Background: Aggressive variant transformation in metastatic castration-resistant prostate cancer (mCRPC) represents an under-recognized phenomenon. There is an urgent need for non-invasive biomarkers to detect these variants and identify treatment alternatives. Methods: A prospective observational pilot study in mCRPC patients receiving treatment with cabazitaxel (CAB) was conducted. Neuromediators were sequentially evaluated and their impact on disease endpoints calculated. Targeted next-generation sequencing (NGS) of cell-free DNA (cfDNA) was also performed in a highly pretreated subset of patients. Results: 23 patients were included. Estimated effects indicate that neuron-specific enolase (NSE) levels at baseline may be correlated with overall survival (NSE unit 18.3 ng/ml: HR1.262 (95% confidence interval (CI) 0.985-1.616)) and that chromogranin A (CGA) may be correlated with progression-free survival (CGA unit 98.1 ng/ml: HR1.341 (95% CI 1.011-1.778)). cfDNA analysis revealed mutations annotated in prostate cancer (PCA) and small cell cancers (SCC). 1 patient showed elevated neuromediators along with annotated mutations in PCA and SCC, potentially indicating aggressive variant cancer. In 3 patients KIT mutations (e.g. pM541L, pV654A) known to be tissue-based biomarkers with level 1 evidence for the treatment with imatinib and sunitinib were found. Conclusions: Sequential analysis of neuromediators and targeted NGS of cfDNA provide insight for the estimation of tumor heterogeneity under therapy with CAB.

Journal Section:
Research Article
Keywords:
Cabazitaxel, CGA, Liquid biopsy, Neuroendocrine, NSE
1.
Dragani TA, Castells A, Kulasingam V, et al.: Major milestones in translational oncology. BMC Med 2016;14:110.
[PubMed]
https://doi.org/10.1186/s12916-016-0654-y
2.
Beltran H, Tomlins S, Aparicio A, et al.: Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res 2014;20:2846-2850.
[PubMed]
https://doi.org/10.1158/1078-0432.CCR-13-3309
3.
Small EJ, Huang J, Youngren J, et al.: Characterization of neuroendocrine prostate cancer (NEPC) in patients with metastatic castration resistant prostate cancer (mCRPC) resistant to abiraterone (Abi) or enzalutamide (Enz): Preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer. J Clin Oncol 2015;33(Suppl):5003-5003.
4.
Beltran H, Prandi D, Mosquera JM, et al.: Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med 2016;22:298-305.
[PubMed]
https://doi.org/10.1038/nm.4045
5.
Epstein JI, Amin MB, Beltran H, et al.: Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol 2014;38:756-767.
[PubMed]
https://doi.org/10.1097/PAS.0000000000000208
6.
Angelsen A, Syversen U, Haugen OA, et al.: Neuroendocrine differentiation in carcinomas of the prostate: do neuroendocrine serum markers reflect immunohistochemical findings? Prostate 1997;30:1-6.
[PubMed]
https://doi.org/10.1002/(SICI)1097-0045(19970101)30:1<1::AID-PROS1>3.0.CO;2-T
7.
Berruti A, Mosca A, Porpiglia F, et al.: Chromogranin A expression in patients with hormone naïve prostate cancer predicts the development of hormone refractory disease. J Urol 2007;178:838-843.
[PubMed]
https://doi.org/10.1016/j.juro.2007.05.018
8.
Genitsch V, Zlobec I, Seiler R, et al.: Neuroendocrine differentiation in metastatic conventional prostate cancer is significantly increased in lymph node metastases compared to the primary tumors. Int J Mol Sci 2017;18:1640.
[PubMed]
https://doi.org/10.3390/ijms18081640
9.
Schwarzenbach H, Alix-Panabières C, Müller I, et al.: Cell-free tumor DNA in blood plasma as a marker for circulating tumor cells in prostate cancer. Clin Cancer Res 2009;15:1032-1038.
[PubMed]
https://doi.org/10.1158/1078-0432.CCR-08-1910
10.
Chedgy ECP, Annala M, Beja K, et al.: Moving toward personalized care: Liquid biopsy predicts response to cisplatin in an unusual case of BRCA2-Null neuroendocrine prostate cancer. Clin Genitourin Cancer 2016;14:e233-e236.
