RESUMEN
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Biomarcadores de Tumor/genética , Terapia Molecular Dirigida/métodos , Estadificación de NeoplasiasRESUMEN
Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.
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Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Pleura , Mesotelioma/diagnóstico , Mesotelioma/terapia , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/terapiaRESUMEN
Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.
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Mesotelioma Maligno , Mesotelioma , Humanos , Oncología Médica , Mesotelioma/diagnóstico , Mesotelioma/terapia , PeritoneoRESUMEN
The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Terapia NeoadyuvanteRESUMEN
Ovarian germ cell tumors (GCT) account for 2% to 3% of malignant ovarian neoplasms in Western countries and typically occur within the first 2 decades. When presenting later in life, GCTs may be associated with epithelial malignancies. In these circumstances, it has been theorized that these tumors may originate from a somatic, rather than germ cell origin, especially in the postmenopausal setting; however, the true derivation is not fully understood. Our database was searched for primary ovarian GCTs associated with a malignant epithelial component in patients above 35 yr of age, from 2006 to 2021. Two cases were identified and in each case, slides were reviewed and targeted next-generation sequencing was utilized to identify and compare gene mutation variants in morphologically distinct components. Patient A is a 58-yr-old, with choriocarcinoma and minor component of mucinous adenocarcinoma, and patient B is a 43-yr-old, with yolk sac tumor and minor component of endometrioid adenocarcinoma. The morphologically distinct areas in each case showed disparate staining patterns; however, next-generation sequencing demonstrated identical mutation variants within both the germ cell and epithelial components. Variants in CDKN2A , PIK3CA , PIK3R1 , and TP53 were present in patient A's tumor, while patient B's tumor showed CTNNB1 , PIK3R1 , and 2 PTEN variants. These mutational patterns are similar to those seen in pure epithelial counterparts, suggesting somatic derivation of the germ cell component. These rare tumors portend a poor prognosis and understanding their origin has clinical and therapeutic implications.
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Adenocarcinoma Mucinoso , Coriocarcinoma , Tumor del Seno Endodérmico , Neoplasias de Células Germinales y Embrionarias , Neoplasias Ováricas , Humanos , Femenino , Adulto , Persona de Mediana Edad , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/genética , Carcinoma Endometrioide , Coriocarcinoma/diagnóstico , Coriocarcinoma/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/genéticaRESUMEN
Based on findings from The Cancer Genome Atlas and the Proactive Molecular Risk Classifier for Endometrial Cancer algorithm, endometrial carcinoma can now be stratified into 4 prognostically distinct subgroups based on molecular alterations and immunohistochemical (IHC) aberrations. In this study, we describe the de novo adoption and clinical reporting of prognostic subgroup classification based on next-generation sequencing (NGS) and IHC analyses of all endometrial carcinoma resections at a single institution, framed by the Exploration, Preparation, Implementation, and Sustainment model. Results from the first 13 months show 188 tumors underwent analysis by a combination of IHC and a medium-sized (56 analyzed genes) NGS-based assay. All cases were assigned as either POLE (POLE-mutated) (5.3%), mismatch repair deficient (27.7%), no specific molecular profile (45.7%), or p53 abnormal (21.3%) inclusive of multiple-classifier cases. NGS-based analysis revealed additional distinctions among the subgroups, including reduced levels of PI3K pathway activation in the p53 abnormal subgroup, an increased rate of CTNNB1 activating mutation in the no specific molecular profile subgroup, and lower TP53 mutation variant allele frequencies in POLE and mismatch repair deficient subgroups compared with the p53 abnormal subgroup. Overall, we describe the testing protocol, reporting, and results of a combination of NGS and IHC to prospectively prognosticate endometrial carcinomas at a single tertiary care center.
