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European Journal of Nuclear Medicine and Molecular Imaging
Published in: European Journal of Nuclear Medicine and Molecular Imaging 7/2018

01-07-2018 | Original Article

PRRT genomic signature in blood for prediction of 177Lu-octreotate efficacy

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

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 7/2018

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Abstract

Background

Peptide receptor radionuclide therapy (PRRT) utilizes somatostatin receptor (SSR) overexpression on neuroendocrine tumors (NET) to deliver targeted radiotherapy. Intensity of uptake at imaging is considered related to efficacy but has low sensitivity. A pretreatment strategy to determine individual PRRT response remains a key unmet need. NET transcript expression in blood integrated with tumor grade provides a PRRT predictive quotient (PPQ) which stratifies PRRT “responders” from “non-responders”. This study clinically validates the utility of the PPQ in NETs.

Methods

The development and validation of the PPQ was undertaken in three independent 177Lu-PRRT treated cohorts. Specificity was tested in two separate somatostatin analog-treated cohorts. Prognostic value of the marker was defined in a cohort of untreated patients. The developmental cohort included lung and gastroenteropancreatic [GEP] NETs (n = 72) from IRST Meldola, Italy. The majority were GEP (71%) and low grade (86% G1-G2). Prospective validation cohorts were from Zentralklinik Bad Berka, Germany (n = 44), and Erasmus Medical Center, Rotterdam, Netherlands (n = 42). Each cohort included predominantly well differentiated, low grade (86–95%) lung and GEP-NETs. The non-PRRT comparator cohorts included SSA cohort I, n = 28 (100% low grade, 100% GEP-NET); SSA cohort II, n = 51 (98% low grade; 76% GEP-NET); and an untreated cohort, n = 44 (64% low grade; 91% GEP-NET). Baseline evaluations included clinical information (disease status, grade, SSR) and biomarker (CgA). NET blood gene transcripts (n = 8: growth factor signaling and metabolism) were measured pre-therapy and integrated with tumor Ki67 using a logistic regression model. This provided a binary output: “predicted responder” (PPQ+); “predicted non-responder” (PPQ-). Treatment response was evaluated using RECIST criteria [Responder (stable, partial and complete response) vs Non-Responder)]. Sample measurement and analyses were blinded to study outcome. Statistical evaluation included Kaplan-Meier survival and standard test evaluation analyses.

Results

In the developmental cohort, 56% responded to PRRT. The PPQ predicted 100% of responders and 84% of non-responders (accuracy: 93%). In the two validation cohorts (response: 64–79%), the PPQ was 95% accurate (Bad Berka: PPQ + =97%, PPQ- = 93%; Rotterdam: PPQ + =94%, PPQ- = 100%). Overall, the median PFS was not reached in PPQ+ vs PPQ- (10–14 months; HR: 18–77, p < 0.0001). In the comparator cohorts, the predictor (PPQ) was 47–50% accurate for SSA-treatment and 50% as a prognostic. No differences in PFS were respectively noted (PPQ+: 10–12 months vs. PPQ-: 9–15 months).

