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Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors

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Abstract

Background

Peptide receptor radionuclide therapy (PRRT) is an effective method for treating neuroendocrine tumors (NETs). It is limited, however, in the prediction of individual tumor response and the precise and early identification of changes in tumor size. Currently, response prediction is based on somatostatin receptor expression and efficacy by morphological imaging and/or chromogranin A (CgA) measurement. The aim of this study was to assess the accuracy of circulating NET transcripts as a measure of PRRT efficacy, and moreover to identify prognostic gene clusters in pretreatment blood that could be interpolated with relevant clinical features in order to define a biological index for the tumor and a predictive quotient for PRRT efficacy.

Methods

NET patients (n = 54), M: F 37:17, median age 66, bronchial: n = 13, GEP-NET: n = 35, CUP: n = 6 were treated with 177Lu-based-PRRT (cumulative activity: 6.5-27.8 GBq, median 18.5). At baseline: 47/54 low-grade (G1/G2; bronchial typical/atypical), 31/49 18FDG positive and 39/54 progressive. Disease status was assessed by RECIST1.1. Transcripts were measured by real-time quantitative reverse transcription PCR (qRT-PCR) and multianalyte algorithmic analysis (NETest); CgA by enzyme-linked immunosorbent assay (ELISA). Gene cluster (GC) derivations: regulatory network, protein:protein interactome analyses. Statistical analyses: chi-square, non-parametric measurements, multiple regression, receiver operating characteristic and Kaplan–Meier survival.

Results

The disease control rate was 72 %. Median PFS was not achieved (follow-up: 1–33 months, median: 16). Only grading was associated with response (p < 0.01). At baseline, 94 % of patients were NETest-positive, while CgA was elevated in 59 %. NETest accurately (89 %, χ2 = 27.4; p = 1.2 × 10−7) correlated with treatment response, while CgA was 24 % accurate. Gene cluster expression (growth-factor signalome and metabolome) had an AUC of 0.74 ± 0.08 (z-statistic = 2.92, p < 0.004) for predicting response (76 % accuracy). Combination with grading reached an AUC: 0.90 ± 0.07, irrespective of tumor origin. Circulating transcripts correlated accurately (94 %) with PRRT responders (SD+PR+CR; 97 %) vs. non-responders (91 %).

Conclusions

Blood NET transcript levels and the predictive quotient (circulating gene clusters+grading) accurately predicted PRRT efficacy. CgA was non-informative.

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    Authors and Affiliations

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

      L. Bodei

    2. LuGenIum Consortium, Milan, Rotterdam, Bad Berka, London, Italy, Netherlands, Germany, UK

      L. Bodei, I. M. Modlin, D. J. Kwekkeboom, E. P. Krenning & R. P. Baum

    3. Wren Laboratories, Branford, CT, USA

      M. Kidd

    4. Yale School of Medicine, 310 Cedar St, New Haven, New Haven, 06510, CT, USA

      I. M. Modlin

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

      S. Severi, S. Nicolini & G. Paganelli

    6. Bering Limited, London, UK

      I. Drozdov

    7. Nuclear Medicine Department, Erasmus Medical Center, Rotterdam, The Netherlands

      D. J. Kwekkeboom & E. P. Krenning

    8. Theranostics Center for Molecular Radiotherapy and Imaging, Zentralklinik Bad Berka, Bad Berka, Germany

      R. P. Baum

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    Correspondence to I. M. Modlin.

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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. This article does not contain any studies with animals performed by any of the authors.

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

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    Bodei, L., Kidd, M., Modlin, I.M. et al. Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors. Eur J Nucl Med Mol Imaging 43, 839–851 (2016). https://doi.org/10.1007/s00259-015-3250-z

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