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EJNMMI Research
Published in: EJNMMI Research 1/2020

Open Access 01-12-2020 | Prostate Cancer | Original research

Neuron-specific enolase has potential value as a biomarker for [18F]FDG/[68Ga]Ga-PSMA-11 PET mismatch findings in advanced mCRPC patients

Authors: Florian Rosar, Kalle Ribbat, Martin Ries, Johannes Linxweiler, Mark Bartholomä, Stephan Maus, Mathias Schreckenberger, Samer Ezziddin, Fadi Khreish

Published in: EJNMMI Research | Issue 1/2020

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Abstract

Background

PSMA-targeted radioligand therapy (PSMA-RLT) yielded impressive results in the metastasized castration-resistant prostate carcinoma (mCRPC) setting. High expression of PSMA is essential for successful PSMA-RLT. However, some patients develop [18F]FDG-avid lesions with low or no PSMA expression ([18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings on PET/CT) in the course of treatment. Those lesions are not affected by PSMA-RLT and a change in therapy management is needed. To enable early mismatch detection, possible blood parameters as indicators for the occurrence of [18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings on PET/CT were evaluated.

Methods

Retrospective study of N = 66 advanced mCRPC patients with dual [68Ga]Ga-PSMA-11 and [18F]FDG PET/CT imaging within 4 weeks, who were referred for or received [177Lu]Lu-PSMA-617 radioligand therapy. Prostate-specific antigen (PSA), neuron-specific enolase (NSE), gamma-glutamyltransferase (GGT), and alkaline phosphatase (ALP) were tested as indicators for the occurrence of [18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings. Additional to absolute values, relative changes (ΔPSA, ΔNSE, ΔGGT, ΔALP) over a period of 4 ± 1 weeks prior to [18F]FDG PET/CT were analyzed.

Results

In total, 41/66 (62%) patients revealed at least one [18F]FDG/[68Ga]Ga-PSMA-11 mismatch finding on PET/CT. These mismatch findings were detected in 13/41 (32%) patients by screening for and in 28/41 (68%) patients during PSMA-RLT. NSE serum level (55.4 ± 44.6 μg/l vs. 18.5 ± 8 μg/l, p < 0.001) and ΔNSE (93.8 ± 124.5% vs. 2.9 ± 39.5%, p < 0.001) were significantly higher in the mismatch group than in the non-mismatch group. No significant differences were found for serum PSA (p = 0.424), ΔPSA (p = 0.417), serum ALP (p = 0.937), ΔALP (p = 0.611), serum GGT (p = 0.773), and ΔGGT (p = 0.971). For NSE and ΔNSE, the maximum value of the Youden index in ROC analysis was at a cut-off level of 26.8 μg/l (sensitivity 78%, specificity 96%) and at + 13.9% (sensitivity 84%, specificity 75%), respectively. An introduced scoring system of both parameters achieved a sensitivity of 90% and a specificity of 88% for the occurrence of [18F]FDG/[68Ga]Ga-PSMA-11 mismatch.

