and Prostatic Diseases (2008) 11, 112–120 & 2008 Nature Publishing Group All rights reserved 1365-7852/08 $30.00 www.nature.com/pcan REVIEW

New circulating biomarkers for

K Bensalah, Y Lotan, JA Karam and SF Shariat Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA

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-b1, interleukin-6, chromogranin A, prostate secretory protein, prostate-specific membrane antigen, PCa-specific autoantibodies and a-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, , and serve as prognosticators, targets and/or surrogate end points of disease progression and response to therapy. Prostate Cancer and Prostatic Diseases (2008) 11, 112–120; doi:10.1038/sj.pcan.4501026; published online 13 November 2007

Keywords: biomarker; prostate-specific antigen; prognosis; detection

Introduction remains an important prognostic marker among men with PCa.4 Prostate cancer (PCa) is the most frequently diagnosed The first and most important concern regarding the cancer among men in the United States, with a lifetime use of PSA is the lack of cancer specificity. A rise of prevalence of one in six men.1 PCa displays a range of the PSA level can reflect the presence of cancerous cells clinical behavior, from a slow-growing tumor of no but can also be related to nonmalignant disorders such as clinical significance to aggressively metastatic and lethal benign prostatic (BPH), infection or chronic disease. The introduction of prostate-specific antigen inflammation. All types of prostatic cells, whether (PSA) revolutionized PCa screening and ushered the normal, hyperplastic or cancerous, synthesize PSA, with PSA era. This has resulted in earlier PCa detection and highest levels found in the transitional zone of the an increase in incidence. However, its use as a screening prostate. Neoplastic cells produce lower levels of PSA tool remains controversial due to questions regarding compared to BPH cells but deliver a greater amount of survival benefit, cost effectiveness and clinical factors PSA into the blood stream, presumably because of the such as the optimal age and total PSA at which to disordered architecture of PCa. Therefore, it has been recommend .2 Recently, Thompson et al.3 showed suggested that total PSA should be considered as a that there is no true PSA cutoff point for identifying significant marker of BPH-related prostate volume, PCa risk in that there are a significant number of men growth and outcome rather than a reliable marker with PSA values o4.0 ng mlÀ1 who actually have PCa. In of PCa.5–7 addition to the controversy surrounding PSA-based Changes in the epidemiology of PCa have strongly screening, there is considerable debate whether PSA limited the correlation between total PSA and the stage of PCa.8–10 PSA can no longer be considered as a classical tumor marker whose levels are directly correlated with increasing stage of the disease. Moreover, the relation- Correspondence: Dr SF Shariat, Department of Urology, University of ship with tumor grade remains unclear since it has been Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, suggested that total PSA expression decreases with Dallas, TX 75390-9110, USA. higher Gleason scores.11,12 Classical prognostic tools E-mail: [email protected] 13 Received 30 July 2007; revised 1 October 2007; accepted 16 October based on pretreatment PSA levels, such as Partin tables 14–16 2007; published online 13 November 2007 and Kattan nomograms have become less reliable Novel blood biomarkers for prostate cancer K Bensalah et al because of the continuous shift toward earlier stages of higher upper normal limit may be used for older men.21 113 the disease at diagnosis. Consequently, the upper limit This modification is meant to improve cancer detection of normality of 4.0 ng mlÀ1, that was set in initial studies, (improve sensitivity) in younger men and decrease the may no longer be optimal since it has been proven that a rate of ‘unnecessary’ (increase specificity) in significant number of remained undetected in older men. However, Bassler et al.22 reported a significant patients with PSA levels below this cutoff point.3,17 loss in sensitivity when the upper limit was increased to Initial reports suggested that men with a slightly 4.5 ng mlÀ1 in men aged 60–69 years. Moreover, Etzioni ‘abnormal’ value (4.0–9.9 ng mlÀ1) had a 22% chance et al.23 found a lower diagnostic accuracy when using of having PCa, and those with a significant rise age-adjusted PSA compared to the normal cutoff of of 410.0 ng mlÀ1 had a 67% risk.18 However, it became 4.0 ng mlÀ1. Thus, the utility of age-specific PSA values quickly clear that these relative risks were in context of a remains controversial. sextant biopsy technique fraught with a high false- negative detection rate, and that the risk of harboring PCa in men with a PSA level