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Review article

Prostate-specific antigen: An evolving role in diagnosis, monitoring,and treatment evaluation in prostate cancer

Heather Payne, F.R.C.P.a,*, Philip Cornford, M.D.b

a Department of Oncology, UCLH NHS Foundation Trust, London, United Kingdomb Department of Urology, The Royal Liverpool University Hospital, Liverpool, United Kingdom

Received 1 October 2009; received in revised form 29 October 2009; accepted 4 November 2009

Abstract

Prostate specific antigen (PSA) was introduced as a prostate cancer screening tool more than 20 years ago. However, there is continuingdebate regarding its utility in screening for prostate cancer. Mass screening is costly, may result in the diagnosis and treatment of prostatecancers that never become clinically significant, and the evidence of a subsequent reduction in mortality is inconclusive. In addition to itsrole in screening, PSA is also used to monitor the progression of the disease, both localized and metastatic. Although the evidence iscontradictory, PSA is still an important tool for monitoring patient progression following treatment of definitive localized prostate cancer.However, its use in monitoring castrate-resistant prostate cancer (CRPC) is more controversial, particularly in the context of novel targetedtreatments, which may have little impact on PSA levels. These issues highlight the urgent need to identify prostate cancer biomarkers thatwill improve early disease detection, increase accuracy of diagnosis, determine the aggressiveness of disease, and monitor treatmentefficacy, particularly in late-stage disease. This review discusses the key issues associated with the use of PSA as an early screening toolfor prostate cancer, as a prognostic marker to measure disease progression in both early- and late-stage prostate cancer, and as a surrogateendpoint in clinical trials with new agents. © 2011 Elsevier Inc. All rights reserved.

Urologic Oncology: Seminars and Original Investigations 29 (2011) 593–601

Keywords: PSA; Prostate; Cancer; Screening; Prognostic; Biomarker

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1. Introduction

Prostate specific antigen (PSA) is a kallikrein-relatedserine protease that is produced almost exclusively by pros-tate epithelial cells [1]. In normal, healthy prostate tissues,PSA is released at high concentrations into the seminal fluidto liquefy it [2]. PSA was identified in seminal fluid in the1960s [3], and its use as a prostate cancer tumor marker waspostulated in the 1970s when it was isolated from normal,benign hypertrophic, and malignant prostate tissues, but notfrom other human tissues [4]. In the mid 1980s, PSA wasntroduced into clinical medicine as an accurate serumarker of prostate cancer [5]. Although prostate cancer cells

roduce less PSA than normal cells, it is thought that theisruption of the prostate architecture in tumors results inhe leakage of PSA into the blood, which causes serum PSAevels to rise up to 105-fold [1]. However, it should be noted

* Corresponding author. Tel.: �44(0)207 380 9150; fax: �44 (0)207224 5706.

iE-mail address: heather_payne@blueyonder.co.uk (H. Payne).

078-1439/$ – see front matter © 2011 Elsevier Inc. All rights reserved.oi:10.1016/j.urolonc.2009.11.003

hat serum PSA levels are raised not only in prostate cancer,ut also in a number of nonmalignant conditions such asenign prostatic hyperplasia, infection, or chronic inflam-ation [3]. Moreover, other factors such as ejaculation,

rostatic manipulation, body weight, carbohydrate intake,nd insulin resistance can all influence serum PSA levels6]. In addition, because PSA production is itself androgen-ependent, PSA level is a less reliable indicator of diseasetatus in androgen-deficient states.

. PSA as a screening tool

Prostate cancer is the second leading cause of cancer-elated death in men in the Western world, and this diseaseill account for an estimated 25% of newly diagnosed male

ancers in the US in 2009 [7,8]. Therefore, an accuratecreening test for prostate cancer would be invaluable toelp reduce deaths from this disease.

A series of 10 criteria for appraising the validity of acreening program were developed by Wilson and Jungner

n the 1960s (Table 1) [9]. In summary, the criteria state that

594 H. Payne, P. Cornford / Urologic Oncology: Seminars and Original Investigations 29 (2011) 593–601

the target disease process should be a common problem,which has a better outcome when treated at an early stage,and that the screening test employed should be acceptable tothe patient, sufficiently sensitive, specific, and cost effec-tive. Sensitivity (true-positive ratio) is defined as the pro-portion of individuals with the target condition in a popu-lation who are correctly identified by a screening test, andspecificity (true-negative ratio) is defined as the proportionof individuals free of the target condition in a populationwho are correctly identified by a screening test [9].

