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

Lookup NU author(s): Professor Steven CliffordORCiD, Dr Ed Schwalbe, Dr Debbie Hicks, Kieran O'Toole, Sarah Nicholson

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Abstract

PURPOSE: To improve stratification of risk-adapted treatment for non-metastatic(M0), standard-risk medulloblastoma patients by prospective evaluation ofbiomarkers of reported biological or prognostic significance, alongsideclinico-pathological variables, within the multi-center HIT-SIOP-PNET4 trial.METHODS: Formalin-fixed paraffin-embedded tumor tissues were collected from 338M0 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 wereheterogeneous when assessed at the cellular copy-number level, and predicted poorprognosis when they occurred against a diploid (ch17(im)/diploid(cen)), but notpolyploid, genetic background. These factors, together with post-surgical tumorresiduum (R+) and radiotherapy delay, were supported as independent prognosticmarkers in multivariate testing. Notably, MYC and MYCN amplification were notassociated with adverse outcome. In cross-validated survival models derived forthe 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, allowingre-classification of 86% as favorable-risk.CONCLUSIONS: Biomarkers, established previously in disease-wide studies, behavedifferently in clinically-defined standard-risk disease. Distinct biomarkers are required to assess disease-risk in this group, and define improvedrisk-stratification models. Routine testing for specific patterns of chromosome17 imbalance at the cellular level, and MBWNT, provides a strong basis forincorporation into future trials.

Publication metadata

Author(s): Clifford SC, Lannering B, Schwalbe EC, Hicks D, O'Toole K, Nicholson SL, Goschzik T, Zur-Mühlen A, Figarella-Branger D, Doz F, Rutkowski S, Gustafsson G, Pietsch T

Publication type: Article

Publication status: Published

Journal: Oncotarget

Year: 2015

Volume: 6

Issue: 36

Pages: 38827-38839

Online publication date: 05/09/2015

Acceptance date: 24/08/2015

ISSN (electronic): 1949-2553

Publisher: Impact Journals

URL: http://dx.doi.org/10.18632/oncotarget.5149

DOI: 10.18632/oncotarget.5149

PubMed id: 26420814

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