Role of free testosterone levels in patients with metastatic castration-resistant prostate cancer receiving second-line therapy

von Klot,Christoph A.; Kuczyk,Markus A.; Boeker,Alena; Reuter,Christoph; Imkamp,Florian; Herrmann,Thomas   R.W.; Tezval,Hossein; Kramer,Mario  W.; Perner,Sven; Merseburger,Axel S.

doi:10.3892/ol.2016.5392

Role of free testosterone levels in patients with metastatic castration-resistant prostate cancer receiving second-line therapy

Authors:
- Christoph A. von Klot
- Markus A. Kuczyk
- Alena Boeker
- Christoph Reuter
- Florian Imkamp
- Thomas R.W. Herrmann
- Hossein Tezval
- Mario W. Kramer
- Sven Perner
- Axel S. Merseburger
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Affiliations: Department of Urology and Urological Oncology, Hannover Medical School, D‑30625 Hannover, Germany, Department of Hematology and Oncology, Hannover Medical School, D‑30625 Hannover, Germany, Department of Urology, Campus Luebeck, University Hospital Schleswig‑Holstein, D-24105 Luebeck, Germany, Pathology Network of the University Hospital of Luebeck and Leibniz Research Center, D-23528 Borstel, Germany
Published online on: November 17, 2016 https://doi.org/10.3892/ol.2016.5392
Pages: 22-28
Copyright: © von Klot et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

A range of new treatment options has recently become available for patients with advanced metastatic castration-resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone is continued when performing chemotherapy or androgen deprivation with new second‑generation therapeutic agents such as enzalutamide or abiraterone acetate. Despite the fact that free testosterone (FT) is the biologically active form, it is common practice that androgen suppression is monitored via total testosterone levels only. The aim of the present study was to evaluate the role of FT as a prognostic biomarker for cancer‑specific survival (CSS) and its feasibility as an ADT monitoring biomarker in patients with mCRPC for the first time. The requirement for continued ADT in mCRPC patients is discussed within the basis of the current literature. A total of 34 patients with continuous measurements of FT levels and mCRPC status underwent therapy with docetaxel, abiraterone acetate, enzalutamide, cabozantinib, carboplatin or cabazitaxel. Data were obtained from the Departments of Urology and Urological Oncology, Hannover Medical School (Hannover, Germany) between March 2009 and April 2014. A cutoff point of 0.5 pg/ml was used to discriminate between patients according to FT levels. Statistical evaluation of CSS was performed by applying Kaplan Meier survival estimates, multivariate Cox regression analyses and log‑rank tests. The median age of all 34 patients was 72 years (range, 51‑86 years). The mean follow‑up interval was 16.1 months (range, 0.7-55.6 months). Despite the fact that all patients were undergoing androgen deprivation, the mean serum FT levels for each patient varied; the mean FT concentration in the cohort was 0.328 pg/ml, ranging from 0.01-9.1 pg/ml. A notable difference with regard to CSS was observed for patients with regard to serum FT concentration; CSS was significantly longer for patients with a serum FT level below the cutoff level (43.6 vs. 17.3 months, respectively, P=0.0063). Upon multivariate Cox regression analysis, the mean FT concentration during treatment remained a significant prognostic factor for CSS (hazard ratio, 1.22; 95% confidence interval, 1.03-1.43; P=0.0182). In conclusion, in patients with mCRPC, the serum FT level is a strong predictor of CSS in patients under therapy with second‑line anti‑hormonal therapeutic medication and chemotherapy. It may be concluded that FT levels should be included into the routine control of androgen suppression while under treatment with ADT and second‑generation hormonal therapy.

