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Articles |
1
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
2
Division of Urologic Surgery, Department of Surgery,
Washington University School of Medicine, St. Louis, MO 63110.
a Address correspondence to this author at: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario, Canada M5G 1X5. Fax 416-586-8628; e-mail ediamandis{at}mtsinai.on.ca
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: We analyzed 206 serum samples (all before treatment was initiated) from men with histologically confirmed benign prostatic hyperplasia (n = 100) or prostatic carcinoma (n = 106) with total PSA in the range of 2.5–10 µg/L. Total and free PSA and hK2 were measured with noncompetitive immunological procedures. Statistical analysis was performed to investigate the potential utility of the various markers or their combinations in discriminating between benign prostatic hyperplasia and prostatic carcinoma.
Results: hK2 concentrations were not statistically different between the two groups of patients. There was a strong positive correlation between hK2 and free PSA in the whole patient population. hK2/free PSA ratio (area under the curve = 0.69) was stronger predictor of prostate cancer than the free/total PSA ratio (area under the curve = 0.64). At 95% specificity, the hK2/free PSA ratio identified 30% of patients with total PSA between 2.5–10 µg/L who had cancer. At 95% specificity, the hK2/free PSA ratio identified 25% of patients with total PSA between 2.5 and 4.5 µg/L who had cancer.
Conclusions: Our data suggest that hK2 in combination with free and total PSA can enhance the biochemical detection of prostate cancer in patients with moderately increased total PSA concentrations. More specifically, the hK2/free PSA ratio appears to be valuable in identifying a subset of patients with total PSA between 2.5 and 4.5 µg/L who have high probability of cancer and who should be considered for biopsy.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To improve the clinical value of PSA, different methods have been
developed, including PSA density (3)(4), PSA
velocity (5), and age-specific reference ranges
(6). Furthermore, it has been shown that measurement of the
different molecular forms of serum PSA (7)(8)
helps to discriminate between CaP and BPH. PSA is present in serum
predominantly bound to proteinase inhibitors
(
1-antichymotrypsin and
2-macroglobulin), but there is also a fraction
of free PSA, an uncomplexed form that is enzymatically inactive. Recent
studies indicate that the free/total PSA ratio in serum is lower in
patients with CaP than in patients with BPH, thus enhancing the
clinical usefulness of PSA testing in CaP screening programs [Scorilas
et al., submitted for publication; and Refs.
(9)(10)(11)(12)(13)].
Human glandular kallikrein (hK2) belongs to the same family of serine proteases as PSA (human kallikrein gene family) and displays a strong structural homology to PSA. Moreover, the two kallikreins share many biochemical properties: they are both primarily localized in the prostate and they are androgen regulated (14). Findings that hK2 cleaves proPSA (244 residues) to generate enzymatically active PSA (237 residues) suggests a physiological role of hK2 in the regulation of PSA (15). These striking similarities led to the investigation of the potential role of hK2 as an additional prostate tumor marker, which may have the potential to enhance the accuracy of diagnosis and prognosis of current PSA testing.
In this study, we measured serum total and free PSA and hK2 in a group of patients with BPH or CaP, in the intermediate range of total PSA of 2.5–10 µg/L. We further analyzed the value of these variables, as well as their various combinations in discriminating between these two clinical entities.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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immunoassays
Concentrations of PSA were measured by the Tandem total PSA and
free PSA monoclonal antibody-based assays (Hybritech) (16).
A new, time-resolved immunofluorometric assay, recently developed in
our laboratory, was used to measure serum hK2 concentrations
(17). Briefly, the hK2 assay uses a mouse monoclonal
anti-hK2 capture antibody [coded G586, supplied by Hybritech (San
Diego, CA) and raised against recombinant hK2], a biotinylated mouse
monoclonal detection antibody (coded 8311; Diagnostic Systems
Laboratories) and alkaline phosphatase-labeled streptavidin. We
measured the alkaline phosphatase activity by adding the substrate
diflunisal phosphate, incubating for 10 min, and then adding a
Tb3+-EDTA developing solution. The fluorescence
was measured on a Cyberfluor 615 Immunoanalyzer (MDS Nordion). The hK2
assay has a detection limit of 0.006 µg/L and has <0.2%
cross-reactivity to PSA. A full description of the method and its
evaluation has been published elsewhere (17).
