PRRT neuroendocrine tumor response monitored using circulating transcript analysis: the NETest

Lisa Bodei, Mark S. Kidd, Aviral Singh, Wouter A. van der Zwan, Stefano Severi, Ignat A. Drozdov, Anna Malczewska, Richard P. Baum, Dik J. Kwekkeboom, Giovanni Paganelli, Eric P. Krenning, Irvin M. Modlin

Research output: Contribution to journalArticle

Abstract

Purpose: Peptide receptor radionuclide therapy (PRRT) is effective for metastatic/inoperable neuroendocrine tumors (NETs). Imaging response assessment is usually efficient subsequent to treatment completion. Blood biomarkers such as PRRT Predictive Quotient (PPQ) and NETest are effective in real-time. PPQ predicts PRRT efficacy; NETest monitors disease. We prospectively evaluated: (1) NETest as a surrogate biomarker for RECIST; (2) the correlation of NETest levels with PPQ prediction. Methods: Three independent 177Lu-PRRT-treated GEP-NET and lung cohorts (Meldola, Italy: n = 72; Bad-Berka, Germany: n = 44; Rotterdam, Netherlands: n = 41). Treatment response: RECIST1.1 (responder (stable, partial, and complete response) vs non-responder). Blood sampling: pre-PRRT, before each cycle and follow-up (2–12 months). PPQ (positive/negative) and NETest (0–100 score) by PCR. Stable < 40; progressive > 40). CgA (ELISA) as comparator. Samples de-identified, measurement and analyses blinded. Kaplan–Meier survival and standard statistics. Results: One hundred twenty-two of the 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly (p < 0.0001) decreased in RECIST “responders” (− 47 ± 3%); in “non-responders,” it remained increased (+ 79 ± 19%) (p < 0.0005). NETest monitoring accuracy was 98% (119/122). Follow-up levels > 40 (progressive) vs stable (< 40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04 (95%CI, 0.02–0.07). PPQ response prediction was accurate in 118 (97%) with a 99% accurate positive and 93% accurate negative prediction. NETest significantly (p < 0.0001) decreased in PPQ-predicted responders (− 46 ± 3%) and remained elevated or increased in PPQ-predicted non-responders (+ 75 ± 19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06 (95%CI, 0.03–0.12). CgA did not reflect PRRT treatment: in RECIST responders decrease in 38% and in non-responders 56% (p = NS). Conclusions: PPQ predicts PRRT response in 97%. NETest accurately monitors PRRT response and is an effective surrogate marker of PRRT radiological response. NETest decrease identified responders and correlated (> 97%) with the pretreatment PPQ response predictor. CgA was non-informative.

Original languageEnglish
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
DOIs
Publication statusAccepted/In press - Jan 1 2019

Keywords

  • Biomarker
  • Liquid biopsy
  • NETest
  • Neuroendocrine
  • PPQ
  • PRRT

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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    Bodei, L., Kidd, M. S., Singh, A., van der Zwan, W. A., Severi, S., Drozdov, I. A., Malczewska, A., Baum, R. P., Kwekkeboom, D. J., Paganelli, G., Krenning, E. P., & Modlin, I. M. (Accepted/In press). PRRT neuroendocrine tumor response monitored using circulating transcript analysis: the NETest. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-019-04601-3