Conclusion

We observed a significantly higher absolute serum concentration and a higher relative increase of NSE in advanced mCRPC patients with [18F]FDG-avid and insufficient PSMA expressing metastases ([18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings on PET/CT) in our cohort. NSE might be used as a potential laboratory indicator for [18F]FDG/[68Ga]Ga-PSMA-11 mismatch findings, if this observation is confirmed in future, ideally prospective, studies in larger patient cohorts.
Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.PubMedCrossRef
2.
Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review: The Epidemiology of CRPC. Int J Clin Pract. 2011;65:1180–92.PubMedCrossRef
3.
Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015;15:701–11.PubMedPubMedCentralCrossRef
4.
Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 2017;71:630–42.PubMedCrossRef
5.
Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated Survival in the TAX 327 Study. J Clin Oncol. 2008;26:242–5.PubMedCrossRef
6.
Tannock IF, Horti J, Oudard S, James ND, Rosenthal MA. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–12.PubMedCrossRef
7.
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138–48.PubMedCrossRef
8.
Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424–33.PubMedPubMedCentralCrossRef
9.
Kratochwil C, Fendler WP, Eiber M, Baum R, Bozkurt MF, Czernin J, et al. EANM procedure guidelines for radionuclide therapy with 177Lu-labelled PSMA-ligands (177Lu-PSMA-RLT). Eur J Nucl Med Mol Imaging. 2019;46:2536–44.PubMedCrossRef
10.
Yadav MP, Ballal S, Tripathi M, Damle NA, Sahoo RK, Seth A, et al. 177Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment. Eur J Nucl Med Mol Imaging. 2017;44:81–91.PubMedCrossRef
11.
Fendler WP, Rahbar K, Herrmann K, Kratochwil C, Eiber M. 177Lu-PSMA radioligand therapy for prostate cancer. J Nucl Med. 2017;58:1196–200.PubMedCrossRef
12.
Kim YJ, Kim Y. Therapeutic responses and survival effects of 177Lu-PSMA-617 radioligand therapy in metastatic castrate-resistant prostate cancer: a meta-analysis. Clin Nucl Med. 2018;43:728–34.PubMedCrossRef
13.
Afshar-Oromieh A, Babich JW, Kratochwil C, Giesel FL, Eisenhut M, Kopka K, et al. The rise of PSMA ligands for diagnosis and therapy of prostate cancer. J Nucl Med. 2016;57:79S–89S.PubMedCrossRef
14.
Heinzel A, Boghos D, Mottaghy FM, Gaertner F, Essler M, von Mallek D, et al. 68Ga-PSMA PET/CT for monitoring response to 177Lu-PSMA-617 radioligand therapy in patients with metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2019;46:1054–62.PubMedCrossRef
15.
Kuten J, Sarid D, Yossepowitch O, Mabjeesh NJ, Even-Sapir E. [68Ga]Ga-PSMA-11 PET/CT for monitoring response to treatment in metastatic prostate cancer: is there any added value over standard follow-up? EJNMMI Res. 2019;9:84.
16.
Rahbar K, Afshar-Oromieh A, Jadvar H, Ahmadzadehfar H. PSMA Theranostics: current status and future directions. Mol Imaging. 2018;17:1–9.CrossRef
17.
Alipour R, Azad A, Hofman MS. Guiding management of therapy in prostate cancer: time to switch from conventional imaging to PSMA PET? Ther Adv Med Oncol. 2019;11:1–14.CrossRef
18.
Emmett L, Crumbaker M, Ho B, Willowson K, Eu P, Ratnayake L, et al. Results of a prospective phase 2 pilot trial of 177Lu–PSMA-617 therapy for metastatic castration-resistant prostate cancer including imaging predictors of treatment response and patterns of progression. Clin Genitourin Cancer. 2019;17:15–22.PubMedCrossRef
19.
20.
Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19:825–33.PubMedCrossRef
21.
Petrylak DP, Crawford ED. Biomarkers for the Management of Castration-Resistant Prostate Cancer: We Are Not There Yet. Target Oncol. 2017;12:401–12.PubMedCrossRef
22.
Heinrich D, Bruland Ø, Guise TA, Suzuki H, Sartor O. Alkaline phosphatase in metastatic castration-resistant prostate cancer: reassessment of an older biomarker. Future Oncol. 2018;14:2543–56.PubMedCrossRef
23.
24.
25.
Fendler WP, Eiber M, Beheshti M, Bomanji J, Ceci F, Cho S, et al. 68Ga-PSMA PET/CT: Joint EANM and SNMMI procedure guideline for prostate cancer imaging: version 1.0. Eur J Nucl Med Mol Imaging. 2017;44:1014–24.PubMedCrossRef
26.
Krause BJ, Beyer T, Bockisch A, Delbeke D, Kotzerke J, Minkov V, et al. FDG-PET/CT in oncology. Nuklearmedizin. Schattauer GmbH. 2007;46:291–301.CrossRef
27.
Schmechel D, Marangos PJ, Brightman M. Neurone-specific enolase is a molecular marker for peripheral and central neuroendocrine cells. Nature. 1978;276:834–6.PubMedCrossRef
28.
Isgrò MA, Bottoni P, Scatena R. Neuron-specific enolase as a biomarker: biochemical and clinical aspects. Adv Exp Med Biol. 2015;867:125–43.PubMedCrossRef
29.
30.
Muoio B, Pascale M, Roggero E. The role of serum neuron-specific enolase in patients with prostate cancer: a systematic review of the recent literature. Int J Biol Markers. 2018;33:10–21.PubMedCrossRef
