Clinical Utility of Molecular Profiling in Recurrent Glioblastoma Multiforme

Introduction: Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor found in adults. GBM has limited therapeutic options. Initial tumor sampling establishes the histopathologic diagnosis, identifies prognostic and therapeutic biomarkers, and provides an opportunity for molecular profiling. By contrast, the utility of repeat tumor sampling and molecular profiling in recurrent GBM is not well established. Clinical Findings: We present a 69-year-old woman with GBM whose tumor recurred after standard treatment with temozolomide (TMZ) and concurrent radiation, followed by adjuvant TMZ. This patient had a methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter, which ordinarily predicts a favorable response to TMZ. Main Diagnosis, Therapeutic Interventions, and Outcomes: Our patient’s recurrent tumor was rechallenged with TMZ based on persistent methylation of the MGMT promoter. However, her tumor was refractory to TMZ, and she floridly progressed through multiple treatments. We performed retrospective molecular profiling using next-generation sequencing (NGS) on her recurrent tumor. The NGS results showed a TMZ hypermutation signature that confers resistance to TMZ. This signature impacted our patient’s treatment plan in real time and prompted an immediate discontinuation of TMZ. Conclusions: Advances in NGS provide further insight into the molecular landscape of GBM. As NGS becomes more timely and cost-effective, molecular profiling of recurrent tumors could impact treatment decisions through either avoiding a particular treatment paradigm or identifying a potential targetable mutation. For this reason, we suggest that clinical practice routinely consider repeat biopsy and molecular profiling for recurrent GBM

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Cancer Stem Cell Assay-Guided Chemotherapy Improves Survival of Patients With Recurrent Glioblastoma in a Randomized Trial

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors. In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24-0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world

The clinical significance of molecular subtyping in glioblastoma

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Three molecular subtypes (Proneural; Classical; Mesenchymal) have been described based on gene expression, but the clinical significance remains unclear. Methods: We studied 26 adult patients with GBM diagnosed between 2014 and 2019 at a single tertiary institution, for whom next generation sequencing and overall survival (OS) data were available. Genes were identified using a CLIA/CAP certified tumor panel. Results: Among 26 patients, the median age was 67 years and 16 (62%) were male. 23 (88%) initial tumors were IDH wildtype and 10 (38%) were MGMT methylated. At diagnosis, 22 (85%) initiated standardized temozolomide chemoradiation and 15 (58%) received bevacizumab, Optune, or an experimental agent. We stratified patients into shorter (OS \u3c 12 months, n=10) and longer (OS \u3e12 months, n=16) survival groups. Patients with longer survival tended to be younger, with higher KPS, and more extensive surgical resection. PTEN variants were more frequent among patients with shorter survival (3/10, 30% versus 0/16, 0%, p = 0.046), as were CDKN2A deletions (5/10, 50% versus 1/16, 6%, p = 0.018); CDK4 amplifications were not informative. TP53 variants were more frequent among longer survivors (9/16, 56% versus 2/10, 20%, p = 0.11), as were PDGFRA variants (2/16, 12.5% versus 0/10, 0%, p = 0.51). Overall, there was no association between EGFR variants and OS (3/10, 30% versus 4/16, 25%, p=1.0), although EGFR vIII was only observed among longer survivors (3/16, 19% versus 0/10, 0% p = 0.26). NF1 mutations were infrequent, with 1 per survival group. Conclusion: The Proneural subtype is associated with longer OS, mutations in TP53 and PDGFRA, and absent PTEN mutations. Our clinical data, although not always significant, were consistent with this. The Classical subtype is characterized by improved treatment sensitivity, EGFR variants, and CDKN2A deletions. Our data were not consistent with this. CDKN2A deletions were associated with shorter OS; EGFR vIII had potentially longer survival, and other EGFR variants had no relationship to OS. The Mesenchymal subtype (associated with NF1) could not be assessed due to low numbers

Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization

PURPOSE: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS: Patients with newly diagnosed O-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided values are reported. The trial is registered with ClinicalTrials.gov identifier: NCT02977780. RESULTS: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided = .523). None of the experimental therapies demonstrated a significant OS benefit ( \u3e .05). CONCLUSION: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial