Proenzyme psa for the early detection of prostate cancer in the 2.5–4.0 ng/ml total psa range: preliminary analysis

doi:10.1016/S0090-4295(02)02398-1

Urology

Volume 61, Issue 2, February 2003, Pages 274-276

https://doi.org/10.1016/S0090-4295(02)02398-1 Get rights and content

Abstract

Objectives

To determine the clinical utility of using proenzyme prostate-specific antigen (pPSA) for early detection of prostate cancer in the 2.5 to 4.0 ng/mL total PSA range. pPSA, the precursor form of PSA that contains a 7 amino acid leader peptide, and truncated forms such as [−2]pPSA and [−4]pPSA can be measured in serum by research immunoassay.

Methods

Archival serum from 119 men (noncancer, 88; cancer, 31), obtained before biopsy and in the total PSA range of 2.5 to 4.0 ng/mL, were assayed for total PSA, free PSA (fPSA), and pPSA. pPSA was defined as the sum of the [−2], [−4], and [−7] forms, and the percent pPSA (%pPSA) was defined as pPSA/fPSA.

Results

pPSA averaged 4.6% ± 0.4% (SEM) of total PSA and 39.3% ± 3.5% of fPSA. PSA and %fPSA values were similar between the noncancer and cancer groups, and %pPSA tended to be higher in the cancer group (50.1% ± 4.4%) compared with the noncancer group (35.5% ± 6.7%; P = 0.07). Using receiver operating characteristic analysis to assess clinical utility, the area under the curve for %pPSA was 0.688 compared with 0.567 for %fPSA. At a fixed sensitivity of 75%, the specificity was significantly greater for %pPSA at 59% compared with %fPSA at 33% (P <0.0001).

Conclusions

In the 2.5 to 4.0 ng/mL total PSA range, 75% of cancers can potentially be detected with 59% of unnecessary biopsies being spared using %pPSA; use of %fPSA would result in sparing only 33% of unnecessary biopsies. A large prospective clinical trial is needed to confirm these preliminary findings.

Section snippets

Material and methods

In this archival study, specimens were obtained before biopsy from 119 men with total PSA concentrations between 2.5 and 4 ng/mL and a mean age of 60 ± 7.8 years (range 42 to 74). Transrectal ultrasound-guided biopsies were performed with ≥12 cores of prostatic tissue obtained. Of the 119 men, 88 (74%) had no evidence of cancer on histologic examination and 31(26%) had a diagnosis of cancer. Nineteen percent had a suspicious digital rectal examination. The specimens, stored at −80°C, were

Results

In this cohort, pPSA averaged 4.6% ± 0.4% (SEM) of total PSA and 39.3% ± 3.5% of fPSA. As shown in Table I, PSA and %fPSA values were similar between the noncancer and cancer groups, and %pPSA tended to be higher in the cancer group (50.1% ± 4.4%) compared with the noncancer group (35.5% ± 6.7%). The clinical utility of %pPSA was compared with that of %fPSA using receiver operating characteristic analysis (Fig. 1). The area under the curve was 0.688 for %pPSA compared with 0.567 for %fPSA,

Comment

Since the discovery in the mid-1990s10, 11 that PSA in serum was composed of a free uncomplexed form and a form complexed to protease inhibitors such as alpha₁-antichymotrypsin, assays for fPSA have been used in combination with total PSA to improve the clinical utility of total PSA alone. Although investigated for use in the lower PSA ranges,12, 13 %fPSA has been shown to be most useful in the 4 to 10 ng/mL total PSA range in which men with prostate cancer have lower concentrations of free,

Conclusions

In this preliminary study, in the 2.5 to 4 ng/mL total PSA range, 75% of cancers can potentially be detected while sparing 59% of unnecessary biopsies using %pPSA. Using %fPSA would result in sparing only 33% of unnecessary biopsies. A large, prospective, clinical trial should be conducted to confirm these new findings.

