Prospective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial.
Prospective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial.
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DOI：
10.1093/noajnl/vdab186
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发表时间：
2022-01
期刊：
影响因子：
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通讯作者：
Markert J
中科院分区：
文献类型：
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作者：
Griguer CE;Oliva CR;Coffey CS;Cudkowicz ME;Conwit RA;Gudjonsdottir AL;Ecklund DJ;Fedler JK;Neill-Hudson TM;Nabors LB;Benge M;Hackney JR;Chase M;Leonard TP;Patel T;Colman H;de la Fuente M;Chaudhary R;Marder K;Kreisl T;Mohile N;Chheda MG;McNeill K;Kumthekar P;Dogan A;Drappatz J;Puduvalli V;Kowalska A;Graber J;Gerstner E;Clark S;Salacz M;Markert J
胶质母细胞瘤（GBM）的5年生存率为3%-5%。GBM治疗包括最大切除术，然后伴随和辅助替莫唑胺（TMZ）放疗。细胞色素C氧化酶（CcO）是一种线粒体酶，参与TMZ的耐药机制。在先前的回顾性试验中，GBM中的CcO活性与临床结局呈负相关。目前的Cyto-C研究旨在前瞻性评估和验证肿瘤CcO活性在新诊断的原发性GBM患者中的预后价值，并与已知的MGMT启动子甲基化状态的预后价值进行比较。这项多机构、设盲、前瞻性生物标志物研究招募了152名新诊断的GBM患者，这些患者将接受手术切除，并将成为标准治疗的候选人。主要终点为总生存期（OS），次要终点为无进展生存期（PFS）。在集中实验室检测肿瘤CcO活性和MGMT启动子甲基化状态。肿瘤CcO活性高低对OS和PFS无显著影响，MGMT启动子甲基化的预后有效性得到证实。值得注意的是，一项计划的探索性分析表明，肿瘤中低CcO活性和MGMT启动子甲基化的组合可能预测长期生存。单独的肿瘤CcO活性不能作为GBM患者的预后标志物。然而，低CcO活性和甲基化MGMT启动子的组合可能揭示GBM患者的亚组具有改善的长期生存，需要进一步评估。我们的工作还表明了进行大型、多机构、前瞻性研究以验证生物标志物的重要性。我们还讨论了在收集这些研究中吸取的经验教训。
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. 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. 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. 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.