above 4.0 was approxi- PSA density mately twice as likely, in the 40–50% range.19 Multiple The calculation of PSAD takes into account the volume of studies have now demonstrated that significant numbers the prostate gland, since it is well established that men of men with ‘normal’ PSA values harbor PCa. The most with larger have higher PSA levels. In theory, definitive was the Prostate Trial, selectively performing a biopsy in men with a higher which determined that there is no PSA level below PSAD would increase the specificity in case of a large which PCa can be ruled out, and no cutoff above which prostate and the sensitivity in case of a small gland. PCa can be assured.20 As a result, it is now clear that men While some studies reported that men with PCa had with PSA values below the artificial 4.0 cutoff are higher PSAD than men with BPH, thereby,24,25 other inaccurately categorized as being normal, and those studies did not confirm these results.26,27 In healthy men, above the cutoff are mischaracterized as being abnormal. most of the serum PSA originates from the transition Moreover, PSA levels in men that have undergone prior zone (TZ) epithelium. In addition, BPH occurs in the TZ treatment for PCa are completely independent of the that in itself is an infrequent site of adenocarcinoma. For reference ranges in widespread laboratory use, making this reason, some authors considered the PSAD-TZ as a such references and thresholds even more meaningless better alternative to PSAD.28 Nevertheless, because of the in this setting. need for transrectal ultrasound to accurately measure Therefore, clinicians and researchers are still on a quest volume, the assessment of PSAD and PSAD-TZ is for novel approaches to improve our ability to detect PCa cumbersome, costly and uncertain as volume results and foretell the course of the disease. New therapeutics, may vary. As such PSAD and PSAD-TZ are not routinely such as chemoprevention, gene therapy and adjuvant used for the screening of PCa, although they may be therapies, will need a more reliable set of markers for useful when considering a repeat biopsy. their development. Because the most useful clinical biomarkers will likely be those that can be assayed from blood, there is much interest in proteomics, which has PSA velocity recently emerged as a promising tool to better under- PSA velocity refers to the serial evaluation of serum PSA stand systems biology. In that setting, many potential concentration over time. Carter et al.29 were the first to PCa blood biomarkers have been identified and are report longitudinal changes in PSA in 1992. Based on a currently under investigation. In this review, we discuss population of PCa, BPH and healthy subjects, they found the importance of molecular forms of PSA and other that a PSAV greater than 0.75 ng mlÀ1 per year was promising candidate blood markers in the management significantly associated with cancer. This PSAV cutoff of PCa. was mainly useful in patients with a PSA level between 4 and 10 ng mlÀ1, yielding specificity greater than 90%. If the initial PSA serum concentration was below 4 ng mlÀ1, the sensitivity became too low for a reliable testing, and Can we improve PCa screening to date, appropriate cutoffs have not been determined. performance with PSA derivatives? The use of PSAV is also limited by physiological 30 À1 fluctuations in PSA concentrations in an individual A PSA above 4 ng ml is not systematically associated and by differences among available PSA assays.31 with cancer. A major concern is to enhance the specificity Infection and chronic inflammation can also be of the test to rule out patients without cancer and confounding factors as they can cause significant avoid unnecessary biopsies. For that purpose, several increases in PSA. It is therefore recommended that a approaches based on PSA derivatives have been inves- minimum of three consecutive PSA measurements tigated including age-specific values, PSA density should be made over a 2-year period.32 More recent (PSAD), PSA density of the transition zone (PSAD-TZ), studies evaluated the PSA velocity prior to PCa treatment PSA velocity and assessment of various isoforms of PSA. to predict tumor stage, grade and time to recurrence after radical . D’Amico and associates33 re- ported significantly shorter time to PSA relapse and Age-adjusted PSA death from PCa in patients with a pretreatment annual The rationale for adjusting PSA levels with the age of the PSA velocity of more than 2.0 ng mlÀ1 among 1054 patient is that PSA correlates linearly with prostate size patients who underwent radical prostatectomy for and the prostate grows with age. Based on this approach, localized PCa. Other studies confirmed that annual a lower cutoff should be used in younger men whereas a PSA velocity prior to diagnosis is a promising approach

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114 to identify candidates who may not benefit from local findings, Shariat et al.9 reported that lower preoperative therapy.34,35 free PSA is an independent predictor of advanced pathologic features and aggressive disease progression in 402 consecutive men treated with radical prostatect- Molecular isoforms of PSA omy and with a PSA less than 10 ng mlÀ1. In contrast, One of the most promising approaches to improve the Graefen43 failed to detect an independent association diagnostic accuracy of the PSA test, especially below between free PSA level and biochemical recurrence in 10 ng mlÀ1, relies on the measurement of different 581 unscreened patients with localized PCa. molecular isoforms of the PSA in the serum, including free (unbound to proteins) and complexed (bound to protease inhibitors) PSA. Free PSA isoforms Approximately 75% of serum PSA is bound to a-1- There are three distinct forms of free PSA in the serum: antichymotropsin to form an inactive enzymatic complex BPH-associated PSA (BPSA), pro-PSA and intact free (PSA–ACT). PSA is also bound to other protease PSA.44 BPSA is produced from the cleavage of amino- inhibitors, although in smaller proportions: 1–2% of total acid residues from intact free PSA. It can be found in the PSA forms a complex with a-1-proteinase inhibitor prostate, blood and semen.44 BPSA seems to be a (PSA–API, also called a-1-antitrypsin) and 5–10% occurs promising marker of BPH since it has shown a direct in complex with a-2-macroglobulin (PSA–A2M). Con- association between its secretion and the volume of the centration of PSA–API is difficult to quantify because its TZ.45 In healthy men, BPSA is undetectable. As such, serum level is very low. PSA–A2M cannot be detected by BPSA is a better predictor of prostate enlargement than conventional immunoassays because of chemical inter- total and free PSA.46 In addition, BPSA is not affected by actions between A2M and PSA epitopes that are targeted age and is significantly higher in the presence of BPH by antibodies used in available commercial PSA assays. symptoms. PSA–ACT and PSA–API are both detected by standard PSA is synthesized as an inactive pro-PSA form that is assays. However, complexed PSA (which comprises both activated by human glandular kallikrein 2 (hK2) upon PSA–ACT and PSA–API) is of poor utility in clinical removal of a short peptide sequence.44 Cancerous prostate practice since PSA–ACT increases whereas PSA–API cells contain higher levels of truncated forms of pro-PSA 36–38 decreases in PCa patients. Complexed PSA is either with remaining amino acids that should have been determined by specific immunoassays or calculated by removed during the activation process. Several studies subtracting free PSA from total PSA. One study suggests have reported interesting results on pro-PSA in PCa. Sokoll that complexed PSA may slightly enhance perfor- and Catalona found that the percentage of pro-PSA could 39 mance in early detection of PCa. However, its diag- significantly decrease the number of unnecessary biopsies nostic superiority over free PSA is not yet established inmenwithaPSAbetween2and4ngmlÀ1.47,48 Moreover, 40 and warrants further investigation. 2-pro-PSA, a truncated form of pro-PSA, had the highest The remainder of total PSA exists as a free, non- specificity for PCa screening and was the most efficient complexed and enzymatically inactive form (free PSA). predictor of PCa aggressiveness.49 41,42 Catalona et al. initially reported that the measure of Intact free PSA is similar to native PSA, but enzyma- the percentage of free PSA ((free PSA/total PSA) Â 100) tically inactive. Nurmikko et al.50 developed an assay to could improve the diagnostic accuracy of the PSA test in measure intact free PSA and found no associated À1 men with a PSA level between 4 and 10 ng ml . They increase in men with PCa although the ratio to free found that with a free PSA greater than 25%, only 8% of PSA was significantly higher (higher than what?). patients had PCa on biopsy whereas if the free PSA was less than 10%, 56% of the men were diagnosed with PCa. On the basis of these findings, in 1998 the FDA (Food and Drug Administration) approved the use of free PSA as an Novel biomarkers for PCa detection and adjunct to total PSA for PCa screening. More recently, the prognostication same team focused on the value of free PSA in the subset of patients with a PSA between 2.5 and 4 ng mlÀ1 and In summary, this review of shortcomings of PSA and its determined that using a free PSA cutoff of 27%, they derivatives highlights the need for more specific and were able to obtain a sensitivity of 90% and avoid 18% of sensitive biomarkers for the diagnosis of PCa, particu- unnecessary biopsies in men older than 50. In their study, larly markers that could predict the behavior of a tumor 83% of the diagnosed cancers were significant. Never- in an individual patient to avoid over treatment of PCa. theless, while it is now recognized that free PSA can Among all previously discussed PSA derivatives, free improve the diagnostic accuracy of total PSA in patients PSA is the only one that is currently commonly used in with a PSA between 4 and 10 ng mlÀ1, the optimal cutoff clinical practice, despite the absence of well-defined value remains subject to debate. In addition, since initial cutoff. With recent advances in the sequencing of human studies on free PSA were done in the era of classical genome, the improvement in high-throughput analysis sextant biopsies, it has recently been suggested that free such as microarrays and the rapid emergence of PSA is not as effective in patients undergoing an proteomics, many new potential biomarkers of PCa are extended 12 core biopsies scheme.19 currently under investigation. The role of free PSA for PCa prognostication remains controversial. For example, Catalona et al.42 reported that 75% of men with a free PSA greater than 15% had Human glandular kallikrein 2 favorable pathological features compared to only 34% of Human glandular kallikrein 2 belongs to a family of 15 patients with a lower free PSA. In accordance with these proteases, from which only 12 were recently character-