PSA screening has been deployed in the detection ofprostate cancer for many years. Previously, the majority ofmen with prostate cancer would have presented with meta-static disease. PSA screening has, therefore, resulted in agreater detection of prostate cancers at an early, localizedand, therefore, more curable stage of the disease [10]. Fur-thermore, the use of PSA monitoring to better identify menwho are at increased risk of developing prostate cancer mayalso facilitate the employment of chemopreventive strate-gies. However, PSA screening is controversial, due to thecost of mass screening, verification bias, the overdiagnosis,and overtreatment of cancers that may never assume clinicalsignificance during a patient’s lifetime, and the conflictingevidence of a subsequent reduction in prostate cancer mor-tality [1,3,11]. Overdiagnosis and overtreatment of the dis-ease can incur increased costs, involve unnecessary treat-ment of nonaggressive cancers, and reduce quality of lifedue to treatment side effects and increased anxiety [3].

Before 2009, significant variation existed in PSA screen-ing guidelines, both between the UK and the US, and withinthe US [12–15]. While the 2001 American Cancer Society(ACS) guidelines recommended that a PSA test should beoffered annually, beginning at the age of 50 years, to menwho have a life expectancy of greater than 10 years [13].Following the publication of ongoing PSA screening clinicaltrials in 2009 [16,17], the ACS [18] and other US societies,including the American Urology Association (AUA) [19],National Comprehensive Cancer Network (NCCN) [20], Ameri-can College of Preventative Medicine (ACPM) [21], and the

Table 1Wilson and Jungner disease screening criteria

1. The disease should be an important public health problem2. There should be an effective treatment for patients with the disease3. Facilities for diagnosis and treatment should be available4. There should be a recognized latent or early symptomatic stage of

the disease5. There should be an effective screening technique for the disease6. The screening tests should be acceptable to the population7. The natural history of the condition, including the development

from latent to declared disease, should be adequately understood8. A strategy for determining which patients should and should not

be treated must exist9. The cost of screening and treating of patients should be

economically acceptable10. Screening should be a continuous process

US Department of Health and Human Services [14] have

aligned their guidelines to highlight that the benefits of screen-ing for prostate cancer are uncertain and that the balance ofbenefits and harms cannot be determined. These organizations,therefore, recommend that men should be informed andeducated on the benefits and risks before deciding to un-dergo PSA testing. The UK National Screening Committeerecently initiated a Prostate Cancer Risk Management Pro-gram to enable men to make informed choices about PSAtesting rather than recommend a prostate cancer screeningprogram [15].

2.1. Evaluation of PSA screening in clinical trials

The value of PSA screening for detection of prostatecancer has been questioned following variable outcomesfrom clinical trials evaluating its utility. Some studies havedemonstrated a reduction in prostate cancer mortality as aresult of PSA screening [22,23], whereas others have shownno significant benefit [24,25]. Many of these trials hadmethodological flaws, limiting their ability to impact oncurrent practice. Two ongoing large scale, randomized, con-trolled trials are investigating the value of PSA screeningfor prostate cancer; the European Randomized Study ofScreening for Prostate Cancer (ERSPC) [16] and the Pros-tate, Lung, Colorectal, and Ovarian (PLCO) [17] cancerscreening trial in the US. Initial results from these trialsadded to the uncertainty over the value of PSA screening forthe detection of prostate cancer [11]. The PLCO studyreported no mortality benefit from combined screening withPSA testing and digital rectal examination (DRE) after 7 to10 years of follow-up [17]. It has been argued that this isbecause the majority of men enrolled had previously under-gone PSA testing. In contrast, the ERSPC trial reported thatPSA screening was associated with a 20% relative reductionin prostate cancer mortality at a median follow-up of 9years, resulting in the reduction of about 7 prostate cancerdeaths per 10,000 men screened [16]. However, the mortal-ity benefit came at a cost of overdiagnosis, as the incidenceof prostate cancer in the screened population was signifi-cantly higher than the incidence of men presenting withclinically significant disease. This was compounded as PSAscreening was associated with approximately 76% falsepositive result (i.e., the test was elevated although there wasno evidence of cancer on the biopsy) [17]. The reduction inmortality reported in the ERSPC study is comparable to thatobserved in screening programs for other cancer types butthe risk of false positives appears to be much greater. Thehigh rate of negative biopsy and false positive results indi-cates that PSA alone is clearly not an effective screeningtechnique. A recent review of the effectiveness of breastcancer screening reported that mortality reductions rangefrom 24% to 48% in women who have attended at least 1screen [26]. The risk of a false positive result in breastcancer screening has been assessed in a Scandinavian study,which reported that the risk of a false positive result over 10

