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The proportion of prostate-specific antigen (PSA) complexed to [[alpha].sub.1]-antichymotrypsin improves the discrimination between prostate cancer and benign prostatic hyperplasia in men with a total PSA of 10 to 30 [micro]g/L.

The diagnostic accuracy of circulating prostate-specific antigen (PSA) [4] for prostate cancer (CaP) is limited because increases are not specific for CaP. Benign conditions of the prostate influence its serum concentration; some patients with benign prostatic hyperplasia (BPH) have increased PSA (1), and many patients with clinically localized CaP do not have increased serum PSA (2). Attempts to improve the diagnostic accuracy of the PSA test include PSA density (3, 4), PSA velocity (5), and age-specific reference intervals (6), none of which has gained wide acceptance.

Active PSA forms complexes in vitro and in vivo with al-antichymotrypsin (a1ACT), [[alpha].sub.2] macroglobulin, protein [[alpha].sub.1] inhibitor, [[alpha].sub.1]-protease inhibitor, and inter-[[alpha].sub.l]-trypsin inhibitor (7-13). Measurement of the proportion of PSA complexed to [[alpha].sub.1]ACT may increase the diagnostic accuracy of PSA testing for early CaP and avoid unnecessary biopsy (7, 8,14). Christensson et al. (15) reported better discrimination using the free-to-total PSA ratio instead of the proportion of PSA complexed to [[alpha].sub.1]ACT. Theoretically, however, the measurement of PSA-[[alpha].sub.1]ACT complex rather than free PSA has potential advantages. The major form of PSA circulating in men with CaP is PSA-[[alpha.sub.1]ACT. Samples with a low total PSA concentration will have minimal amounts of PSA remaining in the free form; thus, free PSA will be more difficult to measure than complexed PSA. Furthermore, in our hands, PSA-[[alpha].sub.1]ACT complex preparations are quite stable, and the imprecision of our assay for PSA-[[alpha].sub.1]ACT (16) is even lower than reported for the free PSA assay (17). A cutoff of 0.80 for the PSA-[[alpha].sub.1]ACT:PSA ratio, rather than a total PSA value of 4 [micro]g/L, increased specificity from 38% to 79% without significantly decreasing sensitivity (82%) in men with total PSA <15 [micro]g/L (14). Moreover, the PSA-[[alpha].sub.1]ACT:PSA ratio in patients with BPH does not vary with age (18), which simplifies its clinical application. In addition, we have reported that neither physiologic changes in total PSA and PSA-[[alpha].sub.1]ACT complex nor the treatment of BPH change the diagnostic efficacy of the PSA-[[alpha].sub.1]ACT:PSA ratio (19).

It is accepted that the use of the free-to-total PSA ratio or the PSA-[[alpha].sub.1]ACT:PSA ratio should be restricted to patients with a total PSA within determined limits (reflex range) (20). Although these limits are variable, patients with total PSA between 4 and 10 [micro]g/L benefit most from the use of these ratios. This is a logical consequence of the predictive value of total PSA for CaP: CaP is unlikely at PSA <3 [micro]g/L, but highly likely at PSA >10 [micro]g/L (21). Nonetheless, previous results suggested that both the PSA-[[alpha].sub.1]ACT:PSA ratio and the free-to-total PSA ratio add diagnostic information even at high PSA concentrations (9,22). These preliminary reports and the optimal results obtained previously by our group, using the PSA-a1ACT: PSA ratio for the detection of CaP in total PSA ranges of 4-10 [micro]g/L (14,16) and <4 [micro]g/L (23), prompted us to evaluate the usefulness of this ratio in patients with high total PSA. In the present study, we analyze a group of patients with total PSA concentrations between 10 and 30 [micro]g/L. The objective was to increase specificity while maintaining sensitivities near 100%.

Materials and Methods

Between January 1995 and May 1998, blood specimens were obtained from 655 consecutive biopsied patients (Caucasian men) before any treatment. All patients had been referred to a urologist for prostatic evaluation in our hospital. A total of 146 patients in whom total PSA was 10-30 [micro]g/L (123 with total PSA between 10 and 20 [micro]g/L, and 23 with total PSA between 20 and 30 [micro]g/L) were included in the study. All patients underwent an ultrasonography-guided needle sextant biopsy, including all suspicious lesions detected by echography. Patients diagnosed with BPH underwent at least two biopsies. On the basis of the histologic analysis, patients were classified as having BPH (n = 66) or CaP (n = 80). The size of the prostate was determined in all CaP and BPH patients by transrectal ultrasonography.