Prostate Cancer and Prostatic Diseases Novel blood biomarkers for prostate cancer K Bensalah et al ized.51 hK2 is a serine protease very similar to PSA (also circulating uPAR to detect PCa are conflicting. McCabe 115 known as hK3). They share an 80% sequence homology et al.66 did not find any significant association between and are both primarily expressed in the prostate gland.51 uPAR levels and the presence of PCa whereas Steuber Despite these structural similarities, hK2 and PSA differ et al.67 recently showed that uPAR fragments were in their enzymatic activity. The levels of hK2 in prostate significant predictors of PCa on biopsy specimens of tissue, plasma semen and serum are less than 2% that of patients with an elevated PSA. uPA and uPAR might also PSA, although hK2 mRNA transcript expression repre- have a prognostic value. Elevated circulating levels of sents half that of total PSA. Similar to PSA, serum hK2 is uPA and uPAR have been linked to PCa stage and present in two forms in the blood: one bound to various metastases.68–70 In these studies, preoperative plasma protease inhibitors, and the other (preponderant) free in uPA was a strong predictor of biochemical recurrence the circulation. Several studies have shown that when after . Both preoperative uPA and uPAR were used in conjunction with free and total PSA serum hK2 associated with features of aggressive biochemical could improve the discrimination of men with PCa from recurrence such as development of distant metastasis men without cancer.52–54 It has also been suggested that suggesting an association with occult metastatic disease hK2 could predict poor differentiation, extracapsular at time of local therapy. Larger multi-institutional studies extension and biochemical recurrence in patients treated are under way to validate the potential role of uPA and with radical prostatectomy.55–57 However, this finding uPAR as markers of metastatic PCa. was not validated by other authors.58 The usefulness of hK2 for the preoperative staging of localized PCa therefore remains controversial. Transforming growth factor-b1 and interleukin-6 Transforming growth factor (TGF)-b1 is a growth factor involved in the regulation of several cellular mechanisms Early prostate cancer antigen including proliferation, immune response, differentiation Early prostate cancer antigen (EPCA) is a nuclear and angiogenesis.71 TGF-b1 has promoted cell progres- matrix protein originally identified through protein sion in PCa models72 and its local expression has been profiling of rat prostate tissue.59 Alterations of nuclear associated with higher tumor grade, tumor and matrix proteins are considered to be associated with metastasis in PCa patients.73,74 Several studies have . Immunohistochemical studies on pros- shown that increased levels of circulating TGF-b1 were tate core biopsies using autoantibodies against EPCA associated with cancer progression, occult and docu- showed a sensitivity and a specificity superior to 80% mented metastasis and biochemical progression in PCa for the diagnosis of PCa.60,61 Interestingly, positive patients.74–76 However, other authors did not confirm staining was also observed in noncancerous tissue