Prostate-specific Antigen Derivatives Research Articles

Kallikreins as Biomarkers for Prostate Cancer

The introduction of testing for prostate-specific antigen (PSA), a member of the fifteen-gene family of kallikrein-related peptidases and also known as kallikrein-related peptidase 3 (KLK3), in blood has revolutionized both the detection and management of prostate cancer. Given the similarities between PSA and other KLK gene family members along with limitations of PSA as a biomarker for prostate cancer mainly in reference to diagnostic specificity, the potential roles of other members of this gene family as well as PSA derivatives and isoforms in the management of prostate cancer have been studied extensively. Of these, approaches to measure distinct molecular forms of PSA (free, intact, complexed PSA, and pro-PSA) combined with kallikrein-related peptidase 2 (KLK2), also known as hK2, have been considered holding particular promise in enhancing the diagnosis of prostate cancer. Recently, an integrated approach of applying a panel of four kallikrein markers has been demonstrated to enhance accuracy in predicting the risk of prostate cancer at biopsy. This review presents an overview of kallikreins, starting with the past and current status of PSA, summarizing published data on the evaluations of various KLKs as biomarkers in the diagnosis, prognostication, and monitoring of prostate cancer.

The Prostate Health Index in predicting initial prostate biopsy outcomes in Asian men with prostate-specific antigen levels of 4–10 ng/mL

To investigate the role of the Prostate Health Index (phi) in prostate cancer (PCa) detection in patients with a prostate-specific antigen (PSA) level of 4-10 ng/mL receiving their first prostatic biopsy in an Asian population. This was a retrospective study of archived serum samples from patients enlisted in our tissue bank. Patients over 50 years old, with PSA level of 4-10 ng/mL, a negative digital rectal examination, and received their first prostatic biopsy between April 2008 and April 2013, were recruited. The serum sample collected before biopsy was retrieved for the measurement of various PSA derivatives and the phi value was calculated for each patient. The performance of these parameters in predicting the prostatic biopsy results was assessed. Two hundred and thirty consecutive patients, with 21 (9.13 %) diagnosed with PCa, were recruited for this study. Statistically significant differences between PCa patients and non-PCa patients were found for total PSA, PSA density, [-2]proPSA (p2PSA), free-to-total PSA ratio (%fPSA), p2PSA-to-free PSA ratio (%p2PSA), and phi. The areas under the curve of the receiver operating characteristic curve for total PSA, PSA density, %fPSA, %p2PSA, and phi were 0.547, 0.634, 0.654, 0.768, and 0.781, respectively. The phi was the best predictor of the prostatic biopsies results. At a sensitivity of 90 %, the use of the phi could have avoided unnecessary biopsies in 104 (45.2 %) patients. Use of the phi could improve the accuracy of PCa detection in patients with an elevated PSA level and thus avoid unnecessary prostatic biopsies.

PSA density: The comeback kid?