Of the 80 patients with CaP, 69 had a clinically localized tumor, 8 showed clinical signs of extracapsular extension, 2 had bone metastases, and 1 showed affected lymphatic nodules. In 21 patients (26%), tumors were well differentiated (Gleason score, 2-4); in 51 patients (64%), they were moderately differentiated (Gleason score, 5-7); and in 8 patients (10%), tumors were poorly differentiated (Gleason score, 8-10).

All blood samples were obtained between 0800 and 0900 before any manipulation that could alter PSA concentrations. The procedures followed were approved by our institutions Institutional Review Board and were in accordance with the Helsinki Declaration of 1975. All patients gave informed consent. Blood samples were collected by venipuncture in tubes containing 0.13 mol/L sodium citrate (1 part citrate and 9 parts blood by volume) and were stored at 24 [+ or -] 2 [degrees]C for 2-3 h. Each sample was centrifuged at 1500g for 30 min, and the plasma was frozen in aliquots stored at -80 [degrees]C for not more than 6 months and thawed immediately before analysis. Each aliquot was thawed only once.

We measured total PSA and PSA-[[alpha].sub.1]ACT complex in plasma samples, using our ELISAs (14,16). Each test was performed without knowledge of the results of the others. The detection limit of the total PSA assay, defined as the PSA concentration that provided an ELISA signal equal to that of the assay buffer plus 3 SD, was 0.2 [micro]g/L, and the CVs were 4.5-7.4% for intraseries and 6.3-10% for interseries determinations. The detection limit of the PSA[[alpha].sub.l]ACT assay was 0.1 [micro]g/L complexed PSA, and the CVs were 6.8-9.3% for intraseries and 8.7-13% for interseries determinations.

All statistical calculations [Student t-test, Mann-Whitney mean nonparametric U-test, and area under the ROC curve (AUC)] were performed using a computer program for medical statistics (MedCalc software). Unless specified, the values represent the mean [+ or -] SD. P <0.05 was considered statistically significant.

We followed the guidelines for publication on studies of diagnostic accuracy of medical tests (24).

Results

We included in the study all 146 patients with a total PSA of 10-30 [micro]g/L. Of the 123 patients with a PSA between 10 and 20 [micro]g/L, 66 had CaP and 57 had BPH. Of the 23 patients with a PSA between 20 and 30 [micro]g/L, 14 had CaP and 9 had BPH. Analysis of the clinical characteristics of the patients (Table 1) indicated no significant differences in age and total PSA between patients with BPH and those with CaP. Prostate volume was significantly greater in BPH than in CaP patients, whereas the concentration of PSA-[alpha]].sub.1]ACT complex and the PSA-[[alpha.].1ACT:PSA ratio were significantly higher in patients with CaP than in those with BPH.

We used ROC curves to assess the performances of the tests. Results for men with total PSA between 10 and 20 [micro]/L are shown in Fig. 1, and Table 2 shows the sensitivity, specificity, and AUC for several cutoff points of each test. The AUC was significantly larger (P <0.0001) for the PSA-[[alpha].sub.1],ACT:PSA ratio and for PSA-[[alpha].sub.1]ACT complex than for total PSA. A cutoff point of 0.62 would have permitted detection of all 66 patients with CaP and avoided 19% of negative biopsies (11 of 57).

In the subset of patients with a total PSA between 20 and 30 [micro]g/L, the AUC for the PSA-[alpha].sub.1]ACT:PSA ratio (0.980) was even greater than in the subset of patients with a PSA between 10 and 20 [micro]g/L (Table 3) and significantly greater than for total PSA (0.750; P = 0.042). Although the number of patients in this group was small, a cutoff point of 0.64 would have permitted detection of all 14 patients with CaP and avoided 6 of the 9 negative biopsies.

