Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial

// Steven C. Clifford 1, * , Birgitta Lannering 2 , Ed C. Schwalbe 1, 3 , Debbie Hicks 1 , Kieran O' Toole 1 , Sarah Leigh Nicholson 1 , Tobias Goschzik 4 , Anja zur Mühlen 4 , Dominique Figarella-Branger 5 , François Doz 6 , Stefan Rutkowski 7 , Göran Gustafsson 8 , Torsten Pietsch 4, * , on behalf of the SIOP-Europe PNET Group 1 Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom 2 Department of Pediatrics, University of Gothenburg and The Queen Silvia Children's Hospital, Gothenburg, Sweden 3 Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom 4 Department of Neuropathology, University of Bonn, Bonn, Germany 5 Department of Pathology and Neuropathology, Assistance Publique Hôpitaux de Marseille, Aix Marseille University, Marseille, France 6 Institut Curie and University Paris Descartes, Paris, France 7 University Medical Center Hamburg-Eppendorf, Hamburg, Germany 8 Karolinska Institute, Stockholm, Sweden * These authors have contributed equally to this work Correspondence to: Steven C. Clifford, e-mail: steve.clifford@ncl.ac.uk Keywords: medulloblastoma, clinical trial, biomarker, stratification Received: July 27, 2015 Accepted: August 24, 2015 Published: September 05, 2015 ABSTRACT 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 (MB WNT ) and genomic copy-number defects (chromosome 17, MYC/MYCN , 9q22 ( PTCH1 ) and DNA ploidy). Clinical characteristics were reviewed centrally. Results: The favorable prognosis of MB WNT was confirmed, however better outcomes were observed for non-MB WNT 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 MB WNT , 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 MB WNT , provides a strong basis for incorporation into future trials.