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The biopsy collection data from two lung cancer trials that required fresh tumor samples be obtained for microarray analysis were reviewed. In the trial for advanced disease, microarray data were obtained on 50 patient samples, giving an overall success rate of 60.2%. The majority of the specimens were obtained through CT-guided lung biopsies (N = 30). In the trial for early-stage patients, 28 tissue specimens were collected from excess tumor after surgical resection with a success rate of 85.7%. This tissue procurement program documents the feasibility in obtaining fresh tumor specimens prospectively that could be used for molecular testing.
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Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Pulmonares/genética , Biomarcadores de Tumor/biosíntesis , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/patología , Ensayos Clínicos como Asunto , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Mutación , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN/genéticaRESUMEN
The NCCN Guidelines for Occult Primary tumors provide recommendations for the evaluation, workup, management, and follow-up of patients with occult primary tumors (cancers of unknown primary). These NCCN Guidelines Insights summarize major discussion points of the 2014 NCCN Occult Primary panel meeting. The panel discussed gene expression profiling (GEP) for the identification of the tissue of origin and concluded that, although GEP has a diagnostic benefit, a clinical benefit has not been demonstrated. The panel recommends against GEP as standard management, although 20% of the panel believes the diagnostic benefit of GEP warrants its routine use. In addition, the panel discussed testing for actionable mutations (eg, ALK) to help guide choice of therapy, but declined to add this recommendation.
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Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Primarias Desconocidas/genética , Biopsia con Aguja Gruesa , Perfilación de la Expresión Génica , Humanos , Mutación , Neoplasias Primarias Desconocidas/terapiaRESUMEN
Many examples highlight the power of gene expression profiles, or signatures, to provide an understanding of biological phenotypes. This is best seen in the context of cancer, where expression signatures have tremendous power to identify new cancer subtypes and to predict clinical outcomes. Gene expression profiles have been developed to personalize medicine, accurately predicting disease recurrence and tumor response to therapy. The use of these signatures as surrogate phenotypes allows us to link diverse experimental systems, which dissect the complexity of biological systems, with the in vivo setting in a way that was not previously feasible. Taken together, these new genomic tools provide the opportunity to develop rational strategies for treating the individual cancer patient.
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Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Neoplasias/genética , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias/patología , Neoplasias/terapia , Valor Predictivo de las PruebasRESUMEN
We investigated the clinical implications of lung developmental transcription factors (TTF-1, NKX2-8, and PAX9) that we recently discovered as cooperating oncogenes activated by way of gene amplification at chromosome 14q13 in lung cancer. Using stable transfectants of human bronchial epithelial cells, RNA expression profiles (signatures) representing activation of the biological pathways defined by each of the 3 genes were determined and used to risk stratify a non-small-cell lung cancer (NSCLC) clinical data set consisting of 91 early stage tumors. Coactivation of the TTF-1 and NKX2-8 pathways identified a cluster of patients with poor survival, representing approximately 20% of patients with early stage NSCLC, whereas activation of individual pathways did not reveal significant prognostic power. Importantly, the poor prognosis associated with coactivation of TTF-1 and NKX2-8 was validated in 2 other independent clinical data sets. Furthermore, lung cancer cell lines showing coactivation of the TTF-1 and NKX2-8 pathways were shown to exhibit resistance to cisplatin, the standard of care for the treatment of NSCLC. This suggests that the cohort of patients with coactivation of TTF-1 and NKX2-8 pathways appears to be resistant to standard cisplatin therapy, suggesting the need for alternative therapies in this cohort of high-risk patients.