After the advent of prostate-specific antigen (PSA) use in prostate cancer detection over 20 years ago, we looked to PSA density (PSAD) to more accurately diagnose cancers by improving the specificity of PSA. PSAD has always struck us as a logical marker and collectively we wanted it to live up to its early promise. To use it clinically, however, we needed to subject our patients to transurethral ultrasound (TRUS) or TRUS biopsy to get some measure of prostate volume. In addition, enough studies failed to clearly show that PSAD could reliably and accurately help us separate cancers from benign disease; PSAD was therefore mostly relegated to the scrapheap of prostate markers and PSA derivatives. More recently, in light of new findings, we are rediscovering PSAD. Several recent papers have demonstrated that PSAD is helpful in predicting Gleason score (GS) upgrading at radical prostatectomy (RP)1,2 and GS upgrading on serial biopsies in men on active surveillance (AS) for apparent low-risk disease.3 Having a low PSAD score has also been shown to be a favourable prognostic variable in men who are candidates for AS.4 In light of this renewed enthusiasm, PSAD is increasingly being evaluated in surgical and AS series. Sfoungaristos and Perimenis retrospectively looked at 285 eligible RP cases performed at their institution over a 10-year period.5 In cases where the pathologist provided the dimensions of the resected gland, the authors determined prostate volume and use the preoperative PSA to calculate PSAD. They found that PSAD was the most important predictor for adverse pathology, including positive margins, extracapsular disease, seminal vesicle invasion and lymph node involvement. Since they did not have preoperative TRUS volumes, they quoted a prior study which showed a strong correlation between TRUS volume and pathological volume. Therefore, they conclude that their study may be used to guide clinical practice when preoperative volumes are actually known.The authors also stated that this lack of TRUS volumes is a limitation of their study. This is certainly true and therefore the findings have limited clinical usefulness. Nonetheless, there are some interesting points for illustration here. This contemporary surgical series shows that PSAD discriminates between low-grade, organ-confined disease and locally advanced, higher grade tumours. This finding may have more relevance in potential AS patients. A recent paper by Corcoran and colleagues demonstrated that PSAD is a very useful predictor of GS upgrading at RP in men with Gleason 6 and 3+4=7 cancers.6 It is in this specific group of mostly low-risk patients where PSAD works best. We clearly need better markers to select men for AS and to predict for worse pathology than what is evident on the initial diagnostic biopsy. To look for unrecognized higher grade disease in our AS patients, we currently perform serial repeat biopsies in the first few years of surveillance. We are coming to understand that some of these occult tumours are located anteriorly and are not accounted for in the biopsy pathology. This also may explain much of the upstaging and upgrading in the accompanying article.5 So, why does PSAD perform better in these surgical and AS series? Part of the answer may lie in the populations being studied. In this month’s article, there is a significant proportion of low Gleason score patients (55% of the series).5 This is obviously true also for AS series. In these populations, the higher PSAD may be caused by the occult tumour volume and grade. It may lose its discriminatory power in the bulkier and initially high-grade tumours, as shown by Corcoran and colleagues.6 So, whereas PSAD has not been helpful in screening and detection, it may have found a new life in today’s AS world of seeking out the unrecognized high-grade tumour. Further study of PSAD’s role in predicting adverse or favourable outcomes in low-risk patients is warranted.

Is there an optimal prostate-specific antigen threshold for prostate biopsy?

Prostate-specific antigen (PSA) remains the best biomarker available for early prostate cancer (PCa) detection. Increasing PSA values are associated with increasing PCa risk. The traditional PSA cut-off of 4 µg/l was lowered because the PCa detection rates are similar in the PSA ranges 2–4 and 4–10 µg/l. This approach increases sensitivity, but also lets the numbers of ‘insignificant cancers’ rise. Thus far, the used PSA cut-offs 2.5, 3 or 4 µg/l provide a reasonable balance between excessive detection rates and the risk of missing relevant PCa. Specificity of PSA has been enhanced by using PSA derivatives, PSA isoforms, new biomarkers and multivariate models. PSA should be used intelligently and several other factors should be considered for a final biopsy decision.

Analysis of Costs of Transrectal Prostate Biopsy

Literature reports mortality and morbidity data from prostatic carcinoma which permit a better use of some routine diagnostic tools such as transrectal ultrasound-guided biopsy. The aim of this work is to quantify the overall cost of transrectal ultrasound biopsy of the prostate (TRUSB) and to assess the economic impact of current procedures for diagnosing prostatic carcinoma. The total cost of TRUSB was calculated with reference to 247 procedures performed in 2008. The following cost factors were evaluated: personnel, materials, maintenance/depreciation of the equipment, energy consumption, and hospital overheads. A literature review was also carried out to check if our extrapolated costs corresponded to those of other authors worldwide, and to consider them in the wider framework of the economic effectiveness of strategies for early diagnosis of cancer of the prostate. The overall cost of TRUSB (8 samples) was EUR 249,000, obtained by adding together the costs of: personnel (EUR 160,000); materials (EUR 59,000); equipment maintenance and depreciation (EUR 12,400); energy consumption (EUR0,1); hospital overheads (EUR 17,500). With extended or saturation biopsies the cost increases for the more time needed by pathologists and can be calculated as EUR 300,000. The literature review points out TRUSB as an invasive tool for diagnosing prostatic carcinoma, clinically and economically controversial. Post-mortem data report the presence of cancer cells in the prostate of 50% of 70-year-old men, while extrapolations calculate a morbidity rate from prostatic carcinoma in 9.5% of 50-year-old men. It is therefore obvious that randomized prostatic biopsies, methods apart, have a good probability of being positive. This probability varies with the patient's age, the level of prostate specific antigen (PSA), the density of PSA/cm3 of prostate volume (PSAD), and the detection by digital exploration and/or positive transrectal ultrasound. CONCLUSIONS. Despite the severe application of all these criteria and the critical assessment of the patient's general conditions, TRUSB is indicated for 16% of the male population over 50 years of age, with obvious economic consequences. Quite recently the clinical utility of assays of PSA derivatives (such as Pro-2PSA) has gained more and more importance. The Pro-2PSA seems to reduce the use of TRUSB.

