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

Primary Neoplasms of the Central Nervous System

Electromagnetic fields (EMF) in the radio frequency energy (RFE) range can affect cells at the molecular level. Here we report a technology that can record the specific RFE signal of a given molecule, in this case the siRNA of epidermal growth factor receptor (EGFR). We demonstrate that cells exposed to this EGFR siRNA RFE signal have a 30-70% reduction of EGFR mRNA expression and ~60% reduction in EGFR protein expression vs. control treated cells. Specificity for EGFR siRNA effect was confirmed via RNA microarray and antibody dot blot array. The EGFR siRNA RFE decreased cell viability, as measured by Calcein-AM measures, LDH release and Caspase 3 cleavage, and increased orthotopic xenograft survival. The outcomes of this study demonstrate that an RFE signal can induce a specific siRNA-like effect on cells. This technology opens vast possibilities of targeting a broader range of molecules with applications in medicine, agriculture and other areas.

Precision knockdown of EGFR gene expression using radio frequency electromagnetic energy.

Brain metastases of breast cancer remain a difficult problem for clinical management. Their incidence appears to be increasing, which is likely due to longer survival times for advanced breast cancer patients as well as additional and improved tools for detection. Molecular features of tumors associated with this syndrome are not yet understood. In general, survival may be improving for brain metastases due to better local control in the CNS, as well as improvements in systemic disease management. Selected patients with brain metastases are able to undergo surgical resection, which has been associated with extended disease control in some patients. However, whole-brain radiation has been the mainstay for treatment for most patients. Stereotactic radiosurgery is playing an increasing role in the primary treatment of brain metastases, as well as for salvage after whole-brain radiation. Recent series have reported median survivals of 13 months or longer with stereotactic radiosurgery. Further improvements in radiation-based approaches may come from ongoing studies of radiosensitizing agents. The ability of systemic treatments to impact brain metastases has been debated, and specific treatment regimens have yet to be defined. New approaches include chemotherapy combinations, biologic therapies and novel drug-delivery strategies.

Brain metastases of breast cancer.

Malignant glioma represents a diverse set of molecularly heterogeneous diseases. Few therapeutic agents have been approved despite decades of clinical trials research and pre-clinical investigation. Attempts to refine neuroimaging criteria and recent discovery of the genomic profiles linking tumor subsets to survival outcomes have spurred discussion on a variety of new approaches in clinical trial design and relevant endpoints. Here we focus on those endpoints in clinical trial design for patients with primary glioma and related issues still to be resolved.

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Clinical trial endpoints for patients with gliomas.

Two patients with esthesioneuroblastomas that disseminated in the central nervous system (CNS) and elsewhere are reported. The latest recurrences in the CNS were 19 years after the diagnosis in patient and 9 years after the diagnosis in the other. Because the treatment of patients with such late recurrences is complicated by previous surgical procedures and radiation therapy, we review therapeutic options for these patients. The literature has not previously stressed the occurrence of late metastases, including those to the CNS, after prolonged disease-free intervals.

Michael D. Prados

Papers

Primary Neoplasms of the Central Nervous System

Precision knockdown of EGFR gene expression using radio frequency electromagnetic energy.

Brain metastases of breast cancer.

Clinical trial endpoints for patients with gliomas.

Late manifestations of esthesioneuroblastomas in the central nervous system: report of two cases.