[PubMed]
https://doi.org/10.1016/j.clgc.2015.12.023
11.
Swanton C, Soria JC, Bardelli A, et al.: Consensus on precision medicine for metastatic cancers: A report from the MAP conference: Table 1. Ann Oncol 2016;27:1443-1448.
[PubMed]
https://doi.org/10.1093/annonc/mdw192
12.
Von Hardenberg J, Schwartz M, Werner T, et al.: Prospective evaluation of neuromediator dynamics in castration-resistant prostate cancer patients during docetaxel. Anticancer Res 2017;37:5117-5124.
[PubMed]
https://doi.org/10.21873/anticanres.11931
13.
Scher HI, Morris MJ, Basch E, Heller G: End points and outcomes in castration-resistant prostate cancer: from clinical trials to clinical practice. J Clin Oncol 2011;29:3695-3704.
[PubMed]
https://doi.org/10.1200/JCO.2011.35.8648
14.
Moore CG, Carter RE, Nietert PJ, Stewart PW: Recommendations for planning pilot studies in clinical and translational research. Clin Transl Sci 2011;4:332-337.
[PubMed]
https://doi.org/10.1111/j.1752-8062.2011.00347.x
15.
Chakravarty D, Gao J, Phillips SM, et al.: OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol 2017;2017.
[PubMed]
16.
Forbes SA, Beare D, Boutselakis H, et al.: COSMIC: Somatic cancer genetics at high-resolution. Nucleic Acids Res 2017;45:D777-D783.
[PubMed]
https://doi.org/10.1093/nar/gkw1121
17.
Robinson D, Van Allen EM, Wu Y-M, et al.: Integrative clinical genomics of advanced prostate cancer. Cell 2015;161:1215-1228.
[PubMed]
https://doi.org/10.1016/j.cell.2015.05.001
18.
Burgio SL, Conteduca V, Menna C, et al.: Chromogranin A predicts outcome in prostate cancer patients treated with abiraterone. Endocr Relat Cancer 2014;21:487-493.
[PubMed]
https://doi.org/10.1530/ERC-14-0071
19.
Heck MM, Thaler MA, Schmid SC, 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.
[PubMed]
https://doi.org/10.1111/bju.13493
20.
Wyatt AW, Annala M, Aggarwal R, et al.: Concordance of circulating tumor DNA and matched metastatic tissue biopsy in prostate cancer. J Natl Cancer Inst 2017;109.
[PubMed]
https://doi.org/10.1093/jnci/djx118
21.
Ulz P, Belic J, Graf R, et al.: Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer. Nat Commun 2016;7:12008.
[PubMed]
https://doi.org/10.1038/ncomms12008
22.
Hong MKH, Macintyre G, Wedge DC, et al.: Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nat Commun 2015;6:6605.
[PubMed]
https://doi.org/10.1038/ncomms7605
23.
Chang MT, Asthana S, Gao SP, et al.: Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. Nat Biotechnol 2015;34:155-163.
[PubMed]
https://doi.org/10.1038/nbt.3391
24.
George J, Lim JS, Jang SJ, et al.: Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47-53.
[PubMed]
https://doi.org/10.1038/nature14664
25.
Sutherland KD, Proost N, Brouns I, et al.: Cell of origin of small cell lung cancer: Inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung. Cancer Cell 2011;19:754-764.
[PubMed]
https://doi.org/10.1016/j.ccr.2011.04.019
26.
Tan HL, Sood A, Rahimi HA, et al.: Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin Cancer Res 2014;20:890-903.
[PubMed]
https://doi.org/10.1158/1078-0432.CCR-13-1982
27.
V P, Shalini CN, Priya S, et al.: Small cell neuroendocrine carcinoma of the cervix: A rare entity. J Clin Diagn Res 2014;8:147-148.
[PubMed]
https://doi.org/10.1158/1078-0432.CCR-13-1982
28.
Wang HT, Yao YH, Li BG, et al.: 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.
[PubMed]
https://doi.org/10.1200/JCO.2013.54.3553
29.
Meder L, König K, Ozretić L, et al.: NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. Int J cancer 2016;138:927-938.
[PubMed]
https://doi.org/10.1002/ijc.29835
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