such correlations.77,78 adjacent to the tumor. In addition, EPCA was expressed Interleukin-6 (IL-6) is a cytokine with variable effects in the precursor lesions such as proliferative atrophy and on immune and hematopoietic mechanisms.79 In vitro prostatic intraepithelial neoplasia, which indicates that and in vivo studies have shown that both IL-6 and its EPCA may be associated with nuclear matrix alterations receptors (IL-6R) were expressed in PCa.80,81 Several that occur during the early steps of carcinogenesis. authors reported that elevated serum levels of IL-6 and More recently, a blood-based assay for EPCA was able to IL-6R were associated with metastatic and hormone- detect patients with PCa in a cohort of 46 individuals refractory disease, and suggested that IL-6 could predict (12 cancers and 34 controls) with high accuracy (92% progression and survival of PCa patients.82,83 sensitivity and 94% specificity).62 Another recent On the basis of these findings, Kattan and associates84 study, using an EPCA serum enzyme-linked immuno- developed and internally validated a prognostic model sorbent assay assay, found similar findings (94% sensi- that incorporates plasma (TGF)-b1 and IL-6R into a tivity and 92% specificity) for PCa detection.63 standard nomogram for prediction of biochemical Interestingly, the EPCA-2 serum assay was effective in recurrence following radical prostatectomy. This combi- differentiating patients with localized disease versus nation of serum markers and classical clinical parameters those with extraprostatic extension (area under the improved the predictive accuracy by a statistically and curve of 0.89; Po0.0001).63 These results are pro- prognostically substantial margin (increase in predictive mising and suggest a potential role for EPCA as a accuracy from 75 to 84%). PCa biomarker, although larger validation studies are warranted. Chromogranin A Chromogranin A is a peptide secreted by neuroendo- Urokinase plasminogen activation system crine cells in the prostate gland. While its function is The urokinase plasminogen activation (uPA) system is unknown,85,86 attention has been dedicated to the involved in the degradation of the extracellular matrix potential prognostic value of chromogranin A. Several thereby permitting cancer progression. The inactive investigators found that increased chromogranin precursor of the serine protease, uPA, binds a specific A levels are associated with high-grade disease, ad- soluble cell-surface receptor (uPAR), promoting the vanced state disease and poor survival, particularly in transformation of plasminogen into plasmin. Plasmin the case of hormone-refractory cancer.87–89 In addition, a subsequently degrades a wide spectrum of extracellular number of studies showed that an elevation of serum matrix proteins through activation of a cascade of chromogranin A preceded PSA increase as a marker of proteases. Increased serum levels of different uPAR progression to hormone-refractory disease. As such, it forms have been associated with a poor prognosis in may be possible to use chromogranin A to monitor various cancers.64,65 Reports concerning the ability of metastatic PCa patients under androgen blockade.90,91

