Longitudinal Molecular Trajectories of Diffuse Glioma in Adults

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear ¹² . Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of difuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specifc gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at diferent rates across the glioma subtypes, and hypermutation was not associated with diferences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner

Establishment of prognostic models for astrocytic and oligodendroglial brain tumors with standardized quantification of marker gene expression and clinical variables.

BackgroundPrognosis models established using multiple molecular markers in cancer along with clinical variables should enable prediction of natural disease progression and residual risk faced by patients. In this study, multivariate Cox proportional hazards analyses were done based on overall survival (OS) of 100 glioblastoma multiformes (GBMs, 92 events), 49 anaplastic astrocytomas (AAs, 33 events), 45 gliomas with oligodendroglial features, including anaplastic oligodendroglioma (AO, 13 events) and oligodendraglioma (O, 9 events). The modeling included two clinical variables (patient age and recurrence at the time of sample collection) and the expression variables of 13 genes selected based on their proven biological and/or prognosis functions in gliomas (ABCG2, BMI1, MELK, MSI1, PROM1, CDK4, EGFR, MMP2, VEGFA, PAX6, PTEN, RPS9, and IGFBP2). Gene expression data was a log-transformed ratio of marker and reference (ACTB) mRNA levels quantified using absolute real-time qRT-PCR.ResultsAge is positively associated with overall grade (4 for GBM, 3 for AA, 2_1 for AO_O), but lacks significant prognostic value in each grade. Recurrence is an unfavorable prognostic factor for AA, but lacks significant prognostic values for GBM and AO_O. Univariate models revealed opposing prognostic effects of ABCG2, MELK, BMI1, PROM1, IGFBP2, PAX6, RPS9, and MSI1 expressions for astrocytic (GBM and AA) and oligodendroglial tumors (AO_O). Multivariate models revealed independent prognostic values for the expressions of MSI1 (unfavorable) in GBM, CDK4 (unfavorable) and MMP2 (favorable) in AA, while IGFBP2 and MELK (unfavorable) in AO_O. With all 13 genes and 2 clinical variables, the model R(2) was 14.2% (P = 0.358) for GBM, 45.2% (P = 0.029) for AA, and 62.2% (P = 0.008) for AO_O.ConclusionThe study signifies the challenge in establishing a significant prognosis model for GBM. Our success in establishing prognosis models for AA and AO_O was largely based on identification of a set of genes with independent prognostic values and application of standardized gene expression quantification to allow formation of a large cohort in analysis

Radiographic read paradigms and the roles of the central imaging laboratory in neuro-oncology clinical trials

Determination of therapeutic benefit in intracranial tumors is intimately dependent on serial assessment of radiographic images. The Response Assessment in Neuro-Oncology (RANO) criteria were established in 2010 to provide an updated framework to better characterize tumor response to contemporary treatments. Since this initial update a number of RANO criteria have provided some basic principles for the interpretation of changes on MR images; however, the details of how to operationalize RANO and other criteria for use in clinical trials are ambiguous and not standardized. In this review article designed for the neuro-oncologist or treating clinician, we outline essential steps for performing radiographic assessments by highlighting primary features of the Imaging Charter (referred to as the Charter for the remainder of this article), a document that describes the clinical trial imaging methodology and methods to ensure operationalization of the Charter into the workings of a clinical trial. Lastly, we provide recommendations for specific changes to optimize this methodology for neuro-oncology, including image registration, requirement of growing tumor for eligibility in trials of recurrent tumor, standardized image acquisition guidelines, and hybrid reader paradigms that allow for both unbiased measurements and more comprehensive interpretation

Phase I trial of aflibercept (VEGF trap) with radiation therapy and concomitant and adjuvant temozolomide in patients with high-grade gliomas

Anti-vascular endothelial growth factor (VEGF) therapy has shown promise in the treatment of high-grade gliomas (HGG). Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for VEGF-A, VEGF-B and placental growth factor, depleting circulating levels of these growth factors. The Adult Brain Tumor Consortium conducted a phase I trial of aflibercept and temozolomide (TMZ) in patients with newly diagnosed HGG with 2 dose levels and a 3+3 design. Three arms using aflibercept were examined; with radiation and concomitant temozolomide; with adjuvant temozolomide using the 5/28 regimen; and with adjuvant temozolomide using the 21/28 day regimen. Fifty-nine patients were enrolled, 21 in arm 1, 20 in arm 2 and 18 in arm 3. Median age was 56 years (24-69); median KPS 90 (60-100). The maximum tolerated dose (MTD) of aflibercept for all 3 arms was 4 mg/kg every 2 weeks. Dose limiting toxicities at the MTD were: Arm 1: 0/21 patients; Arm 2: 2/20 patients (G3 deep vein thrombosis, G4 neutropenia; Arm 3: 3/18 patients) (G4 biopsy-confirmed thrombotic microangiopathy, G3 rash, G4 thrombocytopenia). The median number of cycles of aflibercept was 5 (range, 1-16). All patients stopped treatment; 28 (47%) for disease progression, 21 (36%) for toxicities, 8 (14%) for other reasons, and 2 (3%) patients completed the full treatment course. This study met its primary endpoint and the MTD of aflibercept with radiation and concomitant and adjuvant temozolomide is 4 mg/kg every 2 weeks

Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02.

Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination

Phase I/II study of sorafenib in combination with erlotinib for recurrent glioblastoma as part of a three-arm sequential accrual clinical trial: NABTC 05-02

BackgroundReceptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs.MethodsPatients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6).ResultsSixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated.ConclusionThis study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials

Prioritization schema for immunotherapy clinical trials in glioblastoma

Background: Emerging immunotherapeutic strategies for the treatment of glioblastoma (GBM) such as dendritic cell (DC) vaccines, heat shock proteins, peptide vaccines, and adoptive T-cell therapeutics, to name a few, have transitioned from the bench to clinical trials. With upcoming strategies and developing therapeutics, it is challenging to critically evaluate the practical, clinical potential of individual approaches and to advise patients on the most promising clinical trials. Methods: The authors propose a system to prioritize such therapies in an organized and data-driven fashion. This schema is based on four categories of factors: antigenic target robustness, immune-activation and -effector responses, preclinical vetting, and early evidence of clinical response. Each of these categories is subdivided to focus on the most salient elements for developing a successful immunotherapeutic approach for GBM, and a numerical score is generated. Results: The Score Card reveals therapeutics that have the most robust data to support their use, provides a reference prioritization score, and can be applied in a reiterative fashion with emerging data. Conclusions: The authors hope that this schema will give physicians an evidence-based and rational framework to make the best referral decisions to better guide and serve this patient population