statistically significantly higher levels of tumor-level heterogeneity. Cell-level heterogeneity, reported either as an average or the maximum area of heterogeneity across a slide, had low levels of dependency on the pathologist choice of region, while tumor-level heterogeneity measurements had more dependence on the pathologist choice of regions. HetMap is a measure of heterogeneity, by which pathologists, oncologists, and drug development organizations can view cell-level and tumor-level heterogeneity for a patient for a given marker in the context of an entire patient cohort. Heterogeneity analysis can be used to identify tumors with differing degrees of heterogeneity, or to highlight slides that should be rechecked for QC issues. Tumor heterogeneity plays a significant role in disconcordant reads between pathologists.
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Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Genes erbB-2 , Humanos , Inmunohistoquímica , Coloración y EtiquetadoRESUMEN
"Missed" cases with neurodevelopmental disorders (NDDs) within adult psychiatry services have attracted increasing attention in the last decade. Key questions have been what the prevalence of NDDs (particularly attention-deficit/hyperactivity disorder/ADHD and autism spectrum disorder/ASD) is, and what the clinical and gender characteristics of those with NDD in adult psychiatry are. All first-time attenders at an adult psychiatry clinic serving 18-25 years old were invited to take part in the study regardless of cause of concern. Participation in the study included diagnostic in-depth evaluation performed by experienced adult psychiatrists. Clinical diagnoses (DSM-IV-TR and DSM-5 criteria) were based on all available information (clinical psychiatric interview, clinical observation, and self-rating questionnaires). Almost two thirds (63%) of the study group met criteria for ADHD or ASD. Most of the patients with NDD (particularly the "NDD females") had not been diagnosed in childhood. Twelve percent of the females included had been given an ADHD diagnosis in childhood. In the current study we found that 48% of the females had ADHD. The high male:female NDD ratio reported among children, was not obvious in our NDD group. The results underscore the importance of screening for NDD in adult psychiatric services regardless of referral reason.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Trastornos del Neurodesarrollo , Adolescente , Adulto , Instituciones de Atención Ambulatoria , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/psicología , Niño , Comorbilidad , Femenino , Humanos , Masculino , Trastornos del Neurodesarrollo/epidemiología , Adulto JovenRESUMEN
Gaze patterns during face perception have been shown to relate to psychiatric symptoms. Standard analysis of gaze behavior includes calculating fixations within arbitrarily predetermined areas of interest. In contrast to this approach, we present an objective, data-driven method for the analysis of gaze patterns and their relation to diagnostic test scores. This method was applied to data acquired in an adult sample (N = 111) of psychiatry outpatients while they freely looked at images of human faces. Dimensional symptom scores of autism, attention deficit, and depression were collected. A linear regression model based on Principal Component Analysis coefficients computed for each participant was used to model symptom scores. We found that specific components of gaze patterns predicted autistic traits as well as depression symptoms. Gaze patterns shifted away from the eyes with increasing autism traits, a well-known effect. Additionally, the model revealed a lateralization component, with a reduction of the left visual field bias increasing with both autistic traits and depression symptoms independently. Taken together, our model provides a data-driven alternative for gaze data analysis, which can be applied to dimensionally-, rather than categorically-defined clinical subgroups within a variety of contexts. Methodological and clinical contribution of this approach are discussed.