¿Impacta el criterio para indicar la biopsia prostática sobre su exactitud? Estudio prospectivo llevado a cabo sobre una población de pacientes ambulantes

Introduction Prostate specific antigen (PSA) and digital rectal examination (DRE) are the main tests for initial prostate investigation; there is no consensus about the best criterion for prostate biopsies. We aim to check the accuracy of different criteria in this context including PSA derivatives to detect prostate cancer. Material and methods Four different criteria for indication of prostate biopsy were compared: (A) PSA-density (>15 ng/ ml/ cc); (B) PSA > 2,5ng/ml; (C) PSA-velocity (> 0.7 ng/ ml/ year); (D) free/total PSA ratio (<15%). All biopsies and histopathological examinations were performed by the same urologist and pathologist, respectively. Results The study was performed on 180 consecutive biopsies with 37.7% overall cancer detection rate: 29 (16.1%) performed following criterion A, 42 (23.3%) criterion B, 65 (36.1%) criterion C and 44 (24.4%) criterion D. Based on PSA criteria alone, the predictive positive value (PPV) was 37.9% for criterion A, 33.3% for B, 32.3% for C and 50.0% for criterion D, respectively, (p > 0.05). Associating positive DRE with changed PSA, the PPV increased to 50%, 50%, 43.9% and 68.2% for criteria A, B, C and D, respectively (p > 0.05). In univariate analysis, DRE (positive versus negative), PSA level (>10 ng/ ml versus <4.0 ng/ ml), free/total PSA ratio (<10% versus >15%) and age were associated with PC. In multivariate analysis only positive DRE was associated with prostate cancer. Conclusions All the criteria of PSA derivatives are complementary and useful predictors of cancer risk. However, a positive DRE increased the PPV of PSA derivatives. New tools are needed to improve the accuracy of prostate cancer detection.

Advances in biomarkers for the early diagnosis of prostate cancer

More and more studies have revealed that the level of serum prostate specific antigen(PSA) has little value for early diagnosis of prostate cancer (PCa). For example, negative prostate biopsies are as high as 70%-80% for patients with serum PSA ranging between 4 ng/mL and 10 ng/mL. However, the negative results cannot exclude the existence of cancer. In the studies of the early diagnosis of PCa, investigators focused on seeking biomarkers that have higher sensitivity and specificity. Recently, PSA derivatives, HPC1, PCA3, TMPRSS2: ETS, GSTP1, AMACR, GOLPH2, EPCA, sarcosine, and the combination of multiple biomarkers are widely discussed. In this article, we have reviewed their recent development and the prospective value of the combination of multiple biomarkers, which may be helpful for the early diagnosis and the prognostic monitoring of patients with PCa.

PSA and Beyond: The Past, Present, and Future of Investigative Biomarkers for Prostate Cancer

The discovery of prostate-specific antigen (PSA) as a biomarker represented a major discovery in the early diagnosis and monitoring of prostate cancer. However, the use of PSA is limited by the lack of specificity and an inability to differentiate indolent from life-threatening disease reliably at the time of diagnosis. A multitude of studies have aimed to improve the performance of PSA as well as identify additional biomarkers. The purpose of this study is to review available data on prostate cancer biomarkers for prostate cancer screening and prognostication, including prostatic acid phosphatase, PSA, PSA derivatives (PSA density, free PSA, pro PSA, and PSA kinetics), PCA3, GSTP1, AMACR, and other newly emerging molecular and genetic markers.

