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

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, 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

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 (68)Ga-DOTA-1-Nal(3)-octreotide ((68)Ga-DOTANOC) or (68)Ga-DOTA-Tyr(3)-octreotide ((68)Ga-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 (68)Ga-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 (68)Ga-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.

Keywords: 68Ga-DOTANOC; High-grade glioma; IDH1 mutation; PET/CT; Somatostatin receptor.

Figures

Figure 1
Figure 1
68Ga-DOTA-peptide uptake in PET and its comparison to enhancing tumor volume in MRI-T1-Gad. Time-activity curves show higher 68Ga-DOTA-peptide uptake in HGGs compared to skin but distinctly lower uptake when compared to pituitary gland (A). Tumor SUVmax at 30 to 60 min post-injection correlates to receptor binding potential (B) and to enhancing tumor volume in MRI-T1-Gad (C). However, PET and MRI-T1-Gad tumor volumes show apparent discordance in individual patients (D) (corresponding to patient numbers in Table 1).
Figure 2
Figure 2
68Ga-DOTA-peptide uptake in high-grade gliomas does not correspond to SSTR2 immunohistochemistry. Axial fused PET/MR images 30 to 60 min post-injection, corresponding contrast-enhanced T1-weighted MR images, and tumor SSTR2 IHC from three different patients. Primary glioblastoma (patient no. 17) presents 68Ga-DOTANOC uptake (A) and contrast-enhancement in MRI-T1-Gad (B). Patchy areas of positive SSTR2 staining were observed (C). Another primary glioblastoma (patient no. 15) also shows 68Ga-DOTANOC uptake (D) and contrast enhancement (E). However, SSTR2 IHC was negative (F). Primary oligoastrocytoma (patient no. 10) represents no 68Ga-DOTANOC uptake (G) and no contrast enhancement (H), but high SSTR2 expression in IHC was detected (I). Color scale in PET images is set to maximum (red) 10,000 Bq/ml and minimum (blue) 0 Bq/ml. Bar = 50 μm.
Figure 3
Figure 3
Survival in HGG patients separated by SSTR2 status in immunohistochemistry. Kaplan-Meier curves for progression-free survival (A) and overall survival (B) in HGG patients with positive or negative SSTR2 IHC. Censored data are indicated by vertical lines.

References

    1. 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. doi: 10.1093/neuonc/nou087.
    1. 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.
    1. 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. doi: 10.1007/s00259-001-0717-x.
    1. 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. doi: 10.2967/jnumed.109.072819.
    1. 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.
    1. 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.
    1. 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. doi: 10.1007/s002590050269.
    1. 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. doi: 10.1053/j.semnuclmed.2011.02.001.
    1. 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. doi: 10.1016/S1470-2045(13)70168-2.
    1. 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. doi: 10.1148/radiol.13120118.
    1. 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.
    1. 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. doi: 10.2174/1874471011306020002.
    1. Logan J. Graphical analysis of PET data applied to reversible and irreversible tracers. Nucl Med Biol. 2000;27:661–70. doi: 10.1016/S0969-8051(00)00137-2.
    1. 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. doi: 10.1002/gcc.20927.
    1. 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. doi: 10.1038/bjc.2011.223.
    1. 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.
    1. 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. doi: 10.1007/s00259-012-2124-x.
    1. Horbinski C. What do we know about IDH1/2 mutations so far, and how do we use it? Acta Neuropathol. 2013;125:621–36. doi: 10.1007/s00401-013-1106-9.
    1. 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. doi: 10.1212/WNL.0b013e3182a95680.
    1. 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. doi: 10.1046/j.1365-2826.2002.00801.x.
    1. 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. doi: 10.1097/PAS.0b013e31823d07f3.
    1. 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.
    1. 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. doi: 10.1002/cncr.28341.
    1. 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.
    1. 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. doi: 10.1073/pnas.130196697.
    1. 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.
    1. 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. doi: 10.1007/s00259-003-1255-5.

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