biostudies-literatureGriguer CENational Institute of Neurological Disorders and StrokeNINDS NIH HHSNational Institutes of Healthvdab186https://www.ebi.ac.uk/biostudies/studies/S-EPMC8788017biostudies-literatureUnknown4(1)<h4>Background</h4>Glioblastoma (GBM) has a 5-year survival rate of 3%-5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome C oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of <i>MGMT</i> promoter methylation status.<h4>Methods</h4>This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival (OS) time, and the secondary end point was progression-free survival (PFS) time. Tumor CcO activity and <i>MGMT</i> promoter methylation status were assayed in a centralized laboratory.<h4>Results</h4>OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of <i>MGMT</i> promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and <i>MGMT</i> promoter methylation in tumors may be predictive of long-term survival.<h4>Conclusions</h4>Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated <i>MGMT</i> promoter may reveal a subgroup of GBM patients with improved long-term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.Neuro-oncology advancesProspective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial.PMC8788017U24 NS107128U01 NS093663U01 NS077179U01 NS077352U24 NS107166Dogan AMcNeill KBenge MFedler JKChaudhary RSalacz MConwit RAGerstner ECoffey CSDrappatz JMarkert JOliva CRMarder KNeill-Hudson TMPatel TCudkowicz MEGraber JColman HEcklund DJNabors LBKowalska AHackney JRChheda MGPuduvalli VMohile Nde la Fuente MKreisl TGudjonsdottir ALKumthekar PGriguer CELeonard TPChase MClark SfalseProspective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial.<h4>Background</h4>Glioblastoma (GBM) has a 5-year survival rate of 3%-5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome C oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of <i>MGMT</i> promoter methylation status.<h4>Methods</h4>This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival (OS) time, and the secondary end point was progression-free survival (PFS) time. Tumor CcO activity and <i>MGMT</i> promoter methylation status were assayed in a centralized laboratory.<h4>Results</h4>OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of <i>MGMT</i> promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and <i>MGMT</i> promoter methylation in tumors may be predictive of long-term survival.<h4>Conclusions</h4>Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated <i>MGMT</i> promoter may reveal a subgroup of GBM patients with improved long-term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.2022-01-01T00:00:00Z2022 Jan-Dec2024-11-20T16:58:35.555Z2022-02-11T15:50:09.454ZS-EPMC87880173508805110.1093/noajnl/vdab186