What Are Some New Developments in Prostate Cancer Diagnosis?

The purpose of this article is to summarize up-to-date changes and policies in the diagnosis of prostate cancer. The triads of DRE (digital rectal examination), serum PSA (prostate specific antigen), and TRUS (transrectal ultrasound) that directed prostatic biopsy have been considered a gold standard in the early detection of prostate cancer. Even though PSA is a very useful test, its low specificity has made some controversy until now. Moreover, it is not verified whether PSA screening would contribute to the decline in prostate cancer mortality. TRUS directed prostate biopsy also has some criticisms. For example, appropriate number of biopsy core, determination of whether a patient should undergo a repeat biopsy and its timing remain controversial. This article presents guidelines on prostate cancer diagnosis with partial results of randomized controlled trials to verify aforementioned criticisms Since recently published trials show different results regarding the impact of prostate cancer screening on mortality, further analyses are needed to determine the specific parameters for optimal screening (i.e. the age at which screening should begin, re-screening intervals, the age at which screening should be discontinued, and novel screening biomarkers). Unless a new and effective screening biomarker is discovered, PSA will maintain a superlative position for screening of prostate cancer. Hence, we have to find an optimal cut-off value of PSA derivatives for Korean people. With respect to prostate biopsy, current literatures support the use of more extensive biopsy techniques to increase the likelihood of prostate cancer detection.

Derivatives of prostate‐specific antigen as predictors of incidental prostate cancer

OBJECTIVE To search for an optimal derivative of prostate-specific antigen (PSA) identifying patients at risk of incidental prostate cancer. PATIENTS AND METHODS In all, 693 patients who underwent transurethral resection of the prostate (TURP) with a normal digital rectal examination, no history of prostate cancer and a PSA level of 2.5-10 ng/mL were studied. The total PSA (tPSA), percentage of free/total PSA (%fPSA), complexed PSA (cPSA), PSA density, cPSA density and the ratio of fPSA to cPSA were measured. Specificity, sensitivity, positive and negative predictive values were determined for all possible threshold values indicating the risk of incidental prostate cancer (T1a or T1b). Furthermore, the patients were subdivided according to age and the presence of an indwelling transurethral catheter. The areas under the receiver operating characteristic curves (AUC) were compared. RESULTS In the whole sample, the %fPSA was the best test predicting all incidental prostate cancers (AUC 0.618, reference: tPSA 0.494), whereas cPSA density was the best predictor of T1b disease (AUC 0.720, reference: tPSA 0.548). Stratification by age did not meaningfully alter the results, the presence of a transurethral catheter, however, was associated with a superiority of tests based on fPSA (AUC 0.620-0.670) compared with tests based on tPSA or cPSA (AUC 0.421-0.581). CONCLUSION Replacing tPSA by PSA derivatives (%fPSA or cPSA density) and stratifying by the presence of an indwelling transurethral catheter may improve the prediction of the risk of incidental prostate cancer and spare unnecessary biopsies before TURP in the tPSA range 2.5-10 ng/mL.

Editorial Comment on: Prostate-Specific Antigen Kinetics in Clinical Decision-Making During Active Surveillance for Early Prostate Cancer—A Review

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New circulating biomarkers for prostate cancer

The introduction of prostate-specific antigen (PSA) revolutionized prostate cancer (PCa) screening and ushered the PSA era. However, its use as a screening tool remains controversial and changes in the epidemiology of PCa have strongly limited its prognostic role. Therefore, we need novel approaches to improve our ability to detect PCa and foretell the course of the disease. To improve the specificity of total PSA, several approaches based on PSA derivatives have been investigated such as age-specific values, PSA density (PSAD), PSAD of the transition zone, PSA velocity and assessment of various isoforms of PSA. With recent advances in biotechnology such as high-throughput molecular analyses, many potential blood biomarkers have been identified and are currently under investigation. Given the plethora of candidate PCa biomarkers, we have chosen to discuss a select group of candidate blood-based biomarkers including human glandular kallikrein, early prostate cancer antigens, insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBP-2 and IGFBP-3), urokinase plasminogen activation system, transforming growth factor-beta1, interleukin-6, chromogranin A, prostate secretory protein, prostate-specific membrane antigen, PCa-specific autoantibodies and alpha-methylacyl-CoA racemase. While these and other markers have shown promise in early phase studies, no single biomarker is likely to have the appropriate degree of certainty to dictate treatment decisions. Consequently, the future of cancer prognosis may rely on small panels of markers that can accurately predict PCa presence, stage, metastasis, and serve as prognosticators, targets and/or surrogate end points of disease progression and response to therapy.

