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. 2025 Mar 7;27(3):767-778.
doi: 10.1093/neuonc/noae234.

Clinical and genetic markers of vascular toxicity in glioblastoma patients: Insights from NRG Oncology RTOG-0825

Joshua D Strauss  1   2   3 , Mark R Gilbert  4 , Minesh Mehta  5 , Ang Li  6 , Renke Zhou  7 , Melissa L Bondy  8 , Erik P Sulman  9 , Ying Yuan  10 , Yanhong Liu  11 , Elizabeth Vera  4 , Merideth M Wendland  12 , Volker W Stieber  13   11 , Vinay K Puduvalli  10 , Serah Choi  14 , Nina L Martinez  15 , H Ian Robins  16 , Grant K Hunter  17 , Chi-Fan Lin  6 , Vivian A Guedes  4 , Melissa A Richard  1   2   3 , Stephanie L Pugh  18   19 , Terri S Armstrong  4 , Michael E Scheurer  20   11   1   2   3
Affiliations

Clinical and genetic markers of vascular toxicity in glioblastoma patients: Insights from NRG Oncology RTOG-0825

Joshua D Strauss et al. Neuro Oncol. .

Abstract

Background: Glioblastoma (GBM) is an aggressive form of brain cancer in which treatment is associated with toxicities that can result in therapy discontinuation or death. This analysis investigated clinical and genetic markers of vascular toxicities in GBM patients during active treatment.

Methods: In total, 591 non-Hispanic White GBM patients with clinical data were included in the analysis from NRG RTOG-0825. Genome-wide association studies (GWAS) were performed from genotyped blood samples (N = 367) by occurrence of thrombosis or hypertension (grade ≥ 2). A clinical prediction model was produced for each vascular toxicity. Significant GWAS variants were then added to the clinical model as a single nucleotide polymorphism (SNP)-dose-effect variable to produce the final genetic models.

Results: Thrombosis and hypertension were experienced by 62 (11%) and 59 (10%) patients, respectively. Patients who experienced hypertension displayed improved survival over those without hypertension (median overall survival: 25.72 vs. 15.47 months, p = 0.002). The genetic model of thrombosis included corticosteroid use (odds ratio [OR]: 7.13, p = 0.02), absolute neutrophil count (OR: 1.008, p = 0.19), body surface area (OR: 18.87, p = 0.0008), and SNP-dose effect (3 variants; OR: 3.79, p < 0.0001). The genetic model of hypertension included bevacizumab use (OR: 0.97, p = 0.95) and the SNP-dose effect (6 variants; OR: 4.44, p < 0.0001).

Conclusions: In this study, germline variants were superior in predicting hypertension than clinical variables alone. Additionally, corticosteroid use was a considerable risk factor for thrombosis. Future investigations should confirm the hazard of corticosteroid use on thrombosis and the impact of bevacizumab in other malignancies after accounting for the genetic risk of hypertension.

Keywords: bevacizumab; genome-wide association study; glioblastoma; hypertension; thrombosis.

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Conflict of interest statement

T.S.A., M.L.B., V.A.G., G.K.H., A.L., C.-F.L., S.L.P., M.A.R., H.I.R., M.E.S., J.D.S., E.V., M.M.W., and R.Z. have nothing to disclose. S.C. declares in the last 36 months a relationship with National Institute of Health (co-investigator with salary support), received consulting fees from GT Medical, and received payment or honoraria from Telix Pharmaceuticals, Seagen Inc. M.R.G. declares in the last 36 months payment from George Washington University-Payment to me for a CME course. Y.L. since the initial planning of the work received research funding from 1K07CA181480. N.L.M. declares in the past 36 months a relationship with NCI: Clinical Proteomic Tumor Analysis Consortium; NRG: BN007, BN010 trials; Chimerix: ONC-201-108 trial. Although I serve as site PI for these studies, the payments are made to my institution, Payment or honoraria from MedLink Neurology—Contributed review article “Oligodendroglioma” (payments made to me), Participation in CTI-Clinical Trial Services (3/2022-current)—Serving on DSMB for Bexion Pharmaceutical’s BXQ-250.AH trial (personal consulting engagement (payments made to me). M.M. declares in the past 36 months receiving consulting fees from Consulting: Telix, Kazia, Novocure, Zap, Xoft, and Advisory Board: Mevion Technological Advisory Board, Patents from Baptist Health: Proton Pulsed Reduced Dose Rate radiotherapy (pending), Leadership or fiduciary role for Xcision Board Member: unremunerated and NRG Oncology Brain Tumor Committee Chair, stock with Chimerix. V.K.P. declares since the initial planning of the work grant support from Novocure, Servier, Boehringer-Ingelheim, Insightec, Suntec Medical, Telix, Tango Therapeutics, Guidepoint, Bayer, Orbus therapeutics (Ad board roles in above. Honoraria for self), declares in the past 36 months receiving consulting fees received from Novocure, Servier, Boehringer-Ingelheim, Insightec, Suntec Medical, Telix, Tango Therapeutics, Guidepoint, Bayer, Orbus therapeutics, receiving payment or honoraria from Novocure, Servier, Boehringer-Ingelheim, Insightec, Suntec Medical, Telix, Tango Therapeutics, Guidepoint, Bayer, Orbus therapeutics, receiving support for meetings/travel from Boehringer-Ingelheim, stock or stock options from Gilead, receiving other services from Bexion, Remedy Pharma, Karyopharm, J Int Bio for Drug for preclinical research. V.W.S. declares since the initial planning of the work receiving research funding from Novocure GMBH—Speaker’s Bureau member. I gave 2 talks last year on the use of TTFs in GBM, declared in the past 36 months receiving payment or honoraria from Novocure GMBH-Contract to be on speaker’s bureau (see above). A leadership role as the NRG Group Chair for RTOG. E.P.S. declares since the initial planning of the work receiving research funding from NIH-payment to institution. Y.Y. declares in the past 36 months consulting fees from Polaris Consulting LLC—I am an owner, declares participation on DSMB or Advisory Board for Syneous, PPD.

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