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Gene transcript analysis blood values correlate with 68Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Precise determination of neuroendocrine tumor (NET) disease status and response to therapy remains a rate-limiting concern for disease management. This reflects limitations in biomarker specificity and resolution capacity of imaging. In order to evaluate biomarker precision and identify if combinatorial blood molecular markers and imaging could provide added diagnostic value, we assessed the concordance between 68Ga-somatostatin analog (SSA) positron emission tomography (PET), circulating NET gene transcripts (NETest), chromogranin A (CgA), and Ki-67 in NETs.

Methods

We utilized two independent patient groups with positive 68Ga-SSA PET: data set 1 (68Ga-SSA PETs undertaken for peptide receptor radionuclide therapy (PRRT), as primary or salvage treatment, n = 27) and data set 2 (68Ga-SSA PETs performed in patients referred for initial disease staging or restaging after various therapies, n = 22). We examined the maximum standardized uptake value (SUVmax), circulating gene transcripts, CgA levels, and baseline Ki-67. Regression analyses, generalized linear modeling, and receiver-operating characteristic (ROC) analyses were undertaken to determine the strength of the relationships.

Results

SUVmax measured in two centers were mathematically evaluated (regression modeling) and determined to be comparable. Of 49 patients, 47 (96 %) exhibited a positive NETest. Twenty-six (54 %) had elevated CgA (χ2 = 20.1, p < 2.5×10−6). The majority (78 %) had Ki-67 < 20 %. Gene transcript scores were predictive of imaging with >95 % concordance and significantly correlated with SUVmax (R 2 = 0.31, root-mean-square error = 9.4). The genes MORF4L2 and somatostatin receptors SSTR1, 3, and 5 exhibited the highest correlation with SUVmax. Progressive disease was identified by elevated levels of a quotient of MORF4L2 expression and SUVmax [ROC-derived AUC (R 2 = 0.7, p < 0.05)]. No statistical relationship was identified between CgA and Ki-67 and no relationship with imaging parameters was evident.

Conclusion

68Ga-SSA PET imaging parameters (SUVmax) correlated with a circulating NET transcript signature. Disease status could be predicted by an elevated quotient of gene expression (MORF4L2) and SUVmax. These observations provide the basis for further exploration of strategies that combine imaging parameters and disease-specific molecular data for the improvement of NET management.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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    Authors and Affiliations

    1. Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy

      L. Bodei

    2. Wren Laboratories, 35 NE Industrial Road, Branford, CT, USA

      M. Kidd, I. M. Modlin & I. Drozdov

    3. Department of Nuclear Medicine, Charité University Hospital, Berlin, Germany

      V. Prasad

    4. Nuclear Medicine and Radiometabolic Units, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

      S. Severi & G. Paganelli

    5. Nuclear Medicine, S.Orsola-Malpighi University Hospital, Bologna, Italy

      V. Ambrosini

    6. Nuclear Medicine Department, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands

      D. J. Kwekkeboom & E. P. Krenning

    7. THERANOSTICS Center for Molecular Radiotherapy and Imaging, Zentralklinik Bad Berka, Bad Berka, Germany

      R. P. Baum

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    1. L. Bodei
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    Correspondence to M. Kidd.

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    L. Bodei and M. Kidd contributed equally to this work.

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    Supplementary Figure 1

    Principal competent analysis (A) and hierarchical clustering (B) of information from 68Ga-DOTATOC and 68Ga-DOTANOC scanned patients. Scanned values from DOTANOC were identified as outliers and were not statistically comparable from values for DOTANOC-scanned patients. DIM dimension, D600 and DLS are different scanners used for DOTATOC (GIF 368 kb)

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    Bodei, L., Kidd, M., Modlin, I.M. et al. Gene transcript analysis blood values correlate with 68Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status. Eur J Nucl Med Mol Imaging 42, 1341–1352 (2015). https://doi.org/10.1007/s00259-015-3075-9

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