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Trastorno Autístico , Reconocimiento Facial , Adulto , Ojo , Cara , Fijación Ocular , HumanosRESUMEN
Neoplastic cellularity contributes to the analytic sensitivity of most present technologies for mutation detection, such that they underperform when stroma and inflammatory cells dilute a cancer specimen's variant fraction. Thus, tumor purity assessment by light microscopy is used to determine sample adequacy before sequencing and to interpret the significance of negative results and mutant allele fraction afterwards. However, pathologist estimates of tumor purity are imprecise and have limited reproducibility. With the advent of massively parallel sequencing, large amounts of molecular data can be analyzed by computational purity algorithms. We retrospectively compared tumor purity of 3 computational algorithms with neoplastic cellularity using hematoxylin and eosin light microscopy to determine which was best for clinical evaluation of molecular profiling. Data were analyzed from 881 cancer patients from a clinical trial cohort, LCCC1108 (UNCseq), whose tumors had targeted massively parallel sequencing. Concordance among algorithms was poor, and the specimens analyzed had high rates of algorithm failure partially due to variable tumor purity. Computational tumor purity estimates did not add value beyond the pathologist's estimate of neoplastic cellularity microscopy. To improve present methods, we propose a semiquantitative, clinically applicable strategy based on mutant allele fraction and copy number changes present within a given specimen, which when combined with the morphologic tumor purity estimate, guide the interpretation of next-generation sequencing results in cancer patients.
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Biología Computacional/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Microscopía/métodos , Neoplasias/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Neoplasias/genética , Neoplasias/patología , Guías de Práctica Clínica como Asunto , Estudios Retrospectivos , Adulto JovenRESUMEN
PURPOSE: Pertuzumab, a first-in-class human epidermal receptor 2 (HER2) dimerization inhibitor, is a humanized monoclonal anti-HER2 antibody that binds HER2's dimerization domain and inhibits HER2 signaling. Based on supporting preclinical studies, we undertook a Phase II trial of pertuzumab in patients with recurrent non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Patients with previously treated NSCLC accessible for core biopsy and naive to HER pathway inhibitors were treated with pertuzumab i.v. once every 3 weeks. Tumor assessments were done at 6 and 12 weeks and then every 3 months thereafter. The primary efficacy end point was overall response rate by Response Evaluation Criteria in Solid Tumors. Measurement of tumor glucose metabolism (SUVmax) by F-18-fluorodeoxyglucose positron emission tomography was used as an exploratory pharmacodynamic marker of drug activity. RESULTS: Of 43 patients treated with pertuzumab, no responses were seen; 18 of 43 (41.9%) and 9 of 43 (20.9%) patients had stable disease at 6 and 12 weeks, respectively. The median and 3-month progression-free survival rates (PFS) were 6.1 weeks (95% confidence interval, 5.3-11.3 weeks) and 28.4% (95% confidence interval, 14.4-44.2%), respectively. Of 22 patients who underwent F-18-fluorodeoxyglucose positron emission tomography, six (27.3%) had a metabolic response to pertuzumab as evidenced by decreased SUV max. These patients had prolonged PFS (HR = 0.11, log-rank P value = 0.018) compared with the 16 patients who had no metabolic response. Four patients (9.3%) experienced a grade 3/grade 4 adverse event judged related to pertuzumab; none exhibited grade 3/grade 4 cardiac toxicity. CONCLUSIONS: Pertuzumab is well tolerated as monotherapy. Pharmacodynamic activity correlated with prolonged PFS was detected in a moderate percentage of patients (27.3%). Further clinical development of pertuzumab should focus on rational combinations of pertuzumab with other drugs active in NSCLC.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Receptor ErbB-2/química , Adulto , Anticuerpos Monoclonales Humanizados , Biopsia , Dimerización , Receptores ErbB/metabolismo , Femenino , Fluorodesoxiglucosa F18/farmacología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Tomografía de Emisión de Positrones/métodos , Estructura Terciaria de Proteína , Receptor ErbB-2/antagonistas & inhibidores , Factores de Tiempo , Resultado del TratamientoRESUMEN
Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).Experimental Design: Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints.Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n = 54; GCB, n = 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P = 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively; P = 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively; P = 0.550).Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping. Clin Cancer Res; 23(15); 4127-37. ©2017 AACR.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Pronóstico , Talidomida/análogos & derivados , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Lenalidomida , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Modelos de Riesgos Proporcionales , Rituximab/administración & dosificación , Talidomida/administración & dosificación , Talidomida/efectos adversos , Resultado del Tratamiento , GemcitabinaRESUMEN
