Tumor Markers: An Update on Human Kallikrein 2

The development and use of prostate-specific antigen (PSA) in the early detection and staging of prostate cancer has revolutionized management of this disease. The limited specificity of PSA at total PSA (tPSA) levels lower than 10 ng/mL, however, leads to increased numbers of unnecessary prostate biopsies, with attendant patient anxiety, cost, and potential morbidity. Human glandular kallikrein 2 (hK2) is a prostate-specific kallikrein (produced by the prostatic epithelium with approximately 80% DNA sequence homology with PSA) that is emerging as a potential adjunct to PSA as a prostate cancer tumor marker.¹ In contrast to PSA, hK2 is a potent protease, with more than 20,000 times the activity of the relatively weak protease PSA. In fact, evidence is increasing that hK2 activates and thus regulates PSA. Some key features of hK2 are summarized in Table 1.

Table 1.

Key Features of Human Kallikrein 2 (hK2)

Gene for hK2 is found adjacent to gene for prostate-specific antigen (PSA) on chromosome 19. Like PSA, hK2 is localized to prostatic epithelium. Like PSA, hK2 exists in multiple forms in serum as free and complexed hK2. hK2 is more than 20,000-fold more enzymatically potent than PSA on appropriate substrates. Unlike PSA, hK2 expression increases as prostate cancers become more undifferentiated. Monoclonal antibodies have been produced to detect hK2; these antibodies have an acceptably low cross-reactivity with PSA.

While PSA production is often decreased in poorly differentiated prostate cancers, hK2 production appears to be increased. This differential production may ultimately be the key to defining the clinical role of hK2. Like PSA, hK2 exists in serum in free (unbound) and complexed (bound) forms. Serum levels of hK2 are much lower than tPSA values in the same patient population, typically ranging from 0% to 10% of PSA levels. These low levels, combined with the molecular similarity of hK2 to PSA, have made reliable assay of hK2 levels relatively difficult. Two groups of investigators have recently tackled the problem of defining the clinical role of hK2 using different techniques, reporting results that raise interest in the potential role of hK2 as a prostate cancer tumor marker.

In Prostatism Patients the Ratio of Human Glandular Kallikrein to Free PSA Improves the Discrimination Between Prostate Cancer and Benign Hyperplasia Within the Diagnostic “Gray Zone” of Total PSA 4 to 10 ng/mL

Kwiatkowski MK, Recker F, Piironen T, et al.

Urology. 1998;52:360–365.

Kwiatkowski and associates studied the role of serum hK2 measurement in prostate cancer detection in men with PSA levels of 4 to 10 ng/mL referred for lower urinary tract symptoms. Of these men, 81 underwent transurethral resection of the prostate and 6 underwent radical prostatectomy. The authors determined PSA, percent free PSA (%fPSA), and hK2 levels. They indirectly measured hK2 levels with an assay that measured both PSA and hK2 by using multiple monoclonal antibodies that blocked PSA measurement. With a cut point set to allow 100% sensitivity, hK2/fPSA had a specificity of 48.2%. With cut points set to provide a sensitivity of 94.4%, hK2/fPSA and %fPSA had specificities of 60% and 28%, respectively.

The investigators concluded that hK2/fPSA offered better specificity for the detection of prostate cancer than did the use of tPSA or %fPSA in the range of 4 to 10 ng/mL. This improvement in specificity did not appear to occur at the expense of decreased sensitivity. It should be noted that this study included relatively few men with prostate cancer and that men with hK2 levels lower than 0.05 ng/mL were excluded.

Use of Human Glandular Kallikrein 2 for the Detection of Prostate Cancer: Preliminary Analysis

Partin AW, Catalona WJ, Finlay JA, et al.

Urology. 1999;54:839–845.

Intrigued by the differences in expression and biologic activity of PSA and hK2, Partin and associates characterized the role of hK2 in the detection of prostate cancer using a prototype assay that uses 2 antibodies against total hK2 (thK2). They analyzed 937 archival serum samples from 922 men with PSA levels greater than 2 ng/mL, all with prostate biopsies revealing either cancer (184 men) or benign prostatic tissue (738 men). Of the men studied, 86% had a benign digital rectal examination (DRE). Median age, PSA level, and thK2 levels were similar, while median %fPSA and thK2/fPSA values differed significantly between men with and without prostate cancer.

Multivariate logistic regression analysis identified %fPSA as the best predictor of the presence of prostate cancer, followed by thK2/fPSA. The investigators constructed cut points of %fPSA and thK2/PSA that stratified patients into prostate cancer risk groups. In men with benign DRE results and tPSA levels of 2 to 4 ng/mL, the use of both %fPSA and thK2/fPSA identified 40% of all cancers while requiring biopsy in only 16.5% of the men. Combining %fPSA and thK2/fPSA was also useful in men with benign DRE results and PSA levels between 4 and 10 ng/mL with an initial negative biopsy. In this population, a thK2/fPSA ratio greater than 0.18 predicted a subset of men at greater risk for harboring cancer, supporting a strategy of repeated biopsy in these men.

In summary, Partin and associates demonstrated the reliability of a direct immunoassay for thK2. Multivariate logistic regression was used to compare the utility of %fPSA and thK2/fPSA in prostate cancer detection. While %fPSA outperformed thK2/fPSA, the information provided by these markers was complementary, allowing the greatest specificity for prostate cancer detection. The use of thK2/fPSA in men with PSA levels of 2 to 4 ng/mL identified 40% of all detectable cancers while sparing biopsy in 83% of men without detectable cancer. The thK2/fPSA ratio also appeared to offer promise in helping counsel men with a prior negative biopsy on the need for subsequent biopsy.