We explored the rationale for treating glioblastoma (GBM) with regorafenib. In 103 newly diagnosed GBM patients, we assessed mutations, copy number variants (CNVs), fusions, and overexpression in 46 genes encoding protein kinases (PKs) potentially targeted by regorafenib or its metabolites and performed a functional enrichment analysis to assess their implications in angiogenesis. We analyzed regorafenib’s binding inhibitory activity and target affinity for these 46 PKs and focused on a subset of 18 genes inhibited by regorafenib at clinically achievable concentrations and on 19 genes involved in angiogenesis. Putative oncogenic alterations were defined as oncogenic/likely oncogenic mutations, oncogenic fusions, CNVs > 5, and/or gene overexpression. Regorafenib did not target all 46 PKs. For the 46-gene set, 40 genes (86.9%) and 73 patients (70.8%) harbored at least one alteration in genes encoding targetable PKs, but putative oncogenic alterations were present in only 34 patients (33%). In the 18-gene set, 18 genes (100%) and 48 patients (46.6%) harbored alterations, but putative oncogenic alterations were detected in only 26 patients (25.2%). Thirty patients (29.1%) had oncogenic alterations in the 18-gene set and/or in angiogenesis-related genes. Around 33% of patients had oncogenic alterations in any of the 46 potential targets. Additionally, the suboptimal dosing of regorafenib, due to its poor penetration of the blood–brain barrier, may reduce the likelihood of effectively targeting certain PKs. Future use of multi-target drugs must be guided by a thorough understanding of target presence, effective inhibition, and the drug’s ability to reach brain tumors at adequate concentrations.

While treatments for primary brain tumors increase survival, they have cognitive sequelae. Neurocognition’s anatomical distribution makes it susceptible to brain damage. This study aims to evaluate the contribution of radiotherapy on short-term cognitive impairment. Using a prospective database of cognitive rehabilitation in adults operated on for primary brain tumors, a retrospective sub-analysis of the contribution of radiotherapy was performed. Thirty-four subdivisions of 12 neurocognitive regions were delineated in 48 irradiated patients and 30 non-irradiated patients. In the first group, the correlation between radiation dose and deterioration was evaluated. In all patients, the impact of tumor and surgical changes on dysfunction was calculated and compared with dose-dependent response. The correlation between cognitive status and radiation dose is especially strong and significant in the left hemisphere and in specific subdivisions such as the posterior hippocampus or the dorsolateral prefrontal cortex, with the left prevailing over posterior dominance. Memory is the most affected domain 1 month after radiotherapy, as attention is three months later. The hippocampus is involved in various cognitive domains in addition to memory. The prefrontal subregions and the genu of the corpus callosum are more affected by the relationship with disease and surgical changes than by radiation exposure. Patients ongoing a course of radiotherapy do not benefit from concurrent cognitive rehabilitation. There is a correlation between the dose of radiation received by several encephalic regions and degree of short-term domain-specific cognition decline, considering other factors of risk and cognitive rehabilitation.

BACKGROUND:Glioblastoma (GBM) is the most aggressive adult primary brain cancer, characterized by significant heterogeneity, posing challenges for patient management, treatment planning, and clinical trial stratification. METHODS:We developed a highly reproducible, personalized prognostication, and clinical subgrouping system using machine learning (ML) on routine clinical data, magnetic resonance imaging (MRI), and molecular measures from 2838 demographically diverse patients across 22 institutions and 3 continents. Patients were stratified into favorable, intermediate, and poor prognostic subgroups (I, II, and III) using Kaplan-Meier analysis (Cox proportional model and hazard ratios [HR]). RESULTS:The ML model stratified patients into distinct prognostic subgroups with HRs between subgroups I-II and I-III of 1.62 (95% CI: 1.43-1.84, P < .001) and 3.48 (95% CI: 2.94-4.11, P < .001), respectively. Analysis of imaging features revealed several tumor properties contributing unique prognostic value, supporting the feasibility of a generalizable prognostic classification system in a diverse cohort. CONCLUSIONS:Our ML model demonstrates extensive reproducibility and online accessibility, utilizing routine imaging data rather than complex imaging protocols. This platform offers a unique approach to personalized patient management and clinical trial stratification in GBM.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Despite several investigations in this field, maximal safe resection followed by chemoradiotherapy and adjuvant temozolomide with or without tumor-treating fields remains the standard of care with poor survival outcomes. Many endeavors have failed to make a dramatic change in the outcomes of GBM patients. This study aimed to review the available strategies for newly diagnosed GBM in the neoadjuvant setting, which have been mainly neglected in contrast to other solid tumors.

