Expression of SSTR2a, FAP, HER2 and HER3 as potential radionuclide therapy targets in higher-grade meningioma.

in European journal of nuclear medicine and molecular imaging by Maximilian J Mair, Sabrina Hartenbach, Erwin Tomasich, Sybren L N Maas, Sarah A Bosch, Georg Widhalm, Franziska Eckert, Felix Sahm, Johannes A Hainfellner, Markus Hartenbach, Anna S Berghoff, Matthias Preusser, Nathalie L Albert

TLDR

  • This study evaluated the expression of SSTR2a, FAP, and HER2/HER3 in high-grade meningioma samples and found variable expression of SSTR2a and FAP across meningioma subtypes.
  • The study's findings suggest the need for biomarkers to improve patient selection for radioligand therapy and highlights the importance of understanding meningioma biology for developing effective treatments.

Abstract

High-grade meningiomas have high recurrence rates and limited prognosis. Radioligand therapies are approved in extracranial malignancies, but their value in brain tumours including meningiomas is unclear, as data on target expression is scarce. CNS WHO grade 2 and 3 meningioma samples were immunohistochemically stained for somatostatin receptor 2a (SSTR2a), fibroblast activation protein (FAP), and human epidermal growth factor receptors 2/3 (HER2/HER3). Target expression was correlated with (epi-)genetic tumour subtyping by DNA methylation analysis, genetic alterations, and survival. Meningioma samples of 58 patients were included. SSTR2a expression (membranous/cytoplasmic) was observed in 43/55 (78.2%), and FAP expression in 15/58 (25.9%) evaluable samples, with HER2 and HER3 expression in one specimen each (1.7%). Membranous SSTR2a expression was strong in 18 (32.7%), intermediate in 12 (21.8%), and weak in 11 (20.0%) samples. While SSTR2a expression was more homogenous and mainly seen in regions with higher cellularity, FAP immunoreactivity was predominantly seen in tumour stroma and regions of lower cellularity. SSTR2a immunoreactivity was associated with TRAF7 wildtype status (p = 0.034). FAP expression was more frequent in meningiomas of CNS WHO grade 3 (vs. CNS WHO 2; p < 0.001), and samples with NF2 mutations (p = 0.032) or CDKN2A/B deletions (p = 0.013) compared to wildtype. FAP and SSTR2a expression (present vs. absent) were not associated with overall survival (p > 0.05). SSTR2a and FAP are expressed in high-grade meningioma samples to a variable extent, and differences across meningioma subtypes underscore the need for biomarkers to improve patient selection. Spatial heterogeneity of target expression should be considered in radioligand therapy design.

Overview

  • This study evaluated the expression of somatostatin receptor 2a (SSTR2a), fibroblast activation protein (FAP), and human epidermal growth factor receptors 2/3 (HER2/HER3) in high-grade meningioma samples to determine their potential as targets for radioligand therapy.
  • The study included 58 patients with CNS WHO grade 2 and 3 meningioma samples, which were analyzed for target expression and correlated with (epi-)genetic tumour subtyping, DNA methylation analysis, genetic alterations, and survival.
  • The primary objective of the study was to investigate the expression of SSTR2a, FAP, and HER2/HER3 in high-grade meningioma samples and their association with tumour subtyping, genetic alterations, and patient outcome.

Comparative Analysis & Findings

  • SSTR2a expression was observed in 78.2% of evaluable samples, with membranous expression being strong in 32.7%, intermediate in 21.8%, and weak in 20.0% samples.
  • FAP expression was seen in 25.9% of evaluable samples, with predominantly stromal and low-cellularity region localization.
  • TRAF7 wildtype status was associated with SSTR2a immunoreactivity, while FAP expression was more frequent in CNS WHO grade 3 meningiomas, samples with NF2 mutations, and CDKN2A/B deletions.

Implications and Future Directions

  • The study highlights the need for biomarkers to improve patient selection for radioligand therapy, given the spatial heterogeneity of target expression in meningioma samples.
  • Future studies should consider these findings and design radioligand therapy targeting SSTR2a, FAP, or both, taking into account the variable expression of these targets across meningioma subtypes.
  • The study's results underscore the importance of understanding the biology of meningiomas, particularly high-grade lesions, to develop more effective treatments.
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