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1	Malvezzi M, Bertuccio P, Levi F, La Vecchia C and Negri E: European cancer mortality predictions for the year 2013. Ann Oncol. 24:792–800. 2013. View Article : Google Scholar : PubMed/NCBI
2	Huggins C, Stevens RE and Hodges CV: Studies on prostate cancer. II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 43:209–223. 1941. View Article : Google Scholar
3	Walsh PC: Physiologic basis for hormonal therapy in carcinoma of the prostate. Urol Clin North Am. 2:125–140. 1975.PubMed/NCBI
4	Merseburger AS, Hammerer P, Rozet F, Roumeguère T, Caffo O, da Silva FC and Alcaraz A: Androgen deprivation therapy in castrate-resistant prostate cancer: How important is GnRH agonist backbone therapy? World J Urol. 33:1079–1085. 2015. View Article : Google Scholar : PubMed/NCBI
5	Faris JE and Smith MR: Metabolic sequelae associated with androgen deprivation therapy for prostate cancer. Curr Opin Endocrinol Diabetes Obes. 17:240–246. 2010. View Article : Google Scholar : PubMed/NCBI
6	Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, Mason M, Matveev V, Wiegel T, Zattoni F, et al: EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing and castration-resistant prostate cancer. Eur Urol. 65:467–479. 2014. View Article : Google Scholar : PubMed/NCBI
7	Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, et al: Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: Recommendations of the prostate cancer clinical trials working group. J Clin Oncol. 26:1148–1159. 2008. View Article : Google Scholar : PubMed/NCBI
8	Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, et al: Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: Final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 13:983–992. 2012. View Article : Google Scholar : PubMed/NCBI
9	Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 368:138–148. 2013. View Article : Google Scholar : PubMed/NCBI
10	de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet. 376:1147–1154. 2010. View Article : Google Scholar : PubMed/NCBI
11	Mendel CM: The free hormone hypothesis: A physiologically based mathematical model. Endocr Rev. 10:232–274. 1989. View Article : Google Scholar : PubMed/NCBI
12	Moreno SA, Shyam A and Morgentaler A: Comparison of free testosterone results by analog radioimmunoassay and calculated free testosterone in an ambulatory clinical population. J Sex Med. 7:1948–1953. 2010. View Article : Google Scholar : PubMed/NCBI
13	Trial of Abiraterone Acetate Plus LHRH-therapy Versus Abiraterone Acetate Sparing LHRH-therapy in Patients With Progressive Chemotherapy-naïve Castration-resistant Prostate Cancer (SPARE) (SPARE). https://clinicaltrials.gov/ct2/show/NCT02077634Accessed June 12, 2016.
14	Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET and Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 5:649–655. 1982. View Article : Google Scholar : PubMed/NCBI
15	Reuter CWM, Morgan MA, Ivanyi P, Fenner M, Ganser A and Grünwald V: Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer. World J Urol. 28:391–398. 2010. View Article : Google Scholar : PubMed/NCBI
16	Gleason DF and Mellinger GT: Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol. 111:58–64. 1974.PubMed/NCBI
17	Sobin LH and Compton CC: TNM seventh edition: What's new, what's changed: Communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer. 116:5336–5339. 2010. View Article : Google Scholar : PubMed/NCBI
18	Huggins C and Hodges CV: Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 167:948–952. 2002. View Article : Google Scholar : PubMed/NCBI
19	Attard G, Belldegrun AS and de Bono JS: Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int. 96:1241–1246. 2005. View Article : Google Scholar : PubMed/NCBI
20	Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, et al: Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 324:787–790. 2009. View Article : Google Scholar : PubMed/NCBI