PURPOSE: Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody. Erlotinib HCl (Tarceva, OSI-774; OSI Pharmaceuticals, New York, NY) is a potent, reversible, highly selective and orally available HER-1/epidermal growth factor receptor tyrosine kinase inhibitor. Preclinical data in various xenograft models produced greater growth inhibition than with either agent alone. Additionally, both agents have demonstrated benefit in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A phase I/II study in two centers examined erlotinib and bevacizumab (A+T) in patients with nonsquamous stage IIIB/IV NSCLC with > or = one prior chemotherapy. In phase I, erlotinib 150 mg/day orally plus bevacizumab 15 mg/kg intravenously every 21 days was established as the phase II dose, although no dose-limiting toxicities were observed. Phase II assessed the efficacy and tolerability of A+T at this dose. Pharmacokinetic parameters were evaluated. ResultsForty patients were enrolled and treated in this study (34 patients at phase II dose); the median age was 59 years (range, 36 to 72 years), 21 were female, 30 had adenocarcinoma histology, nine were never-smokers, and 22 had > or = two prior regimens (three patients had > or = four prior regimens). The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between A + T. Eight patients (20.0%; 95% CI, 7.6% to 32.4%) had partial responses and 26 (65.0%; 95% CI, 50.2% to 79.8%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. CONCLUSION: Encouraging antitumor activity and safety of A + T support further development of this combination for patients with advanced NSCLC and other solid tumors.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Carcinoma de Pulmón de Células no Pequeñas/patología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Clorhidrato de Erlotinib , Femenino , Humanos , Infusiones Intravenosas , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/administración & dosificación , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Epidermal growth factor receptor (EGFR) mutations have been associated with tumor response to treatment with single-agent EGFR inhibitors in patients with relapsed non-small-cell lung cancer (NSCLC). The implications of EGFR mutations in patients treated with EGFR inhibitors plus first-line chemotherapy are unknown. KRAS is frequently activated in NSCLC. The relationship of KRAS mutations to outcome after EGFR inhibitor treatment has not been described. PATIENTS AND METHODS: Previously untreated patients with advanced NSCLC in the phase III TRIBUTE study who were randomly assigned to carboplatin and paclitaxel with erlotinib or placebo were assessed for survival, response, and time to progression (TTP). EGFR exons 18 through 21 and KRAS exon 2 were sequenced in tumors from 274 patients. Outcomes were correlated with EGFR and KRAS mutations in retrospective subset analyses. RESULTS: EGFR mutations were detected in 13% of tumors and were associated with longer survival, irrespective of treatment (P < .001). Among erlotinib-treated patients, EGFR mutations were associated with improved response rate (P < .05) and there was a trend toward an erlotinib benefit on TTP (P = .092), but not improved survival (P = .96). KRAS mutations (21% of tumors) were associated with significantly decreased TTP and survival in erlotinib plus chemotherapy-treated patients. CONCLUSION: EGFR mutations may be a positive prognostic factor for survival in advanced NSCLC patients treated with chemotherapy with or without erlotinib, and may predict greater likelihood of response. Patients with KRAS-mutant NSCLC showed poorer clinical outcomes when treated with erlotinib and chemotherapy. Further studies are needed to confirm the findings of this retrospective subset analysis.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Genes ras , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Quinazolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carboplatino/administración & dosificación , Terapia Combinada , Análisis Mutacional de ADN , Clorhidrato de Erlotinib , Femenino , Humanos , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Placebos , Valor Predictivo de las Pruebas , Pronóstico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Significant improvements in the outcome of non-small cell lung carcinoma (NSCLC) have been reported in patients treated with the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. To discover biomarkers for the enrichment of patients who might benefit from treatment, a pharmacogenomic approach was used to identify gene signatures that may predict erlotinib activity using in vitro model systems. Erlotinib sensitivity in a panel of 42 NSCLC cell lines was determined by EGFR-mediated proliferative potential, EGFR mutations, and/or EGFR gene amplification, thus supporting an underlying biological mechanism of receptor