Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial
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Steven C. Clifford1,*, Birgitta Lannering2, Ed C. Schwalbe1,3, Debbie Hicks1, Kieran O' Toole1, Sarah Leigh Nicholson1, Tobias Goschzik4, Anja zur Mühlen4, Dominique Figarella-Branger5, François Doz6, Stefan Rutkowski7, Göran Gustafsson8, Torsten Pietsch4,*, on behalf of the SIOP-Europe PNET Group
1Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom
2Department of Pediatrics, University of Gothenburg and The Queen Silvia Children's Hospital, Gothenburg, Sweden
3Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom
4Department of Neuropathology, University of Bonn, Bonn, Germany
5Department of Pathology and Neuropathology, Assistance Publique Hôpitaux de Marseille, Aix Marseille University, Marseille, France
6Institut Curie and University Paris Descartes, Paris, France
7University Medical Center Hamburg-Eppendorf, Hamburg, Germany
8Karolinska Institute, Stockholm, Sweden
*These authors have contributed equally to this work
Steven C. Clifford, e-mail: firstname.lastname@example.org
Keywords: medulloblastoma, clinical trial, biomarker, stratification
Received: July 27, 2015 Accepted: August 24, 2015 Published: September 05, 2015
Purpose: 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.
Conclusion: 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.
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