Proton pump inhibitors are detrimental to overall survival of patients with glioblastoma multiforme: results from a nationwide real-world evidence database

Background Aldehyde dehydrogenase-1A1 (ALDH1A1) is a primary metabolic enzyme impacting outcome of chemotherapy, including temozolomide, the standard-of-care (SOC) for glioblastoma multiforme (GBM). High expression of ALDH1A1 is associated with poor prognosis in multiple cancers. Proton pump inhibitors (PPIs) are often prescribed to manage corticosteroid-induced gastrointestinal toxicity but were recently identified as strong inducers of ALDH1A1, suggesting a negative impact on survival. Methods Real-world data on GBM patients was annotated from electronic medical records (EMR) according to the prospective observational study, XCELSIOR ([NCT03793088][1]). Patients with IDH1/2 mutations were excluded. Causal effects on survival were analyzed using a multivariate, time-varying Cox Proportional Hazard (CPH) model with stratifications including MGMT methylation status, age, sex, duration of corticosteroid use, extent of resection, starting SOC, and PPI use. Results EMR data from 554 GBM patients across 225 cancer centers was collected, with 72% of patients receiving care from academic medical centers. Patients treated with PPIs had numerically lower median overall survival (mOS) and 2-year OS rates in the total population and across most strata, with the greatest difference for MGMT-methylated patients (mOS 29.2 mo vs. 40.1 mo). In a time-varying multivariate CPH analysis of the above strata, PPIs caused an adverse effect on survival (HR 1.67 [95% CI 1.15-2.44], p=0.007). Conclusions Evidence from a nationwide cancer registry has suggested PPIs have a strong detrimental effect on OS for GBM patients, particularly those with MGMT promoter methylation. This suggests PPIs should be avoided for prophylactic management of gastrointestinal toxicity in patients with GBM receiving SOC chemoradiotherapy. Key Points Importance of the Study Recent molecular evidence suggests off-target activity of proton pump inhibitors (PPIs) may counteract the activity of alkylating chemotherapy in glioblastoma clinical care. Utilizing a time-varying cox proportional hazard model and abstracted clinical data from medical records according to a nationwide observational research protocol, we found PPIs were significantly associated with greater risk of death, independent of corticosteroid use. Importantly, the detrimental effect was most impactful for patients with methylated MGMT promoters who gain the most benefit from standard-of-care temozolomide treatment and experience the best outcomes. ### Competing Interest Statement MPC: Employment Cellworks; Stock and Other Ownership Interests Bugworks; DelMar Pharmaceuticals; Neurovigil; Honoraria Guardant Health; Consulting or Advisory Role Omicure; Speakers' Bureau Guardant Health; Research Funding Exact Sciences JQ, AW, AA, ZDC, and TJS: Employment xCures; Stock and Other Ownership Interests xCures MAS: Employment xCures; Leadership xCures; Stock and Other Ownership Interests xCures; Consulting or Advisory Role BioNTech; Marinus Pharmaceuticals; Patents, Royalties, Other Intellectual Property Various patents on software for AI-based clinical decision support technology SK: Stock and Other Ownership Interests xCures; Honoraria Jubilant Biosys; Pyramid Biosciences; Consulting or Advisory Role Biocept; iCAD; xCures; Research Funding AIVITA Biomedical, Inc. (Inst); Bayer (Inst); Biocept (Inst); Blue Earth Diagnostics (Inst); Boehringer Ingelheim (Inst); Boston Biomedical (Inst); Caris MPI (Inst); cns pharmaceuticals (Inst); EpicentRx (Inst); Lilly (Inst); Oblato (Inst); Orbus therapeutics (Inst) ### Funding Statement No external funding was received for this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Genetic Alliance Central IRB gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03793088&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F30%2F2024.01.28.24301899.atom