methods Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. results A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.

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Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

The cBio Cancer Genomics Portal (http://cbioportal.org) is an open-access resource for interactive exploration of multidimensional cancer genomics data sets, currently providing access to data from more than 5,000 tumor samples from 20 cancer studies. The cBio Cancer Genomics Portal significantly lowers the barriers between complex genomic data and cancer researchers who want rapid, intuitive, and high-quality access to molecular profiles and clinical attributes from large-scale cancer genomics projects and empowers researchers to translate these rich data sets into biologic insights and clinical applications.

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The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data

The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.

Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal

Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

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Integrative genomics viewer

We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.

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Comprehensive molecular portraits of human breast tumours


 Despite advances in understanding the biology of diffuse midline gliomas (DMGs), clinical outcomes have not significantly improved. Therapy development is limited by: lack of preclinical data across multiple models and laboratories, limited knowledge about blood-brain barrier penetrance, and lack of multi-agent therapeutic approaches. We aimed to address these limitations by designing and implementing an innovative platform clinical trial (DMG-ACT). DMG-ACT is an open-label, multi-institutional, international trial of combination therapy for patients with DMG between 2 and 39 years of age. This study utilizes a novel Bayesian drug combination platform design with adaptive shrinkage (ComPAS). ComPAS allows for ongoing assessment of therapy efficacy with data borrowing across arms and the ability to eliminate ineffective drug combinations and add new promising combinations throughout the trial. The current treatment arms include ONC201 in combination with paxalisib. Patients enter one of three cohorts: newly-diagnosed (Cohort 1), post-radiation (Cohort 2), and relapsed/progressive (Cohort 3). Each cohort offers a target validation phase for patients who have not yet undergone biopsy to assess intratumoral pharmacokinetics/pharmacodynamics of pre-biopsy, single-agent dosing. Cohorts 1 and 3 offer radiation (Cohort 1) or re-irradiation (Cohort 3) with concomitant single-agent therapy followed by maintenance with combination therapy. The primary efficacy endpoints are median progression-free survival at 6 months (Cohorts 1 and 2) and overall survival at 7 months (Cohort 3). Exploratory endpoints include intratumoral drug concentrations; toxicity profile of combination therapy during radiation; toxicity profile and efficacy of combination therapy; CSF, ctDNA, stool, and flow cytometry biomarker analyses; and health related quality of life, cognitive, and patient/proxy-reported outcome measures. Additional therapy combinations that have shown additive or synergistic benefit in preclinical testing will be incorporated in future trial iterations and several are currently in development. The trial was launched in October 2021, with a total of 21 patients enrolled as of May 2022.

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Ctni-09. diffuse midline glioma-adaptive combinatory trial (dmg-act): a combination platform trial in pediatric and young adult patients with diffuse midline glioma

Michael D. Prados

Papers

Ctni-09. diffuse midline glioma-adaptive combinatory trial (dmg-act): a combination platform trial in pediatric and young adult patients with diffuse midline glioma