screens was up to 22% [27]. Ongoing analyses on quality of

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595H. Payne, P. Cornford / Urologic Oncology: Seminars and Original Investigations 29 (2011) 593–601

life and cost effectiveness from the ERSPC and PLCOscreening trials, along with other large trials, such as theProstate Testing for Cancer and Treatment (PROTECT)trial in the UK [28], are needed to help settle the ongoingPSA screening debate (Table 2). These findings highlightthat not all of the criteria for an effective screening tool,outlined by Wilson and Jungner, are fulfilled by PSA aloneas a marker of prostate cancer.

3. PSA as a marker of prostate cancer diseaseprogression

In addition to the controversy surrounding PSA-basedscreening, there is an ongoing debate on the role of PSA asa prognostic factor in men who have been diagnosed withprostate cancer.

3.1. PSA as a prognostic factor in early-stage prostatecancer

Early-stage prostate cancer tumors are known to secretePSA, which can be used as a biomarker to monitor responseto therapy and disease progression, and can aid treatmentdecisions. PSA levels can be used preoperatively to predictoutcomes after radical prostatectomy. Freedland et al. [29]emonstrated that preoperative PSA levels were signifi-antly related to advanced, high-grade disease and biochem-cal progression. Other groups have shown PSA to be anndependent predictor of all pathologic stages of prostateancer over time [30]. Following therapy for localized pros-ate cancer, PSA levels can be monitored to detect recurrentancer before the tumor would be detectable by any othereans. In particular, the PSA doubling time (PSA-DT) has

een shown to stratify the risk of clinical progression forhose men with a rising PSA after radical treatment [31,32].

These studies demonstrate the predictive value of PSA fol-lowing treatment for early-stage prostate cancer.

Although PSA is useful for monitoring early-stage pros-tate cancer, the treatments administered for this disease canimpact PSA levels. For example, although a steady declinein PSA occurs following radiotherapy, an initial ‘PSAbounce’ is often observed, especially with brachytherapy,which can affect disease monitoring. This transient increasein PSA levels is benign and subsequently drops to ‘pre-bounce’ levels [33]. This phenomenon is thought to occurthrough a combination of the release of PSA as a result ofcell death and/or through the increased release of PSA intothe serum because of altered vascular permeability as aconsequence of inflammation and/or radiation [33].

The majority of men diagnosed with prostate cancer whoelect to be treated with definitive radiotherapy or brachy-therapy will also receive additional neoadjuvant hormonetherapy. Those men with high risk disease will continuewith hormone manipulation in an adjuvant setting for up to

2–3 years. PSA levels are usually suppressed by the time T

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596 H. Payne, P. Cornford / Urologic Oncology: Seminars and Original Investigations 29 (2011) 593–601

radiotherapy commences. However, once hormone therapyis halted, PSA levels will rise due to recovery of the residualnormal prostate tissue. The Phoenix definition of biochem-ical failure following radiotherapy (with or without hor-mone therapy) was developed to determine whether radio-therapy continues to be effective in suppressing the prostatecancer, with biochemical failure determined to be a rise of2 ng/ml above an initial PSA nadir [34].

Hormonal manipulations including androgen deprivationherapy (ADT) result in a lowering of PSA levels, bothhrough tumor regression and via direct suppression of an-rogen-dependent PSA gene transcription [35]. Followinghis initial decrease, PSA levels then stabilize on continuedreatment. The PSA nadir on ADT is thought to be anmportant prognostic parameter and has been associatedith time to androgen-independent progression, clinicalrogression, and death [1]. An increase in PSA levels indi-ates renewed tumor growth as well as reactivation of thendrogen receptor, a common feature of CRPC [1]. CRPC isonfirmed once there is evidence of cancer progressionollowing initial hormone therapy (indicated by PSA ormaging) despite castrate levels of testosterone.

