Abstract
ObjectivesTo assess the combined role of tumor vascularity, estimated from perfusion MRI, and MGMT methylation status on overall survival (OS) in patients with glioblastoma.MethodsA multicentric international dataset including 96 patients from NCT03439332 clinical study were used to study the prognostic relationships between MGMT and perfusion markers. Relative cerebral blood volume (rCBV) in the most vascularized tumor regions was automatically obtained from preoperative MRIs using ONCOhabitats online analysis service. Cox survival regression models and stratification strategies were conducted to define a subpopulation that is particularly favored by MGMT methylation in terms of OS.ResultsrCBV distributions did not differ significantly (p > 0.05) in the methylated and the non-methylated subpopulations. In patients with moderately vascularized tumors (rCBV < 10.73), MGMT methylation was a positive predictive factor for OS (HR = 2.73, p = 0.003, AUC = 0.70). In patients with highly vascularized tumors (rCBV > 10.73), however, there was no significant effect of MGMT methylation (HR = 1.72, p = 0.10, AUC = 0.56).ConclusionsOur results indicate the existence of complementary prognostic information provided by MGMT methylation and rCBV. Perfusion markers could identify a subpopulation of patients who will benefit the most from MGMT methylation. Not considering this information may lead to bias in the interpretation of clinical studies.Key Points• MRI perfusion provides complementary prognostic information to MGMT methylation.• MGMT methylation improves prognosis in glioblastoma patients with moderate vascular profile.• Failure to consider these relations may lead to bias in the interpretation of clinical studies.
Highlights
Gliomas are the most common malignant primary central nervous system tumors, with an estimated annual incidence of 3.21 per 100,000 individuals in the USA [1]
Of the 110 patients included from the NCT03439332 dataset, six exams were excluded because of processing errors with the automatic processing pipeline, five exams were excluded due to noise or MR artifacts that precluded dynamic susceptibility contrast (DSC) quantification, one exam was excluded due to inability to differentiate between tumor vascularity and reactive meningeal enhancement, and two cases were excluded because MRI perfusion field of view did not cover the entire lesion
No significant relationships have been found between IDH1 mutation and methylation of the O6methylguanine-DNA methyltransferase (MGMT) methylation status (p = 0.39), nor between IDH1 mutation and rCBVHAT values (p = 0.15)
Summary
Gliomas are the most common malignant primary central nervous system tumors, with an estimated annual incidence of 3.21 per 100,000 individuals in the USA [1]. Adequate clinical and molecular biomarkers are needed for accurate estimations of prognosis and optimal treatment selections. Inactivation through promoter methylation of the O6methylguanine-DNA methyltransferase (MGMT) gene, which impairs the ability to repair DNA damaged induced by alkylating agents such as TMZ [5], has been described as a relevant biomarker for clinical decision-making in glioblastoma treatment. In a post hoc analysis of a phase III trial, MGMT promoter methylation was associated with a 2-year survival increase in TMZ-treated glioblastoma patients from 14 to 46% [6]. Current guidelines support the use of MGMT methylation as a predictive biomarker in patients older than 70 years with isocitrate dehydrogenase (IDH) wild-type grade IV gliomas [8]
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