Prostate specific antigen as a clinical biomarker for prostate cancer: what's the take home message?

Prostate specific antigen (PSA) continues to be challenged as a legitimate clinical biomarker in early detection of prostate cancer due to lack of specificity for malignant transformation. Skepticism surrounding the utility of serum PSA as a clinical marker is not new and many questioned its initial use in widespread prostate cancer screening due to non-specific expression and low predictive value for cancer detection. Despite these initial concerns, serum PSA measurement along with digital rectal examination (DRE) is currently the accepted practice for prostate cancer screening in the United States with hundreds of thousands of men undergoing serum PSA measurement annually. In contrast to its role for early detection, serum PSA measurement as a surrogate for prostate cancer recurrence (biochemical failure) following curative intent therapy has consummate clinical utility in post-treatment surveillance. As thousands of men each year are aggressively treated for potentially curable prostate cancer, development of simple and effective diagnostic tools for detecting treatment failures should be an important area of biomedical and clinical investigation. We have constructed and tested a home-based prostate cancer surveillance device for use by patients to detect PSA from blood obtained by finger stick. Our initial results suggest that home based PSA testing is feasible and may have clinical utility in management of men treated for prostate cancer.     

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.     

Screening for prostate cancer

Screening for prostate cancer has shown great promise in its ability to detect prostate cancer at a curable stage; however, significant problems exist with respect to our knowledge of its impact on prostate cancer mortality. For the properly informed patient with at least a 10-year life expectancy, it would seem that early detection efforts utilizing digital rectal examination (DRE) and serum prostate-specific antigen (PSA) determination are beneficial. Considerable controversy abounds about early detection and screening and will continue until definitive proof of decreased prostate cancer mortality as a result of effective early detection and treatment regimens is demonstrated. Until then, all men with at least a 10-year life expectancy should be counseled as to the potential benefits and risks. The salient literature is reviewed and commentary made as to the benefits of screening methods that can be invoked as well as their limitations and potential liabilities.     

PSA and other tissue kallikreins for prostate cancer detection

Prostate cancer is the most common neoplasia of middle-aged men. Prostate specific antigen (PSA) is the first FDA-approved tumour marker for early detection of cancer and it is now in widespread clinical use. The discovery of different PSA molecular forms in serum (free PSA, PSA complexed with various protease inhibitors) in the early 1990s renewed clinical research to enhance the specificity of PSA. Also, the use of a homologous prostate-localised antigen, human glandular kallikrein 2 (KLK2) may further reduce the number of unnecessary prostate biopsies. More recently, promising data is emerging regarding molecular forms of free PSA (proPSA, BPSA, 'intact' PSA) and other members of the expanded human kallikrein family. These new findings may add substantial clinical information for early detection of prostate cancer.     

PCA3: from basic molecular science to the clinical lab

Prostate cancer is the second leading cause of cancer deaths in men in the United States. Use of the serum prostate specific antigen (PSA) test to screen men for prostate cancer since the late 1980s has improved the early detection of prostate cancer, however low specificity of the test translates to numerous false positive results and many unnecessary biopsies. New biomarkers to aid in prostate cancer diagnosis are emerging and prostate cancer gene 3 (PCA3) is one such marker. PCA3 is a noncoding RNA that is highly over-expressed in prostate cancer tissue compared to benign tissue. A non-invasive test for PCA3 was developed using whole urine collected after a digital rectal exam (DRE). Numerous clinical studies have demonstrated the utility of PCA3 for the diagnosis of prostate cancer and some studies suggest that PCA3 may also have prognostic value. The use of PCA3 in combination with serum PSA and other clinical information enhances the diagnostic accuracy of prostate cancer detection and will enable physicians to make more informed decisions with patients at risk for prostate cancer.     

Advances in the application of prostate-specific antigen in the detection of early-stage prostate cancer

Prostate-specific antigen (PSA) has revolutionized the detection of prostate cancer. PSA-based screening has been shown to be effective in detecting prostate cancer at an early, potentially curable stage; however, this tumor marker is limited by appreciable false-positive and false-negative results. This is especially problematic when the PSA level is in the upper limit of normal (2.5 to 4.0 ng/mL) or the intermediately increased range (4.1 to 10.0 ng/mL). Several PSA-related indexes and assays have been proposed in an attempt to improve the power of PSA in the early detection of prostate cancer: PSA density (PSAD), age-referenced PSA, volume-referenced PSA, PSAD of the transition zone (PSA-TZ), ProstAsure Index, (Global Health Net, Savannah, GA) and percent free PSA. These indexes may improve the sensitivity and specificity of PSA-based screening, facilitating the early detection of prostate cancer and reducing the number of unnecessary biopsies.     