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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Humanos , Inmunoterapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Oncología Médica , Recurrencia Local de NeoplasiaAsunto(s)
Transfusión Fetomaterna , Enfermedad Injerto contra Huésped , Complicaciones del Embarazo , Humanos , Feto/inmunología , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas , Femenino , Embarazo , Complicaciones del Embarazo/inmunología , Transfusión Fetomaterna/complicaciones , Transfusión Fetomaterna/inmunologíaRESUMEN
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Humanos , Inmunoterapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapiaRESUMEN
BACKGROUND: This multicenter, retrospective study explored the value of oncogene driver subtype, programmed death-1 ligand (PD-L1) status, and smoking status for predicting which patients with oncogene-driven non-small cell lung cancer (NSCLC) would benefit from treatment with programmed death-1 (PD-1)/PD-L1 inhibitors. METHODS: The clinical features, PD-L1 tumor proportion scores, and PD-1/PD-L1 inhibitor (PDi) outcomes (objective response rate and progression-free survival) of patients who had advanced NSCLC with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutations or common, actionable oncogenic drivers were captured. RESULTS: In total, 189 oncogene-positive patients were analyzed. Of these, 104 received a PDi, and 108 had undergone prior PD-L1 testing. The frequency of PD-L1 positivity (≥1%) was higher in patients who had KRAS mutations (P = .031), smokers (P = .006), and non-Asian patients (P = .002). Multivariable analysis indicated that smoking status (P < .001) was the only factor associated significantly with KRAS mutation. The objective response rate to PDi treatment was 16.9% (11 of 65 patients) among smokers (17.3% in the KRAS-mutant and 15.4% in the non-KRAS-mutant smoker subgroups), which was significantly higher than the 0% rate (0 of 26 patients; P = .019) among never-smokers. In subgroup analyses, progression-free survival was influenced by KRAS mutation status (median, 4.57 vs 1.63 months; P = .004), smoking status (4.07 vs 1.73 months; P = .004), PD-L1 positivity (3.8 vs 1.2 months; P = .040), and non-Asian race (3.0 vs 1.97 months; P = .046). In multivariable analysis, only smoking status (P = .008) remained a significant predictor when a PD-L1 level ≥1% was used. However, both smoking status (P = .001) and PD-L1 status (P = .028) were independent predictors when a PD-L1 level ≥50% was used. CONCLUSIONS: Among associated clinical features among patients who have NSCLC with oncogenic drivers, smoking status potentially was the most important, easily available predictor of single PDi efficacy.
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Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Fumar/epidemiología , Anciano , Quinasa de Linfoma Anaplásico/genética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Receptores ErbB/genética , Femenino , Fusión Génica , Humanos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación , Nivolumab/uso terapéutico , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-ret/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor ErbB-2/genéticaRESUMEN
Reports regarding the frequency of SMAD4 loss in human head and neck squamous cell carcinoma (HNSCC) vary significantly. We have shown that SMAD4 deletion contributes to HNSCC initiation and progression. Therefore, accurately detecting genetic SMAD4 loss is critical to determine prognosis and therapeutic interventions in personalized medicine. We developed a SMAD4 fluorescence in situ hybridization (FISH) assay to identify chromosomal SMAD4 loss at the single cell level of primary HNSCC specimens and patient derived xenograft (PDX) tumors derived from HNSCCs. SMAD4 heterozygous loss was detected in 35% of primary HNSCCs and 41.3% of PDX tumors. Additionally, 4.3% of PDX tumors had SMAD4 homozygous loss. These frequencies of SMAD4 loss were similar to those in The Cancer Genome Atlas (TCGA). However, we identified significant heterogeneities of SMAD4 loss (partial or complete) among cells within each tumor. We also found that aneuploidy (monosomy and polysomy) contributed greatly to how to define chromosomal SMAD4 deletion. Furthermore, in cultured PDX tumors, SMAD4 mutant cells outcompeted SMAD4 wildtype cells, resulting in establishing homogenous SMAD4 mutant HNSCC cell lines with partial or complete genomic SMAD4 loss, suggesting a survival advantage of SMAD4 mutant cells. Taken together, our study reveals inter- and intra-tumor heterogeneities of SMAD4 chromosomal loss in HNSCCs. Further, SMAD4 FISH assay provides a platform for future clinical diagnosis of SMAD4 chromosomal loss that potentially serves as a molecular marker for prognosis and therapeutic intervention in cancer patients.
