TY - JOUR

T1 - Pharmacokinetic analysis of [68Ga]Ga-DOTA-TOC PET in meningiomas for assessment of in vivo somatostatin receptor subtype 2

AU - Bashir, Asma

AU - Vestergaard, Mark Bitsch

AU - Binderup, Tina

AU - Broholm, Helle

AU - Marner, Lisbeth

AU - Ziebell, Morten

AU - Fugleholm, Kåre

AU - Mathiesen, Tiit

AU - Kjaer, Andreas

AU - Law, Ian

PY - 2020

Y1 - 2020

N2 - Purpose DOTA-D-Phe(1)-Tyr(3)-octreotide with gallium-68 ([Ga-68]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 [Ga-68]Ga-DOTA-TOC accumulation and SSTR2 is unknown. We conducted a correlative analysis of a range of [Ga-68]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. Methods Fifteen patients with MRI-presumed or recurrent meningiomas underwent a 60-min dynamic [Ga-68]Ga-DOTA-TOC PET/CT before surgery. The PET data comprised maximum and mean standardized uptake values (SUVmax, SUVmean) 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. Results Histopathology revealed 12 World Health Organization (WHO) grade I and three WHO grade II meningiomas showing no link to SSTR2. The majority of [Ga-68]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 (TBRmean) (r = 0.757,P = 0.001) and SUVmean(r = 0.714,P = 0.003). Significant positive correlations were also found between [Ga-68]Ga-DOTA-TOC PET metrics, and VEGFA andV(B). SSTR2 mRNA was moderately correlated with VEGFA (r = 0.539,P = 0.038). Neither [Ga-68]Ga-DOTA-TOC PET metrics nor SSTR2 were correlated with proliferation or inflammation. Conclusion [Ga-68]Ga-DOTA-TOC accumulation in meningiomas is associated with SSTR2 binding and vascularization with TBR(mean)being the best PET metric for assessing SSTR2.

AB - Purpose DOTA-D-Phe(1)-Tyr(3)-octreotide with gallium-68 ([Ga-68]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 [Ga-68]Ga-DOTA-TOC accumulation and SSTR2 is unknown. We conducted a correlative analysis of a range of [Ga-68]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. Methods Fifteen patients with MRI-presumed or recurrent meningiomas underwent a 60-min dynamic [Ga-68]Ga-DOTA-TOC PET/CT before surgery. The PET data comprised maximum and mean standardized uptake values (SUVmax, SUVmean) 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. Results Histopathology revealed 12 World Health Organization (WHO) grade I and three WHO grade II meningiomas showing no link to SSTR2. The majority of [Ga-68]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 (TBRmean) (r = 0.757,P = 0.001) and SUVmean(r = 0.714,P = 0.003). Significant positive correlations were also found between [Ga-68]Ga-DOTA-TOC PET metrics, and VEGFA andV(B). SSTR2 mRNA was moderately correlated with VEGFA (r = 0.539,P = 0.038). Neither [Ga-68]Ga-DOTA-TOC PET metrics nor SSTR2 were correlated with proliferation or inflammation. Conclusion [Ga-68]Ga-DOTA-TOC accumulation in meningiomas is associated with SSTR2 binding and vascularization with TBR(mean)being the best PET metric for assessing SSTR2.

KW - Meningioma

KW - [Ga-68]Ga-DOTA-TOC

KW - SSTR2

KW - VEGFA

KW - ENDOTHELIAL GROWTH-FACTOR

KW - PHASE-II TRIAL

KW - GA-68-DOTATOC

KW - THERAPY

KW - EXPRESSION

KW - TUMORS

KW - Y-90-DOTATOC

KW - PREDICTOR

KW - RECURRENT

KW - PATTERNS

U2 - 10.1007/s00259-020-04759-1

DO - 10.1007/s00259-020-04759-1

M3 - Journal article

C2 - 32170347

VL - 47

SP - 2577

EP - 2588

JO - European Journal of Nuclear Medicine and Molecular Imaging

JF - European Journal of Nuclear Medicine and Molecular Imaging

SN - 1619-7070

IS - 11

ER -