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Serum markers in prostate cancer detection

Bratt, Olaa,b; Lilja, Hansa,c,d,e,f

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doi: 10.1097/MOU.0000000000000128
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No biomarker has affected the clinical management of cancer more than prostate-specific antigen (PSA). Since its introduction in clinical practice in the late 1980s and early 1990s, PSA testing has led to a doubling of the incidence of prostate cancer and a marked migration to earlier stages at diagnosis in most Western countries [1,2]. In addition to changing the epidemiology of prostate cancer, PSA testing of men without clinical signs of prostate cancer has created a new ‘disease entity’: men with increased PSA but no prostate cancer diagnosis. Managing these men occupies large healthcare resources. The increased use of PSA has been followed by decreasing prostate cancer mortality [1,2,3▪]. However, PSA testing has also led to overdiagnosis of many indolent cancers that would not have caused clinical disease [4]. Autopsy studies have consistently shown that the prevalence of clinically undetected prostate cancer increases with age from at least 20% among men aged 50–70 years to 70% among men in their nineties [5]. As moderately increased PSA values are more often caused by benign prostatic hyperplasia than by cancer, systematic prostate biopsies in men with clinically benign prostates will inevitably sometimes detect clinically insignificant cancer. The Prostate Cancer Prevention Trial, in which all men underwent prostate biopsy regardless of the PSA value, may be used to illustrate the detection of clinically insignificant prostate [6]. After 7 years, 24% of the men in the placebo arm were diagnosed with prostate cancer, which is almost 10 times the percentage of deaths in US men that were contributed to prostate cancer at that time [7]. Also, the European Randomized study of Screening for Prostate Cancer (ERSPC) [8,9▪▪] has reported considerable overdiagnosis of prostate cancer resulting from systematic PSA testing. The harms caused by overdiagnosis and overtreatment were the main reason for the US Preventive Services Task Force's decision in 2012 to recommend against PSA testing in the absence of clinical signs or symptoms suggestive of prostate cancer [10]. However, this recommendation has been criticized [11]. The ERSPC showed a 27% decrease in prostate cancer mortality among screened men after 13 years follow-up [9▪▪]. That no benefit of screening was reported from the American screening study [12] is most likely explained by widespread PSA testing before inclusion in the control arm and by low biopsy compliance among screen-positive men [11]. Although the utility of PSA as a diagnostic biomarker has been questioned [13], it is clear that it is an extremely powerful clinical tool in the low and high ranges. Low PSA levels (<0.5–1 ng/ml) almost entirely exclude clinically significant prostate cancer and predict a very low risk of advanced prostate cancer up to 25 years ahead [14–20]. Almost all men with PSA values more than 50 ng/ml have advanced prostate cancer, unless they have an acute urinary infection [21]. The challenge is how to manage men with intermediate PSA values, in whom the specificity of PSA is poor. There are urgent needs for complementary tools for these men. As there is increasing evidence for that Gleason grade 3 prostate cancer rarely progresses to metastatic disease [22,23], the review focuses on the detection of Gleason grade 4 to 5 cancer and the prediction of metastatic and lethal prostate cancer. It includes research published from March 2013 through August 2014.

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The evidence is accumulating for the predictive value of low PSA values. In a Swiss study [24▪], only 0.2% of 5000 men with an initial PSA value below 1 ng/ml were diagnosed with aggressive prostate cancer within 8 years. Similar results were reported in a smaller, American study [25]. In a study based on frozen blood plasma, only 0.1% of 10 000 Swedish 45–49 years old men with PSA values below the median (0.7 ng/ml) developed metastatic prostate cancer within 15 years [26▪▪]. A Danish case-control study [27▪] reported a more than doubled risk of aggressive prostate cancer within 14 years for men aged 50–64 years with an initial PSA of 0.8–1.5 ng/ml and a six-fold increased risk for men with an initial PSA of 1.5–2.7 ng/ml, compared with the men whose initial PSA value was below 0.8 ng/ml. A population-based Swedish study, based on frozen blood samples from 17 837 men, showed an only 0.4% risk of metastatic prostate cancer within 20 years for the two-thirds of men aged 50 years who had a PSA less than 1 ng/ml (P. Stattin, A.J. Vickers, D.D. Sjoberg, et al., in preparation). The corresponding risk for men aged 60 years was 0.7%. The prospective Olmsted County study [25] has reported a similarly high negative predictive value of a PSA less than 1 ng/ml for men in their forties. Using the US Surveillance, Epidemiology and End Results database, Vickers et al.[28] demonstrated that most of the overdiagnosis of clinically insignificant prostate cancer is caused by systematic prostate biopsies in men older than 60 years with PSA values above 1 ng/ml.