In summary, although concerns exist over the use of PSAs a prognostic marker, and consideration needs to be giveno the impact of prostate cancer treatments, PSA is still anmportant tool for monitoring patient progression followingreatment of definitive localized prostate cancer.

.2. PSA as a prognostic factor in advanced prostateancer

As prostate cancer progresses, the utility of PSA as a prog-ostic factor decreases. The tumor may expand without aoncomitant increase in PSA levels, either because little PSAs being produced (due to tumor cell dedifferentiation forxample) or because PSA production is being suppressed byreatment with antiandrogens. Prostate cancer tumors becomeuch more heterogeneous as the disease progresses, both be-

ween patients and, importantly, within the same patient, lead-ng to variability in tumor PSA expression that could result inalse positive or false negative PSA test results [36].

. PSA as a surrogate marker of prostate cancerisease progression in clinical trials

Surrogate endpoints are commonly used in clinical trialsvaluating the efficacy of new developmental therapies. Aurrogate endpoint should be associated with a clinicallyeaningful outcome, completely encompassing the net ef-

ect of any treatment on that outcome. To confirm surrogacyn patients treated with new vs. standard interventions, thereust be strong correlation between the relative effect of the

reatment on the surrogate and on the true endpoint [37]. Inatients with early-stage prostate cancer, a post-treatment

SA-DT within 3 months of radical prostatectomy or radi-

ation therapy has been suggested to be a surrogate markerfor prostate cancer-specific mortality [38]. In patients with aPSA-DT of less than 3 months following such treatments, ithas been recommended that ADT or alternative novel ap-proaches should be initiated to delay the imminent sequelaof metastatic disease [38]. In contrast, despite extensiveinvestigation of PSA as a surrogate endpoint in a range ofclinical trials in patients with CRPC, the use of a PSA-basedendpoint for overall survival in these patients is currentlyunder scrutiny [39].

4.1. PSA as a surrogate endpoint for survival followingchemotherapy

PSA levels have been measured in studies evaluatingcytotoxic chemotherapy in patients with CRPC with con-flicting results [1,40–43]. For example, in the SWOG99–16 study that compared docetaxel and estramustine withmitoxantrone and prednisone for treatment of advancedCRPC, PSA was demonstrated to be a good surrogate markerfor overall survival as the decline in PSA levels correlated witha significant improvement in overall survival [41]. In contrast,other studies of chemotherapeutic agents have reported PSA tobe a poor surrogate marker for overall survival in patients withCRPC. The phase II ASCENT study comparing DN-101 plusdocetaxel vs. docetaxel alone demonstrated that PSA levelswere a poor surrogate endpoint for survival in patients withCRPC. DN-101 treatment was associated with a significantimprovement in overall survival (median overall survival:DN-101 plus docetaxel, 24.5 months [estimated]; placeboplus docetaxel, 16.4 months; HR 0.67; 95% CI 0.45, 0.97;P � 0.04), but not a significant decline of �50% PSA levels(�50% PSA decline; DN-101 plus docetaxel, 58%; placeboplus docetaxel, 49%; P � 0.16), suggesting no relationshipbetween PSA levels and survival [43]. Furthermore, in theTAX-327 study comparing weekly and 3-weekly schedulesof docetaxel plus prednisone vs. mitoxantrone plus prednisone,a similar decline of �50% PSA was observed with bothdocetaxel regimens, however, this did not translate into animprovement in overall survival in the weekly docetaxel group[42]. A re-analysis of the TAX-327 study did, however, reportthat a �30% decline in PSA (as opposed to the previousanalysis of �50%) within 3 months of chemotherapy initiationwas a moderate surrogate marker for overall survival [40].

4.2. PSA as a surrogate endpoint for survival followingtreatment with targeted agents

PSA response to therapy is dependent on the mechanismof action of the treatment modality. Cytotoxic agents suchas docetaxel directly kill cancer cells, whereas targetedtherapies can exert their effect via cytostatic, antiprolifera-tive, or other nontoxic mechanisms, which may have lessimpact on PSA levels [44]. Clinical trials of novel targetedagents in which PSA has been used as a surrogate marker

for disease progression and overall survival have reported

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597H. Payne, P. Cornford / Urologic Oncology: Seminars and Original Investigations 29 (2011) 593–601

inconsistent PSA responses, even across trials of the samedrug [45,46]. Learnings from a number of recent studies oftargeted agents that have evaluated PSA in patients withCRPC (discussed below) highlight some of these issues.