activation. A strong multigene signature indicative of an epithelial to mesenchymal transition (EMT) was identified as a determinant of insensitivity to erlotinib through both supervised and unsupervised gene expression approaches. This observation was further supported by expression analysis of classic EMT marker proteins, including E-cadherin and vimentin. To investigate the clinical relevance of these findings, we examined expression of the epithelial marker E-cadherin by immunohistochemistry on primary tumor samples from subjects enrolled in a randomized NSCLC clinical trial in which erlotinib in combination with chemotherapy previously failed to show clinical activity. The majority (75%) of the 87 subjects tested showed strong E-cadherin staining and exhibited a significantly longer time to progression (hazard ratio, 0.37; log rank P=0.0028) and a nonsignificant trend toward longer survival with erlotinib plus chemotherapy treatment versus chemotherapy alone. These data support a potential role for EMT as a determinant of EGFR activity in NSCLC tumor cells and E-cadherin expression as a novel biomarker predicting clinical activity of the EGFR inhibitor erlotinib in NSCLC patients.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Cadherinas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Epitelio/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Antineoplásicos/farmacología , Biomarcadores de Tumor/análisis , Cadherinas/análisis , Cadherinas/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Epitelio/química , Epitelio/patología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib , Amplificación de Genes , Genes Relacionados con las Neoplasias/genética , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/diagnóstico , Mesodermo/química , Mesodermo/metabolismo , Mesodermo/patología , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Farmacogenética , Fenotipo , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Resultado del Tratamiento , Vimentina/análisis , Vimentina/genética , Vimentina/metabolismoRESUMEN
We conducted an expression analysis of prostate stem cell antigen (PSCA)in normal urogenital tissues, benign prostatic hyperplasia (n = 21), prostatic intraepithelial neoplasia (n = 33), and primary (n = 137) and metastatic (n = 42) prostate adenocarcinoma, using isotopic in situ hybridization on tissue microarrays. In normal prostate, we observe PSCA expression in the terminally differentiated, secretory epithelium; strong expression was also seen in normal urothelium. Forty-eight percent of primary and 64% of metastatic prostatic adenocarcinomas expressed PSCA RNA. Our studies did not confirm a positive correlation between level of PSCA RNA expression and high Gleason grade. We characterized monoclonal anti-PSCA antibodies that recognize PSCA expressed on the surface of live cells, are efficiently internalized after antigen recognition, and kill tumor cells in vitro in an antigen-specific fashion upon conjugation with maytansinoid. Unconjugated anti-PSCA antibodies demonstrated efficacy against PSCA-positive tumors by delaying progressive tumor growth in vivo. Maytansinoid-conjugated antibodies caused complete regression of established tumors in a large proportion of animals. Our results strongly suggest that maytansinoid-conjugated anti-PSCA monoclonal antibodies should be evaluated as a therapeutic modality for patients with advanced prostate cancer.
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Adenocarcinoma/inmunología , Adenocarcinoma/terapia , Anticuerpos Monoclonales/farmacología , Glicoproteínas de Membrana/inmunología , Proteínas de Neoplasias/inmunología , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/terapia , Adenocarcinoma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Antígenos de Neoplasias , Femenino , Proteínas Ligadas a GPI , Humanos , Inmunización Pasiva/métodos , Inmunotoxinas/farmacocinética , Inmunotoxinas/farmacología , Hibridación in Situ , Masculino , Maitansina/farmacocinética , Maitansina/farmacología , Glicoproteínas de Membrana/biosíntesis , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Neoplasias de la Próstata/metabolismoRESUMEN
Human papillomaviruses (HPV) are oncogenic DNA viruses implicated in squamous cell carcinomas of several anatomic sites, as well as endocervical adenocarcinomas. Identification of HPV is an actionable finding in some carcinomas, potentially influencing tumor classification, prognosis, and management. We incorporated capture probes for oncogenic HPV strains 16 and 18 into a broader next-generation sequencing (NGS) panel designed to identify actionable mutations in solid malignancies. A total of 21 head and neck, genitourinary, and gynecologic squamous cell carcinomas and endocervical adenocarcinomas were sequenced as part of the UNCSeq project. Using p16 immunohistochemical results as the gold standard, we set a cutoff for proportion of aligned HPV reads that maximized performance of our NGS assay (92% sensitive, 100% specific for HPV). These results suggest that sequencing of oncogenic pathogens can be incorporated into targeted NGS panels, extending the clinical utility of genomic assays.
