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

Purpose: 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.

Methods: 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.

Results: 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).

Conclusion: 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.