21	Perachino M, Cavalli V and Bravi F: Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: Prognostic significance? BJU Int. 105:648–651. 2010. View Article : Google Scholar : PubMed/NCBI
22	Morote J, Orsola A, Planas J, Trilla E, Raventós CX, Cecchini L and Catalán R: Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol. 178:1290–1295. 2007. View Article : Google Scholar : PubMed/NCBI
23	Byar DP: Proceedings: The veterans administration cooperative urological research group's studies of cancer of the prostate. Cancer. 32:1126–1130. 1973. View Article : Google Scholar : PubMed/NCBI
24	Hussain M, Wolf M, Marshall E, Crawford ED and Eisenberger M: Effects of continued androgen-deprivation therapy and other prognostic factors on response and survival in phase II chemotherapy trials for hormone-refractory prostate cancer: A southwest oncology group report. J Clin Oncol. 12:1868–1875. 1994.PubMed/NCBI
25	Taylor CD, Elson P and Trump DL: Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol. 11:2167–2172. 1993.PubMed/NCBI
26	de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, et al: COU-AA-301 Investigators: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 364:1995–2005. 2011. View Article : Google Scholar : PubMed/NCBI
27	Ryan CJ, Peng W, Kheoh T, Welkowsky E, Haqq CM, Chandler DW, Scher HI and Molina A: Androgen dynamics and serum PSA in patients treated with abiraterone acetate. Prostate Cancer Prostatic Dis. 17:192–198. 2014. View Article : Google Scholar : PubMed/NCBI
28	Oefelein MG and Cornum R: Failure to achieve castrate levels of testosterone during luteinizing hormone releasing hormone agonist therapy: The case for monitoring serum testosterone and a treatment decision algorithm. J Urol. 164:726–729. 2000. View Article : Google Scholar : PubMed/NCBI
29	Sharifi R and Browneller R: Leuprolide Study Group: Serum testosterone suppression and potential for agonistic stimulation during chronic treatment with monthly and 3-month depot formulations of leuprolide acetate for advanced prostate cancer. J Urol. 168:1001–1004. 2002. View Article : Google Scholar : PubMed/NCBI
30	Smith MR: Obesity and sex steroids during gonadotropin-releasing hormone agonist treatment for prostate cancer. Clin Cancer Res. 13:241–245. 2007. View Article : Google Scholar : PubMed/NCBI
31	Colombel M, Symmans F, Gil S, O'Toole KM, Chopin D, Benson M, Olsson CA, Korsmeyer S and Buttyan R: Detection of the apoptosis-suppressing oncoprotein bc1-2 in hormone-refractory human prostate cancers. Am J Pathol. 143:390–400. 1993.PubMed/NCBI
32	Sun M, Yang L, Feldman RI, Sun XM, Bhalla KN, Jove R, Nicosia SV and Cheng JQ: Activation of phosphatidylinositol 3-kinase/Akt pathway by androgen through interaction of p85alpha, androgen receptor, and src. J Biol Chem. 278:42992–43000. 2003. View Article : Google Scholar : PubMed/NCBI
33	Craft N, Shostak Y, Carey M and Sawyers CL: A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the hER-2/neu tyrosine kinase. Nat Med. 5:280–285. 1999. View Article : Google Scholar : PubMed/NCBI
34	Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, et al: AR-v7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 371:1028–1038. 2014. View Article : Google Scholar : PubMed/NCBI
35	Egan A, Dong Y, Zhang H, Qi Y, Balk SP and Sartor O: Castration-resistant prostate cancer: Adaptive responses in the androgen axis. Cancer Treat Rev. 40:426–433. 2014. View Article : Google Scholar : PubMed/NCBI
36	Merseburger AS, Kuczyk MA and Wolff JM: Pathophysiology and therapy of castration-resistant prostate cancer. Urologe A. 52:219–225. 2013. View Article : Google Scholar : PubMed/NCBI
37	Pinski J, Xiong S, Wang Q, Stanczyk F, Hawes D and Liu SV: Effect of luteinizing hormone on the steroidogenic pathway in prostate cancer. Prostate. 71:892–898. 2011. View Article : Google Scholar : PubMed/NCBI
38	Mostaghel EA, Nelson PS, Lange P, Lin DW, Taplin ME, Balk S, Ellis W, Kantoff P, Marck B, Tamae D, et al: Targeted androgen pathway suppression in localized prostate cancer: A pilot study. J Clin Oncol. 32:229–237. 2014. View Article : Google Scholar : PubMed/NCBI