Advances in molecular and imaging biomarkers in lower-grade gliomas

ABSTRACT

Introduction

Lower-grade (grade 2–3) gliomas (LGGs) constitutes a group of primary brain tumors with variable clinical behaviors and treatment responses. Recent advancements in molecular biology have redefined their classification, and novel imaging modalities emerged for the noninvasive diagnosis and follow-up.

Areas covered

This review comprehensively analyses the current knowledge on molecular and imaging biomarkers in LGGs. Key molecular alterations, such as IDH mutations and 1p/19q codeletion, are discussed for their prognostic and predictive implications in guiding treatment decisions. Moreover, the authors explore theranostic biomarkers for the potential of tailored therapies. Additionally, they also describe the utility of advanced imaging modalities, including widely available techniques, as dynamic susceptibility contrast perfusion-weighted imaging and less validated, emerging approaches, for the noninvasive LGGs characterization and follow-up.

Expert opinion

The integration of molecular markers enhanced the stratification of LGGs, leading to the new concept of integrated histomolecular classification. While the IDH mutation is an established key prognostic and predictive marker, recent results from IDH inhibitors trials showed its potential value as a theranostic marker. In this setting, advanced MRI techniques such as 2-D-hydroxyglutarate spectroscopy are very promising for the noninvasive diagnosis and monitoring of LGGs. This progress offers exciting prospects for personalized medicine and improved treatment outcomes in LGGs.

KEYWORDS:

• Lower-grade gliomas
• IDH mutation
• IDH wildtype
• integrated histomolecular classification
• IDH inhibitors
• 2-HG spectroscopy

Article highlights

• The discovery of recurrent IDH mutations and 1p/19q chromosome codeletion in LGGs redefined the classification of these tumors, under the principles of the integrated histomolecular diagnosis.

• IDH mutations and 1p/19q codeletion have not only nosological and prognostic but also predictive properties, informing on the potential benefit of therapeutic interventions (surgical resection, radiotherapy, and chemotherapy).

• IDH inhibitor vorasidenib improves progression-free survival of patients with non-enhancing grade 2 IDH mutant gliomas, representing a successful targeted therapy in LGGs and highlighting the potential of IDH inhibition in early stages of the disease.

• IDHwt LGGs are challenging due to their heterogeneity, with some resembling GBMs and others displaying a more indolent course and/or actionable alterations, emphasizing the need for comprehensive molecular characterization to guide prognosis and treatment decisions.

• 2HG accumulation in IDH mutant tumors can be noninvasively visualized via magnetic resonance spectroscopy, making it a promising imaging biomarker in diagnosis and monitoring of LGGs.

• Other advanced MRI techniques, such as DWI, PWI, APTw, and combined MRI-PET, have shown promises for noninvasive characterization of LGGs, although widespread implementation is currently limited by technical challenges, lack of validation, and standardization.

• The T2-FLAIR mismatch sign has been proposed as a poorly sensitive but highly specific biomarker for IDH mutant astrocytomas, albeit in adult individuals with a suspected LGG.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.