A phase II trial of the selective endothelin A (ETA)receptor antagonist atrasentan in patients defined as havinghormone-refractory prostate cancer reported no reduction inthe primary endpoint of time to disease progression relativeto placebo. However, a significant improvement in the sec-ondary endpoint of median time to PSA progression wasobserved [45]. Two subsequent phase III trials in the met-astatic and nonmetastatic hormone-refractory prostate can-cer setting failed to meet their primary endpoint of time todisease progression or time to PSA progression [46,47],despite evidence of biological effects on PSA and bone alka-line phosphatase as markers of disease burden [46]. Differ-ences were observed, however, between US and non-US pa-tients in time to disease progression in the nonmetastatichormone-refractory prostate cancer trial, likely due to pre-mature treatment discontinuation [47]. Although PSA levelswere not formally considered indicative of disease progres-sion, the discontinuation rate based on PSA was four timeshigher in US patients [47], thus skewing any true beneficialeffect of the drug. This study also highlights the importanceof patient and physician education on the role of PSA duringthe progression of prostate cancer [48].

A phase II study of zibotentan (ZD4054), a specific ETA

receptor antagonist, in patients with metastatic hormone-resistant prostate cancer (HRPC) showed no significant de-cline in PSA levels despite promising improvement in over-all survival compared with placebo [49]. Based on theseresults and the findings from the atrasentan trials, PSA levelswere not selected as a primary endpoint in the ongoing phaseIII ENTHUSE clinical program investigating zibotentan inpatients with metastatic and non-metastatic HRPC [50].

Discordance between PSA progression and improve-ments in bone scans in the initial part of a 2-stage phase IIstudy of the oral multikinase inhibitor sorafenib led to aprotocol amendment to remove PSA-defined progression asa criterion in the second part of the study [51].

These and other studies with novel agents indicate thatPSA is not consistently useful as a surrogate endpoint inclinical trials of treatments for CRPC. In particular, PSAshould not be regarded as the standard measure to assess thepotential of novel targeted agents for the treatment ofCRPC. This has been discussed by the Prostate CancerClinical Trials Working Group 2 (PCWG2) [52], who haverecently updated the outcome measures for clinical trialsthat evaluate systemic treatment for patients with CRPC.The PCWG2 highlighted that PSA response should not bethe sole criterion for clinical decisions, and in the absence ofother clinical indicators of disease progression, early changesin PSA levels are not sufficient to justify discontinuation ofa study drug. In addition, they recommended that drug evalu-ation pathways specific to the mechanism of action of the drug

should be developed; cytotoxic drug trials should include a

assessments of both control/relieve/eliminate or prevent/delay endpoints, and trials for noncytotoxic agents should bedesigned with prevent/delay endpoints [52]. Indeed, potentialbenefits of this approach were demonstrated when the use ofclinical progression (radiographic or symptomatic) mea-sures safely extended treatment despite PSA progression ina recent exploratory analysis of data from a phase II trial ofdocetaxel, bevacizumab, and thalidomide in patients withmetastatic CRPC. Furthermore, the continuation of treat-ment in this study was associated with improved survivalcompared with discontinuation based solely on PSA pro-gression [53].

5. Novel biomarkers for prostate cancer detection,prognosis, and progression

The limitations of PSA presented in this review demon-strate the need for new biomarkers that are more selectiveand specific for the detection and progression of prostatecancer. Other kallikrein markers such as percentage-freePSA and human glandular kallikrein 2 (hK2) are promisingfor the detection and prognosis of prostate cancer as they aremore specifically associated with malignancy than total PSA[54]. In addition, a number of novel biomarkers are currentlybeing investigated to more accurately diagnose and predictclinical response in prostate cancer (Table 3). These includeserum markers (e.g., circulating tumor cells [CTC] and earlyprostate cancer antigen [EPCA]), tissue markers (e.g.,�-methylacyl coenzyme A racemaster [AMACR]), and urinemarkers (e.g., prostate cancer antigen 3 [PCA3]), which arebriefly described below. An in-depth explanation of thesenovel biomarkers lies beyond the scope of this review; for amore detailed description of these biomarkers, refer to Lin2009 [55] and Makarov et al. 2009 [56]. Ultimately, com-ined analysis of PSA along with novel serum and geneticarkers that are currently being investigated may offer aore effective and individualized method of prostate cancer

iagnosis and prognosis [39].

