Abstract

BACKGROUND

Survival in glioblastoma patients is usually in the range of 12–15 months, and less than 5% of patients survive 5 years from diagnosis. Little is known about factors influencing long-term survival.

METHODS

A consortium generously funded by the Brain Tumor Funders’ Collaborative comprising more than 20 clinical sites in Europe, the US, and Australia registers patients with glioblastoma who survived for at least 5 years. The aim of the study is a better understanding of factors contributing to prolonged survival by assessment of (i) clinical features, (ii) molecular parameters, (iii) therapy and quality of life-related factors, and (iv) immunological parameters. The histopathological diagnosis of glioblastoma is centrally reviewed at study entry. Clinical characteristics including imaging data are collected at the European Organisation for Research and Treatment of Cancer (EORTC) in Brussels, Belgium. Comprehensive molecular analyses are performed at the German Cancer Research Center (DKFZ), Germany. Immunological parameters are analyzed in Zurich, Switzerland. Alive patients are followed by neurocognitive assessments additionally.

RESULTS

At the cut-off of May 30, 2017, 182 patients have been registered by 17 sites; 107 patients are alive, more than half of which contribute to the neurocognitive assessments and patient-related outcome studies, as well as the immunological studies. First comprehensive results of disease characteristics with a cut-off of September 30, 2017, will be presented.

CONCLUSIONS

The collaborative effort of this consortium by comprehensive characterization of molecular parameters, immunological aspects, and individual clinical and therapy-related determinants will contribute to a better understanding of factors that modulate the course of this disease.

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.

Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.