statistical analysis
Several functions between PSA and hK2 were calculated, and
descriptive statistics for these variables were performed for each
group of patients. Because the distributions of total PSA, free PSA,
and hK2 in the BPH and CaP patients were not gaussian, the analyses of
differences between these variables in the two groups were performed
with the nonparametric Mann–Whitney U-test. Relationships
between different variables were assessed by the Spearman correlation
coefficient. ROC curves were constructed for total PSA and the
free/total PSA and hK2/free PSA ratios, plotting sensitivity vs (1
- specificity), and the areas under the ROC curves (AUCs) were
calculated. Univariate and multivariate unconditional logistic
regression models were developed to evaluate the ability of PSA and hK2
concentrations to predict the presence of CaP. For all analyses,
P <0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Total PSA values were 2.61–9.55 µg/L in BPH patients, with a
mean ± SE of 5.23 ± 0.16 µg/L, and 1.78–10 µg/L in CaP
patients, with a mean ± SE of 4.99 ± 0.17 µg/L. No
statistically significant difference was found in total PSA
concentrations between the two groups of patients. Free PSA
concentrations were 0.31–4.93 µg/L (mean ± SE, 1.03 ±
0.056 µg/L) and 0.15–2.59 µg/L (mean ± SE, 0.78 ±
0.043 µg/L) in patients with benign and malignant prostatic disease,
respectively (P <0.001). The mean ± SE of the
free/total PSA ratio was 0.20 ± 0.008 (range, 0.062–0.53) in
patients with BPH and 0.16 ± 0.007 (range, 0.02–0.41) in
patients with CaP (P <0.001). hK2 was detected in all
samples from BPH patients and ranged from 0.032 to 1.80 µg/L, the
mean ± SE being 0.73 ± 0.043 µg/L. In the CaP patients,
hK2 concentrations were between 0.031 and 2.79 µg/L, with a mean
± SE value of 0.79 ± 0.048 µg/L. The distribution of hK2
values was not different between the two groups of patients. In
general, the concentration of free PSA was lower, whereas the hK2
concentration was slightly increased, in the CaP patients when compared
with the respective values in the BPH patients (Fig. 1
). Several functions between PSA and hK2 (ratios, logarithmic
ratios, differences) were calculated and evaluated for their
discriminatory potential between BPH and CaP (data not shown). We
observed that the hK2/free PSA ratio had good discriminatory power, and
we further pursued its analysis. The mean ± SE value of the
hK2/free PSA ratio was 0.77 ± 0.041 in patients with BPH, whereas
it was 1.18 ± 0.075 in patients with CaP (P <0.001).
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In the group of patients with BPH, we found a strong positive correlation between hK2 and free PSA concentrations (Spearman correlation coefficient rs = 0.512; P <0.001), as well as between hK2 and free/total PSA ratio (rs = 0.413; P <0.001). hK2 and total PSA concentrations also correlated but less strongly (rs = 0.215; P = 0.031). In patients with CaP, a positive correlation between hK2 and free PSA (rs = 0.429; P <0.001), as well as between hK2 and the free/total PSA ratio (rs = 0.372; P <0.001) was also found. On the other hand, there was no significant correlation between hK2 and total PSA. The hK2/free PSA ratio did not correlate with the free/total PSA ratio in the BPH patients, whereas the two ratios showed a negative correlation in the CaP patients (rs = -0.26; P = 0.007).
The distributions of the free/total PSA ratios in the two groups of
patients are presented in Fig. 2
. With a cutoff value of 0.27 (95% sensitivity, 17%
specificity), 17% of biopsies could have been avoided in BPH
patients, whereas 5% of the cancers would have been missed. In Fig. 3
, the distribution of hK2/free PSA ratios in the same population
of patients is shown. At a putative cutoff of 1.5 (95% specificity),
the sensitivity was 30%.
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ROC analyses were performed to show the relative potential of the total PSA concentration and the free/total PSA and hK2/free PSA ratios in the discrimination of CaP and BPH. The free/total PSA ratio [AUC, 0.64; 95% confidence intervals (CI), 0.57–0.72] was significantly more predictive of cancer than total PSA concentration alone (AUC, 0.56; 95% CI, 0.48–0.64), as reported previously (7)(8)(9)(10)(11)(12)(13). Interestingly, the hK2/free PSA ratio is more discriminative between the two clinical conditions (AUC, 0.69; 95% CI, 0.61–0.76). ROC analysis for the hK2/(free/total PSA) ratio showed that this variable also has differentiating power (AUC, 0.67; 95% CI, 0.60–0.74).
