Introduction: High baseline YKL-40 serum levels are associated with drug resistance in several solid tumours. However, their role in predicting docetaxel (DOC) resistance in prostate cancer (PCa) is unknown. Methods: Pre-treatment serum levels of YKL-40 and prostate-specific antigen (PSA) were analyzed in 109 castration-resistant prostate cancer patients who underwent DOC-therapy. Responsive patients were retreated by repeated series of DOC. Results were compared with the clinical parameters as well as overall (OS) and disease-specific survival (DSS). Results: YKL-40 but not PSA serum levels were significantly higher in patients with baseline resistance to DOC (p = 0.035). Higher YKL-40 and PSA levels were detected in patients with bone metastasis (p = 0.032; p = 0.010) and in those who were not pre-treated with radical prostatectomy (p = 0.011, p = 0.008). High YKL-40 levels were associated with shorter OS (p = 0.037) and DSS (p = 0.017) in patients who received DOC in the first-line setting. In multivariable analysis, ECOG performance status (p = 0.009), presence of any metastases (p = 0.016) and high PSA levels (p = 0.005) remained independent predictors for DSS. Conclusions: YKL-40 may help to identify patients with baseline resistance to DOC and therefore may help to optimize treatment decisions. In accordance, high pre-treatment YKL-40 serum levels were associated with shorter OS and DSS in patients who received DOC as first-line therapy.

Keywords:
Prostate cancer, YKL-40, Castratation-resistant prostate cancer, Drug resistance, Prognosis, Docetaxel
1.
Torre LA, Siegel RL, Ward EM, Jemal A: Global cancer incidence and mortality rates and trends – an update. Cancer Epidemiol Biomarkers Prev 2016; 25: 16–27.
2.
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.
3.
Galsky MD, Vogelzang NJ: Docetaxel-based combination therapy for castration-resistant prostate cancer. Ann Oncol 2010; 21: 2135–2144.
4.
Pagliarulo V, Bracarda S, Eisenberger MA, Mottet N, Schröder FH, Sternberg CN, et al: Contemporary role of androgen deprivation therapy for prostate cancer. Eur Urol 2012; 61: 11–25.
5.
Harris WP, Mostaghel EA, Nelson PS, Montgomery B: Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol 2009; 6: 76–85.
6.
Virgo KS, Basch E, Loblaw DA, Oliver TK, Rumble RB, Carducci MA, et al: Second-line hormonal therapy for men with chemotherapy-naïve, castration-resistant prostate cancer: American Society of Clinical Oncology Provisional Clinical Opinion. J Clin Oncol 2017; 35: 1952–1964.
7.
De Dosso S, Berthold DR: Docetaxel in the management of prostate cancer: current standard of care and future directions. Expert Opin Pharmacother 2008; 9: 1969–1979.
8.
Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015; 373: 737–746.
9.
James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, et al: Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2061; 387: 1163–1177.
10.
Crawford ED, Shore ND, Petrylak DP, Higano CS, Ryan CJ: Abiraterone acetate and prednisone in chemotherapy-naïve prostate cancer patients: rationale, evidence and clinical utility. Ther Adv Med Oncol 2017; 9: 319–333.
11.
Leão R, Domingos C, Figueiredo A, Hamilton R, Tabori U, Castelo-Branco P: Cancer stem cells in prostate cancer: implications for targeted therapy. Urol Int 2017; 99: 125–136.
12.
Roslind A, Johansen JS: YKL-40: a novel marker shared by chronic inflammation and oncogenic transformation. Methods Mol Biol 2009; 511: 159–184.
13.
Jeet V, Tevz G, Lehman M, Hollier B, Nelson C: Elevated YKL40 is associated with advanced prostate cancer (PCa) and positively regulates invasion and migration of PCa cells. Endocr Relat Cancer 2014; 21: 723–737.
14.
Vom Dorp F, Tschirdewahn S, Niedworok C, Reis H, Krause H, Kempkensteffen C, et al: Circulating and tissue expression levels of YKL-40 in renal cell cancer. J Urol 2016; 195: 1120–1125.
15.
