Identification of germline cancer predisposition variants in pediatric sarcoma patients from somatic tumor testing

Genetic predisposition is an important risk factor for cancer in children and adolescents but detailed associations of individual genetic mutations to childhood cancer are still under intense investigation. Among pediatric cancers, sarcomas can arise in the setting of cancer predisposition syndromes. The association of sarcomas with these syndromes is often missed, due to the rarity and heterogeneity of sarcomas and the limited search of cancer genetic syndromes. This study included 43 pediatric and young adult patients with different sarcoma subtypes. Tumor profiling was undertaken using the Oncomine Childhood Cancer Research Assay (Thermo Fisher Scientific). Sequencing results were reviewed for potential germline alterations in clinically relevant genes associated with cancer predisposition syndromes. Jongmans¿ criteria were taken into consideration for the patient selection. Fifteen patients were selected as having potential pathogenic germline variants due to tumor sequencing that identified variants in the following genes: CDKN2A, NF1, NF2, RB1, SMARCA4, SMARCB1 and TP53. The variants found in NF1 and CDKN2A in two different patients were detected in the germline, confirming the diagnosis of a cancer predisposition syndrome. We have shown that the results of somatic testing can be used to identify those at risk of an underlying cancer predisposition syndrome

Utilidad de los estudios genómicos basados en paneles de NGS (Next Generation Sequencing) para el manejo clínico de los sarcomas en pacientes pediátricos

Las técnicas genómicas permiten el diagnóstico y manejo de niños y adultos jóvenes con sarcomas mediante la identificación de pacientes de alto riesgo y de aquellos que pueden beneficiarse de una terapia dirigida o de la participación en ensayos clínicos. Objetivo: analizar el rendimiento de un panel de genes NGS para el manejo clínico de pacientes con sarcoma pediátrico. Se estudiaron 53 pacientes pediátricos y adultos jóvenes diagnosticados de sarcoma, procedentes de dos centros españoles. Los datos genómicos se obtuvieron utilizando el Oncomine Childhood Cancer Research Assay, y se categorizaron según su valor diagnóstico, predictivo o pronóstico. En 44 (83%) de los 53 pacientes se identificó al menos una alteración genética. En el 80% de estos pacientes se obtuvo (n = 11) o cambió (n = 9) el diagnóstico, por lo que los datos genómicos afectaron al tratamiento. El diagnóstico inicial erróneo más frecuente fue el de sarcoma de Ewing, en lugar de liposarcoma mixoide (FUS-DDDIT3), tumor rabdoide de tejidos blandos (SMARCB1) o histiocitoma fibroso angiomatoide (EWSR1-CREB1). En nuestra serie, dos pacientes tenían una alteración genética con una terapia dirigida aprobada por la FDA, y el 30% tenía al menos una alteración potencialmente procesable. Los estudios genómicos basados en NGS son útiles y factibles en el diagnóstico y manejo clínico de los sarcomas pediátricos. La caracterización genómica de estos tumores raros y heterogéneos también ayuda en la búsqueda de biomarcadores pronósticos y oportunidades terapéuticas

Current status of precision medicine in pediatric oncology in Spain: a consensus report by the Spanish Society of Paediatric Haematology and Oncology (SEHOP)

The study analyzes the current status of personalized medicine in pediatric oncology in Spain. It gathers national data on the tumor molecular studies and genomic sequencing carried out at diagnosis and at relapse, the centers that perform these studies, the technology used and the interpretation and clinical applicability of the results. Current challenges and future directions to achieve a coordinated national personalized medicine strategy in pediatric oncology are also discussed. Next generation sequencing-based (NGS) gene panels are the technology used in the majority of centers and financial limitations are the main reason for not incorporating these studies into routine care. Nowadays, the application of precision medicine in pediatric oncology is a reality in a great number of Spanish centers. However, its implementation is uneven and lacks standardization of protocols; therefore, national coordination to overcome the inequalities is required. Collaborative work within the Personalized Medicine Group of SEHOP is an adequate framework for encouraging a step forward in the effort to move precision medicine into the national healthcare system.SEHOP has received financial support for this project in the form of unrestricted collaboration in the logistics of expert meeting from Bayer.Peer reviewe

Oncolytic DNX-2401 virus for pediatric diffuse intrinsic pontine glioma

Background: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking. Methods: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses. Results: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire. Conclusions: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.)