Prostate-specific antigen levels in 1695 men without evidence of prostate cancer. Findings of the American Cancer Society National Prostate Cancer Detection Project.

The American Cancer Society National Prostate Cancer Detection Project is a prospective, multidisciplinary, and multicenter trial to assess the potential for early detection of prostate cancer by transrectal ultrasonography (TRUS), digital rectal examination (DRE), and serum prostate-specific antigen assay (PSA). By November 1990, 2805 men between the ages of 55 and 70 years with no known signs or symptoms of prostate cancer were enrolled in the study, which is planned to run for 5 years. Annual TRUS, DRE, and PSA tests were done on these subjects, and biopsies were recommended for suspicious lesions when detected. To study the performance of PSA testing in presumed normal subjects, all men were eliminated who had (1) prostate cancer detected on their initial examinations and proven by biopsy or (2) cancer detected during the year or subsequent examinations. Additionally, all men with TRUS or DRE findings that were interpreted as suspicious for cancer but who are being followed and have not yet had biopsies done were removed from this series. This left a unique, extensively screened group of 1695 men who were free of prostate cancer, as far as could be determined. Analyses of the PSA levels in this large population in the appropriate age range for increasing risk of prostate cancer revealed several important findings. First, there was a direct relationship between serum PSA levels and estimated prostate volume for both the currently available monoclonal and polyclonal PSA assays. Individuals with benign prostatic hyperplasia and larger gland volume have a higher normal limit of PSA than men with normal gland volume. Second, analyses showed no relationship between age and PSA levels or between symptoms of prostatism and PSA levels independent of gland enlargement. It was concluded that volume-adjusted upper limits of normal PSA can be determined for different levels of specificity desired. This information may be applicable to the use of PSA in men not already suspected of having prostate cancer and may increase its effectiveness as a tool for early detection.     

Prostate-specific antigen in clinical practice

Currently, in the United States (US), most prostate cancers are diagnosed through screening with digital rectal examination (DRE) and measurement of serum prostate-specific antigen (PSA). The serum PSA level correlates directly with prostate cancer risk and aggressiveness, as well as the outcomes after treatment. PSA testing is also useful in monitoring patients for tumor recurrence after treatment. PSA testing has limited specificity for prostate cancer detection, and its appropriate clinical application has been the topic of debate. Accordingly, several variations on the PSA measurement have emerged as useful adjuncts for prostate cancer screening. These take into consideration additional factors, such as the proportion of different PSA isoforms (free PSA, complexed PSA, pro-PSA and B PSA), the prostate volume (PSA density), and the rate of change in PSA levels over time (PSA velocity or PSA doubling time). Widespread PSA screening is associated with a 75% reduction in the proportion of men who present with metastatic disease since 1985-89 in the US and a 32.5% reduction in the age-adjusted prostate cancer mortality rate through 2003. The history and evidence underlying each of these parameters are reviewed in the following article.     

Prostate-specific antigen (PSA) best practice policy. American Urological Association (AUA)

Prostate cancer is one of the most common forms of noncutaneous cancer in men in the United States. Despite its prevalence, the natural history of this disease is remarkably heterogeneous. In many patients, the cancer progresses slowly, resulting in moderately or poorly differentiated tumors that remain localized to the prostate gland. Although potentially life-threatening, such cancers are often curable. In other patients, however, tumor growth is rapid and can spread beyond the confines of the prostate. In such cases, the cancer is not curable, and long-term survival is considerably diminished. Strategies for managing prostate cancer have therefore been aimed at early detection and local treatment of the cancer. Prostate-specific antigen (PSA) is a tumor marker currently used for early detection of prostate cancer. Measurement of serum PSA levels has significant clinical application in other areas of prostate disease management. The purpose of this report is to provide current information on the use of PSA testing for: (1) the evaluation of men at risk for prostate cancer, (2) assistance in pretreatment staging, and (3) the posttreatment monitoring and management of men with this disease. The following summary is based on a review of the literature and the expert opinions of a multispecialty panel convened by the American Urological Association (AUA). It is intended to serve as a resource for urologists and primary care physicians.     

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.     

Molecular forms of prostate-specific antigen and human kallikrein 2 as promising tools for early diagnosis of prostate cancer.