31.
Marcus DM, Goodman M, Jani AB, Osunkoya AO, Rossi PJ. A comprehensive review of incidence and survival in patients with rare histological variants of prostate cancer in the United States from 1973 to 2008. Prostate Cancer Prostatic Dis. 2012;15:283–8.PubMedCrossRef
32.
Beltran H, Tomlins S, Aparicio A, Arora V, Rickman D, Ayala G, et al. Aggressive variants of castration resistant prostate cancer. Clin Cancer Res. 2014;20:2846–50.PubMedPubMedCentralCrossRef
33.
Aggarwal R, Zhang T, Small EJ, Armstrong AJ. Neuroendocrine prostate cancer: subtypes, biology, and clinical outcomes. J Natl Compr Canc Netw. 2014;12:719–26.PubMedCrossRef
34.
Ismail AHR, Landry F, Aprikian AG, Chevalier S. Androgen ablation promotes neuroendocrine cell differentiation in dog and human prostate. Prostate. 2002;51:117–25.CrossRef
35.
Hu C-D. Choo R. Huang J. Neuroendocrine differentiation in prostate cancer: a mechanism of radioresistance and treatment failure. Front Oncol. 2015;5:90.PubMed
36.
Xing N, Qian J, Bostwick D, Bergstralh E, Young CY. Neuroendocrine cells in human prostate over-express the anti-apoptosis protein survivin. Prostate. 2001;48:7–15.PubMedCrossRef
37.
Heinrich E, Probst K, Michel MS, Trojan L. Gastrin-releasing peptide: predictor of castration-resistant prostate cancer? The Prostate. 2011;71:642–8.PubMedCrossRef
38.
Usmani S, Ahmed N, Marafi F, Rasheed R, Amanguno HG, Al KF. Molecular imaging in neuroendocrine differentiation of prostate cancer: 68Ga-PSMA versus 68Ga-DOTA NOC PET-CT. Clin Nucl Med. 2017;42:410–3.PubMedCrossRef
39.
Chakraborty PS, Tripathi M, Agarwal KK, Kumar R, Vijay MK, Bal C. Metastatic poorly differentiated prostatic carcinoma with neuroendocrine differentiation: negative on 68Ga-PSMA PET/CT. Clin Nucl Med. 2015;40:e163–6.PubMedCrossRef
40.
Tosoian JJ, Gorin MA, Rowe SP, Andreas D, Szabo Z, Pienta KJ, et al. Correlation of PSMA-targeted 18F-DCFPyL PET/CT findings with immunohistochemical and genomic data in a patient with metastatic neuroendocrine prostate cancer. Clin Genitourin Cancer. 2017;15:e65–8.PubMedCrossRef
41.
Bakht MK, Derecichei I, Li Y, Ferraiuolo R-M, Dunning M, Oh SW, et al. Neuroendocrine differentiation of prostate cancer leads to PSMA suppression. Endocr Relat Cancer. 2018;26:131–46.PubMed
42.
Stewart GD, Gray K, Pennington CJ, Edwards DR, Riddick ACP, Ross JA, et al. Analysis of hypoxia-associated gene expression in prostate cancer: lysyl oxidase and glucose transporter-1 expression correlate with Gleason score. Oncol Rep. 2008;20:1561–7.PubMed
43.
Meziou S, Ringuette Goulet C, Hovington H, Lefebvre V, Lavallée É, Bergeron M, et al. GLUT1 expression in high-risk prostate cancer: correlation with 18F-FDG-PET/CT and clinical outcome. Prostate Cancer Prostatic Dis. 2020.
44.
45.
Parida GK, Tripathy S, Datta Gupta S, Singhal A, Kumar R, Bal C, et al. Adenocarcinoma prostate with neuroendocrine differentiation: potential utility of 18F-FDG PET/CT and 68Ga-DOTANOC PET/CT over 68Ga-PSMA PET/CT. Clin Nucl Med. 2018;43:248–9.PubMedCrossRef
46.
Spratt DE, Gavane S, Tarlinton L, Fareedy SB, Doran MG, Zelefsky MJ, et al. Utility of FDG-PET in clinical neuroendocrine prostate cancer. Prostate. 2014;74:1153–9.PubMedPubMedCentralCrossRef
47.
Thang SP, Violet J, Sandhu S, Iravani A, Akhurst T, Kong G, et al. Poor outcomes for patients with metastatic castration-resistant prostate cancer with low prostate-specific membrane antigen (PSMA) expression deemed ineligible for 177Lu-labelled PSMA radioligand therapy. Eur Urol Oncol. 2019;2:670–6.PubMedCrossRef
48.
Rathke H, Holland-Letz T, Mier W, Flechsig P, Mavriopoulou E, Röhrich M, et al. Response prediction of 177Lu-PSMA-617 RLT using PSA, Chromogranin A, and LDH. J Nucl Med. 2019;jnumed.119.231431.
49.
Yordanova A, Linden P, Hauser S, Feldmann G, Brossart P, Fimmers R, et al. The value of tumor markers in men with metastatic prostate cancer undergoing [177Lu]Lu-PSMA therapy. The Prostate. 2020;80:17–27.PubMedCrossRef
50.
Heck MM, Tauber R, Schwaiger S, Retz M, D’Alessandria C, Maurer T, et al. Treatment outcome, toxicity, and predictive factors for radioligand therapy with 177Lu-PSMA-I&T in metastatic castration-resistant prostate cancer. European Urology. 2019;75:920–6.PubMedCrossRef
Metadata
Title
Neuron-specific enolase has potential value as a biomarker for [18F]FDG/[68Ga]Ga-PSMA-11 PET mismatch findings in advanced mCRPC patients
Authors
Florian Rosar
Kalle Ribbat
Martin Ries
Johannes Linxweiler
Mark Bartholomä
Stephan Maus
Mathias Schreckenberger
Samer Ezziddin
Fadi Khreish
Publication date
01-12-2020
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2020
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-020-00640-2

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