The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60

The aim of this study was to determine how TERTp mutations impact glioblastoma prognosis. Materials and Methods: TERTp mutations were assessed in a retrospective cohort of 258 uniformly treated glioblastoma patients. RNA-sequencing and whole exome sequencing results were available in a subset of patients. Results: Overall, there were no differences in outcomes between patients with mutated TERTp-wt or TERTp. However, we found significant differences according to the type of TERTp mutation. Progression-free survival (mPFS) was 9.1 months for those with the C250T mutation and 7 months for those with either the C228T mutation or TERTp-wt (p = 0.016). Overall survival (mOS) was 21.9 and 15 months, respectively (p = 0.026). This differential effect was more pronounced in patients with MGMTp methylation (mPFS: p = 0.008; mOS: p = 0.021). Multivariate analysis identified the C250T mutation as an independent prognostic factor for longer mOS (HR 0.69; p = 0.044). We found no differences according to TERTp mutation status in molecular alterations common in glioblastoma, nor in copy number variants in genes related to alternative lengthening of telomeres. Nevertheless, in the gene enrichment analysis adjusted for MGMTp methylation status, some Reactome gene sets were differentially enriched, suggesting that the C250T mutation may exert a lesser effect on telomeres or chromosomes. Conclusions: In our series, patients exhibiting the C250T mutation had a more favorable prognosis compared to those with either TERPp-wt or TERTp C228T mutations. Additionally, our findings suggest a reduced involvement of the C250T mutation in the underlying biological mechanisms related to telomeres.

Abstract BACKGROUND Glioblastoma is an infiltrative primary brain tumor with poor prognosis despite multimodal therapy. Recurrence is inevitable secondary to tumor cell infiltration in the peritumoral tissues, beyond contrast enhancing margins, which is the target for surgical resection. We hypothesize that a machine learning model constructed from a diverse, inter-institutional dataset can improve accuracy of generated tumor infiltration maps, thus guiding precision targeted therapies. METHODS 731 MRI scans of treatment-naïve glioblastoma patients from 10 institutions were included. All patients had pre-operative multiparametric-MRI (T1, T1Gd, T2, T2-FLAIR, ADC), and underwent complete resection of the enhancing tumor followed by standard-of-care chemoradiotherapy. 42 patients were used as an independent validation set, and 689 were used for training. Of these 239 patients had histopathologically confirmed recurrence with corresponding MRI scans, which were used as ground-truth for evaluating the location of recurrence using a leave-one-site-out (LSO) method. An AI model combining deep learning and SVM was used to develop a predictive model for infiltration. We validated the generalizability of our results in an unseen, multi-institutional data set. RESULTS Our model predicted locations of recurrence with odds ratio (99% CI) 37.6 (37.1-38.1) on the LSO testing set and 24.3 (23.4-25.2) on the validation set, indicating that areas labeled highly infiltrated were over 37 and 24 times more likely to coincide with future recurrence respectively. CONCLUSIONS We demonstrate that AI-based pattern analysis from multiparametric-MRI can predict tumor infiltration in peritumoral regions with high likelihood of recurrence by decrypting the visually imperceptible heterogeneity of peritumoral tissue. Model performance improved from training on a larger/diverse dataset and combining results of multiple AI methods. Independent validation confirmed the model’s ability to generalize to unseen data. We believe this will serve to advance AI-based biomarkers for predicting future recurrence and facilitate development of multi-modal targeted therapies in this era of precision neuro-oncology.