Univariate logistic regression models were developed to evaluate the
value of PSA and hK2 concentrations in the discrimination between BPH
and CaP patients (Table 3
). These models demonstrated that patients with high hK2/free
PSA ratios were at increased risk to have CaP (crude odds ratio, 3.44;
95% CI, 1.95–6.05). In the multivariate analysis, the logistic
regression models were adjusted for total PSA, the free/total PSA and
hK2/free PSA ratios, digital rectal examination (DRE), and patient age;
all of these covariates were used as continuous variables, except the
DRE, which was used as a categorical variable. The hK2/free PSA ratio
was an independent factor for discriminating between BPH and CaP
patients (crude odds ratio, 2.93; 95% CI, 1.51–5.71). The free/total
PSA ratio added significantly to the prognostic power of this
multivariate model (crude odds ratio, 0.41; 95% CI, 0.19–0.86; Table 4
).
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To further investigate the discriminatory value of the hK2/free PSA
ratio in relation to the free/total PSA ratio, another logistic
regression model was developed that adjusted for only these two ratios.
This model also confirmed the higher potential of the hK2/free PSA
ratio in discriminating BPH from CaP patients (crude odds ratio for
hK2/free PSA, 3.35; 95% CI, 1.89–5.94; crude odds ratio for
free/total PSA, 0.47; 95% CI, 0.23–0.96). We calculated log
likelihood scores for this multivariate logistic regression model,
which incorporates both of the ratios, for each patient. From these
data, by picking different thresholds for the regression function
values, we devised a ROC curve (Fig. 4
) that shows the added value of using both ratios together in a
multivariate function (AUC, 0.72; 95% CI, 0.65–0.78).
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In Fig. 5
, the distributions of hK2/free PSA ratios in patients with BPH
or CaP and total PSA <4.5 µg/L are presented. At a specificity of
95%, the sensitivity of the ratio in ruling-in cancer was 25%. Among
42 patients who had total PSA <4.5 µg/L and a hK2/free PSA ratio of
1.0, 30 had cancer and 12 had BPH. However, among 42 patients who
have total PSA <4.5 µg/L and a hK2/free PSA ratio <1.0, 19 had CaP
and 23 had BPH.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the current study, we analyzed serum samples from 206 men, 50–75
years of age, with total PSA values of 2.5–10 µg/L. Recently,
Catalona et al. (13) reported that a 25% free PSA cutoff
detected 95% of cancers while avoiding 20% of biopsies in a cohort of
patients with total PSA concentrations of 4.0–10.0 µg/L. This is in
agreement with the data presented here, where at the same sensitivity
(95%), the specificity was 17%, with the free/total PSA ratio being
27% (Fig. 2
). The AUC was significantly higher for the free/total PSA
ratio (0.64) than for total PSA (0.56), confirming the data published
previously (11)(13).
Early studies demonstrated that hK2 is present in serum of patients with increased PSA, suggesting that it may be a new CaP marker (18)(19). Darson et al. (20) found that hK2 expression is tumor associated, in contrast to PSA, which is expressed at higher concentrations in noncancerous prostate cells. Studies are now underway to investigate the molecular form(s) of hK2 that will provide the most useful clinical information with respect to both screening and staging of CaP. Recent data show that the concentration of the precursor form of hK2 (prohK2) is increased in prostatic cancer tissue compared with BPH or healthy tissue (21), as well as in the serum of patients with prostatic disease (22).
In our study, we detected substantial amounts of hK2 in all serum samples. The hK2 absolute concentrations that we report are approximately ninefold higher than values reported previously by others (23). We speculate, as also mentioned elsewhere (24), that these differences may be attributable to standardization and/or to different recognition of hK2 molecular forms by the assays used. We found no statistically significant difference in hK2 values between BPH and CaP patients. A positive correlation between hK2 and free PSA was observed in the whole population of patients. hK2 also correlated with total PSA in patients with BPH, whereas this was not the case in patients with CaP. Our data suggest that hK2 alone cannot discriminate between benign and malignant prostatic diseases in patients with PSA values within the diagnostic gray zone. However, other groups have reported that hK2 concentrations differ significantly between the two groups of patients and that they are not directly proportional to PSA serum concentrations in either BPH or cancer (25). The fact that we have analyzed a selected population of patients (with moderately increased PSA) may account, to some extent, for these differences.
