RESUMEN
PURPOSE: Our study aimed to explore real-world treatment scenarios for children and adolescents with neurotrophic tropomyosin receptor kinase (NTRK)-fused tumors, emphasizing access, responses, side effects, and outcomes. PATIENTS AND METHODS: Pooled clinical data from 17 pediatric cases (11 soft-tissue sarcomas, five brain tumors, and one neuroblastoma) treated with larotrectinib and radiologic images for 14 patients were centrally reviewed. Testing for gene fusions was prompted by poor response to treatment, tumor progression, or aggressiveness. RESULTS: Six different NTRK fusion subtypes were detected, and various payment sources for testing and medication were reported. Radiologic review revealed objective tumor responses (OR) in 11 of 14 patients: Complete responses: two; partial responses: nine; and stable disease: three cases. Grades 1 or 2 Common Terminology Criteria for Adverse Events adverse effects were reported in five patients. Regarding the entire cohort's clinical information, 15 of 17 patients remain alive (median observation time: 25 months): four with no evidence of disease and 11 alive with disease (10 without progression). One patient developed resistance to the NTRK inhibitor and died from disease progression while another patient died due to an unrelated cause. CONCLUSION: This real-world study confirms favorable agnostic tumor OR rates to larotrectinib in children with NTRK-fused tumors. Better coordination to facilitate access to medication remains a challenge, particularly in middle-income countries like Brazil.
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Inhibidores de Proteínas Quinasas , Pirazoles , Humanos , Niño , Masculino , Femenino , Adolescente , Pirazoles/uso terapéutico , Preescolar , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Receptor trkA/genética , Receptor trkA/antagonistas & inhibidores , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Sarcoma/tratamiento farmacológico , Sarcoma/genética , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/genética , Lactante , Receptor trkB/genética , Receptor trkC/genética , Ensayos Clínicos como AsuntoRESUMEN
The recent identification of rearrangements of neurotrophic tyrosine receptor kinase (NTRK) genes and the development of specific fusion protein inhibitors, such as larotrectinib and entrectinib, have revolutionised the diagnostic and clinical management of patients presenting with tumours with these alterations. Tumours that harbour NTRK fusions are found in both adults and children; and they are either rare tumours with common NTRK fusions that may be diagnostic, or more prevalent tumours with rare NTRK fusions. To assess currently available evidence on this matter, three key Spanish medical societies (the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Pathological Anatomy (SEAP), and the Spanish Society of Paediatric Haematology and Oncology (SEHOP) have brought together a group of experts to develop a consensus document that includes guidelines on the diagnostic, clinical, and therapeutic aspects of NTRK-fusion tumours. This document also discusses the challenges related to the routine detection of these genetic alterations in a mostly public Health Care System.
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Consenso , Glicoproteínas de Membrana/genética , Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Receptor trkA/genética , Receptor trkB/genética , Receptor trkC/genética , Adulto , Factores de Edad , Benzamidas/uso terapéutico , Niño , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Indazoles/uso terapéutico , Terapia Molecular Dirigida , Neoplasias/diagnóstico , Neoplasias/terapia , Proteínas de Fusión Oncogénica/análisis , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sociedades Médicas , EspañaRESUMEN
Introduction: Neurotrophin-3 (NT-3) is thought to play a role in the neurobiological processes implicated in mood and anxiety disorders. NT-3 is a potential pharmacological target for mood disorders because of its effects on monoamine neurotransmitters, regulation of synaptic plasticity and neurogenesis, brain-derived neurotrophic factor (BDNF) signaling boosting, and modulation of the hypothalamic-pituitary-adrenal (HPA) axis. The mechanisms underlying NT-3 anxiolytic properties are less clear and require further exploration and definition. Areas covered: The evidence that supports NT-3 as a pharmacological target for anxiety and mood disorders is presented and this is followed by a reflection on the quandaries, stumbling blocks, and future perspectives for this novel target. Expert opinion: There is evidence for miRNAs being key post-transcriptional regulators of neurotrophin-3 receptor gene (NTRK3) in anxiety disorders; however, the anxiolytic properties of NT-3 need further examination and delineation. Moreover, NT-3 expression by non-neuronal cells and its role in brain circuits that participate in anxiety and mood disorders require further scrutiny. Further work is vital before progression into clinical trials can be realized.
