Pharmacokinetic analysis of [⁶⁸Ga]Ga-DOTA-TOC PET in meningiomas for assessment of in vivo somatostatin receptor subtype 2.

Abstract

DOTA-D-Phe¹-Tyr³-octreotide with gallium-68 ([⁶⁸Ga]Ga-DOTA-TOC) is one of the PET tracers that forms the basis for peptide receptor radionuclide therapy based on somatostatin receptor subtype 2 (SSTR2) expression in meningiomas. Yet, the quantitative relationship between [⁶⁸Ga]Ga-DOTA-TOC accumulation and SSTR2 is unknown. We conducted a correlative analysis of a range of [⁶⁸Ga]Ga-DOTA-TOC PET metric(s) as imaging surrogate(s) of the receptor binding in meningiomas by correlating the PET results with SSTR2 expression from surgical specimens. We additionally investigated possible influences of secondary biological factors such as vascularization, inflammation and proliferation. Fifteen patients with MRI-presumed or recurrent meningiomas underwent a 60-min dynamic [⁶⁸Ga]Ga-DOTA-TOC PET/CT before surgery. The PET data comprised maximum and mean standardized uptake values (SUV_max, SUV_mean) with and without normalization to reference regions, and quantitative measurements derived from kinetic modelling using a reversible two-tissue compartment model with the fractional blood volume (V_B). Expressions of SSTR2 and proliferation (Ki-67, phosphohistone-H3, proliferating cell nuclear antigen) were determined by immunohistochemistry and/or quantitative polymerase chain reaction (qPCR), while biomarkers of vascularization (vascular endothelial growth factor A (VEGFA), endothelial marker CD34) and inflammation (cytokine interleukin-18, microglia/macrophage-specific marker CD68) by qPCR. Histopathology revealed 12 World Health Organization (WHO) grade I and three WHO grade II meningiomas showing no link to SSTR2. The majority of [⁶⁸Ga]Ga-DOTA-TOC PET metrics showed significant associations with SSTR2 protein, while all PET metrics were positively correlated with SSTR2 mRNA with the best results for mean tumour-to-blood ratio (TBR_mean) (r = 0.757, P = 0.001) and SUV_mean (r = 0.714, P = 0.003). Significant positive correlations were also found between [⁶⁸Ga]Ga-DOTA-TOC PET metrics, and VEGFA and V_B. SSTR2 mRNA was moderately correlated with VEGFA (r = 0.539, P = 0.038). Neither [⁶⁸Ga]Ga-DOTA-TOC PET metrics nor SSTR2 were correlated with proliferation or inflammation. [⁶⁸Ga]Ga-DOTA-TOC accumulation in meningiomas is associated with SSTR2 binding and vascularization with TBR_mean being the best PET metric for assessing SSTR2.