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Open Access 01-12-2015 | Original research

Somatostatin receptor subtype 2 in high-grade gliomas: PET/CT with ⁶⁸Ga-DOTA-peptides, correlation to prognostic markers, and implications for targeted radiotherapy

Authors: Aida Kiviniemi, Maria Gardberg, Janek Frantzén, Marko Pesola, Ville Vuorinen, Riitta Parkkola, Tuula Tolvanen, Sami Suilamo, Jarkko Johansson, Pauliina Luoto, Jukka Kemppainen, Anne Roivainen, Heikki Minn

Published in: EJNMMI Research | Issue 1/2015

Abstract

Background

High-grade gliomas (HGGs) express somatostatin receptors (SSTR), rendering them candidates for peptide receptor radionuclide therapy (PRRT). Our purpose was to evaluate the potential of ⁶⁸Ga-DOTA-1-Nal³-octreotide (⁶⁸Ga-DOTANOC) or ⁶⁸Ga-DOTA-Tyr³-octreotide (⁶⁸Ga-DOTATOC) to target SSTR subtype 2 (SSTR₂) in HGGs, and to study the association between SSTR₂ expression and established biomarkers.

Methods

Twenty-seven patients (mean age 52 years) with primary or recurrent HGG prospectively underwent ⁶⁸Ga-DOTA-peptide positron emission tomography/computed tomography (PET/CT) before resection. Maximum standardized uptake values (SUVmax) and receptor binding potential (BP) were calculated on PET/CT and disruption of blood–brain barrier (BBB) from contrast-enhanced T1-weighted magnetic resonance imaging (MRI-T1-Gad). Tumor volume concordance between PET and MRI-T1-Gad was assessed by Dice similarity coefficient (DC) and correlation by Spearman’s rank. Immunohistochemically determined SSTR₂ status was compared to receptor imaging findings, prognostic biomarkers, and survival with Kruskal-Wallis, Pearson chi-square, and multivariate Cox regression, respectively.

Results

All 19 HGGs with disrupted BBB demonstrated tracer uptake. Tumor SUVmax (2.25 ± 1.33) correlated with MRI-T1-Gad (r = 0.713, P = 0.001) although DC 0.41 ± 0.19 suggested limited concordance. SSTR₂ immunohistochemistry was regarded as positive in nine HGGs (32%) but no correlation with SUVmax or BP was found. By contrast, SSTR₂ expression was associated with IDH1 mutation (P = 0.007), oligodendroglioma component (P = 0.010), lower grade (P = 0.005), absence of EGFR amplification (P = 0.021), and longer progression-free survival (HR 0.161, CI 0.037 to 0.704, P = 0.015).

Conclusions

In HGGs, uptake of ⁶⁸Ga-DOTA-peptides is associated with disrupted BBB and cannot be predicted by SSTR₂ immunohistochemistry. Thus, PET/CT shows limited value to detect HGGs suitable for PRRT. However, high SSTR₂ expression portends favorable outcome along with established biomarkers such as IDH1 mutation.

Trial registration

ClinicalTrials.gov NCT01460706

Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, et al. The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol. 2014;16:896–913.CrossRefPubMed

Merlo A, Hausmann O, Wasner M, Steiner P, Otte A, Jermann E, et al. Locoregional regulatory peptide receptor targeting with the diffusible somatostatin analogue 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC): a pilot study in human gliomas. Clin Cancer Res. 1999;5:1025–33.PubMed

Schumacher T, Hofer S, Eichhorn K, Wasner M, Zimmerer S, Freitag P, et al. Local injection of the 90Y-labelled peptidic vector DOTATOC to control gliomas of WHO grades II and III: an extended pilot study. Eur J Nucl Med Mol Imaging. 2002;29:486–93.CrossRefPubMed

Heute D, Kostron H, von Guggenberg E, Ingorokva S, Gabriel M, Dobrozemsky G, et al. Response of recurrent high-grade glioma to treatment with (90)Y-DOTATOC. J Nucl Med. 2010;51:397–400.CrossRefPubMed

Reubi JC, Lang W, Maurer R, Koper JW, Lamberts SW. Distribution and biochemical characterization of somatostatin receptors in tumors of the human central nervous system. Cancer Res. 1987;47:5758–64.PubMed

Mawrin C, Schulz S, Pauli SU, Treuheit T, Diete S, Dietzmann K, et al. Differential expression of sst1, sst2A, and sst3 somatostatin receptor proteins in low-grade and high-grade astrocytomas. J Neuropathol Exp Neurol. 2004;63:13–9.PubMed

Schmidt M, Scheidhauer K, Luyken C, Voth E, Hildebrandt G, Klug N, et al. Somatostatin receptor imaging in intracranial tumours. Eur J Nucl Med. 1998;25:675–86.CrossRefPubMed

Breeman WA, de Blois E, Sze Chan H, Konijnenberg M, Kwekkeboom DJ, Krenning EP. (68)Ga-labeled DOTA-peptides and (68)Ga-labeled radiopharmaceuticals for positron emission tomography: current status of research, clinical applications, and future perspectives. Semin Nucl Med. 2011;41:314–21.CrossRefPubMed

Weller M, Pfister SM, Wick W, Hegi ME, Reifenberger G, Stupp R. Molecular neuro-oncology in clinical practice: a new horizon. Lancet Oncol. 2013;14:e370–9.CrossRefPubMed

10.