[FIGURE 1 OMITTED]

Discussion

Our results show that a cutoff of 0.62 for the PSA-[[alpha].sub.1]ACT: PSA ratio identified all cases of CaP in the group of men with total PSA between 10 and 20 [micro]g/L and could have prevented biopsies in 11 of the 57 patients with BPH. The diagnostic accuracy was even higher in patients with total PSA between 20 and 30 [micro]g/L. Although the number of patients in this total PSA range is small, the results suggest that the use of a cutoff of 0.64 would have permitted correct diagnosis of the 14 patients with CaP and avoided 6 unnecessary biopsies.

To our knowledge, there is only one report in the literature evaluating the diagnostic accuracy and potential utility of the proportion of PSA complexed to [[alpha].sub.1]ACT in the differentiation between CaP and BPH at high total PSA (9). In this study, the proportion of PSA complexed to [[alpha].sub.1]ACT was higher in CaP than in BPH patients, even in the range of total PSA between 10 and 20 [micro]g/L. However, because the report by Christensson et al. (15) showed better discrimination between CaP and BPH with the free-to-total PSA ratio rather than the PSA-[[alpha].sub.1]ACT:PSA ratio, most laboratories followed their recommendations, and for a few years, the free-to-total PSA ratio was the only marker used. In general, all groups agreed that, compared with total PSA, the free-to-total PSA ratio increases specificity while retaining sensitivity, avoiding a significant number of unnecessary biopsies (25-32). Nevertheless, there are some discrepancies in these studies: e.g., the cutoff point used for the free-to-total PSA ratio in these studies varied between 0.15 and 0.25 and the proportion of unnecessary biopsies that would have been avoided in the different series ranged between 13% and 65%. Some authors have even questioned the clinical utility of the free-to-total PSA ratio (27, 28). These differences have been attributed to differences in study design and the use of different assays. Nevertheless, most authors concur that measurement of the free-to-total PSA ratio should be restricted to patients with a narrow total PSA interval, the reflex range (20), the range with the highest diagnostic efficacy. The lower limit of this range varies between 2 and 4 [micro]g/L, whereas the higher limit ranges from 10 to 20 [micro]g/L, although the most accepted reflex range is 4-10 [micro]g/L. This is a logical consequence of the predictive value of total PSA concentrations because the probability of CaP is low for total PSA concentrations <3-4 [micro]g/L and very high (>50%) for concentrations >10 [micro]/L (21). Nevertheless, Virtanen et al. (22) showed that the free-to-total PSA ratio might also be used to evaluate the need for a biopsy in the total PSA range between 10 and 30 [micro]g/L.

From a theoretical point of view, measuring the PSA[[alpha].sub.l]ACT complex, rather than free PSA, has a potential advantage in test samples with low total PSA. In such samples, only a minimal fraction of PSA is in the free form, with most circulating PSA bound in the PSA-[[alpha].sub.1]ACT complex. Furthermore, in our hands, the PSA-[[alpha.sub.1]ACT complex is quite stable, and the CVs of our assay for PSA-[[alpha].sub.1]ACT (16) are even lower than those usually reported for the free PSA assay. Finally, the use of plasma rather than serum seems to improve the utility of the PSA-[[alpha.sub.1]ACT:PSA ratio in the early detection of CaP (16).