.1. CTCs

CTCs are cells that have detached from the developingumor into the circulation. Increased numbers of serumTCs have been detected in patients with CRPC, and CTC

evels have been reported to predict survival in these pa-ients [57]. A study by Okegawa et al. demonstrated thatverall survival was significantly increased (P � 0.001) inatients who had less than 5 CTCs per 7.5 ml of bloodompared with those patients who had greater than 5 CTCs57]. In another study investigating the effect of chemother-py in patients with CRPC, CTCs were used to monitorreatment response and predict patient outcome. Thistudy reported that elevated pretreatment CTCs were

ssociated with decreased overall survival [58]. The po-

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598 H. Payne, P. Cornford / Urologic Oncology: Seminars and Original Investigations 29 (2011) 593–601

tential link of CTCs with survival is currently beinginvestigated in trials of the CYP17 enzyme inhibitorabiraterone acetate, where CTCs have been incorporatedas an exploratory endpoint [59].

5.2. EPCA

The EPCA series of proteins identified in prostate cancertissue, but not in benign tissues or benign prostatic hyper-plasia tissues [60], are a promising group of biomarkers forthe early detection of prostate cancer. Immunostaining ofEPCA in human prostate needle cores can differentiate menwith and without prostate cancer by evaluating histologi-cally normal tissues adjacent to areas of benign glands ofprostate cancer tissues [56]. Although it is detected in be-nign tissues, EPCA is potentially more cancer-specific thanPSA. The sensitivity and specificity of EPCA for detectingprostate cancer have been reported to be 84% and 85%,respectively [61]. EPCA-2 is a nuclear structural proteinassociated with prostate cancer. In a study of 385 patientswith a wide variety of cancer (organ confined and non-organdefined prostate cancer, in addition to patients with othercancers) and normal controls, an EPCA-2 serum ELISA wasshown to have 92% specificity and 94% sensitivity fordetecting prostate cancer, whereas in the same group ofpatients the specificity of PSA was only 65%. Furthermore,this study demonstrated promise for this biomarker due tothe high accuracy in differentiating between localized andextracapsular disease (P � 0.0001), which was in contrast

Table 3Novel biomarkers for prostate cancer

Potential marker Des

Circulating tumor cells (CTC) CircEarly prostate cancer antigen (EPCA) NucProstate-specific membrane antigen (PSMA) TypHuman glandular kallikrein 2 (hK2) Prosm/z 7771 UnkTransforming growth factor-�1 (TGF-�1) Mulnterleukin-6 (IL-6) and IL-6 receptors (IL-6R) Mulascular cell adhesion molecule (VCAM) Cellatrix metalloproteinase-2 (MMP-2) Cellone-specific alkaline phosphatase (bALP) Marotal alkaline phosphatase (tALP) Marross-linked C-terminal of type 1 collagen (CTx) Mar-terminal telopeptides of type 1 collagen (ICTP) Marmino-terminal procollagen propeptides of type 1 collagen (PINP) Maroluble ErbB3 (sErbB3) Mar

�-methylacyl coenzyme A racemaster (AMACR) FatDM2 Neg

tui-67 Marrostate cancer antigen 3 (PCA3) Genarcosine N-malgranulin B S-10MPRSS2:ER gene fusions Gen

to PSA (P � 0.05) [62]. P

5.3. AMACR

AMACR is an enzyme involved in fat metabolism, which isstrongly expressed in prostate cancer tissues. AMACR mRNAlevels have been shown to be up-regulated 9-fold in 88% ofprostate cancer tissues compared with normal prostate tissues,and the up-regulation of AMACR protein has been demon-strated to be localized to the peroxisome [63]. A study reportedthat immunohistochemical staining of AMACR had 97% sen-sitivity and 100% specificity for prostate cancer detection from94 needle biopsy specimens [64]. A small study used PCR todetect AMACR from mRNA isolated from urine samplesfollowing prostatic massage. The normalization of AMACRlevels to cellular PSA mRNA levels with a diagnostic cut-offvalue of 2 standard deviations above the mean demonstrated100% specificity (correctly identifying 9/9 noncancerous con-trols) and 70% sensitivity (correctly identifying 7/10 patientswith prostate cancer) for prostate cancer detection [65]. Arecent study of 92 patients (43 with and 49 without prostatecancer) used quantitative RT-PCR to detect AMACR in urinesamples, which demonstrated 70% sensitivity and 71% spec-ificity, and was significantly superior (P � 0.006) to PSA (P �.306) in detecting prostate cancer [66].