The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. Of the combined 205 patients, 57 (28

Abstract BACKGROUND We previously reported on progression-free survival of our randomized phase 3 trial [Lancet Oncol. 2016;17:1521-1532]. Here we report results of long-term follow-up (FU) including overall survival (OS) and molecular subgroup analyses. METHODS 487 patients were randomized between 2005-2012 to either standard radiotherapy (RT, 50.4 Gy/ 28 fractions) or primary dose-dense temozolomide [TMZ] chemotherapy (75 mg/m² daily x 21/28 days, up to 12 cycles). Treatment at progression was at investigators discretion and commonly included cross-over to the alternative treatment modality. RESULTS At a median follow-up of 13 years, 68% of patients had died. Median age at inclusion was 45 years (range 18-75), 96% had a performance status of 0-1. There was no significant difference in PFS nor OS: PFS was 3.6 years (95% CI: 3.0-4.1) and 3.1 years (95% CI: 2.7-3.6), HR 1.12 (95% CI: 0.92-1.36); OS 6.6 years (95% CI: 5.8-7.5) and 8.0 years (95% CI: 6.9-9.1), HR 0.87 (95% CI: 0.69-1.09), for RT or TMZ, respectively. Subgroup analyses were performed for patients when available tissue allowed for molecular analyses (n=351/487,73%). In astrocytoma, IDHmt/1p/19q non-codeleted (n = 178), median OS with RT was 6.6 years (95% CI: 5.3-7.6) and with TMZ was 6.7 years (95% CI: 5.7-8.0); HR 0.98 (95% CI: 0.67-1.44). For oligodendroglioma, IDHmt/codeleted (n = 109) median OS with RT was 12.9 years (95% CI: 9.4 - NE) and with TMZ 14.9 years (95% CI: 10.1 - NE); HR 1.01 (95% CI: 0.56-1.81). For a heterogenous group of IDHwt tumors (n = 64), median OS with RT was 2.5 years (95% CI: 1.8-3.3) and with TMZ 4.7 years (95% CI: 2.2-7.2); HR 0.37 (95% CI: 0.18-0.77). CONCLUSIONS Primary treatment with RT or TMZ provided comparable PFS and OS. Choice of primary treatment can be tailored to individual tumor characteristics and patient preference.

Background. Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT -> TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier. Methods. European Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT -> TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors. Results. The trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm. Conclusions. Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.

Primary brain tumors (pBT) are a heterogeneous group of neoplasms. Disruption of TP53 tumor suppressor is a common event and MDM2 amplification is a major cause of functional loss of TP53 in patients (pts) with glioblastoma (GBM). We describe the characteristics of a pBT cohort with next-generation sequencing (NGS) and MDM2 alterations (MDM2alt). Patients with pBT who had NGS [Foundation Medicine®, local NGS, Caris®, Oncomine®, copy number (CN) and fusion panels] from the multicentric retrospective database ESCAT-pBTs were included. MDM2alt and the relation with other molecular and clinical findings was explored. In GBM, overall survival (OS) was estimated using Kaplan-Meier, with a comparative of survival distribution in MDM2alt and non-alt groups using log rank test. A total of 493 pts were included between Feb 2018 and Jan 2023 at 8 hospitals in Spain. Median age was 51.6 years (y) (3.3-83.8), 12.2% had ECOG ≥2, 39% were women, 27% were ≤40y and 69% had a diagnosis of GBM (WHO 2021). TP53 mutated(mt) was found in 32% of pBT (mutually exclusive with MDM2alt) and 22% had IDH1mt. Overall prevalence of MDM2alt was 8.5%, 11.8% in GBM and 1.3% in other pBT (p<0.001). Main coexisting alteration (alt) in MDM2alt pts was CDK4 gain in 71.4% compared to 5,7% in non-alt (p<0.001). A similar frequency of PI3KCA/PTENmt was observed in GBM MDM2alt and non-alt groups (38% vs 50%, p=0.15). No significant difference was found in GBM MDM2alt vs non-alt in EGFR amplifications (43% vs 32%; p=0.10) and EGFRmt (19% vs 19%; p=0.84). Median TMB was 5.2 mut/Mb in GBM pts. Median OS in GBM was 22.8 months (mo) (95%CI, 20.3-25.2). In MDM2alt group, median OS was 26.5 mo (95%CI 19.2-33.6), while median OS in non-alt was 22.6 mo (95%CI 20.2-25). No statistically significant differences were found in OS among MDM2alt and non-alt groups (p=0.07). MDM2alt is a common genomic event in molecularly defined GBM and has low prevalence in other pBT. MDM2alt did not appear to be prognostic. MDM2alt associated with high prevalence of CDK4 gain, suggesting a molecularly defined subgroup with chromosomal instability and the potential for targeted therapy with CDK4/6 plus MDM2 inhibitors in clinical trials. These findings enlighten further development of treatment strategies for MDM2alt GBM pts.