Becker et al. (26) recently reported that the hK2/free PSA
ratio is higher in CaP patients than non-cancer subjects. To examine
the potential clinical utility of this ratio in the discrimination
between BPH and CaP in patients with moderately increased PSA, we
performed statistical analysis of this variable. The results showed
that the hK2/free PSA ratio is significantly higher in a proportion of
CaP patients, suggesting that this ratio may be a potential new
prostatic marker. Of interest is the finding that all BPH patients had
hK2/free PSA ratios below 1.7 (Fig. 3
). We also constructed ROC curves
(Fig. 4
) and performed multivariate analysis to further investigate the
potential of the hK2/free PSA ratio in the differentiation between the
two diseases (Table 4
). This ratio appears to have a greater potential
in discriminating the CaP patients than the free/total PSA ratio.
Furthermore, an additional multivariate logistic regression model was
developed to assess the diagnostic value of these two ratios combined.
The ROC curve derived (Fig. 4
) demonstrates the superiority of using
the combination of the two ratios. This variable seems promising and
may have real clinical merit in the future, after larger clinical
studies establish cutoff values for both ratios.
Among the other functions of hK2 and PSA that we analyzed, the hK2/(free/total PSA) ratio showed a discriminatory efficacy slightly inferior to that of the hK2/free PSA ratio. However, we observed that all patients with hK2/free PSA ratios >1.5 and hK2/(free/total PSA) ratios>7.3 had CaP (data not shown). The combination of these two ratios was able to discriminate 37% of CaP patients with 95% specificity. Therefore, it seems that this concept has the potential to function as a new, valuable marker in the discrimination of CaP patients with moderately increased total PSA ranges.
It is now recommended that all patients with total PSA >10 µg/L and
all patients with total PSA >4 µg/L and a percentage of free PSA
<25% be biopsied (13). Thus, even if the hK2/free PSA
ratio is >1.7 in this group of patients, suggesting that they are very
likely to have cancer (Fig. 3
), they will still be biopsied for
confirmation. Consequently, the number of unnecessary biopsies will not
be reduced if the hK2/free PSA ratio is used in patients with total PSA
>4 µg/L. However, when total PSA is <4 µg/L, biopsy is not
recommended (13). In Fig. 5
we present data supporting the
notion that patients with an increased hK2/free PSA ratio and total PSA
<4.5 µg/L are at a substantially increased risk of having CaP.
Although our data are preliminary and need confirmation, it seems that
these patients with total PSA between 2.5 and 4.5 µg/L who have
hK2/free PSA ratios >1.0 may be good candidates for biopsy because
they have a greater than 35% chance of having cancer (30 patients out
of a total of 84 patients). Of 42 biopsies performed in this group of
patients with total PSA between 2.5 and 4.5 µg/L and hK2/free PSA
ratios >1, 30 (71%) will be diagnosed as cancer. We here draw
attention to the fact that our groups of patients have been selected
and do not represent the distribution of all men in a general
population who have total PSA between 2.5 and 4.5 µg/L. In our
population, 49 of 84 (58%) have cancer, whereas it is known that
the prevalence of cancer in men with total PSA between 2.5 and 4.5
µg/L is ~20% (13).
Kwiatkowski et al. (27) also reported that the hK2/free PSA ratio has a potential discriminatory power in prostatism patients within the diagnostic gray zone of total PSA 4–10 µg/L. In that report, hK2 was determined by an indirect assay, which had a functional sensitivity limit almost 10 times lower than ours. This explains the variations in hK2 concentrations and in hK2/free PSA ratios reported in the two studies. Another difference was the small number of subjects used for the generation of their ROC curves, leading to a possible overestimation of the discriminating power of hK2/free PSA ratio.
In conclusion, we investigated the potential utility of hK2 in the discrimination between CaP and BPH in the total PSA range of 2.5–10 µg/L. We found that in this selected population of patients, hK2 could play a useful diagnostic role, but only in combination with free PSA and free/total PSA ratio. This approach could identify a subgroup of patients with low total PSA (e.g., between 2.5 and 4.5 µg/L) who probably would not be biopsied on the basis of their total PSA alone but who are at high risk of having cancer and should be considered for biopsy. This new diagnostic modality is complementary to the free/total PSA ratio because the former has utility in ruling-in CaP, whereas the latter has utility in ruling-out CaP. Larger multicenter clinical trials, including a greater number of controls, are necessary to further evaluate the use of this new approach in the differential diagnosis of CaP and BPH and to establish putative cutoff values.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer. Cancer Res 1991;51:222-226.
1-antichymotrypsin as an indicator of prostate cancer. J Urol 1993;150:100-105.
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