Prospective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial

Corinne E Griguer; Claudia R Oliva; Christopher S Coffey; Merit E Cudkowicz; Robin A Conwit; Anna L Gudjonsdottir; Dixie J Ecklund; Janel K Fedler; Tina M Neill-Hudson; Louis B Nabors; Melanie Benge; James R Hackney; Marianne Chase; Timothy P Leonard; Toral Patel; Howard Colman; Macarena de la Fuente; Rekha Chaudhary; Karen Marder; Teri Kreisl; Nimish Mohile; Milan G Chheda; Katharine McNeill; Priya Kumthekar; Aclan Dogan; Jan Drappatz; Vinay Puduvalli; Agnes Kowalska; Jerome Graber; Elizabeth Gerstner; Stephen Clark; Michael Salacz; James Markert

doi:10.1093/noajnl/vdab186

Prospective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial

Neurooncol Adv. 2021 Dec 24;4(1):vdab186. doi: 10.1093/noajnl/vdab186. eCollection 2022 Jan-Dec.

Authors

Corinne E Griguer¹, Claudia R Oliva¹, Christopher S Coffey², Merit E Cudkowicz³, Robin A Conwit⁴, Anna L Gudjonsdottir², Dixie J Ecklund², Janel K Fedler², Tina M Neill-Hudson², Louis B Nabors⁵, Melanie Benge⁵, James R Hackney⁶, Marianne Chase³, Timothy P Leonard³, Toral Patel⁷, Howard Colman⁸, Macarena de la Fuente⁹, Rekha Chaudhary¹⁰, Karen Marder¹¹, Teri Kreisl¹¹, Nimish Mohile⁶, Milan G Chheda¹², Katharine McNeill¹³, Priya Kumthekar¹⁴, Aclan Dogan¹⁵, Jan Drappatz¹⁶, Vinay Puduvalli¹⁷, Agnes Kowalska¹⁸, Jerome Graber¹⁹, Elizabeth Gerstner³, Stephen Clark²⁰, Michael Salacz²¹, James Markert²²

Affiliations

¹ Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, USA.
² Department of Biostatistics, University of Iowa, Iowa City, Iowa, USA.
³ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁴ NINDS, National Institutes of Health, Bethesda, Maryland, USA.
⁵ Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁶ Department of Pathology, Division of Neuropathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁷ Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
⁸ Department of Neurosurgery, University of Utah, Salt Lake City, Utah, USA.
⁹ School of Medicine, University of Miami, Miami, Florida, USA.
¹⁰ Department Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
¹¹ Division of Neuro-Oncology, Columbia University Health Sciences, New York, New York, USA.
¹² Departments of Medicine and Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
¹³ Montefiore Medical Center, Bronx, New York, USA.
¹⁴ Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
¹⁵ Department of Neurosurgery, Oregon Health and Science University, Portland, Oregon, USA.
¹⁶ Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
¹⁷ Department of Neuro-Oncology, Ohio State University, Columbus, Ohio, USA.
¹⁸ Department of Neurology, State University of New York, Stony Brook, New York, New York, USA.
¹⁹ Alvord Brain Tumor Center, Swedish Medical Center, Seattle, Washington, USA.
²⁰ Department of Neurology, Vanderbilt University, Nashville, Tennessee, USA.
²¹ Department Internal Medicine, University of Kansas Hospital, Kansas City, Kansas, USA.
²² Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Abstract

Background: 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 MGMT promoter methylation status.

Methods: 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 MGMT promoter methylation status were assayed in a centralized laboratory.

Results: OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival.

Conclusions: Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT 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.

Keywords: MGMT; biomarker; cytochrome C oxidase; glioblastoma; prospective clinical trial.

Abstract

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