These findings are used to create screening algorithms that test almost half of the male population only 3 times, for example at age 50, 55, and 60 years [29]. Although such individualized, risk-based screening would decrease screening costs, the low specificity of any reasonable PSA cut-off remains a cause of overdiagnosis of clinically insignificant cancer.


In a study based on more than 200 000 Californian men aged more than 45 years with at least three PSA values during 10 years of follow-up, the median annual PSA increase was 8–11% in the men who were diagnosed with prostate cancer and only 2.5% in those who were not [30]. A Danish study [19], including 121 prostate cancer patients and 382 control subjects, showed highly significant differences in PSA velocity between patients and controls during the 20 years that preceded the patients’ diagnosis. The age-adjusted prostate cancer mortality was 3.4 times higher for men with a PSA velocity more than 0.35 ng/ml/year than for those with lower PSA velocity. However, despite these positive results, a recent review concluded that PSA velocity adds little or no clinically useful information compared with the absolute PSA value alone [31] and that the negative conclusion in an earlier systematic review of PSA velocity is still valid [32].


Much of the overdiagnosis of indolent cancers is caused by the current practice of performing systematic prostate biopsies in men with PSA values of 2–10 ng/ml and no suspicion of cancer on digital rectal examination [28]. The purpose of introducing new serum markers for prostate cancer screening would mainly be to complement PSA as a primary screening test, using the additional test(s) to identify which men with PSA 2–10 ng/ml need further investigations.

Recent research has focused on the development, and analytical and clinical validation, of different kallikrein-marker assays, such as distinct variants of the heterogeneous-free, unbound PSA forms in blood: proPSA and intact PSA (iPSA). proPSA is an inactive precursor of PSA, which can be cleaved in vitro by the kallikrein-related peptidase 2 (hK2) and other kallikreins proteases, resulting in the ‘mature’ form of PSA. Several truncated forms of proPSA (e.g., [-2] proPSA) may be detected at higher levels in the circulation in men with prostate cancer than in men with benign prostates. iPSA is the noncatalytic single-chain form of free PSA (fPSA) as opposed to the nicked, internally cleaved forms of fPSA.

A panel of four kallikrein markers in blood

The panel of four kallikrein markers in blood (4KRK) comprises fPSA, single-chain iPSA, total PSA (tPSA), and hK2 [33]. The previously mentioned study by Stattin and coworkers showed that the 4KRK panel could identify a large group (59%) of 1692 men aged 50 years with a PSA value of more than 2 ng/ml who had only a 1% risk of metastatic prostate cancer within 20 years (P. Stattin, A.J. Vickers, D.D. Sjoberg, et al., in preparation). It seems reasonable not to immediately apply further investigations to men with such a low risk, but to instead continue screening and act only on increasing PSA values or 4KLK risk category. The risk of metastases for the remaining 41% of the men was 7.6%. The corresponding figures for men aged 60 years with a PSA value more than 2 ng/ml were 1.4% risk of metastatic disease for 28% of the men and 15% risk for the remaining 72%. In 202 men with PSA more than 3 ng/ml on repeat screening in the Rotterdam section of the ERSPC, the 4KRK panel performed equivalently to prostate cancer antigen 3 (PCA3) in a multivariable model [34].

Also, %fPSA alone has been shown to predict aggressive prostate cancer. Men aged 50–58 years with %fPSA below the median value 20% had a 2.4-fold increased risk of aggressive prostate cancer within 14 years, compared with men with more than 20%fPSA [27▪]. One third of the men younger than 58 years had less than 15%fPSA; their risk was increased 11-fold [27▪].


More than 70 single nucleotide polymorphisms (SNPs) that may be used to complement PSA as a screening test have been identified [35]. Some of these polymorphisms affect the expression of the hK3 gene, encoding for PSA, causing an interindividual variation in the effects of benign hyperplasia and cancer on serum PSA. In a report from the ProtecT study [36], seven SNPs were associated with prostate cancer among men with low PSA values but not among men with high PSA values, suggesting that these SNPs affect PSA expression. Correction for the effects of four SNPs resulted in an 18–22% reduction of men meeting biopsy thresholds in a population of men of Caucasian ethnicity [37]. A later study showed similar results in African-American men [38].


Evaluating men with increased PSA levels in clinical practice is different to the population-based screening setting, as additional information can be obtained by digital rectal examination, transrectal ultrasound, MRI, and the family history [39]. Men with increased PSA levels who have a prostatic nodule or a high PSA density are usually recommended prostate biopsies. The potential value of additional serum markers in the clinical setting would thus be greatest for men with a tPSA of 2–10 ng/ml and a benign prostatic enlargement on digital rectal examination (i.e., a low PSA density).

