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, 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

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.

© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Figures

Figure 1.
Figure 1.
Kaplan-Meier survival curves in patients with newly diagnosed GBM. (A, B) Median OS (A) and median PFS (B) in the full cohort. (C, D) Median OS (C) and PFS (D) in patients stratified by tumor CcO/CS activity. Low tumor CcO activity (blue line) was defined as CcO/CS ≤ 4 and high tumor CcO activity (red line) was defined as CcO/CS > 4. Abbreviations: CcO, cytochrome C oxidase; CS, citrate synthase; GBM, glioblastoma; OS, overall survival; PFS, progression-free survival.
Figure 2.
Figure 2.
Kaplan-Meier survival curves in patients with newly diagnosed GBM stratified by tumor MGMT promoter methylation status. (A) Median OS by MGMT promoter methylation status. (B) Median PFS by MGMT promoter methylation status. Abbreviations: GBM, glioblastoma; OS, overall survival; PFS, progression-free survival.
Figure 3.
Figure 3.
Median survival, log-rank, and Wilcoxon weighted log-rank test for OS by tumor CcO activity and MGMT promoter methylation subgroups. (A) Kaplan-Meier survival function estimate of OS in the high tumor CcO activity group by MGMT promoter status. (B) Kaplan-Meier survival function estimate of OS in the low tumor CcO activity group by MGMT promoter status. Abbreviations: CcO, cytochrome C oxidase; OS, overall survival.

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