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Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Proteínas de Unión al ADN/metabolismo , Proteínas de Homeodominio/metabolismo , Factor de Transcripción PAX9/metabolismo , Factores de Transcripción/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Cromosomas Humanos Par 14 , Estudios de Cohortes , Amplificación de Genes , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares , Oncogenes , Pronóstico , Medición de Riesgo , Tasa de SupervivenciaRESUMEN
Introduction: Most patients with advanced NSCLC will experience disease progression and death within 2 years. Novel approaches are needed to improve outcomes. Methods: We conducted an open-label, nonrandomized, phase 2 trial in patients with treatment-naive, advanced NSCLC to assess the safety and efficacy of nivolumab 360 mg every 3 weeks, ipilimumab 1 mg/kg every 6 weeks, and four to six cycles of paclitaxel 80 mg/m2 on days 1 and 8 of every 21-day treatment. The primary end point of the study was median progression-free survival (PFS), with secondary end points of safety, objective response rate, and median overall survival (OS). Results: A total of 46 patients underwent consent and received treatment. The median age was 66 (range: 48-82) years, most had adenocarcinoma (63%), and 50% (23) had programmed death-ligand 1 greater than or equal to 1%. The median follow-up on the study as of October 2021 was 19 months. The primary end point of median PFS was 9.4 months (95% confidence interval [CI]: 5.9-16.6) in all patients regardless of programmed death-ligand 1 expression. The objective response rate for patients in the study was 47.8% (95% CI: 33.4-62.3). The 12-month OS rate was 69.5% (95% CI: 53%-81%), and median OS was not yet reached. Treatment-related grade greater than or equal to 3 adverse events was found in 54.3% of the patients. Conclusions: The toxicity observed was consistent with other reported chemo-immunotherapeutic combinations and was manageable. The primary end point of exceeding median PFS of 9 months was achieved with nivolumab, ipilimumab, and weekly paclitaxel and should be evaluated further in a randomized trial.
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CONTEXT: Gene expression profiling may be useful in examining differences underlying age- and sex-specific outcomes in non-small cell lung cancer (NSCLC). OBJECTIVE: To describe clinically relevant differences in the underlying biology of NSCLC based on patient age and sex. DESIGN, SETTING, AND PATIENTS: Retrospective analysis of 787 patients with predominantly early stage NSCLC performed at Duke University, Durham, North Carolina, from July 2008 to June 2009. Lung tumor samples with corresponding microarray and clinical data were used. All patients were divided into subgroups based on age (< 70 vs > or = 70 years old) or sex. Gene expression signatures representing oncogenic pathway activation and tumor biology/microenvironment status were applied to these samples to obtain patterns of activation/deregulation. MAIN OUTCOME MEASURES: Patterns of oncogenic and molecular signaling pathway activation that are reproducible and correlate with 5-year recurrence-free patient survival. RESULTS: Low- and high-risk patient clusters/cohorts were identified with the longest and shortest 5-year recurrence-free survival, respectively, within the age and sex NSCLC subgroups. These cohorts of NSCLC demonstrate similar patterns of pathway activation. In patients younger than 70 years, high-risk patients, with the shortest recurrence-free survival, demonstrated increased activation of the Src (25% vs 6%; P<.001) and tumor necrosis factor (76% vs 42%; P<.001) pathways compared with low-risk patients. High-risk patients aged 70 years or older demonstrated increased activation of the wound healing (40% vs 24%; P = .02) and invasiveness (64% vs 20%; P<.001) pathways compared with low-risk patients. In women, high-risk patients demonstrated increased activation of the invasiveness (99% vs 2%; P<.001) and STAT3 (72% vs 35%; P<.001) pathways while high-risk men demonstrated increased activation of the STAT3 (87% vs 18%; P<.001), tumor necrosis factor (90% vs 46%; P<.001), EGFR (13% vs 2%; P = .003), and wound healing (50% vs 22%; P<.001) pathways. Multivariate analyses confirmed the independent clinical relevance of the pathway-based subphenotypes in women (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.34-3.03; P<.001) and patients younger than 70 years (HR, 1.83; 95% CI, 1.24-2.71; P = .003). All observations were reproducible in split sample analyses. CONCLUSIONS: Among a cohort of patients with NSCLC, subgroups defined by oncogenic pathway activation profiles were associated with recurrence-free survival. These findings require validation in independent patient data sets.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Perfilación de la Expresión Génica , Neoplasias Pulmonares/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Oncogenes/genética , Pronóstico , Estudios Retrospectivos , Factores Sexuales , Análisis de SupervivenciaRESUMEN