Prostate-specific antigen (PSA) is the most useful marker in the early detection of prostate cancer and for the monitoring of patients with this diagnosis. Molecular forms of PSA and also human kallikrein 2 have been used to discriminate between benign prostatic hyperplasia and prostate cancer as well as for the detection of prostate cancer within the gray zone of PSA. In this respect, a literature survey on the diagnostic validity of free PSA (fPSA) related to total PSA (tPSA), PSA bound to alpha1-antichymotrypsin (ACT-PSA), and complexed PSA is given together with our results. The ratio of fPSA:tPSA has been shown to improve the specificity of prostate cancer diagnosis on the basis of tPSA measurements. Unnecessary biopsies can be reduced by about 19-64% in the total PSA range of 4-10 microg/liter while only missing 5-10% of cancers. Furthermore, carcinomas in patients with PSA values <4 microg/liter can be detected, indicating an improved sensitivity because of the percent fPSA at low PSA values. ACT-PSA or complexed PSA alone and the calculated derivatives are not superior in their discriminatory power compared with the percent fPSA. The diagnostic significance of the other molecular PSA forms and human kallikrein 2 needs to be evaluated in more extensive clinical trials.     

Biomarkers for prostate cancer detection

Since its approval by the US FDA in 1986, prostate-specific antigen (PSA) has been employed to monitor men with a diagnosis of prostate cancer. In 1994, PSA was approved for use in prostate cancer screening and has been employed worldwide. However, due to the limited specificity of PSA for the disease, novel biomarkers are needed for detecting prostate cancer and for determining which cancers need to be treated. This review will discuss the development of new biomarkers for prostate cancer detection and disease prognostication, focusing on recent progress and particular topical issues related to the development and validation of these new markers.     

Clinical usefulness of free PSA in early detection of prostate cancer.

OBJECTIVE: Measurement of serum prostate-specific antigen (PSA) is widely used as an aid in early detection of prostate cancer. Most patients with prostate cancer and a PSA level less than 10.0 ng/ml have early-stage disease. Thus, the detection of prostate cancer in its potentially curable stages requires the use of low PSA cutoffs, inevitably leading to many unnecessary biopsies. The combined use of free PSA and total PSA increases specificity of early detection. To develop risk assessment guidelines and a cutoff value of ratio of free (f) to total (t) PSA with a high predictive value for prostate cancer in men to whom the test would be applied in real life practice, a multicenter early detection trial was initiated. PATIENTS AND METHODS: In one week in November 1997, 963 urologists prospectively examined 11,644 men between 45 and 75 years by digital rectal examination (DRE) and prostate-specific antigen with 4.0 ng/ml as cutoff. Data of physical examination were collected by questionnaire. At this time participants were not aware of their PSA values. Suspicious findings were further investigated with sextant biopsy. Prostate volume was determined with transrectal ultrasound (TRUS). Different cutoff levels were correlated to age and detection rate. RESULTS: From1,115 biopsied men, the data of 633 men fulfilled the criteria DRE-negative, TRUS-estimated volume, and PSA 4.0-10.0 ng/ml. In that cohort 91 cancers were detected. Percentage of fPSA was significantly more predictive of cancer than tPSA (p < 0.001). The area under the ROC curve was 0.72 for percent fPSA (% fPSA) and 0.62 for total PSA. The cancer risk nearly doubled using a cutoff of 10% fPSA, the median %PSA level of the detected cancers. A better discrimination of cancer and noncancer especially in the age group above 70 years is possible. Using a cutoff of 16% fPSA increases positive predictive value (PPV) to 25% missing only 4% of cancers. Nearly 45% of the biopsies could be avoided. In the age group 45-69 years, a cutoff of 20% fPSA leads to PPV of 15%, missing 6% of cancers. Unnecessary biopsies could be avoided in 12%. CONCLUSIONS: Using % fPSA in early detection of prostate cancer reduces the number of unnecessary biopsies, especially in men with negative rectal examination in the PSA range of 4.0-10.0 ng/ml. In order to diminish biopsy rate in men 70 years or older a cutoff of 16% fPSA should be used. A cutoff of 20% fPSA in men younger than 70 years is recommended to increase sensitivity in that age group.     

