Maria V Corrias1, Stefano Parodi1, Andrei Tchirkov2, Tim Lammens3, Ales Vicha4, Claudia Pasqualini5, Catarina Träger6, Yania Yáñez7, Sandro Dallorso1, Luigi Varesio1, Roberto Luksch8, Genevieve Laureys3, Dominique Valteau-Couanet5, Adela Canete7, Ulrike Pöetschger9, Ruth Ladenstein9, Susan A Burchill10. 1. Unit of Experimental Therapy in Oncology, Istituto Giannina Gaslini, Genoa, Italy. 2. CHU Clermont-Ferrand, Service de Cytogénétique Médicale and Université Clermont Auvergne, Clermont-Ferrand, France. 3. Department of Pediatric Hematology/Oncology, Ghent University Hospital, Ghent, Belgium. 4. Department of Pediatric Hematology and Oncology, 2nd Medical Faculty Charles University and Faculty Hospital Motol, Prague, Czech Republic. 5. Department of Child and Adolescent Cancer, Institut Gustave Roussy, Villejuif, France. 6. Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. 7. Oncología Pediátrica, Hospital Universitari i Politècnic La Fe, Valencia, Spain. 8. Department of Pediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 9. Department of Pediatric Oncology, CCRI/St. Anna Children's Hospital, Vienna, Austria. 10. Children's Cancer Research Group, Leeds Institute of Cancer and Pathology, Leeds, United Kingdom.
Abstract
BACKGROUND: The purpose of this study was to evaluate whether levels of neuroblastoma mRNAs in bone marrow and peripheral blood from stage M infants (≤12 months of age at diagnosis, MYCN amplified) and toddlers (between 12 and 18 months, any MYCN status) predict event-free survival (EFS). METHODS: Bone marrow aspirates and peripheral blood samples from 97 infants/toddlers enrolled in the European High-Risk Neuroblastoma trial were collected at diagnosis in PAXgene™ blood RNA tubes. Samples were analyzed by reverse transcription quantitative polymerase chain reaction according to standardized procedures. RESULTS: Bone marrow tyrosine hydroxylase (TH) or paired-like homeobox 2b (PHOX2B) levels in the highest tertile were associated with worse EFS; hazard ratios, adjusted for age and MYCN status, were 1.5 and 1.8 respectively. Expression of both TH and PHOX2B in the highest tertile predicted worse outcome (p = 0.015), and identified 20 (23%) infants/toddlers with 5-year EFS of 20% (95%CI: 4%-44%). Prognostic significance was maintained after adjusting for over-fitting bias (p = 0.038), age and MYCN status. In peripheral blood, PHOX2B levels in the highest tertile predicted a two-fold increased risk of an event (p = 0.032), and identified 23 (34%) infants/toddlers with 5-year EFS of 29% (95%CI: 12%-48%). Time-dependent receiver operating characteristic analysis confirmed the prognostic value of combined TH and PHOX2B in bone marrow and of PHOX2B in peripheral blood during the first year of follow-up. CONCLUSIONS: High levels of bone marrow TH and PHOX2B and of peripheral blood PHOX2B at diagnosis allow early identification of a group of high-risk infant and toddlers with neuroblastoma who may be candidates for alternative treatments. Integration with additional biomarkers, as well as validation in additional international trials is warranted.
BACKGROUND: The purpose of this study was to evaluate whether levels of neuroblastoma mRNAs in bone marrow and peripheral blood from stage M infants (≤12 months of age at diagnosis, MYCN amplified) and toddlers (between 12 and 18 months, any MYCN status) predict event-free survival (EFS). METHODS: Bone marrow aspirates and peripheral blood samples from 97 infants/toddlers enrolled in the European High-Risk Neuroblastoma trial were collected at diagnosis in PAXgene™ blood RNA tubes. Samples were analyzed by reverse transcription quantitative polymerase chain reaction according to standardized procedures. RESULTS: Bone marrow tyrosine hydroxylase (TH) or paired-like homeobox 2b (PHOX2B) levels in the highest tertile were associated with worse EFS; hazard ratios, adjusted for age and MYCN status, were 1.5 and 1.8 respectively. Expression of both TH and PHOX2B in the highest tertile predicted worse outcome (p = 0.015), and identified 20 (23%) infants/toddlers with 5-year EFS of 20% (95%CI: 4%-44%). Prognostic significance was maintained after adjusting for over-fitting bias (p = 0.038), age and MYCN status. In peripheral blood, PHOX2B levels in the highest tertile predicted a two-fold increased risk of an event (p = 0.032), and identified 23 (34%) infants/toddlers with 5-year EFS of 29% (95%CI: 12%-48%). Time-dependent receiver operating characteristic analysis confirmed the prognostic value of combined TH and PHOX2B in bone marrow and of PHOX2B in peripheral blood during the first year of follow-up. CONCLUSIONS: High levels of bone marrow TH and PHOX2B and of peripheral blood PHOX2B at diagnosis allow early identification of a group of high-risk infant and toddlers with neuroblastoma who may be candidates for alternative treatments. Integration with additional biomarkers, as well as validation in additional international trials is warranted.
Authors: Ruben Van Paemel; Roos Vlug; Katleen De Preter; Nadine Van Roy; Frank Speleman; Leen Willems; Tim Lammens; Geneviève Laureys; Gudrun Schleiermacher; Godelieve A M Tytgat; Kathy Astrahantseff; Hedwig Deubzer; Bram De Wilde Journal: Eur J Pediatr Date: 2020-01-03 Impact factor: 3.183