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Trastornos de Ansiedad/tratamiento farmacológico , Trastorno Depresivo Mayor/tratamiento farmacológico , Neurotrofina 3/metabolismo , Animales , Trastornos de Ansiedad/fisiopatología , Trastorno Depresivo Mayor/fisiopatología , Humanos , MicroARNs/genética , Terapia Molecular Dirigida , Trastornos del Humor/tratamiento farmacológico , Trastornos del Humor/fisiopatología , Receptor trkC/genéticaRESUMEN
In 2011 the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP) started a joint project to establish guidelines on biomarker testing in patients with advanced non-small-cell lung cancer (NSCLC) based on current evidence. As this field is constantly evolving, these guidelines have been updated, previously in 2012 and 2015 and now in 2019. Current evidence suggests that the mandatory tests to conduct in all patients with advanced NSCLC are for EGFR and BRAF mutations, ALK and ROS1 rearrangements and PD-L1 expression. The growing need to study other emerging biomarkers has promoted the routine use of massive sequencing (next-generation sequencing, NGS). The coordination of every professional involved and the prioritisation of the most suitable tests and technologies for each case remains a challenge.
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Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Quinasa de Linfoma Anaplásico/genética , Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , ADN Tumoral Circulante , Receptores ErbB/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Biopsia Líquida , Neoplasias Pulmonares/genética , Glicoproteínas de Membrana/genética , Células Neoplásicas Circulantes , Reacción en Cadena de la Polimerasa , 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 , Receptor ErbB-2/genética , Receptor trkA/genética , Receptor trkB/genética , Receptor trkC/genética , Sociedades Médicas , EspañaRESUMEN
OBJECTIVE: PTC-specific analysis identified novel fusions involving RET, BRAF, NTRK1, NTRK3, AGK and ALK genes in adults and pediatric PTCs. Although many novel fusions are PTC-specific events and, therefore, are ideal for diagnosis purposes, validation across additional and larger patient cohorts is essential for introducing these potential diagnostic or prognostic biomarkers into the clinical practice. As most of the BRAF, NTRK3 and ALK fusions were initially found in pediatric PTC or in more aggressive thyroid carcinomas, and there is a great disparity across population, in this study, we screened a large set of adult-sporadic PTC cases for the most prevalent kinase fusion lately described in the TCGA. DESIGN AND METHODS: The prevalence of the fusions was determined by RT-PCR in 71 classical PTC, 45 follicular variants of PTC (FVPTC), 19 follicular thyroid adenomas (FTAs) and 22 follicular thyroid carcinomas (FTCs). RESULTS: ETV6-NTRK3 was exclusively found in FVPTC, in both encapsulated and infiltrative variants, but was not found in FTAs and FTCs. STRN-ALK was found in both classical PTC and FVPTC. No AGK-BRAF fusion was identified in this series, endorsing that AGK-BRAF is a genetic event mainly associated with pediatric PTCs. CONCLUSIONS: The identification of kinase fusions in thyroid carcinomas helps to expand our knowledge about the landscape of oncogenic alterations in PTC. As ETV6-NTRK3 and STRN-ALK are recurrent and not identified in benign lesions, they can certainly help with diagnosis of thyroid nodules. Further analysis is needed to define if they can also be useful for prognosis and guiding therapy.
