New Circulating Biomarkers for Prostate Cancer
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Prostate Cancer 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 prostate cancer 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, metastasis, 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 hyperplasia (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 biopsy.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’ biopsies (increase specificity) in significant number of cancers 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 prostates have higher PSA levels. In theory, definitive was the Prostate Cancer Prevention 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.