Purpose: To evaluate whether serum neuroendocrine markers could effectively predict treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: The PubMed, Cochrane Library and Embase databases were sought to identify eligible studies concerning serum neuroendocrine markers and the prognosis of post-treatment mCRPC from inception to April 2018. The association between serum neuroendocrine markers, that is, chromogranin A (CgA) and neurone-specific enolase (NSE), levels and the prognosis of post-treatment mCRPC were summarized using a random-effects model and hazard ratio (HR) with 95% CI Sensitivity analyses were conducted to assess potential bias. Results: A total of 234 participants are included in this meta-analysis (mean age = 71.3 years) from 6 studies. The pooled results show that higher markers’ levels at baseline in patients were associated with unfavorable overall survival (OS; univariate analysis: HR 3.775, 95% CI 1.469–9.698, p = 0.006; multivariate analysis: HR 3.838, 95% CI 1.774–8.304, p = 0.001), and a similar situation was observed in progression-free survival (PFS; univariate analysis: HR 2.785, 95% CI 1.315–5.898, p = 0.007; multivariate analysis: HR 1.266, 95% CI 1.017–1.577, p = 0.035). Estimates of the total effects were generally consistent in the sensitivity analysis. Publication bias was observed when performing the univariate analysis of PFS, and we have the explanation accordingly. Conclusions: The results of this pooled analysis confirm serum neuroendocrine markers could be the effective predictor of treatment outcome in patients with mCRPC. In addition, a combination of CgA and NSE is more valuable to predict worse OS. Further randomized case-control trials are required to validate this relationship.

Keywords:
Castration-resistant prostate cancer, Chromogranin A, Neurone-specific enolase, Neuroendocrine, Meta-analysis
1.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136:E359–E386.
2.
Smith MR, Kabbinavar F, Saad F, Hussain A, Gittelman MC, Bilhartz DL, et al: Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol 2005; 23: 2918–2925.
3.
Pienta KJ, Bradley D: Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res 2006; 12: 1665–1671.
4.
Mottet N, Bellmunt J, Briers E, Bolla M, Bourke L, Cornford P, et al: (2018) Guidelines on Prostate Cancer: European Association of Urology.https://uroweb.org/guideline/prostate-cancer/ (accessed September 2018).
5.
Yuan X, Cai C, Chen S, Chen S, Yu Z, Balk SP: Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis. Oncogene 2014; 33: 2815–2825.
6.
Longo DL: New therapies for castration-resistant prostate cancer. N Engl J Med 2010; 363: 479–481.
7.
Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, et al: Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic -castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015; 16: 152–160.
8.
Beer TM, Tombal B: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 1755–1756.
9.
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187–1197.
10.
Miyoshi Y, Ohtaka M, Kawahara T, Ohtake S, Yasui M, Uemura K, et al: Prediction of time to castration-resistant prostate cancer using low-molecular-weight protein tyrosine phosphatase expression for men with metastatic hormone-naïve prostate cancer. Urol Int 2018; 16: 1–6.
11.
Lin D, Wyatt AW, Xue H, Wang Y, Dong X, Haegert A, et al: High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development. Cancer Res 2014; 74: 1272–1283.
12.
Dang Q, Li L, Xie H, He D, Chen J, Song W, et al: Anti-androgen enzalutamide enhances prostate cancer neuroendocrine (NE) differentiation via altering the infiltrated mast cells → androgen receptor (AR) miRNA32 signals. Mol Oncol 2015; 9: 1241–1251.
13.
Niu Y, Guo C, Wen S, Tian J, Luo J, Wang K, et al: ADT with antiandrogens in prostate cancer induces adverse effect of increasing resistance, neuroendocrine differentiation and tumor metastasis. Cancer Lett 2018; 439: 47–55.
14.
Matei DV, Renne G, Pimentel M, Sandri MT, Zorzino L, Botteri E, et al: Neuroendocrine differentiation in castration-resistant prostate cancer: a systematic diagnostic attempt. Clin Genitourin Cancer 2012; 10: 164–173.
15.
Helpap B, Köllermann J, Oehler U: Neuroendocrine differentiation in prostatic carcinomas: histogenesis, biology, clinical relevance, and future therapeutical perspectives. Urol Int 1999; 62: 133–138.
16.
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: 2846–2850.
17.
Epstein JI, Amin MB, Beltran H, Lotan TL, Mosquera JM, Reuter VE, et al: Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol 2014; 38: 756–767.
18.
Sciarra A, Di Silverio F, Autran AM, Salciccia S, Gentilucci A, Alfarone A, et al: Distribution of high chromogranin A serum levels in patients with nonmetastatic and metastatic prostate adenocarcinoma. Urol Int 2009; 82: 147–151.
19.
Sainio M, Visakorpi T, Tolonen T, Ilvesaro J, Bova GS: Expression of neuroendocrine differentiation markers in lethal metastatic castration-resistant prostate cancer. Pathol Res Pract 2018; 214: 848–856.
20.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009; 6:e1000100.
21.
Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J: The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol 2003; 3: 25.
22.
Higgins JP, Thompson SG: Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–1558.
23.
Begg CB, Berlin JA: Publication bias and dissemination of clinical research. J Natl Cancer Inst 1989; 81: 107–115.
24.
Heck MM, Thaler MA, Schmid SC, Seitz AK, Tauber R, Kübler H, et al: Chromogranin A and neurone-specific enolase serum levels as predictors of treatment outcome in patients with metastatic castration-resistant prostate cancer undergoing abiraterone therapy. BJU Int 2017; 119: 30–37.