Prostate Cancer and Prostatic Diseases Novel blood biomarkers for prostate cancer K Bensalah et al

116 Prostate secretory protein (PSP) complex technique and assess the potential prognostic PSP94 (also known as h-microseminoprotein) is one of value of autoantibodies in PCa. the most abundant proteins in the semen. PSP94 exists in two forms in the serum: one free form and one complexed to a binding protein (PSBP). In a recent study, PSBP and the ratio of bound PSP94/free PSP94 were Insulin-like growth factors family independent predictors of biochemical recurrence in Epidemiological studies have found high circulating patients who underwent radical prostatectomy, after insulin-like growth factor-I (IGF-I) and low IGF-binding adjustment for total PSA, Gleason sum and surgical protein 3 (IGFBP-3) levels to be associated with an 103,104 margin status.92 However, further large prospective increased risk of PCa development. However, in studies are warranted to confirm these preliminary these studies, total PSA remained by far the best findings. predictor of PCa. Moreover, there is no difference in circulating IGF-1 levels between men with PCa and cancer-free controls.105 In addition, there was no relation- Prostate-specific membrane antigen ship between IGF-I and established markers of aggres- Prostate-specific membrane antigen (PSMA) is a glyco- sive disease, cancer progression or metastasis.105 protein highly expressed in normal and cancerous Conversely, plasma IGFBP-2 was significantly elevated epithelial prostatic cells. High levels of PSMA have also in patients with PCa compared to men without PCa and been detected in the serum of PCa patients.93 The exact were inversely correlated with the prostate volume and function of PSMA remains unclear. The interest of features of aggressive disease.105 In the same study, PSMA, as a potential diagnostic and prognostic marker serum level of IGFBP-3 (the main carrier of IGF-I) was of PCa, has been evaluated by several authors with lowest in patients with bone metastases but no difference inconclusive results. Some studies reported a strong was seen between nonmetastatic PCa and healthy correlation between PSMA and the degree of tumor subjects. Moreover, lower levels of IGFBP-2 and -3 could differentiation and the stage of disease,94,95 whereas predict cancer progression when adjusting for preopera- others did not.58,96 In addition, PSMA has been used in tive PSA, Gleason score and clinical stage in patients conjunction with an indium-111-labeled monoclonal with localized disease undergoing radical prostatectomy. antibody as a radiodiagnostic marker for in vivo Hence, it seems that the interest of IGF-1 is limited to its detection of PCa recurrence and metastasis (Prostascint, association with preclinical stages of PCa, whereas the Cytogen, Princeton, NJ, USA). Elgamal et al.97 showed IGFBPs appear to play a direct role in PCa detection and that Prostascint is more sensitive and accurate than CT, prognosis. MRI and ultrasound for the diagnosis of local or regional invasion.

Prostate cancer-specific autoantibodies and Conclusions a-methylacyl-CoA racemase Early detection of PCa was made possible 20 years Autoantibodies, such as those detected in autoimmune ago by the introduction of PSA in the clinical practice. and infectious diseases, can be produced by cancer However, PCa screening remains controversial, because patients in response to tumor-associated antigens of the risk of over diagnosis and over treatment and the overexpressed in cancerous cells. a-Methylacyl-CoA inability to detect a significant proportion of dangerous racemase (AMACR) is an enzyme involved in fat tumors. Furthermore, to date, there is no conclusive metabolism, which has a strong expression in PCa evidence that the use of PSA has reduced mortality tissues.98 Immunostaining, using monoclonal antibodies from PCa. to AMACR, is routinely used for the diagnosis of PCa Several new biomarkers have shown promises in yielding high diagnostic accuracy (sensitivity 97% and preliminary studies. However, no single biomarker is specificity 92%).99 A humoral response to tumor-related likely to have the desired level of diagnostic accuracy autoantibodies can be detected in the serum through and the appropriate degree of certainty to foretell the amplification with high-affinity antibodies and T cells. course of PCa. The future of cancer profiling might rely Autoantibodies to AMACR have been detected in the on the combination of a panel of markers that can give blood of PCa patients and a recent study showed that accurate molecular staging and indicate the likelihood of they could help distinguish cancerous from healthy aggressive behavior. patients with more accuracy than PSA, holding promises To achieve this, further refinement of available for a new diagnostic test.100 Other autoantibodies to high-throughput technology platforms may be able to antigens expressed in PCa (huntington-interacting pro- identify the specific molecular profile of PCa that tein 1, protasomes) have also been detected and it has discriminates patients with cancer from healthy subjects. been reported that their combination could improve the With newly discovered genes and molecular markers screening performance reaching a specificity of 97%.101 reaching record levels, there is a need for appropriate Recently, using a so-called ‘immunomics’ technique, clinical guidelines and protocols to ensure a systematic Wang et al.102 analyzed the overall humoral response and critical evaluation of each potential test prior to against specific tumoral antigens in PCa and were able to their introduction in patient care. By doing so, there is identify multiple antigens. With this panel of autoanti- great hope that a time will come when new biomarkers bodies, they could detect PCa with a sensitivity of 81.6% will be translated into simple diagnostic kits which are and a specificity of 88.2%, which was more accurate than easy to use and improve detection, monitoring and PSA alone. Additional studies are needed to validate this management of PCa.

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