Prostate-specific antigen and prostate-specific antigen derivatives as predictors of benign prostatic hyperplasia progression

Benign prostatic hyperplasia (BPH) is the most common urologic affliction in aging men, leading to adverse clinical outcomes in a significant proportion of the population. Serum prostate-specific antigen (PSA) has been established as a marker for prostate cancer for the past two decades but more recently has been recognized as an equally important marker of BPH presence and progression. Over this time, the discovery and study of multiple isoforms of PSA have led to even more sensitive and specific methods to differentiate BPH from prostate cancer. Herein we review the expression, processing, and biochemistry of PSA and its derivatives and discuss the potential of these isoforms, both individually and in combination, to serve as determinants of BPH severity and progression.

Prostate-specific antigen and prostate-specific antigen derivatives as predictors of benign prostatic hyperplasia progression

Prostate-specific antigen and prostate-specific antigen derivatives as predictors of benign prostatic hyperplasia progression

Prostate-specific antigen and related isoforms in the diagnosis and management of prostate cancer.

Despite its unparalleled merits for prostate cancer detection and staging, prostate-specific antigen (PSA) is not a marker for prostate cancer only, but also is expressed in benign conditions. For early detection, limitations of PSA are obvious. Its widespread use has led to an extensive amount of expensive and often unnecessary diagnostic procedures associated with significant morbidity. Total PSA derivatives may enhance the accuracy of prostate cancer diagnosis. The ratio of free-to-total PSA improves specificity while maintaining a high sensitivity for prostate cancer detection for men with a total PSA of 2.5 to 10 ng/mL. Human glandular kallikrein also has the potential to be a valuable tool in combination with total and free PSA for early diagnosis of prostate cancer. Complex PSA seems to be a reliable tool to improve specificity at high sensitivity levels in men with suspected prostate cancer (mainly in PSA levels below 4 ng/mL). Newly discovered isoforms of free PSA also may impact early detection of prostate cancer with encouraging preliminary results that warrant further clinical investigation.

Comparison of Total Prostate-Specific Antigen and Derivative Levels in a Screening Population of Black, White, and Korean-American Men

Numerous studies have assessed serum total PSA (tPSA) levels among different races. We extended the serum biomarker profiling using prostate-specific antigen (PSA) derivatives in age-matched screening populations that included white, black, and Korean-American patients. The median ages were 61 years for white and black patients and 63 years for Korean-American patients. Serum samples from 70 men in each ethnic group were analyzed using 3 different tPSA assays (Tosoh AIA 600II, Bayer Immuno-1, Roche Elecsys 2010). The percentage of free PSA (fPSA) was measured directly by Roche Elecsys 2010 immunoassay and then calculated from complexed PSA (cPSA) and tPSA results determined with the Bayer Immuno-1. The percentage of cPSA was determined using cPSA and tPSA assayed by the Immuno-1 method. Statistical analyses included nonparametric Kruskal-Wallis and analysis of variance (ANOVA) evaluations. There were no differences noted in the tPSA values based on ANOVA among the 3 races irrespective of the assay platform methodology employed. Also, the PSA derivatives, percentages of fPSA and cPSA, evaluated using the Kruskal-Wallis test, showed no significant differences for either derivative assayed on 2 different assay platforms among the 3 groups. In a contemporary screening population comparing tPSA, percentage of fPSA, and percentage of cPSA levels in 3 races, there were no significant differences identified among the groups.

Combined use of prostate-specific antigen derivatives decreases the number of unnecessary biopsies to detect prostate cancer.