Özdemir E, Çiçek T, Kaya MO: Association of serum YKL-40 level with tumor burden and metastatic stage of prostate cancer. Urol J 2012; 9: 568–573.
16.
Ku BM, Lee YK, Ryu J, Jeong JY, Choi J, Eun KM, et al: CHI3L1 (YKL-40) is expressed in human gliomas and regulates the invasion, growth and survival of glioma cells. Int J Cancer 2011; 128: 1316–1326.
17.
Bubley GJ, Carducci M, Dahut W, et al: Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999; 17: 3461–3467.
18.
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216.
19.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM; Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics: Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 2005; 97: 1180–1184.
20.
Gogas H, Eggermont AM, Hauschild A, Hersey P, Mohr P, Schadendorf D, et al: Biomarkers in melanoma. Ann Oncol 2009; 20(suppl 6):vi8–vi13.
21.
Demaria S, Pikarsky E, Karin M, Coussens LM, Chen YC, El-Omar EM, et al: Cancer and inflammation: promise for biologic therapy. J Immunother 2010; 33: 335–351.
22.
Li TM, Liu SC, Huang YH, Huang CC, Hsu CJ, Tsai CH, et al: YKL-40-induced inhibition of miR-590-3p promotes interleukin-18 expression and angiogenesis of endothelial progenitor cells. Int J Mol Sci 2017; 18:pii:E920.
23.
Johansen JS, Brasso K, Iversen P, Teisner B, Garnero P, Price PA, et al: Changes of biochemical markers of bone turnover and YKL-40 following hormonal treatment for metastatic prostate cancer are related to survival. Clin Cancer Res 2007; 13: 3244–3249.
24.
Johansen JS, Jensen BV, Roslind A, Nielsen D, Price PA: Serum YKL-40, a new prognostic biomarker in cancer patients? Cancer Epidemiol Biomarkers Prev 2006; 15: 194–202.
25.
Kucur M, Isman FK, Balci C, Onal B, Hacibekiroglu M, Ozkan F, et al: Serum YKL-40 levels and chitotriosidase activity as potential biomarkers in primary prostate cancer and benign prostatic hyperplasia. Urol Oncol 2008; 26: 47–52.
26.
Kjaergaard AD, Nordestgaard BG, Johansen JS, Bojesen SE: Observational and genetic plasma YKL-40 and cancer in 96,099 individuals from the general population. Int J Cancer 2015; 137: 2696–2704.
27.
Tschirdewahn S, Reis H, Niedworok C, Nyirady P, Szendröi A, Schmid KW, et al: Prognostic effect of serum and tissue YKL-40 levels in bladder cancer. Urol Oncol 2014; 32: 663–669.
28.
Hao H, Wang L, Chen H, Xie L, Bai T, Liu H, Wang D: YKL-40 promotes the migration and invasion of prostate cancer cells by regulating epithelial mesenchymal transition. Am J Transl Res 2017; 9: 3749–3757.
29.
Windrichova J, Fuchsova R, Kucera R, Topolcan O, Fiala O, Finek J, et al: Testing of a novel cancer metastatic multiplex panel for the detection of bone-metastatic disease – a pilot study. Anticancer Res 2016; 36: 1973–1978.
30.
Brasso K, Christensen IJ, Johansen JS, Teisner B, Garnero P, Price PA, et al: Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma. Prostate 2006; 66: 503–513.
31.
Senetta R, Duregon E, Sonetto C, Spadi R, Mistrangelo M, Racca P, et al: YKL-40/c-Met expression in rectal cancer biopsies predicts tumor regression following neoadjuvant chemoradiotherapy: a multi-institutional study. PLoS One 2015; 10:e0123759.
32.
Akiyama Y, Ashizawa T, Komiyama M, Miyata H, Oshita C, Omiya M, et al: YKL-40 downregulation is a key factor to overcome temozolomide resistance in a glioblastoma cell line. Oncol Rep 2014; 32: 159–166.
33.
Chiang YC, Lin HW, Chang CF, Chang MC, Fu CF, Chen TC, et al: Overexpression of CHI3L1 is associated with chemoresistance and poor outcome of epithelial ovarian carcinoma. Oncotarget 2015; 6: 39740–39755.
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2018
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