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Secuenciación de Nucleótidos de Alto Rendimiento , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Neoplasias del Cuello Uterino/complicaciones , Neoplasias del Cuello Uterino/diagnóstico , Femenino , Genes p16 , Humanos , Inmunohistoquímica , Papillomaviridae/genética , Neoplasias del Cuello Uterino/patologíaRESUMEN
Most cancer deaths are due to metastases. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells could be helpful to assess patient risk of metastatic disease, even among those otherwise diagnosed with local disease. Previous studies of EMT markers and patient outcomes used inconsistent methods and did not compare the clinical impact of different expression cut points for the same marker. Using digital image analysis, we measured the EMT markers Snail and E-cadherin in primary tumor specimens from 190 subjects in tissue microarrays from a population-based prospective cohort of colorectal cancer patients and estimated their associations with time-to-death. After measuring continuous marker expression data, we performed a systematic search for the cut point for each marker with the best model fit between dichotomous marker expression and time-to-death. We also assessed the potential clinical impact of different cut points for the same marker. After dichotomizing expression status at the statistically-optimal cut point, we found that Snail expression was not associated with time-to-death. When measured as a weighted average of tumor cores, low E-cadherin expression was associated with a greater risk of dying within 5 years of surgery than high expression (risk difference = 33 %, 95 % confidence interval 3-62 %). Identifying a clinically-optimal cut point for an EMT marker requires trade-offs between strength and precision of the association with patient outcomes, as well as consideration of the number of patients whose treatments might change based on using the marker at a given cut point.
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Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal/fisiología , Metástasis de la Neoplasia/patología , Anciano , Cadherinas/análisis , Neoplasias Colorrectales/mortalidad , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores de Transcripción de la Familia Snail , Análisis de Matrices Tisulares , Factores de Transcripción/análisisRESUMEN
The recent FDA approval of the MiSeqDx platform provides a unique opportunity to develop targeted next generation sequencing (NGS) panels for human disease, including cancer. We have developed a scalable, targeted panel-based assay termed UNCseq, which involves a NGS panel of over 200 cancer-associated genes and a standardized downstream bioinformatics pipeline for detection of single nucleotide variations (SNV) as well as small insertions and deletions (indel). In addition, we developed a novel algorithm, NGScopy, designed for samples with sparse sequencing coverage to detect large-scale copy number variations (CNV), similar to human SNP Array 6.0 as well as small-scale intragenic CNV. Overall, we applied this assay to 100 snap-frozen lung cancer specimens lacking same-patient germline DNA (07-0120 tissue cohort) and validated our results against Sanger sequencing, SNP Array, and our recently published integrated DNA-seq/RNA-seq assay, UNCqeR, where RNA-seq of same-patient tumor specimens confirmed SNV detected by DNA-seq, if RNA-seq coverage depth was adequate. In addition, we applied the UNCseq assay on an independent lung cancer tumor tissue collection with available same-patient germline DNA (11-1115 tissue cohort) and confirmed mutations using assays performed in a CLIA-certified laboratory. We conclude that UNCseq can identify SNV, indel, and CNV in tumor specimens lacking germline DNA in a cost-efficient fashion.