The authors evaluated the prostate cancer detection rate in Turkish patients with prostate-specific antigen (PSA) levels of 4 ng/ml to 10 ng/ml and who had normal digital rectal examination (DRE) findings. They also aimed to evaluate the value of PSA density and percent free PSA in minimizing unnecessary prostate biopsies for these PSA ranges. This prospective study included 134 consecutive men referred for early prostate cancer detection or lower urinary tract symptoms. All men underwent transrectal ultrasound with systematic sextant needle biopsies. The ability of PSA density and percent free PSA to improve the power of PSA in the detection of prostate cancer was evaluated with statistical analyses as well as receiver operating characteristics curves. Among the 134 men, 124 (92.5%) had a benign histology and 10 (7.5%) had cancer diagnosed on the initial biopsies. Despite the disappointing results in regard to the sensitivity and specificity of PSA derivatives alone, the combination of PSA density and percent free PSA significantly increased the area under the curve compared with the use of each test alone. To increase the specificity of PSA in this patient population, the authors recommend combining two PSA derivatives in deciding whether to perform a biopsy. In a PSA range of 4 ng/ml to 10 ng/ml and with normal DRE, a percent free PSA < 21% and a PSA density > 0.18 yields highest specificity with 90% sensitivity.

The necessity of a second prostate biopsy cannot be predicted by PSA or PSA derivatives (density or free:total ratio) in men with prior negative prostatic biopsies

Serum prostate specific antigen, prostate specific antigen density and free:total prostate specific antigen are known to be useful for determining the risk of prostate cancer in patients undergoing prostate cancer screening. The patient with a positive biopsy presents no future prostate specific antigen dilemma. Those with negative biopsies often go on to numerous repeat biopsies. Our goal was to establish criteria that could be used to identify patients who will require repeat prostate biopsies (possibly false negative initial biopsy), while not exposing the low risk population (probable true negative initial biopsy) to additional invasive procedures. Between March 1991 and March 1998, 148 patients who had a biopsy for an elevated prostate specific antigen value (4.1-10.0) or an altered digital rectal examination, had no cancer found in the specimen. From these, 51 (34.4%) had repeated biopsies, while the others persisted on close follow-up. We examined their serum prostate specific antigen, prostate specific antigen density and free:total prostate specific antigen value, as well as their age and histology results of the initial and repeat biopsy, to determine if any predictor of the need for a repeat biopsy could be identified. Eight (15.7%) from 51 men who had repeat biopsy had prostate cancer detected. Forty three (84.3%) patients persisted with a negative biopsy, despite filling the criteria for re-biopsy. Multivariate analysis failed to identify any significant predictors of prostate cancer in the repeat biopsy group. Despite initial success, the prostate specific antigen derivatives and free:total prostate specific antigen have not safely limited the number of biopsies performed for an abnormal prostate specific antigen (4.1-10.0). Neither prostate specific antigen density nor free:total prostate specific antigen predicted the need for repeat biopsy in this specific group. The results of this ongoing study demonstrate that to date, prostate specific antigen and prostate specific antigen derivatives can not be utilized to determine which patients will be at high risk for requiring repeat prostate biopsy. All patients must be closely monitored for evidence of a change in status from benign to malignant disease, and new markers for this purpose are urgently needed.

Prostate-specific antigen: current status.

Prostate-specific antigen (PSA) is the most important of all tumor markers in that it has significant applications in all aspects of the management of men with prostatic disease. Certainly, the most important utilization of PSA is for the early detection of this most ubiquitous of all human neoplasms. This article reviews the salient features of PSA, with particular emphasis on strategies to improve its utility in the diagnosis of prostate cancer. So-called PSA derivatives--including age-specific PSA, PSA velocity, and PSA density--are discussed. With the recognition of molecular forms of PSA, however, the ratio of free-to-total PSA, and now the complex form of PSA, have been shown to be more specific indicators of the presence of malignancy. Significant public interest and research efforts in prostate cancer have resulted in numerous advances over the past decade. The discovery of PSA and the development of assays to measure it will undoubtedly be recorded as one of the most important advances in the management of men with prostate cancer.