25.
Fan L, Wang Y, Chi C, Pan J, Xun S, Xin Z, et al: Chromogranin A and neurone-specific enolase variations during the first 3 months of abiraterone therapy predict outcomes in patients with metastatic castration-resistant prostate cancer. BJU Int 2017; 120: 226–232.
26.
VON Hardenberg J, Schwartz M, Werner T, Fuxius S, Müller M, Frangenheim T, et al: Prospective evaluation of neuromediator dynamics in castration-resistant prostate cancer patients during docetaxel. Anticancer Res 2017; 37: 5117–5124.
27.
Conteduca V, Burgio SL, Menna C, Carretta E, Rossi L, Bianchi E, et al: Chromogranin A is a potential prognostic marker in prostate cancer patients treated with enzalutamide. Prostate 2014; 74: 1691–1696.
28.
Burgio SL, Conteduca V, Menna C, Carretta E, Rossi L, Bianchi E, et al: Chromogranin A predicts outcome in prostate cancer patients treated with abiraterone. Endocr Relat Cancer 2014; 21: 487–493.
29.
Sarkar D, Singh SK, Mandal AK, Agarwal MM, Mete UK, Kumar S, et al: Plasma chromogranin A: clinical implications in patients with castrate resistant prostate cancer receiving docetaxel chemotherapy. Cancer Biomark 2010–2011; 8: 81–87.
30.
Oliver T, Wilson P, Ansell W, Philp T, Chinegwundoh F, Shamash J, et al: A prospective audit of intermittent anti-androgen verses pituitary blockade suggests a bipolar androgen type strategy may be safe in untreated prostate cancer. Urol Int 2018; 100: 172–180.
31.
Perner S, Cronauer MV, Schrader AJ, Klocker H, Culig Z, Baniahmad A: Adaptive responses of androgen receptor signaling in castration-resistant prostate cancer. Oncotarget 2015; 6: 35542–35555.
32.
Wang HT, Yao YH, Li BG, Tang Y, Chang JW, Zhang J: Neuroendocrine prostate cancer (NEPC) progressing from conventional prostatic adenocarcinoma: factors associated with time to development of NEPC and survival from NEPC diagnosis-a systematic review and pooled analysis. J Clin Oncol 2014; 32: 3383–3390.
33.
Conteduca V, Aieta M, Amadori D, De Giorgi U: Neuroendocrine differentiation in prostate cancer: current and emerging therapy strategies. Crit Rev Oncol Hematol 2014; 92: 11–24.
34.
Kamiya N, Akakura K, Suzuki H, Isshiki S, Komiya A, Ueda T, et al: Pretreatment serum level of neuron specific enolase (NSE) as a prognostic factor in metastatic prostate cancer patients treated with endocrine therapy. Eur Urol 2003; 44: 309–314; discussion 314.
35.
Hvamstad T, Jordal A, Hekmat N, Paus E, Fosså SD: Neuroendocrine serum tumour markers in hormone-resistant prostate cancer. Eur Urol 2003; 44: 215–221.
36.
Korse CM, Taal BG, Vincent A, van Velthuysen ML, Baas P, Buning-Kager JC, et al: Choice of tumour markers in patients with neuroendocrine tumours is dependent on the histological grade. a marker study of chromogranin A, neuron specific enolase, Progastrin-releasing peptide and cytokeratin fragments. Eur J Cancer 2012; 48: 662–671.
37.
Dong B, Fan L, Wang Y, Chi C, Ma X, Wang R, et al: Influence of abiraterone acetate on neuroendocrine differentiation in chemotherapy-naive metastatic castration-resistant prostate cancer. Prostate 2017; 77: 1373–1380.
38.
Berruti A, Dogliotti L, Mosca A, Bellina M, Mari M, Torta M, et al: Circulating neuroendocrine markers in patients with prostate carcinoma. Cancer 2000; 88: 2590–2597.
39.
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.
40.
Komiya A, Yasuda K, Watanabe A, Fujiuchi Y, Tsuzuki T, Fuse H: The prognostic significance of loss of the androgen receptor and neuroendocrine differentiation in prostate biopsy specimens among castration-resistant prostate cancer patients. Mol Clin Oncol 2013; 1: 257–262.
41.
Berruti A, Mosca A, Tucci M, Terrone C, Torta M, Tarabuzzi R, et al: Independent prognostic role of circulating chromogranin A in prostate cancer patients with hormone-refractory disease. Endocr Relat Cancer 2005; 12: 109–117.
42.
Conteduca V, Aieta M, Amadori D, De Giorgi U: Neuroendocrine differentiation in prostate cancer: current and emerging therapy strategies. Crit Rev Oncol Hematol 2014; 92: 11–24.
43.
Buttigliero C, Tucci M, Bertaglia V, Vignani F, Bironzo P, Di Maio M, et al: Understanding and overcoming the mechanisms of primary and acquired resistance to abiraterone and enzalutamide in castration resistant prostate cancer. Cancer Treat Rev 2015; 41: 884–892.
44.
Cabrespine A, Guy L, Gachon F, Curé H, Chollet P, Bay JO: Circulating chromogranin a and hormone refractory prostate cancer chemotherapy. J Urol 2006; 175: 1347–1352.
© 2018 S. Karger AG, Basel
2018
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.