Conclusion

The PPQ derived from circulating NET specific genes and tumor grade prior to the initiation of therapy is a highly specific predictor of the efficacy of PRRT with an accuracy of 95%.
Appendix
Available only for authorised users
Literature
1.
Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9:61–72.
2.
Pavel M, Valle JW, Eriksson B, Rinke A, Caplin M, Chen J, et al. ENETS consensus guidelines for the standards of care in neuroendocrine neoplasms: systemic therapy - biotherapy and novel targeted agents. Neuroendocrinology. 2017;105:266–80.CrossRefPubMed
3.
Faggiano A, Lo Calzo F, Pizza G, Modica R, Colao A. The safety of available treatments options for neuroendocrine tumors. Expert Opin Drug Saf. 2017;16:1149–61.CrossRefPubMed
4.
Oberg K, Krenning E, Sundin A, Bodei L, Kidd M, Tesselaar M, et al. A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management. Endocrine connections. 2016;5:174–87.CrossRefPubMedPubMedCentral
5.
Bodei L, Kwekkeboom DJ, Kidd M, Modlin IM, Krenning EP. Radiolabeled Somatostatin analogue therapy of gastroenteropancreatic cancer. Semin Nucl Med. 2016;46:225–38.CrossRefPubMed
6.
7.
Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, et al. Long-term efficacy, survival, and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. J Clin Oncol : Off J Am Assoc Cancer Res. 2017;23:4617–24.
8.
Sansovini M, Severi S, Ambrosetti A, Monti M, Nanni O, Sarnelli A, et al. Treatment with the radiolabelled somatostatin analog Lu-DOTATATE for advanced pancreatic neuroendocrine tumors. Neuroendocrinology. 2013;97:347–54.CrossRefPubMed
9.
Ezziddin S, Khalaf F, Vanezi M, Haslerud T, Mayer K, Al Zreiqat A, et al. Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2014;41:925–33.CrossRefPubMed
10.
Mariniello A, Bodei L, Tinelli C, Baio SM, Gilardi L, Colandrea M, et al. Long-term results of PRRT in advanced bronchopulmonary carcinoid. Eur J Nucl Med Mol Imaging. 2016;43:441–52.CrossRefPubMed
11.
Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376:125–35.CrossRefPubMedPubMedCentral
12.
Kwekkeboom DJ, Kam BL, van Essen M, Teunissen JJ, van Eijck CH, Valkema R, et al. Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocr Relat Cancer. 2010;17:R53–73.CrossRefPubMed
13.
Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol. 2011;29:2416–23.CrossRefPubMed
14.
Sabet A, Dautzenberg K, Haslerud T, Aouf A, Sabet A, Simon B, et al. Specific efficacy of peptide receptor radionuclide therapy with (177)Lu-octreotate in advanced neuroendocrine tumours of the small intestine. Eur J Nucl Med Mol Imaging. 2015;42:1238–46.CrossRefPubMed
15.
Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. Clin Canc Res: Off J Am Assoc Cancer Res. 2008;26:2124–30.
16.
Kidd M, Drozdov I, Modlin I. Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status. Endocr Relat Cancer. 2015;22:561–75.CrossRefPubMed
17.
Bodei L, Kidd M, Modlin IM, Severi S, Drozdov I, Nicolini S, 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. 2016;43:839–51.CrossRefPubMed
18.
19.
Beaver JA, Tzou A, Blumenthal GM, McKee AE, Kim G, Pazdur R, et al. An FDA perspective on the regulatory implications of complex signatures to predict response to targeted therapies. Clin Cancer Res. 2017;23:1368–72.CrossRefPubMed
20.
Cwikla JB, Bodei L, Kolasinska-Cwikla A, Sankowski A, Modlin IM, Kidd M. Circulating transcript analysis (NETest) in GEP-NETs treated with Somatostatin analogs defines therapy. J Clin Endocrinol Metab. 2015;100:E1437–45.CrossRefPubMed
21.
Bodei L, Cremonesi M, Grana CM, Fazio N, Iodice S, Baio SM, et al. Peptide receptor radionuclide therapy with (177)Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38:2125–35.CrossRefPubMed
22.
Bosman FT. WHO classification of tumours of the digestive system. 4th ed. Lyon: IARC Press, 2010
23.
Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC (ed). Pathology and genetics of tumours of the lung, pleura, thymus and heart. Geneva: WHO Press, 2004
24.
Li XJ, Hayward C, Fong PY, Dominguez M, Hunsucker SW, Lee LW, et al. A blood-based proteomic classifier for the molecular characterization of pulmonary nodules. Sci Transl Med. 2013;5:207ra142.PubMedPubMedCentral
25.
Vachani A, Pass HI, Rom WN, Midthun DE, Edell ES, Laviolette M, et al. Validation of a multiprotein plasma classifier to identify benign lung nodules. J Thorac Oncol. 2015;10:629–37.CrossRefPubMedPubMedCentral
