Human glandular kallikrein 2 levels in serum for discrimination of pathologically organ‐confined from locally‐advanced prostate cancer in total PSA‐levels below 10 ng/ml
Authors: Haese Alexander , Graefen Markus , Steuber Thomas , Becker Charlotte , Pettersson Kim , Piironen Timo , Noldus Joachim , Huland Hartwig , Lilja Hans 
Published: August 2002

Background

We measured serum levels of human glandular kallikrein 2 (hK2) in patients treated with radical retropubic prostatectomy (rrP) for clinically localized prostate cancer (PCa) with a total PSA (tPSA)‐level below 10 ng/ml to investigate whether hK2 can be applied to preoperatively distinguish organ‐confined (pT2a/b) from nonorgan‐confined (≥ pT3a)‐PCa more accurately than total PSA. Further, we evaluated hK2, free‐ and tPSA‐concentrations in all pathologic stages of PCa.

Methods

161 serum samples from men scheduled for rrP were collected 1 day before surgery prior to any prostatic manipulation. Pathologic work‐up revealed ≥ pT3a‐PCa in 48 and pT2a/b‐PCa in 113 patients. HK2‐levels in serum were measured using an immunofluorometric assay with an analytical sensitivity of 0.5 pg/ml, a functional sensitivity of 5 pg/ml and insignificant cross‐reactivity with PSA (< 0.005%). Total (tPSA) and free PSA (fPSA) levels were measured using a commercially available assay from which we calculated %fPSA and an algorithm that combined hK2 and PSA‐levels [hK2] × [tPSA/fPSA]. Means, medians, and ranges were calculated for pT2a/b vs. ≥ pT3a‐PCa and for all pathologic stages. Statistical significance of differences was calculated using Mann–Whitney‐U and Kruskal–Wallis tests. Calculation of receiver‐operator‐characteristic (ROC) curves were performed for hK2, [hK2] × [tPSA/fPSA] and tPSA to compare diagnostic performance.

Results

A mean tPSA level in serum of 6.12 ng/ml in ≥ pT3a‐PCa was not significantly different (P = 0.366) from 5.78 ng/ml in pT2a/b‐PCa. Also, there were no statistically significantly different levels of fPSA (P = 0.947) or %fPSA (0.292) for these two groups. By contrast, mean hK2‐level in pT2a/b‐PCa of 80 pg/ml was significantly different (P = 0.004) from a mean hK2 level of 120 pg/ml in ≥ pT3a‐PCa as shown by Mann–Whitney‐analysis Moreover, the algorithm of [hK2] × [tPSA/fPSA] was significantly lower (P = 0.0004) in pT2a/b‐PCa vs.  ≥ pT3a‐PCa. Calculation of areas under curve (AUC) by receiver‐operator‐characteristics (ROC) demonstrated that the AUC for hK2 (0.64) was larger and the AUC for [hK2] × [tPSA/fPSA] (=0.68) significantly larger (P = 0.007) compared to the AUC of tPSA (0.55).

Furthermore, Kruskal–Wallis Test revealed a highly significant correlation to pathologic stage using hK2 (P = 0.008) and [hK2] × [tPSA/fPSA] (P = 0.0015) compared to no significant differences in serum concentration of tPSA (P = 0.296). Also at tPSA‐levels from 10–20 ng/ml, the hK2‐levels in pT2a/b‐PCa were close to significantly different (P = 0.051) from those in men with  ≥ pT3a‐PCa, while the algorithm of [hK2] × [tPSA/fPSA] in that tPSA‐range was significantly lower (P = 0.002) in pT2a/b‐PCa compared to  ≥ pT3a0‐PCa.

Conclusions

Highly significant differences in serum concentration enable hK2 to be a powerful predictor of organ‐confined disease and pathologic stage of clinically localized prostate cancer, especially in the PSA‐range below 10 ng/ml. As such, there are important clinical consequences for the application of hK2 for the adequate treatment of prostate cancer patients, i.e., the option of nerve‐sparing surgery. Prostate 49:101–109, 2001. © 2001 Wiley‐Liss, Inc.