Gutman DA, Cooper LA, Hwang SN, Holder CA, Gao J, Aurora TD, et al. MR imaging predictors of molecular profile and survival: multi-institutional study of the TCGA glioblastoma data set. Radiology. 2013;267:560–9.CrossRefPubMedCentralPubMed

11.

Weller M, Stupp R, Hegi ME, van den Bent M, Tonn JC, Sanson M, et al. Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. Neuro Oncol. 2012;14 Suppl 4:iv100–8.PubMed

12.

Belosi F, Cicoria G, Lodi F, Malizia C, Fanti S, Boschi S, et al. Generator breakthrough and radionuclidic purification in automated synthesis of 68Ga-DOTANOC. Curr Radiopharm. 2013;6:72–7.CrossRefPubMed

13.

Logan J. Graphical analysis of PET data applied to reversible and irreversible tracers. Nucl Med Biol. 2000;27:661–70.CrossRefPubMed

14.

Tuononen K, Tynninen O, Sarhadi VK, Tyybakinoja A, Lindlof M, Antikainen M, et al. The hypermethylation of the O6-methylguanine-DNA methyltransferase gene promoter in gliomas - correlation with array comparative genome hybridization results and IDH1 mutation. Genes Chromosomes Cancer. 2012;51:20–9.CrossRefPubMed

15.

Ålgars A, Lintunen M, Carpen O, Ristamäki R, Sundström J. EGFR gene copy number assessment from areas with highest EGFR expression predicts response to anti-EGFR therapy in colorectal cancer. Br J Cancer. 2011;105:255–62.CrossRefPubMedCentralPubMed

16.

Haldemann AR, Rosler H, Barth A, Waser B, Geiger L, Godoy N, et al. Somatostatin receptor scintigraphy in central nervous system tumors: role of blood–brain barrier permeability. J Nucl Med. 1995;36:403–10.PubMed

17.

Hanscheid H, Sweeney RA, Flentje M, Buck AK, Lohr M, Samnick S, et al. PET SUV correlates with radionuclide uptake in peptide receptor therapy in meningioma. Eur J Nucl Med Mol Imaging. 2012;39:1284–8.CrossRefPubMed

18.

Horbinski C. What do we know about IDH1/2 mutations so far, and how do we use it? Acta Neuropathol. 2013;125:621–36.CrossRefPubMedCentralPubMed

19.

Wick W, Meisner C, Hentschel B, Platten M, Schilling A, Wiestler B, et al. Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology. 2013;81:1515–22.CrossRefPubMed

20.

Cervera P, Videau C, Viollet C, Petrucci C, Lacombe J, Winsky-Sommerer R, et al. Comparison of somatostatin receptor expression in human gliomas and medulloblastomas. J Neuroendocrinol. 2002;14:458–71.CrossRefPubMed

21.

Korner M, Waser B, Schonbrunn A, Perren A, Reubi JC. Somatostatin receptor subtype 2A immunohistochemistry using a new monoclonal antibody selects tumors suitable for in vivo somatostatin receptor targeting. Am J Surg Pathol. 2012;36:242–52.CrossRefPubMedCentralPubMed

22.

Smith JS, Perry A, Borell TJ, Lee HK, O’Fallon J, Hosek SM, et al. Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol. 2000;18:636–45.PubMed

23.

Okuwaki K, Kida M, Mikami T, Yamauchi H, Imaizumi H, Miyazawa S, et al. Clinicopathologic characteristics of pancreatic neuroendocrine tumors and relation of somatostatin receptor type 2A to outcomes. Cancer. 2013;119:4094–102.CrossRefPubMed

24.

Raggi CC, Maggi M, Renzi D, Calabro A, Bagnoni ML, Scaruffi P, et al. Quantitative determination of sst2 gene expression in neuroblastoma tumor predicts patient outcome. J Clin Endocrinol Metab. 2000;85:3866–73.PubMed

25.

Benali N, Cordelier P, Calise D, Pages P, Rochaix P, Nagy A, et al. Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238. Proc Natl Acad Sci U S A. 2000;97:9180–5.CrossRefPubMedCentralPubMed

26.

Vernejoul F, Faure P, Benali N, Calise D, Tiraby G, Pradayrol L, et al. Antitumor effect of in vivo somatostatin receptor subtype 2 gene transfer in primary and metastatic pancreatic cancer models. Cancer Res. 2002;62:6124–31.PubMed

27.

Wild D, Schmitt JS, Ginj M, Macke HR, Bernard BF, Krenning E, et al. DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals. Eur J Nucl Med Mol Imaging. 2003;30:1338–47.CrossRefPubMed

Title: Somatostatin receptor subtype 2 in high-grade gliomas: PET/CT with 68Ga-DOTA-peptides, correlation to prognostic markers, and implications for targeted radiotherapy
Authors: Aida Kiviniemi
Maria Gardberg
Janek Frantzén
Marko Pesola
Ville Vuorinen
Riitta Parkkola
Tuula Tolvanen
Sami Suilamo
Jarkko Johansson
Pauliina Luoto
Jukka Kemppainen
Anne Roivainen
Heikki Minn
Publication date: 01-12-2015
Publisher: Springer Berlin Heidelberg
Published in: EJNMMI Research / Issue 1/2015
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-015-0106-2

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Somatostatin receptor subtype 2 in high-grade gliomas: PET/CT with ⁶⁸Ga-DOTA-peptides, correlation to prognostic markers, and implications for targeted radiotherapy

Abstract

Background

Methods

Results

Conclusions

Trial registration

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Trial registration

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