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Carcinoma de Células Escamosas/genética , Aberraciones Cromosómicas , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Heterogeneidad Genética , Neoplasias de Cabeza y Cuello/genética , Proteína Smad4/genética , Animales , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/patología , Humanos , Hibridación Fluorescente in Situ , Ratones , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as "preferred interventions," whereas others are categorized as either "other recommended interventions" or "useful under certain circumstances."
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inmunoterapia/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Guías de Práctica Clínica como Asunto/normas , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patologíaRESUMEN
BACKGROUND: Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M. METHODS: In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles. RESULTS: A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51). CONCLUSIONS: Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).
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Acrilamidas/administración & dosificación , Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Acrilamidas/efectos adversos , Acrilamidas/farmacocinética , Anciano , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Relación Dosis-Respuesta a Droga , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Hiperglucemia/inducido químicamente , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/farmacocinéticaRESUMEN
The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added.
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Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Molecular Dirigida/normas , Antineoplásicos Inmunológicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/inmunología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Oncología Médica/normas , Terapia Molecular Dirigida/métodos , Mutación , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como Asunto , Sociedades Médicas/normas , Estados UnidosRESUMEN
This selection from the NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) focuses on targeted therapies and immunotherapies for metastatic NSCLC, because therapeutic recommendations are rapidly changing for metastatic disease. For example, new recommendations were added for atezolizumab, ceritinib, osimertinib, and pembrolizumab for the 2017 updates.
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Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Biomarcadores , Carcinoma de Pulmón de Células no Pequeñas/etiología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Ensayos Clínicos como Asunto , Terapia Combinada , Manejo de la Enfermedad , Humanos , Inmunoterapia , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/mortalidad , Terapia Molecular Dirigida , Metástasis de la Neoplasia , Pronóstico , Recurrencia , Resultado del TratamientoRESUMEN
The WNT signaling cascade is integral in numerous biological processes including embryonic development, cell cycle regulation, inflammation, and cancer. Hyperactivation of WNT signaling secondary to alterations to varying nodes of the pathway have been identified in multiple tumor types. These alterations converge into increased tumorigenicity, sustained proliferation, and enhanced metastatic potential. This review seeks to evaluate the evidence supporting the WNT pathway in cancer, the therapeutic strategies in modulating this pathway, and potential challenges in drug development.
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Antineoplásicos/farmacología , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Vía de Señalización Wnt/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Péptidos y Proteínas de Señalización Intercelular/inmunología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
We report three examples of a composite pleomorphic xanthoastrocytoma-epithelioid glioneuronal tumor (PXAEGT) occurring in an adolescent male and two young women. All were superficial and two were located in proximity to the optic nerves. Previously reported composite PXA-gangliogliomas (PXA-GG), have been considered "collision tumors" since little intermingling of the two elements has been present. In contrast, we hypothesized that the two elements of the PXA-EGT might instead derive from a common origin. To test this, we sampled the separate regions of these biphasic tumors and assessed each component for the BRAF V600E mutation, a genetic feature seen in two-thirds of pure PXAs. The BRAF mutation was found in both tumor areas in all cases, suggesting a common origin for the components, rather than a collision tumor. These biphasic PXA-EGT cases represent a new histomorphological combination of neuroepithelial neoplastic elements. These cases further expand the range of glial neoplasia in which epithelioid morphology is encountered, and add to the growing list of biphasic tumors harboring the BRAF V600E mutation.