.4. PCA3

The PCA3 gene, a noncoding segment of mRNA locatedn chromosome 9, is overexpressed in prostate cancer cellsompared with normal cells. The PCA3 urine diagnostic testas recently developed into an ‘easy-to-use’ standard assay.

Method of detection Potential type of marker

prostate cancer cells Serum marker Diagnostic and prognostictrix protein Serum marker Diagnosticmbrane glycoprotein Serum marker Diagnosticcretary protein Serum marker Diagnostic and prognosticrotein Serum marker Diagnosticonal cytokine Serum marker Diagnosticonal cytokine Serum marker Diagnostic and prognosticon molecule Serum marker Prognosticon molecule Serum marker Prognosticbone turnover Serum marker Prognosticbone turnover Serum marker Prognosticbone turnover Serum marker Prognosticbone turnover Serum marker Prognosticbone turnover Serum marker Prognosticbone turnover Serum marker Prognosticlism enzyme Tissue marker Diagnostic and prognosticgulator of p53ppressor

Tissue marker Prognostic

cellular proliferation Tissue marker Prognosticrker Urine markers Diagnosticerivative of glycine Urine markers Diagnosticum binding protein Urine markers Diagnosticrker Urine markers Diagnostic

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599H. Payne, P. Cornford / Urologic Oncology: Seminars and Original Investigations 29 (2011) 593–601

biopsy based on pre-existing risk factors (n � 70) andhealthy men with no known risk factors (n � 52). This studydemonstrated that PCA3 had 69% and 79% sensitivity andspecificity, respectively, whereas serum PSA demonstratedthe same sensitivity however, it was only 60% specific [67].More recently, a multicenter study of 586 men with a serumPSA level of 3–15 ng/mL used a time-resolved fluores-cence-based variant of the PCA3 test. This study confirmedthe greater specificity of PCA3 compared with PSA, withAUC values of 0.66 and 0.57 for PCA3 and PSA, respec-tively, for predicting a positive biopsy [68].

These biomarkers offer improved sensitivity and speci-ficity for prostate cancer screening. However, the heteroge-neous nature of prostate cancer suggests that a combinationof markers is likely to provide the most accurate, predictivevalue. For example, in one recent study, the combinedanalysis of urinary AMACR and PCA3 improved sensitivityand specificity compared with either test alone [66]. Cur-rently, the cost of screening with novel biomarkers com-pares disadvantageously with the cost of screening withPSA. For example, in the UK a PSA test costs up to £30[69] whereas tests for PCA3 and CTCs can cost as much as£400 [70] and £150 [71], respectively. However, if the useof novel biomarkers can increase the sensitivity and speci-ficity of prostate cancer detection, the need for costly biop-sies and unnecessary treatments could be reduced.

6. Conclusions

Controversy persists regarding the use of PSA as a screen-ing tool to detect prostate cancer. Given the uncertain risk:benefit outcomes of early PSA testing, many guidelines nowhighlight the need for men to be well informed and welleducated on the benefits and risks of the PSA test beforedeciding to undergo screening. Further analysis of the ERSPCand PLCO trials, along with the results of other ongoing largetrials such as PROTECT should help clarify the utility of PSAas a large scale screening tool for the detection of prostatecancer. PSA does currently play a role as a prognostic tool forearly-stage prostate cancer, but is less reliable in late-stagedisease where it should be employed with other prognostictests. The highly variable PSA responses in clinical trials ofnovel targeted agents for the treatment of CRPC suggest thatPSA levels are not a reliable surrogate endpoint in this setting.New biomarkers are being identified although more research isneeded to validate these as markers for use in the diagnosis andmonitoring of disease progression, and as surrogate endpointsin clinical trials.

Acknowledgments

The authors thank Dr. Claire Routley, from Mudskipper,

who provided editorial assistance funded by AstraZeneca.

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