Our assay for PSA-[[alpha.sub.1]ACT complex is methodologically different from that recently described and commercialized. Our assay is a sandwich ELISA that specifically measures the complex between PSA and its major plasma inhibitor, [[alpha.sub.l]ACT, using anti-PSA as the capture antibody and labeled anti-[[alpha.sub.1]ACT as detection antibody. The commercial assay (33) uses a preliminary step to mask all free PSA in the sample and then measures the PSA complexed to any plasma inhibitor, including [[alpha].sub.1]ACT and [[alpha].sub.l]-protease inhibitor. The first reports on the commercial assay showed contradictory results. Brawer et al. (34) claimed that the complexed PSA alone (as measured with the commercial assay) showed a diagnostic efficacy similar to that obtained with the free-to-total PSA ratio, and an even higher efficacy in the total PSA range between 4 and 10 [micro]g/L. However, Stamey and Yemoto (35) found that the commercial complex assay alone did not improve the efficacy of the free-to-total PSA ratio and that it was necessary to use the complexed-to-total PSA ratio to find improvement. The discrepancies may be attributed to differences in the series of patients with respect to prostate volume. In any case, with the commercial complexed PSA assay, the use of either the complexed PSA alone (34) or the complexed-to-total PSA ratio (35) was equivalent to, but did not improve on, the efficacy of the free-to-total PSA ratio. According to a previous report (16), our PSA-[[alpha].sub.1]ACT:PSA ratio showed better diagnostic accuracy than the free-to-total PSA assay, especially in plasma samples. However, it will be necessary to perform further studies to directly compare both complexed PSA assays. It has been reported that PSA-[[alpha].sub.1-protease inhibitor complex, which is detected with the commercial assay but not with our assay for PSA-[[alpha.sub.1]ACT, decreases in CaP, whereas PSA-[[alpha].sub.1]ACT increases (36). This fact may give a theoretical advantage to our PSA-[[alpha].sub.1]ACT complex assay over the commercial complexed PSA assay (36).

It is possible that some of the patients with total PSA >10 [micro]g/L might have undiagnosed CaP. In fact, repeat biopsies increase (15-20%) the detection rate of CaP (37). In the present study, this bias was reduced by the fact that all patients had undergone at least two prostatic biopsies, including the transition zone in the second biopsy.

Prospective studies with larger numbers of participants are necessary to determine whether the PSA[[alpha].sub.l]ACT:PSA ratio is useful to avoid prostatic biopsies in men with total PSA >10 [micro]g/L or whether it may be used as a criterion for rebiopsy. Nevertheless, our results suggest that in men with total PSA between 10 and 30 [micro]g/L, it is possible to establish a reasonably low cutoff point for the PSA-[[alpha].sub.1],ACT:PSA ratio, e.g., 0.7, to avoid rebiopsies in these patients. Only when total PSA or the ratio increases would a rebiopsy be indicated. This work was supported in part by Research Grants 99/1035 and 01/1148 from the Fondo de Investigacion Sanitaria (Madrid, Spain).

Received January 8, 2002; accepted March 22, 2002.

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(32.) Morote J, Raventos CX, Lorente JA, Lopez MA, Encabo G, de Torres I, et al. Comparison of percent free prostate specific antigen and prostate specific density as methods to enhance prostate specific antigen specificity in early prostate detection in men with normal rectal examination and prostate specific antigen between 4.1 and 10 ng/mL. J Urol 1997;158:502-4.

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(35.) Stamey TA, Yemoto CE. Examination of the 3 molecular forms of serum prostate specific antigen for distinguishing negative from positive biopsy: relationship to transition zone volume. J Urol 2000;163:119-25.

(36.) Finne P, Zang WM, Auvinen A, Leinonen J, Maattanen L, Rannikko S, et al. Use of the complex between prostate specific antigen and a1-protease inhibitor for screening prostate cancer. J Urol 2000; 164:1956-60.

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[4] Nonstandard abbreviations: PSA, prostate-specific antigen; CaP, prostate cancer; BPH, benign prostatic hyperplasia; [[alpha].sub.1]ACT, [[alpha.sub.1],-antichymotrypsin; and AUC, area under the ROC curve.

MANUEL MARTINEZ, [1] FRANCISCO ESPANA [2]* MONTSERRAT ROYO [2] JOSE M. ALAPONT, [1] SILVIA NAVARRO, [2] AMPARO ESTELLES [2] JUSTO AZNAR, [3] CESAR D. VERA, [1] and JUAN F. JIMENEZ-CRUZ [1]

[1] Department of Urology, [2] Research Center, and [3] Department of Clinical Pathology, La Fe University Hospital, 46009 Valencia, Spain.

*Address correspondence to this author at: Hospital Universitario La Fe, Centro de Investigaci6n, Avda. Campanar 21, 46009 Valencia, Spain. Fax 34-96-3868718; e-mail espanya-fra@gva.es.
Table 1. Clinical characteristics of 66 patients with BPH
and 80 with Cap (total PSA between 10 and 30 [micro]g/L).

