Inclusion bias of patients with genetically different glioblastoma subgroups in clinical trials

The revised fourth edition of the World Health Organization (WHO) classification of brain tumors from 2016 differentiates diffusely infiltrating malignant astrocytomas with necrosis and/or vascular proliferates into the 3 genetic subgroups isocitrate dehydrogenase (IDH) wild-type, IDH mutated, and H3K27M mutated.¹ In particular, the differentiation of the IDH status allows considerable clinical conclusions regarding the prognosis.^2,3 The largest molecular subgroup by far are patients with glioblastoma without IDH mutation. This subgroup can also be further differentiated on a molecular level. The "Heidelberg brain tumor classifier" currently contains about 6 epigenetic subgroups of glioblastomas without an IDH mutation.⁴ If one analyzes these glioblastoma patients by expression profiling, then at least 4 molecular subgroups are found.^5,6 However, all these molecular classifications of glioblastomas without IDH mutation require a technically and thus also economically sophisticated infrastructure, which can currently be provided by only a few well-established neuro-oncological institutions. In addition, it has not yet been conclusively resolved whether these high-throughput methods can be used to identify prognostically relevant molecular subgroups. The demand is correspondingly high for further molecular differentiation of the large bunch of IDH wild-type glioblastomas using only a few markers to generate prognostic conclusions, which can also be investigated in an averagely equipped neuropathology.