On the use of prostate-specific antigen for screening of prostate cancer in European Randomised Study for Screening of Prostate Cancer

Prostate-specific antigen (PSA) has been the main drive for early detection of prostate cancer (PCa), including in population-based screening as in the European Randomised Study for Screening of Prostate Cancer (ERSPC). The specificity of PSA to indicate men with biopsy detectable prostate cancer can be improved by adding information obtained by new biomarkers, such as PSA isoforms. This improvement is needed to increase the efficacy of the screening procedure for the population-based as well as the individual screening. Various PSA isoforms, kallikreins and molecular markers have been validated in various cohorts from ERSPC of men with and without PCa in order to design the optimal diagnostic procedure for screening asymptomatic men. So far, most promising results have been obtained from the analysis of free PSA, proPSA, nicked PSA and hK2. The use of free PSA in addition to total PSA reduces the number of negative sextant biopsies at a PSA cut-off level of 3 ng/ml at initial screening with 30%, at the cost of losing 10% of detectable cancers that are predominantly well differentiated on histology. Further addition of PSA isoforms and hK2 only improve ROC curves in selected samples by a maximum of 5%. Molecular markers like PCA3 and TMPRSS2 in urine do not appear to be useful but they have been assessed insufficiently so far. The level of PSA at initial screening is highly predictive for the chance of being diagnosed with PCa later on in life. The changes in PSA over time after initial screening (like PSA-velocity and PSA-doubling time) are statistically different between men with detectable cancers versus those without (PSA-doubling time 5.1 versus 6.1 years), but this does not contribute significantly to population-based screening overall. Changes in specificity need to be related to a cost efficacy evaluation in the final analysis of ERSPC.     

Cancer surveillance using registry data: Results and recommendations for the Lithuanian national prostate cancer early detection programme

IntroductionWe describe long term trends in prostate cancer epidemiology in Lithuania, where a national prostate specific antigen (PSA) test based early detection programme has been running since 2006.MethodsWe used population-based cancer registry data, supplemented by information on PSA testing, life expectancy and mortality from Lithuania to examine age-specific prostate cancer incidence, mortality and survival trends among men aged 40+ between 1978 and 2009, as well as life expectancy of screening-eligible men, and the proportion of men with a first PSA test per year since the programme started.ResultsThe number of prostate cancer patients rose from 2.237 in 1990–1994 to 15.294 in 2005–2009. By 2010, around 70% of the eligible population was tested, on average around two times. The early detection programme brought about the highest prostate cancer incidence peaks ever seen in a country to date. Recent incidence and survival rises in the age groups 75–84 suggest PSA testing in the elderly non-eligible population. Life expectancy of men aged 70–74 indicates that less than 30% of patients will live for 15 years and may have a chance to benefit from early detection.ConclusionsEarly detection among men aged 70–74, and particularly among the elderly (75+) may have to be reconsidered. Life expectancy assessment before testing, avoiding a second test among men with low PSA values and increasing the threshold for further evaluation and the screening interval may help reducing harm. Publishing information on treatment modalities, side-effects and patient reported quality of life is recommended.     

Tumor markers in prostate cancer--clinical significance and future prospect of prostate specific antigen (PSA)

Prostate specific antigen (PSA), which has high organ specificity, is an excellent tumor marker that has played a significant role in the diagnosis and treatment of prostate cancer. Screening for prostate cancer using PSA is now widely employed in Japan, and increased detection of cases with organ-confined prostate cancer is hoped to result in a decreased number of cancer-specific deaths. Although PSA has also played a critical role in as a marker for staging, assessment of treatment, and recurrence of prostate cancer, many useless biopsies are performed due to its low cancer specificity. To increase the specificity in prostate cancer detection, PSA-related markers including PSAD (PSAPZD), PSAV, and age-specific PSA were advocated, and the ratio of free PSA to total PSA (% free PSA) is also used in a clinical setting. However, since those markers can not satisfactorily exclude benign prostate diseases, various molecular forms of PSA have been analyzed using proteomics and glycomics. Recently, it was demonstrated that plasma free PSA consisted of precursor PSA (pPSA) and other isoforms, suggesting that [-2] pPSA may be a helpful marker for prostate cancer. Our group reported that a sugar chain structure of PSA in the serum of prostate cancer patients is different from that of patients with benign prostate hyperplasia. The different sugar chain structure of PSA can be easily detected by a conventional method and is expected to be useful for differential diagnosis between malignant and benign prostate diseases.     

