Practice-changing developments in neuro-oncology: embracing heterogeneity

Neuro-oncology has made fundamental progress during the past two decades. Embracing high-throughput ‘omics’ strategies, we have dramatically increased our knowledge on the development and on therapeutic vulnerabilities of brain tumors, including gliomas, brain metastases, medulloblastomas and primary central nervous system (CNS) lymphomas. This knowledge has enabled defining patient subgroups particularly benefitting from approved treatments such as irradiation and alkylating chemotherapy based on high-precision molecularly based stratification, thereby improving treatment outcome and avoiding treatment-related side effects. While this knowledge has not yet translated into the approval of novel therapeutic modalities, advancements in molecular diagnostics, imaging, and therapy development that have already resulted in a number of major practice-changing developments improving outcome of patients with brain tumors.

The 2016 World Health Organization (WHO) classification of CNS tumors has, for the first time, implemented key and disease-defining molecular alterations into the classification of brain tumors. ¹ Embracing these molecular hallmarks, the new WHO classification both appreciates and promotes the practice that patients should be treated according to the molecular status of their tumor. With less biased, purely molecular classifications currently being developed, ² this new WHO classification is important in several aspects, which can be exemplified best by the help of mutations in the gene for isocitrate dehydrogenase (IDH), which are frequent in diffuse astrocytomas: first, the molecular status determines the natural course of disease. For instance, patients with glioblastoma and IDH mutations display a better outcome than patients with IDH wildtype glioblastoma. ³ In contemporary clinical trials for glioblastoma patients, the small subgroup of patients with IDH mutant tumors is consequently excluded. Second, the molecular status determines key features on magnetic resonance imaging, an integral diagnostic tool for the assessment of outcome. For instance, astrocytomas with IDH mutations display a distinct metabolic profile, which can be picked up using magnetic resonance spectroscopy. ⁴ These novel tools as well as new approaches employing radiomics will complement current standards defined by the Response Assessment in Neuro-Oncology working group. Third, the molecular alteration itself may serve as a therapeutic target. For instance, mutant IDH is currently targeted in clinical trials by specific pharmacologic inhibitors ⁵ or vaccines. ⁶ With novel molecularly-targeted approaches rapidly evolving the precise definition and standard application of molecular diagnostics will become more important. Forth, and this leads to the main future challenge in developing targeted treatments, the clonality of the molecular alteration matters. IDH mutations are driver mutations at the top of the phylogenetic tree of astrocytoma. This means that this mutation will be propagated to all subsequent daughter cells independent of further subclonal events. Hence, IDH and other driver mutations are present in all cells of a given tumor and not subject to spatial or temporal heterogeneity, as IDH mutations are rarely lost. By contrast, there are many examples of subclonal mutations occurring as secondary, tertiary or later events and thus only present in a fraction of tumor cells. These subclonal mutations are subject to deletion either during natural evolution of as a mechanism of resistance, when specifically targeted. Here, the variant III of the epidermal growth factor receptor (EGFRvIII) is a good example of a subclonal molecular alteration deleted during tumor progression. Consequently, efforts to specifically target this variant using a vaccine have not been successful in a randomized phase III clinical trial. ⁷ Importantly, the clonal evolution is both an inherent and largely stochastic process in the natural development of tumors, but also a directed process in response to therapy such as alkylating chemotherapy to promote resistance. ⁸ To complicate matters further, as a result of this clonal evolution there is not only temporal, but also spatial heterogeneity, meaning that the molecular profiles of a given tumor will not only differ fundamentally from primary to recurrent tumor but also between different areas of the same tumor. ⁹

While many of these general concepts of cancer biology, which equally apply to other types of brain tumors including brain metastases have been discovered in neuro-oncology, the field already looks ahead and asks: What are the therapeutic implications? There is no other way than to embrace this heterogeneity and feed this knowledge into therapeutic concepts. With exciting new therapeutic options to implement truly personalized therapeutic strategies, such as vaccines targeting immunogenic mutations, into standard radiochemotherapy, ¹⁰ the key question is: What is the clonality of the molecular alteration to be targeted? Irrespective of the therapeutic modality, subclonal molecular alterations always bear the risk of evasive resistance through clonal deletion. Consequently, therapeutic strategies should either mitigate the risk of evasive resistance by targeting multiple molecular alterations or focus on those mutations, that are at the top of the phylogenetic tree of clonal evolution, such as the IDH mutation.

With all these important but complicated considerations in mind, we should not forget the considerable achievements, which have been made in neuro-oncology, with advancements in molecular diagnostics, imaging, and therapy development that have already resulted in a number of major practice-changing developments improving outcome of patients with brain tumors.

This Special Collection on Neuro-Oncology in Therapeutic Advances in Neurological Disorders is a tribute particularly to the recent practice-changing developments in neuro-oncology, and covers important disease entities such as glioma, brain metastases and primary CNS lymphoma, and also highlights key developments in molecular diagnostics and imaging.