PLASMATIC SIL 6R/IL-6 RATIO AS APOTENTIAL PREDICTOR OF HIGH GLEASON SUM AT RADICAL PROSTATECTOMY

Background: Approximately 40% of males with low Gleason grade clinically localized prostate cancer (PCa) at biopsy were finally diagnosed with high Gleason grade PCa at radical prostatectomy (RP). Therefore, a more reliable assessment of the Gleason grade prior to RP is required. Readily available modalities such as circulating biomarkers may be useful for this purpose. The aim of this study was to evaluate the ability of preoperative interleukin 6 (IL-6) and its soluble receptor (sIL-6R), as well as urokinase-type plasminogen activator (u- PA), its receptor (u-PAR) and the inhibitor (PAI-1) to predict Gleason score upgrading. Patients and Methods: A total of 51 PCa patients with biopsy Gleason score ≤7 were studied. Preoperative serum samples were collected prior to digital rectal examination (DRE) and TRUS. Blood was collected into non-heparinized tubes and serum was separated within 1 h of blood collection. The serum was stored at –80˚C and then thawed just prior to testing. Serum levels of PSA, free-PSA and IL-6 were measured using the Immulite 2000 automated assay (DPC, Los Angeles, CA, USA). The concentrations of sIL-6R (R&D Systems, Minneapolis, MN, USA), uPA, uPAR and PAI- 1 (Assaypro, Winfield, MO, USA) in serum were determined according to the manufacturer’s instructions using the ELISA test. Every sample was run in duplicate and the mean was used. The differences between the two measurements were minimal. Results: GS upgrading was defined as a Gleason sum increase between biopsy and RP from ≤7 to >7, since this is important for the therapeutic strategy. On this basis, an upgrade was noted in 5 (10%) samples. Median sIL-6R values were found to be significantly higher in patients with GS upgrading (difference in medians, 28.40 ng/ml; 95% CI, 5.60-49.44; p=0.024). The association between sIL-6R and GS upgrading became more significant by using the sIL-6R/IL-6 ratio (difference in medians, 7.77; 95% CI, 1.72-11.28; p=0.011). Sensitivity and specificity of sIL-6R and the sIL-6R/IL-6 ratio were explored by ROC curve analysis (Figure 1). Figure 1. ROC analysis comparing sIL-6R (--) and sIL-6R/IL-6 ratio (–). The results indicated an extremely good ability to predict the probability of biopsy Gleason sum upgrading of the two parameters (sIL-6R: AUC=0.80; 95% CI, 0.63-0.97; p=0.026. sIL-6R/IL-6 ratio: AUC=0.84; 95% CI, 0.69-0.98; p=0.014). The optimal cut-off point for sIL-6R was 76.5 ng/ml, providing a sensitivity of 80% and a specificity of 76%, whereas for the sIL-6R/IL-6 ratio the optimal cut-off point was 13.5 with comparable sensitivity (80%), but higher specificity (83%). Discussion and Conclusion: sIL-6R may be a significant circulating biomarker employed to predict GS upgrading in patients with a biopsy GS ≤7. Moreover, this ability appears to be enhanced by calculating the sIL-6R/IL-6 ratio. These findings may provide an additional ‘staging tool’ for PCa patients, which may be of great significance in guiding clinicians’ treatment choices, according to current guidelines. 1 Shariat SF, Andrews B, Kattan MW, Kim J, Wheeler TM and Slawin KM: Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis. Urology 58: 1008-1015, 2001. 2 Spiotto MT and Chung TD: STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells. Prostate 42: 186-195, 2000. 3 Deeble PD, Murphy DJ, Parsons SJ and Cox ME: Interleukin-6-and cyclic AMP-mediated signaling potentiates neuroendocrine differentiation of LNCaP prostate tumor cells. Mol Cell Biol 21: 84718482, 2001.