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Emerging PSA-based tests to improve screening
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Numerous truncated or clipped forms of proPSA may arise due to the incomplete removal of the 7-amino-acid leader sequence. These and other forms of PSA may be released more freely within the circulation of men with prostate cancer.61–73 It has recently been demonstrated that the levels of [-2] proPSA are higher in prostate cancer than the benign setting and that the use of this biomarker significantly improves the rate of cancer detection compared with using total PSA (tPSA) and the free-to-total PSA ratio.66,74–87
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Citation Excerpt :
In a study of 119 men (88 with no cancer and 31 with cancer), at a fixed sensitivity of 75%, specificity was significantly greater for percentage of proPSA at 59% compared with percentage of fPSA at 33% (P<0.0001), which indicated that 75% of these cancers could potentially be detected using percentage of proPSA and sparing 59% of unnecessary biopsies, whereas the use of percentage of fPSA would result in sparing only 33% of unnecessary biopsies in the 2.5 to 4.0 ng/ml tPSA range. Identification of the cancer samples was also improved by percentage of proPSA in samples with 4 to 10 ng/ml tPSA and percentage of fPSA<15%, with optimal results in the subgroup of patients with percentage of fPSA<15% [32]. Another study on 161 patients enrolled in a cancer early detection biomarker program with a percentage of fPSA less than 15% showed that the ratio of proPSA and BPSA can distinguish cancer with greater accuracy when the percentage of fPSA is very low (<15%), and may, therefore, provide better clinical utility in this lower range of percentage of fPSA [33].
Many aspects of prostate cancer diagnosis and treatment could be greatly advanced with new, effective biomarkers. Prostate-specific antigen (PSA) has multiple weaknesses as a biomarker, such as not distinguishing well between cancer and benign prostatic hyperplasia or between indolent and aggressive cancers, thus leading to overtreatment, especially unnecessary biopsies. PSA also often fails to indicate accurately which patients are responding to a given treatment. Yet PSA is the only prostate cancer biomarker routinely used by urologists. Here, we provide updated information on the most relevant of the other biomarkers currently in use or in development for prostate cancer.
Recent research shows improvement over using PSA alone by comparing total PSA (tPSA) or free PSA (fPSA) with new, related markers, such as prostate cancer antigen (PCA) 3, the individual molecular forms of PSA (proPSA, benign PSA, and intact PSA), and kallikreins other than PSA. Promising results have also been seen with the use of the fusion gene TMPRSS2:ERG and with various forms of the urokinase plasminogen activation receptor. Initially, there were high hopes for early PCA, but those data were not reproducible and thus research on early PCA has been abandoned.
Much work remains to be done before any of these biomarkers are fully validated and accepted. Currently, the only markers discussed in this paper with Food and Drug Administration-approved tests are PCA 3 and an isoform of proPSA, [-2]proPSA. Assays are in development for most of the other biomarkers described in this paper. While the biomarker validation process can be long and filled with obstacles, the rewards will be great—in terms of both patient care and costs to the health care system.
From prostate-specific antigen (PSA) to (-2) pro-prostate-specific antigen and Phi index, evolution of a prostatic biomarker: Emerging role in the management of prostate cancer
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ProPSA, a new biomarker for the detection and management of prostate cancer
2013, Revista del Laboratorio Clinico
La descripción de las nuevas isoformas del PSA libre, como el proPSA, que se asocia a la presencia de cáncer de próstata, ha ampliado las herramientas disponibles para la detección de este tumor. Tras la comercialización de un ensayo para medir [–2] proPSA, una de las fracciones del proPSA, disponemos de datos que avalan el empleo del porcentaje de [–2] proPSA en relación con el PSA libre (%[–2] proPSA) y del prostate health index (phi) que valora conjuntamente [–2] proPSA, PSA libre y PSA total. Los resultados disponibles indican que estos tests permiten reducir el número de biopsias negativas cuando se comparan con el porcentaje del PSA libre. Por otro lado, tanto el %[–2] proPSA como el phi se relacionan con tumores particularmente agresivos, por lo que podrían ser tests útiles para seleccionar qué pacientes podrían beneficiarse de una vigilancia activa y qué pacientes deben ser sometidos a un tratamiento curativo.
The description of new PSA isoforms associated with prostate cancer, such as proPSA, has expanded the available tools for the detection of this tumor. Since the marketing of an assay for the measurement of [–2] proPSA, one of the fractions of proPSA, we have positive data on the use of the percentage of [–2] proPSA in relation to free PSA (%[–2] proPSA) and the prostate health index (phi), which measures [–2] proPSA, total PSA and free PSA together. The available results suggest that the use of these tests would lead to a reduction in the number of negative biopsies compared with the percentage of free PSA. On other hand, both %[–2] proPSA and phi are related to particularly aggressive tumors, so they could be useful to select patients for active surveillance, and to decide which patients must be treated.
The utility of the [−2]pro-prostate-specific antigen level as a prognostic marker in patients with castration-resistant prostate cancer treated with enzalutamide
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^☆: This study was partially supported by Hybritech Beckman Coulter, Inc. and by National Cancer Institute Early Detection Research Network Grant No. CA 8623-02.

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Rapid communicationProenzyme psa for the early detection of prostate cancer in the 2.5–4.0 ng/ml total psa range: preliminary analysis☆

Abstract

Objectives

Methods

Results

Conclusions

Section snippets

Material and methods

Results

Comment

Conclusions

J Urol

Urol Clin North Am

J Urol

Urology

Urology

Urology

Urology

J Urol

Longitudinal screening for prostate cancer with prostate-specific antigen

JAMA

Rapid communication
Proenzyme psa for the early detection of prostate cancer in the 2.5–4.0 ng/ml total psa range: preliminary analysis☆