title: Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial.
abstract: OBJECTIVE
  To improve stratification of risk-adapted treatment for non-metastatic (M0), standard-risk medulloblastoma patients by prospective evaluation of biomarkers of reported biological or prognostic significance, alongside clinico-pathological variables, within the multi-center HIT-SIOP-PNET4 trial.
  
  
  METHODS
  Formalin-fixed paraffin-embedded tumor tissues were collected from 338 M0 patients (>4.0 years at diagnosis) for pathology review and assessment of the WNT subgroup (MBWNT) and genomic copy-number defects (chromosome 17, MYC/MYCN, 9q22 (PTCH1) and DNA ploidy). Clinical characteristics were reviewed centrally.
  
  
  RESULTS
  The favorable prognosis of MBWNT was confirmed, however better outcomes were observed for non-MBWNT tumors in this clinical risk-defined cohort compared to previous disease-wide clinical trials. Chromosome 17p/q defects were heterogeneous when assessed at the cellular copy-number level, and predicted poor prognosis when they occurred against a diploid (ch17(im)/diploid(cen)), but not polyploid, genetic background. These factors, together with post-surgical tumor residuum (R+) and radiotherapy delay, were supported as independent prognostic markers in multivariate testing. Notably, MYC and MYCN amplification were not associated with adverse outcome. In cross-validated survival models derived for the clinical standard-risk (M0/R0) disease group, (ch17(im)/diploid(cen); 14% of patients) predicted high disease-risk, while the outcomes of patients without (ch17(im)/diploid(cen)) did not differ significantly from MBWNT, allowing re-classification of 86% as favorable-risk.
  
  
  CONCLUSIONS
  Biomarkers, established previously in disease-wide studies, behave differently in clinically-defined standard-risk disease. Distinct biomarkers are required to assess disease-risk in this group, and define improved risk-stratification models. Routine testing for specific patterns of chromosome 17 imbalance at the cellular level, and MBWNT, provides a strong basis for incorporation into future trials.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
authors.affiliation: Department of Pediatrics, University of Gothenburg and The Queen Silvia Children's Hospital, Gothenburg, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Lannering
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.|Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom.
authors.forename: Ed C
authors.initials: EC
authors.lastname: Schwalbe
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Debbie
authors.initials: D
authors.lastname: Hicks
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Kieran
authors.initials: K
authors.lastname: O'Toole
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Sarah Leigh
authors.initials: SL
authors.lastname: Nicholson
authors.affiliation: Department of Neuropathology, University of Bonn, Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Goschzik
authors.affiliation: Department of Neuropathology, University of Bonn, Bonn, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Zur Mühlen
authors.affiliation: Department of Pathology and Neuropathology, Assistance Publique Hôpitaux de Marseille, Aix Marseille University, Marseille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.affiliation: Institut Curie and University Paris Descartes, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Doz
authors.affiliation: University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rutkowski
authors.affiliation: Karolinska Institute, Stockholm, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Gustafsson
authors.affiliation: Department of Neuropathology, University of Bonn, Bonn, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002528:Cerebellar Neoplasms / Q000737:chemistry* / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17; D015331:Cohort Studies; D005260:Female; D005557:Formaldehyde; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000737:chemistry* / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D016612:Paraffin Embedding; D011379:Prognosis; D012307:Risk Factors; D016707:Tissue Fixation; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D005557:Formaldehyde
keywords: biomarker; clinical trial; medulloblastoma; stratification