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Biomarcadores de Tumor/metabolismo , Proteínas de Unión a Calmodulina/metabolismo , Carcinoma Papilar/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Proto-Oncogénicas c-ets/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptor trkC/metabolismo , Proteínas Represoras/metabolismo , Neoplasias de la Tiroides/metabolismo , Adulto , Quinasa de Linfoma Anaplásico , Biomarcadores de Tumor/genética , Proteínas de Unión a Calmodulina/genética , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/genética , Estudios de Cohortes , Femenino , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Unión Proteica/fisiología , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptor trkC/genética , Proteínas Represoras/genética , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Adulto Joven , Proteína ETS de Variante de Translocación 6RESUMEN
BACKGROUND: Previous studies reported significant differences in the clinical presentation and outcomes of papillary thyroid carcinoma (PTC) in pediatric patients compared with adults. Previous studies have suggested that the clinicopathological differences observed between pediatric and adult PTCs may be due the existence of distinct genetic alterations. However, the knowledge of genetic events in pediatric PTCs is based primarily on studies in radiation-exposed PTCs or in the few studies that enrolled predominantly adolescent patients. The aim of this study was to characterize the known oncogenic alterations of the MAPK pathway found in adult and radiation-exposed PTCs in a cohort of predominantly sporadic pediatric PTC patients. METHODS: Thirty-five pediatric PTCs were screened for the most prevalent fusions (RET/PTC1, RET/PTC2, RET/PTC3, ETV6-NTRK3, and AGK-BRAF) and point mutations (BRAFV600E and NRASQ61) described in sporadic pediatric PTCs. The mutational status was correlated with clinicopathological data. RESULTS: Mutations were found in 20 out of 35 (57%) PTC cases. Fusion oncogenes were the main genetic alterations found. RET/PTC1-3 rearrangements were found in 13 (37%), ETV6-NTRK3 in 3 (9%), AGK-BRAF in 4 (11%), and BRAFV600E in 3 (9%). No mutation was found in NRASQ61. BRAFV600E was associated with older age and larger tumor size (p < 0.05), and RET/PTC3 was associated with a larger tumor size and multifocality (p < 0.05). CONCLUSIONS: The genetic signature in this cohort was remarkably different than that observed in adults. Although observed at a lower prevalence, the spectrum of mutations was quite similar to that described in radiation-exposed pediatric PTCs. As mutations were unidentifiable in over 40% of the PTC cases, more comprehensive studies conducted in these patients will help to decipher the genetic landscape of sporadic pediatric PTCs.
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Carcinoma Papilar/genética , Fusión de Oncogenes/genética , Neoplasias de la Tiroides/genética , Adolescente , Niño , Preescolar , Estudios de Cohortes , Femenino , GTP Fosfohidrolasas/genética , Humanos , Masculino , Proteínas de la Membrana/genética , Coactivadores de Receptor Nuclear/genética , Receptor Patched-1/genética , Receptor Patched-2/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Mutación Puntual , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Proto-Oncogénicas c-ret/genética , Receptor trkC/genética , Proteínas Represoras/genética , Cáncer Papilar Tiroideo , Proteína ETS de Variante de Translocación 6RESUMEN
BACKGROUND: The aims of this study were to define the mRNA expression profiles of MYCN, DDX1, TrkA, and TrkC in biopsy tumor samples from 64 Brazilian patients with neuroblastomas of different risk stages and to correlate altered expression with prognostic values. PROCEDURE: Patients were retrospectively classified into low- (n = 11), intermediate- (n = 18), and high-risk (n = 35) groups using standard criteria. The mRNA levels of the above genes were measured by quantitative real-time polymerase chain reaction. Univariate analyses were performed and survival curves were plotted by the Kaplan-Meier method. RESULTS: Of the 64 patients, 53% were female and 62.5% were older than 18 months. The 5-year overall survival (OS) for the entire cohort was 40.3%, with inferior median OS in patients identified in the intermediate- and high-risk groups. A significant difference in OS with respect to TrkA mRNA expression was found for the high-risk group vs. either the low- or intermediate-risk groups (P < 0.01, log rank test). Within the intermediate-risk group, neuroblastoma patients with positive TrkA mRNA expression had better clinical outcomes than patients with no TrkA transcript expression (P = 0.004). Another difference in OS was only found between the intermediate- and high-risk groups (P < 0.027, log rank test). No significant correlation of mRNA expression and survival outcome could be detected for the MYCN, DDX1. CONCLUSIONS: Positive expression of TrkA mRNA may be a clinically useful addition to the current risk classification system, allowing the identification of NB tumors with favorable prognosis.