 BPH (a) (n = 66)

Age, years 68.0 (63.7-75.5)
 [68.7 [+ or -] 8.8]
Prostate volume, 57.3 (43.8-75.2)
 mL [65.2 [+ or -] 34.1]
Total PSA, 13.4 (11.9-18.0)
 [micro]g/L (T) [15.5 [+ or -] 5.1]
[PSA-[alpha].sub.1]ACT, 9.6 (8.1-12.0)
 [micro]g/L (C) [10.4 [+ or -] 3.3]
C/T 0.70 (0.62-0.75)
 [0.68 [+ or -] 0.12]

 CaP (a) (n = 80) P

Age, years 70.0 (67.0-75.0) 0.19
 [70.6 [+ or -] 6.6]
Prostate volume, 35.8 (25.3-48.3) <0.0001
 mL [42.8 [+ or -] 30.3]
Total PSA, 15.2 (12.0-18.7) 0.28
 [micro]g/L (T) [16.0 [+ or -] 6.0]
[PSA-[alpha].sub.1]ACT, 13.0 (10.9-16.8) <0.0001
 [micro]g/L (C) [13.9[+ or -] 4.4]
C/T 0.87 (0.81-0.93) <0.0001
 [0.86 [+ or -] 0.09]

(a) Values represent median with the first and third quartiles in
parentheses and mean [+ or -] SD in brackets.

Table 2. Sensitivity, specificity, and AUC for total PSA,
[PSA-[alpha].sub.1]ACT, and complexed-to-total PSA ratio
(C/T) for men with total PSA between 10 and 20 [micro]g/L.

Assay Cutpoint, Pg/L Sensitivity, %

Total PSA, [micro]g/L (T) [greater than 100
 or equal
 to]10
 >10.1 89.4
PSA-a1ACT, [micro]g/L (C) >5.95 100
 >7.22 95.5
 >8.10 89.4
 >8.80 80.3
C/T >0.62 100
 >0.65 95.5
 >0.71 90.2
 >0.76 80.3

Assay Specificity, % AUC (95% CI) (a)

Total PSA, [micro]g/L (T) 0 0.507 (0.415-0.595) (b)
 5.3 P <0.0001
 P <0.0001
PSA-a1ACT, [micro]g/L (C) 8.8 0.710 (0.620-0.785) (c)
 19.3
 28.1
 43.9
C/T 19.3 0.851 (0.773-0.910)
 28.1
 56.3
 73.7

(a) CI, confidence interval.

(b) P <0.0001 for the differences in AUC for total PSA vs
[PSA-[alpha].sub.1]ACT and total PSA vs C/T.

(c) P = 0.01 for the difference in AUC for
[PSA-[alpha].sub.1]ACT vs C/T.

Table 3. Sensitivity, specificity, and AUC for total PSA,
[PSA-[alpha].sub.1]ACT, and complexed-to-total PSA ratio for men
with total PSA between 20 and 30 [micro]ag/L.

Assay Cutpoint Sensitivity, %

Total PSA, [micro]g/L (T) >23.0 100
 >23.7 88.9
PSA-a1ACT, [micro]g/L (C) >16.3 100
 >17.5 92.9
C/T >0.64 100
 >0.75 92.9

Assay Specificity, % AUC (95% CI) (a)

Total PSA, [micro]g/L (T) 50.0 0.750 (0.512-0.893) (b)
 57.1
PSA-a1ACT, [micro]g/L (C) 55.6 0.857 (0.636-0.962) (c)
 66.7
C/T 66.7 0.981 (0.817-0.986)
 100

(a) CI, confidence interval.

(b) P = 0.306 for the difference in AUC for total PSA vs
[PSA-[alpha].sub.1]ACT and 0.042 for total PSA vs C/T.

(c) P = 0.054 for the difference in AUC for
[PSA-[alpha].sub.1]ACT vs C/T.
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Title Annotation:Cancer Diagnostics: Discovery and Clinical Applications
Author:Martinez, Manuel; Espana, Francisco; Royo, Montserrat; Alapont, Jose M.; Navarro, Silvia; Estelles,
Publication:Clinical Chemistry
Article Type:Clinical report
Date:Aug 1, 2002
Words:4555
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