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Astrocitoma/genética , Astrocitoma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Ganglioglioma/genética , Ganglioglioma/patología , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Adolescente , Astrocitoma/cirugía , Neoplasias Encefálicas/cirugía , ADN/genética , Células Epitelioides/patología , Femenino , Ganglioglioma/cirugía , Cefalea/etiología , Humanos , Inmunohistoquímica , Hemorragias Intracraneales/complicaciones , Hemorragias Intracraneales/patología , Imagen por Resonancia Magnética , Masculino , Trastornos Mentales/etiología , Microscopía Electrónica , Paresia/etiología , Reacción en Cadena de la Polimerasa , Proteínas S100/metabolismo , Trastornos del Habla/etiología , Adulto JovenRESUMEN
Introduction: Acquired MET gene amplification, MET exon 14 skip mutations, or MET fusions can emerge as resistance mechanisms to tyrosine kinase inhibitors (TKIs) in patients with lung cancer. The efficacy and safety of combining MET TKIs (such as crizotinib, capmatinib, or tepotinib) with parent TKIs to target acquired MET resistance are not well characterized. Methods: Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added. Clinicopathologic features, radiographic response (by means of Response Evaluation Criteria in Solid Tumors version 1.1), survival outcomes, adverse events (AEs) (by means of Common Terminology Criteria for Adverse Events version 5.0), and genomic data were collected. Survival outcomes were assessed using Kaplan-Meier methods. Multivariate modeling adjusted for lines of therapy, brain metastases, TP53 mutations, and oligometastatic disease. Results: Within the MET cohort, median age was 56 years (range: 36-83 y). Most patients were never smokers (28 of 41, 68.3%). Baseline brain metastases were common (21 of 41, 51%). The most common oncogenes in the MET cohort were EGFR (30 of 41, 73.2%), ALK (seven of 41, 17.1%), and ROS1 (two of 41, 4.9%). Co-occurring TP53 mutations (32 of 41, 78%) were frequent. Acquired MET alterations included MET gene amplification (37 of 41, 90%), MET exon 14 mutations (two of 41, 5%), and MET gene fusions (two of 41, 5%). After multivariate adjustment, the objective response rate (ORR) was higher in the MET cohort versus the chemotherapy cohort (ORR: 69.2% versus 20%, p < 0.001). Within the MET cohort, MET gene copy number (≥10 versus 6-10) did not affect radiographic response (54.5% versus 68.4%, p = 0.698). There was no difference in ORR on the basis of MET TKI used (F [2, 36] = 0.021, p = 0.978). There was no difference in progression-free survival (5 versus 6 mo; hazard ratio = 0.64; 95% confidence interval: 0.34-1.23, p = 0.18) or overall survival (13 versus 11 mo; hazard ratio = 0.75; 95% confidence interval: 0.42-1.35, p = 0.34) between the MET and chemotherapy cohorts. In the MET cohort, dose reductions for MET TKI-related toxicities were common (17 of 41, 41.4%) but less frequent for parent TKIs (two of 41, 5%). Grade 3 AEs were not significant between crizotinib, capmatinib, and tepotinib (p = 0.3). The discontinuation rate of MET TKIs was 17% with no significant differences between MET TKIs (p = 0.315). Among pre- and post-treatment biopsies (n = 17) in the MET cohort, the most common next-generation sequencing findings were loss of MET gene amplification (15 of 17, 88.2%), MET on-target mutations (seven of 17, 41.2%), new Ras-Raf-MAPK alterations (three of 17, 17.6%), and EGFR gene amplification (two of 17, 11.7%). Conclusions: The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.
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PURPOSE: To assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR-mutated non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling. RESULTS: A total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%). CONCLUSION: Treatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.
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In series dominated by adenocarcinoma histology, approximately 5% of non-small cell lung cancers (NSCLCs) harbor an anaplastic lymphoma kinase (ALK) gene rearrangement. Crizotinib, a tyrosine kinase inhibitor with significant activity against ALK, has demonstrated high response rates and prolonged progression-free survival in ALK-positive patients enrolled in phase 1/2 clinical trials. In 2011, crizotinib received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of proven ALK-positive NSCLC using an FDA-approved diagnostic test. Currently, only break-apart fluorescence in situ hybridization testing is FDA approved as a companion diagnostic for crizotinib; however, many other assays are available or in development. In the current review, the authors summarize the diagnostic tests available, or likely to become available, that could be used to identify patients with ALK-positive NSCLC, highlighting the pros and cons of each.