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

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 tri...

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Autores principales: Clifford, Steven C., Lannering, Birgitta, Schwalbe, Ed C., Hicks, Debbie, O' Toole, Kieran, Nicholson, Sarah Leigh, Goschzik, Tobias, zur Mühlen, Anja, Figarella-Branger, Dominique, Doz, François, Rutkowski, Stefan, Gustafsson, Göran, Pietsch, Torsten
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770740/
https://www.ncbi.nlm.nih.gov/pubmed/26420814
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author Clifford, Steven C.
Lannering, Birgitta
Schwalbe, Ed C.
Hicks, Debbie
O' Toole, Kieran
Nicholson, Sarah Leigh
Goschzik, Tobias
zur Mühlen, Anja
Figarella-Branger, Dominique
Doz, François
Rutkowski, Stefan
Gustafsson, Göran
Pietsch, Torsten
author_facet Clifford, Steven C.
Lannering, Birgitta
Schwalbe, Ed C.
Hicks, Debbie
O' Toole, Kieran
Nicholson, Sarah Leigh
Goschzik, Tobias
zur Mühlen, Anja
Figarella-Branger, Dominique
Doz, François
Rutkowski, Stefan
Gustafsson, Göran
Pietsch, Torsten
author_sort Clifford, Steven C.
collection PubMed
description 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.
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spelling pubmed-47707402016-03-21 Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial Clifford, Steven C. Lannering, Birgitta Schwalbe, Ed C. Hicks, Debbie O' Toole, Kieran Nicholson, Sarah Leigh Goschzik, Tobias zur Mühlen, Anja Figarella-Branger, Dominique Doz, François Rutkowski, Stefan Gustafsson, Göran Pietsch, Torsten Oncotarget Research Paper 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. Impact Journals LLC 2015-09-05 /pmc/articles/PMC4770740/ /pubmed/26420814 Text en Copyright: © 2015 Clifford et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Clifford, Steven C.
Lannering, Birgitta
Schwalbe, Ed C.
Hicks, Debbie
O' Toole, Kieran
Nicholson, Sarah Leigh
Goschzik, Tobias
zur Mühlen, Anja
Figarella-Branger, Dominique
Doz, François
Rutkowski, Stefan
Gustafsson, Göran
Pietsch, Torsten
Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial
title Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial
title_full Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial
title_fullStr Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial
title_full_unstemmed Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial
title_short Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial
title_sort biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: results from the multi-center hit-siop-pnet4 clinical trial
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770740/
https://www.ncbi.nlm.nih.gov/pubmed/26420814
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