PURPOSE: Creating an effective platform for multidisciplinary tumor conferences can be challenging in the rural community setting. The Duke Cancer Network created an Internet-based platform for a multidisciplinary conference to enhance the care of patients with lung cancer. This conference incorporates providers from different physical locations within a rural community and affiliated providers from a university-based cancer center 2 hours away. An electronic Web conferencing tool connects providers aurally and visually. METHODS: Conferences were set up using a commercially available Web conferencing platform. The video platform provides a secure Web site coupled with a secure teleconference platform to ensure patient confidentiality. Multiple disciplines are invited to participate, including radiology, radiation oncology, thoracic surgery, pathology, and medical oncology. Participants only need telephone access and Internet connection to participate. RESULTS: Patient histories and physicals are presented, and the Web conferencing platform allows radiologic and histologic images to be reviewed. Treatment plans for patients are discussed, allowing providers to coordinate care among the different subspecialties. Patients who need referral to the affiliated university-based cancer center for specialized services are identified. Pertinent treatment guidelines and journal articles are reviewed. On average, there are 10 participants with one to two cases presented per session. CONCLUSION: The use of a Web conferencing platform allows subspecialty providers throughout the community and hours away to discuss lung cancer patient cases. This platform increases convenience for providers, eliminating travel to a central location. Coordination of care for patients requiring multidisciplinary care is facilitated, shortening evaluation time before definitive treatment plan.
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Servicios de Salud Comunitaria , Prestación Integrada de Atención de Salud , Neoplasias Pulmonares , Informática Médica/métodos , Manejo de Atención al Paciente , Interfaz Usuario-Computador , Servicios de Salud Comunitaria/métodos , Prestación Integrada de Atención de Salud/métodos , Humanos , Internet , Manejo de Atención al Paciente/métodos , TelecomunicacionesRESUMEN
PURPOSE: Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities are the result of a common biological phenotype, such as regulatory pathways. EXPERIMENTAL DESIGN: Lung cancer cell lines with corresponding gene expression data and genes associated with an embryonic stem cell identity were used to develop a signature of embryonic stemness (ES) activity specific to lung adenocarcinoma. Biological characteristics were elucidated as a function of cancer biology/oncogenic pathway dysregulation. The ES signature was applied to three independent early-stage (I-IIIa) lung adenocarcinoma data sets with clinically annotated gene expression data. The relationship between the ES phenotype and cisplatin (current standard of care) sensitivity was evaluated. RESULTS: Pathway analysis identified specific regulatory networks [Ras (P = 0.0005), Myc (P = 0.0224), wound healing (P < 0.0001), chromosomal instability (P < 0.0001), and invasiveness (P < 0.0001)] associated with the ES phenotype. The prognostic relevance of the ES signature, as related to patient survival, was characterized in three cohorts [CALGB 9761 (n = 82; P = 0.0001), National Cancer Institute Director's Challenge Consortium (n = 442; P = 0.0002), and Duke (n = 45; P = 0.06)]. The ES signature was not prognostic in prostate, breast, or ovarian adenocarcinomas. Lung tumors (n = 569) and adenocarcinoma cell lines (n = 31) expressing the ES phenotype were more likely to be resistant to cisplatin (P < 0.0001 and P = 0.006, respectively). CONCLUSIONS: Lung adenocarcinomas that share a common gene expression pattern with normal human embryonic stem cells were associated with decreased survival, increased biological complexity, and increased likelihood of resistance to cisplatin. This indicates the aggressiveness of these tumors.
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PURPOSE: To define the biology driving the aggressive nature of acute myeloid leukemia (AML) in elderly patients. PATIENTS AND METHODS: Clinically annotated microarray data from 425 patients with newly diagnosed de novo AML from two publicly available data sets were analyzed after age-specific cohorts (young