26.
Kaijser J, Sayasneh A, Van Hoorde K, Ghaem-Maghami S, Bourne T, Timmerman D, et al. Presurgical diagnosis of adnexal tumours using mathematical models and scoring systems: a systematic review and meta-analysis. Hum Reprod Update. 2014;20:449–62.CrossRefPubMed
27.
28.
Frank R, Hargreaves R. Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov. 2003;2:566–80.CrossRefPubMed
29.
Oksuz MO, Winter L, Pfannenberg C, Reischl G, Mussig K, Bares R, et al. Peptide receptor radionuclide therapy of neuroendocrine tumors with (90)Y-DOTATOC: is treatment response predictable by pre-therapeutic uptake of (68)Ga-DOTATOC? Diagnos Interven Imaging 2014;95:289-300.
30.
Gabriel M, Oberauer A, Dobrozemsky G, Decristoforo C, Putzer D, Kendler D, et al. 68Ga-DOTA-Tyr3-octreotide PET for assessing response to somatostatin-receptor-mediated radionuclide therapy. J Nucl Med: Off Publ, Soc Nucl Med. 2009;50:1427–34.CrossRef
31.
Blaickner M, Baum RP. Relevance of PET for pretherapeutic prediction of doses in peptide receptor radionuclide therapy. PET Clin. 2014;9:99–112.CrossRefPubMed
32.
Wu Y, Pfeifer AK, Myschetzky R, Garbyal RS, Rasmussen P, Knigge U, et al. Induction of Anti-Tumor Immune Responses by Peptide Receptor Radionuclide Therapy with (177)Lu-DOTATATE in a Murine Model of a Human Neuroendocrine Tumor. Diagnostics (Basel, Switzerland). 2013;3:344–55.
33.
Yang Z, Tang LH, Klimstra DS. Effect of tumor heterogeneity on the assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: implications for prognostic stratification. Am J Surg Pathol. 2011;35:853–60.CrossRefPubMed
34.
Sansovini M, Severi S, Ianniello A, Nicolini S, Fantini L, Mezzenga E, et al. Long-term follow-up and role of FDG PET in advanced pancreatic neuroendocrine patients treated with 177Lu-D OTATATE. Eur J Nucl Med Mol Imaging. 2017;44:490–9.CrossRefPubMed
35.
Ezziddin S, Attassi M, Yong-Hing CJ, Ahmadzadehfar H, Willinek W, Grunwald F, et al. Predictors of long-term outcome in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors after peptide receptor radionuclide therapy with 177Lu-octreotate. J Nucl Med. 2014;55:183–90.CrossRefPubMed
36.
Ezziddin S, Sabet A, Heinemann F, Yong-Hing CJ, Ahmadzadehfar H, Guhlke S, et al. Response and long-term control of bone metastases after peptide receptor radionuclide therapy with (177)Lu-octreotate. J Nucl Med. 2011;52:1197–203.CrossRefPubMed
37.
Haug AR, Auernhammer CJ, Wangler B, Schmidt GP, Uebleis C, Goke B, et al. 68Ga-DOTATATE PET/CT for the early prediction of response to somatostatin receptor-mediated radionuclide therapy in patients with well-differentiated neuroendocrine tumors. J Nucl Med: Off Publ, Soc Nucl Med. 2010;51:1349–56.CrossRef
38.
Yang Z, Tang LH, Klimstra DS. Gastroenteropancreatic neuroendocrine neoplasms: historical context and current issues. Semin Diagn Pathol. 2013;30:186–96.CrossRefPubMed
39.
Valli A, Rodriguez M, Moutsianas L, Fischer R, Fedele V, Huang HL, et al. Hypoxia induces a lipogenic cancer cell phenotype via HIF1alpha-dependent and -independent pathways. Oncotarget. 2015;6:1920–41.CrossRefPubMed
40.
Olsson AH, Yang BT, Hall E, Taneera J, Salehi A, Nitert MD, et al. Decreased expression of genes involved in oxidative phosphorylation in human pancreatic islets from patients with type 2 diabetes. Eur J Endocrinol. 2011;165:589–95.CrossRefPubMedPubMedCentral
41.
Day TF, Mewani RR, Starr J, Li X, Chakravarty D, Ressom H, et al. Transcriptome and proteome analyses of TNFAIP8 knockdown cancer cells reveal new insights into molecular determinants of cell survival and tumor progression. Methods Mol Biol. 2017;1513:83–100.CrossRefPubMed
42.
43.
Kidd M, Modlin IM. Therapy: the role of liquid biopsies to manage and predict PRRT for NETs. Nat Rev Gastroenterol Hepatol. 2017;14:331–2.CrossRefPubMed
Metadata
Title
PRRT genomic signature in blood for prediction of 177Lu-octreotate efficacy
Authors
Lisa Bodei
Mark S. Kidd
Aviral Singh
Wouter A. van der Zwan
Stefano Severi
Ignat A. Drozdov
Jaroslaw Cwikla
Richard P. Baum
Dik J. Kwekkeboom
Giovanni Paganelli
Eric P. Krenning
Irvin M. Modlin
Publication date
01-07-2018
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 7/2018
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-018-3967-6

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