The prostate health index and proPSA

The prostate health index (PHI) combines tPSA, %fPSA, and [-2] proPSA [40]. According to a meta-analysis of eight studies, comprising 2969 men, PHI is superior to %fPSA alone for prostate cancer detection at first biopsy in men with tPSA values of 2–10 ng/ml [41▪▪]. The area under the receiver operating curve for detection of prostate cancer was 0.74 for PHI and 0.63 for %fPSA. It is, however, unclear whether PHI is superior to [-2] proPSA alone in men with PSA in this ‘gray zone’ [42▪▪,43▪▪,44]. The value of PHI has been confirmed in an Asian population [45]. PHI and [-2] proPSA alone both discriminate between high and low-grade cancer [46–49,50▪] and between organ-confined and extraprostatic prostate cancer [50▪].

By applying the PHI test to 646 men with PSA values between 2 and 10 ng/ml who had no previous prostate biopsies, 16% of the biopsies could have been avoided at the cost of missing three of 139 cancers with Gleason score 7 and none with Gleason score 8–10 cancer [42▪▪]. The performance of the PHI test among the men with clinically benign prostate was not reported. The same group of researchers used data from five European tertiary care centers to validate a nomogram, on the basis of age, previous prostate biopsy, findings on digital rectal examination, prostate volume, and PHI, in patients scheduled for a prostate biopsy [51]. With a cut-off set so that 20% of the men would have avoided a 12-core biopsy, only two of 204 with Gleason score 7–10 cancers would have been missed among 883 men.

Inflammation decreases the %fPSA, making the discrimination between prostate cancer and prostate inflammation difficult. However, [-2] proPSA and PHI may discriminate chronic histologic prostatic inflammation from cancer in men with tPSA values of 4–10 ng/ml and a normal digital rectal examination [52].

PHI performed similarly to the urinary prostate cancer markers PCA3 and the gene fusion TMPRSS2:ERG[46,53,54]. The combination of PHI with any of these urinary markers was not better than using PHI alone [46,53,54].

The four kallikrein panel

In a recent study of 531 men with PSA 3–15 ng/ml undergoing first-time prostate biopsy, the 4KRK panel performed similar to PHI [55▪]. A cut-off for biopsy at 10% predicted risk of high-grade cancer by the 4KRK panel or at PHI 39 would reduce the number of men undergoing biopsy with 29% at the cost of delaying diagnosis for 10% of the men with high-grade cancers. A report from the ProtecT study showed that the 4KRK panel significantly increased the area under the receiver operating curve for detection of high-risk prostate cancer in 6606 men who underwent 10-core prostate biopsies because of PSA at least 3 ng/ml (R.J. Bryant, D.D. Sjoberg, A.J. Vickers, et al., in preparation). Almost half (43%) of the biopsies could have been avoided if the 4 KRK panel had been used, at the cost of reducing the detection rate of high-risk cancer from 13% to 12%. As the 4KRK panel discriminates between low and high-risk prostate cancer, it may be useful also for selecting prostate cancer patients for active surveillance [56].

Serum kallikreins in hypogonadal men

The expression of the prostate-specific kallikreins genes is androgen dependent. Prostate cancer may, therefore, not increase PSA values in hypogonadal men as much as in men with normal plasma testosterone values [57]. Correcting tPSA values and PHI for bioavailable testosterone enhances the detection of prostate cancer [57,58▪].


The recent advances in clinical research on serum biomarkers for prostate cancer detection have been in the kallikrein field. Low PSA levels have proved to be a powerful predictor of future risk of advanced prostate cancer. Individualized, risk differentiated screening algorithms based on PSA values may decrease the costs of PSA-based screening. A trial testing this concept was started recently. The PHI, proPSA, and the 4KRK panel may identify which men with PSA values of 2–10 ng/ml should be recommended imaging or prostate biopsies. However, prospective studies are needed to establish their role in prostate cancer screening. Important areas of uncertainty include the performance of the different kallikrein tests in men treated with 5-alpha-reductase inhibitors and in men at a genetically defined increased risk of prostate cancer.


Hans Lilja receives funding support from the National Cancer Institute (R33 CA127768, R01 CA160816, and P50 CA092629), the Sidney Kimmel Center for Prostate and Urologic Cancers, David H. Koch through the Prostate Cancer Foundation, the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Program, Swedish Cancer Society (projects no. 11–0624), and Fundacion Federico SA.

Conflicts of interest

Hans Lilja holds patents for fPSA, hK2, and iPSA assays, and is named as coinventor on a patent application for intact/nicked PSA assays and for a statistical method for predicting the result of a prostate biopsy. Ola Bratt has no conflicts of interest.


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest


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biomarkers; diagnosis; kallikreins; prostate-specific antigen; prostatic neoplasms

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