Abstract BACKGROUND Glioblastoma (GB) has a poor prognosis with median overall survival of 12-14 months. According to literature, patients surviving more than two years has progressively increased since 2005 and represent approximately 18% of this population, being considered long-term survivors (LTS). The aim of this study is to retrospectively analyze GB LTS treated in our Neurooncology Unit. MATERIAL AND METHODS From December 2009 to March 2021, 49 GB LTS patients were identified in our oncology data base, representing 21,7% of GB patients electronically registered during the same period. Patients were diagnosed and treated for GB according to the current WHO CNS classification at the time of diagnosis. Clinical and molecular characteristics as well as treatment and survival data were analyzed. Classic prognostic factors were analyzed including contact with the subventricular zone (SVZ) which has been identified as prognostic factor in some previous studies. RESULTS Median age at diagnosis was 57 years (range: 30-75 years). Median overall survival (OS) and median time to first progression were 43.6 months and 20.7 months respectively, with 9 patients alive and 6 patients without recurrence at the time of analyses. Rate of patients surviving more than 3, 4, 5 and 7 years were 55,1%, 20,4%, 12,24% and 6,12% respectively. Patients received a median of 2 rescue treatments after first relapse (range: 0-6 lines), including systemic therapies, surgery and re-irradiation. Rates for gross total resection, subtotal resection and biopsy were 32,6%, 47% and 20,4% respectively. pMGMT methylated patients and lesions without SVZ contact rates were 73,5% and 42,8% respectively. IDH analyses was available for 61.22% of our GB LTS patients (90% were IDH wild type and 10% mutant IDH, which according to WHO CNS 2021 classification would actually be defined as Astrocytoma grade 4). No statistical differences for OS or time to first progression were found according to sex, age (<55 years versus ≥55 years), pMGMT methylation status; Karnofsky performance status (≤70% versus >70%) and contact or not with the SVZ. CONCLUSION Classical prognostic factors did not show statistical differences for OS and time to first recurrence in our GB LTS sample, which could be explained by the small number of patients in the sample and the absence of statistically comparable differentiated groups for some of the variables. Larger and prospective analyses of GB LTS are needed. Molecular analyses with next generation sequencing (NGS) technics and radiomics analyses could apport new information predicting GB LTS.

Patient characteristics and molecular subtypes

Abstract BACKGROUND The standard of care for patients with newly diagnosed glioblastoma includes maximum safe resection followed by radiotherapy (RT) with concomitant and maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Among potential new therapeutic strategies, targeting the proteasome has been considered promising because of its implication in numerous biological processes in tumors cells. Marizomib is a novel small molecule proteasome inhibitor that crosses the blood brain barrier and showed signs of activity in recurrent glioblastoma. METHODS EORTC 1709/CCTG CE.8 was a randomized, controlled, multicenter, open label phase 3 superiority trial. Major inclusion criteria were histologically confirmed newly diagnosed glioblastoma, age of 18 years or older and a Karnofsky performance status (KPS) > 70. Patients with tumors known to harbor an isocitrate dehydrogenase mutation were not eligible. RESULTS The trial was opened at 82 institutions in Europe, Canada and the US and 749 patients (of 750 planned) were randomized in a 1:1 ratio. Following a pre-planned interim analysis and a recommendation of the independent data monitoring committee, enrolment was discontinued. No significant difference in the median OS (mOS) was observed (standard arm: 17 months, marizomib arm: 16.5 months; p = 0.64; HR = 1.04). Median PFS was 6.0 vs. 6.3 months (p = 0.67; HR = 0.97). Patients with tumors harboring an unmethylated O6-methylguanine DNA methyltransferase (MGMT) promoter had a mOS of 14.5 months in the standard therapy group and 15.1 months in the marizomib arm (p = 0.27, HR = 1.13). Among patients with an MGMT promoter-methylated tumor, median OS was 29.4 months in the marizomib arm and 25.5 months in the standard arm (p = 0.41, HR = 0.86). More CTCAE grade 3/4 treatment-emergent adverse events were noticed in the marizomib arm than in the standard arm. CONCLUSIONS The addition of marizomib to standard temozolomide-based radiochemotherapy was associated with more toxicity but did not confer a survival benefit in glioblastoma patients, independent of the MGMT promoter methylation status.