Human Kallikrein-2, Prostate Specific Antigen and Free- Prostate Specific Antigen in Combination to Discriminate Prostate Cancer from Benign Diseases in Syrian Patients

Background: The high incidence of prostate cancer as the most common malignancy in males in many countriesraises the question of developing reliable detection tests. The prostate specific antigen (PSA) test is the mostwidely used for screening for prostate cancer; however, its low specificity elevates the number of unnecessarilybiopsies. Serum human kallikrein-2 (hK2) is considered as a promising marker, and especially its ratio to fPSA,for predicting the presence of malignancy to select the best choice referring to biopsy or surveillance. In this study,we investigated the role of hK2 and its combinations with other markers to discriminate prostate cancer frombenign diseases in Syrian patients. Materials and Methods: In this prospective oriented cross-sectional cohortstudy, serum samples were collected from patients referred to many Hospitals in Damascus, Syria, between May2011 and March 2012, and diagnosed with biopsy proven benign prostate hyperplasia (BPH) or prostate cancer(PCa). Serum was analyzed for hK2, PSA and fPSA, and the ratios of fPSA/PSA and hK2/fPSA were calculated.Results: We found that mean hK2/fPSA ratios were significantly higher (P=0.01) in prostate cancer patientsthan in the BPH or control groups. Also the ratio hk2/fPSA gave the largest area under the curve (AUC:0.96)which was significantly larger than for fPSA/PSA (AUC:0.41) indicative of higher specificity. Conclusions: Ourresults demonstrate that the ratio of hK2/fPSA might be superior to the use of fPSA/PSA alone. The hK2 couldbe shown to enhance the early detection of prostate cancer; especially the ratio hK2/fPSA improves specificityand hence may reduce the number of negative biopsies.     

African American men, prostate cancer early detection examination use, and informed decision-making.

It is well known that African American men are more likely to be diagnosed with metastatic prostate cancer than White men. Racial variation in the use of prostate cancer early detection modalities (ie, digital rectal examination [DRE] and prostate-specific antigen [PSA] testing) has been suggested as a major reason for this differential. Several factors may help to explain the reported low levels of DRE and PSA test utilization among African American men, including background sociodemographic characteristics, medical history, and cognitive and psychosocial perceptions. In this review, the impact of these characteristics on prostate cancer early detection examination utilization is explored. Findings from studies showing race-related differences in cognitive and psychosocial factors are presented. Preparatory education for informed decision-making is suggested as an approach to help minimize racial differences in cognitive and psychosocial factors that influence the use of prostate cancer early detection modalities. The need to facilitate informed decision-making along the continuum of care is highlighted.     

Prostate-specific antigen and its related parameters in detecting prostate cancer

Prostate-specific antigen (PSA) is the most useful tumor marker available today. However, its inability to clearly distinguish between prostate cancer and benign prostatic hyperplasia may result in serial and unnecessary prostate biopsies. Various attempts have been made to improve its specificity. PSA-related parameters including PSA density, PSA density for the transition zone, age- or race-specific PSA reference range, PSA velocity, and percent free PSA are the most promising approaches available at present.     

Endoglin (CD105) as a urinary and serum marker of prostate cancer

We have previously shown that endoglin (CD105) is upregulated in prostatic fluid of men with large volume prostate cancer. We chose to assess endoglin levels in urine and serum from men with prostate cancer or at increased risk for the disease: Urine samples were collected after digital rectal examination (DRE) from 99 men whose cancer status was confirmed by biopsy, and serum samples were collected from 20 men without prostate cancer at low risk for the disease and from 69 men diagnosed with prostate cancer that subsequently underwent radical prostatectomy (30 pT2, 39 pT3). Endoglin levels were assessed by ELISA. Urinary endoglin was elevated in men with biopsy‐positive prostate cancer compared to biopsy‐negative men (p = 0.0014). Urinary endoglin levels in men with prostate cancer correlated with radical prostatectomy tumor volume. The area under the receiver operating characteristic (ROC) curve was 0.72 for urinary endoglin and 0.50 for serum prostate‐specific antigen (PSA; sensitivity for cancer detection 73%, specificity 63%). There were no differences in serum endoglin between normal and cancer cases, but there were increases in serum endoglin in non‐organ confined (NOC, pT3+) versus organ‐confined (OC, pT2) cases (p = 0.0004). The area under the ROC curve was 0.75 for serum endoglin and 0.63 for PSA for predicting NOC status, with a sensitivity of 67% and a specificity of 80%. In conclusion, elevations in post‐DRE urinary endoglin suggest there may be value in further studying endoglin as a urinary biomarker of prostate cancer. Endoglin levels in both urine and serum may aid in prostate cancer detection and prognostication. © 2008 Wiley‐Liss, Inc.