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 . 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 . 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 . 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 . 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 . However, this recommendation has been criticized . 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  is most likely explained by widespread PSA testing before inclusion in the control arm and by low biopsy compliance among screen-positive men . Although the utility of PSA as a diagnostic biomarker has been questioned , 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 . 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.
PROSTATE-SPECIFIC ANTIGEN AS A PREDICTOR OF FUTURE ADVANCED PROSTATE CANCER
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 . 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  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. 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 . 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.
PROSTATE-SPECIFIC ANTIGEN VELOCITY
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 . A Danish study , 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  and that the negative conclusion in an earlier systematic review of PSA velocity is still valid .
ADDITIONAL KALLIKREIN-BASED TESTS FOR SCREENING
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 . 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 . 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 .
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▪].
THE INTERACTION BETWEEN PROSTATE-SPECIFIC ANTIGEN AND GENETIC MARKERS
More than 70 single nucleotide polymorphisms (SNPs) that may be used to complement PSA as a screening test have been identified . 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 , 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 . A later study showed similar results in African-American men .
KALLIKREIN-BASED TESTS IN CLINICAL PRACTICE
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 . 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 . 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 . 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 . 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 .
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 .
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 . 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.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014; 64:9–29.
2. Welch HG, Albertsen PC. Prostate cancer diagnosis
and treatment after the introduction of prostate-specific antigen
screening: 1986–2005. J Natl Cancer Inst 2009; 101:1325–1329.
3▪. Stattin P, Carlsson S, Holmstrom B, et al. Prostate cancer mortality in areas with high and low prostate cancer incidence. J Natl Cancer Inst 2014; 106:dju007.
This nationwide, population-based study shows a significant relation between more common use of PSA testing and lower prostate cancer mortality in Swedish counties.
4. Loeb S, Bjurlin MA, Nicholson J, et al. Overdiagnosis and overtreatment of prostate cancer. Eur Urol 2014; 65:1046–1055.
5. Leal J, Hamdy F, Wolstenholme J. Estimating age and ethnic variation in the histological prevalence of prostate cancer to inform the impact of screening policies. Int J Urol 2014; 21:786–792.
6. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349:215–224.
7. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004; 54:8–29.
8. Draisma G, Etzioni R, Tsodikov A, et al. Lead time and overdiagnosis in prostate-specific antigen
screening: importance of methods and context. J Natl Cancer Inst 2009; 101:374–383.
9▪▪. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 2014; [Epub ahead of print].
The latest update of the European screening study.
10. Moyer VA. US Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012; 157:120–134.
11. Carlsson S, Vickers AJ, Roobol M, et al. Prostate cancer screening: facts, statistics, and interpretation in response to the US Preventive Services Task Force review. J Clin Oncol 2012; 30:2581–2584.
12. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst 2012; 104:125–132.
13. Stamey TA, Caldwell M, McNeal JE, et al. The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years? J Urol 2004; 172:1297–1301.
14. Kuller LH, Thomas A, Grandits G, et al. Elevated prostate-specific antigen
levels up to 25 years prior to death from prostate cancer. Cancer Epidemiol Biomarkers
Prev 2004; 13:373–377.
15. Lilja H, Ulmert D, Björk T, et al. Long-term prediction of prostate cancer up to 25 years before diagnosis
of prostate cancer using prostate kallikreins
measured at age 44 to 50 years. J Clin Oncol 2007; 25:431–436.
16. Ulmert D, Cronin AM, Bjork T, et al. Prostate-specific antigen
at or before age 50 as a predictor of advanced prostate cancer diagnosed up to 25 years later: a case-control study. BMC Med 2008; 6:6.
17. Tang P, Sun L, Uhlman MA, et al. Baseline PSA as a predictor of prostate cancer-specific mortality over the past 2 decades: Duke University experience. Cancer 2010; 116:4711–4717.
18. Vickers AJ, Cronin AM, Björk T, et al. Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study. BMJ 2010; 341:c4521.
19. Orsted DD, Bojesen SE, Kamstrup PR, Nordestgaard BG. Long-term prostate-specific antigen
velocity in improved classification of prostate cancer risk and mortality. Eur Urol 2013; 64:384–393.
20. Lilja H, Cronin AM, Dahlin A, et al. Prediction of significant prostate cancer diagnosed 20 to 30 years later with a single measure of prostate-specific antigen
at or before age 50. Cancer 2011; 117:1210–1219.
21. Gerstenbluth RE, Seftel AD, Hampel N, et al. The accuracy of the increased prostate specific antigen level (greater than or equal to 20 ng./ml.) in predicting prostate cancer: is biopsy always required? J Urol 2002; 168:1990–1993.
22. Ross HM, Kryvenko ON, Cowan JE, et al. Do adenocarcinomas of the prostate with Gleason score (GS) ≤6 have the potential to metastasize to lymph nodes? Am J Surg Pathol 2012; 36:1346–1352.
23. Van der Kwast TH, Roobol MJ. Defining the threshold for significant versus insignificant prostate cancer. Nat Rev Urol 2013; 10:473–482.
24▪. Randazzo M, Beatrice J, Huber A, et al. A ‘PSA pyramid’ for men with initial prostate-specific antigen
≤3 ng/ml: a plea for individualized prostate cancer screening. Eur Urol 2014; [Epub ahead of print].
This study describes the risk of cancer within 10 years for men in the Swiss part of the European screening study. Long PSA testing intervals are safe for the many men with a low initial PSA level.
25. Weight CJ, Kim SP, Jacobson DJ, et al. Men (aged 40–49 years) with a single baseline prostate-specific antigen
below 1.0 ng/mL have a very low long-term risk of prostate cancer: results from a prospectively screened population cohort. Urology 2013; 82:1211–1217.
26▪▪. Vickers AJ, Ulmert D, Sjoberg DD, et al. Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40–55 and long term risk of metastasis: case-control study. BMJ 2013; 346:f2023.
A population-based study with 27 years’ median follow-up showing that the PSA level at age 40–55 years is a powerful predictor of metastatic prostate cancer.
27▪. Larsen SB, Brasso K, Iversen P, et al. Baseline prostate-specific antigen
measurements and subsequent prostate cancer risk in the Danish Diet, Cancer and Health cohort. Eur J Cancer 2013; 49:3041–3048.
A case-control study showing that the baseline PSA level and the free-to-tPSA ratio at is strongly associated with the risk of aggressive prostate cancer up to 14 years later.
28. Vickers AJ, Sjoberg DD, Ulmert D, et al. Empirical estimates of prostate cancer overdiagnosis by age and prostate-specific antigen
. BMC Med 2014; 12:26.
29. Arsov C, Becker N, Hadaschik BA, et al. Prospective randomized evaluation of risk-adapted prostate-specific antigen
screening in young men: the PROBASE trial. Eur Urol 2013; 64:873–875.
30. Wallner LP, Frencher SK, Hsu JW, et al. Changes in serum prostate-specific antigen
levels and the identification of prostate cancer in a large managed care population. BJU Int 2013; 111:1245–1252.
31. Vickers AJ, Thompson IM, Klein E, et al. A commentary on PSA velocity and doubling time for clinical decisions in prostate cancer. Urology 2014; 83:592–596.
32. Vickers AJ, Savage C, O’Brien MF, Lilja H. Systematic review of pretreatment prostate-specific antigen
velocity and doubling time as predictors for prostate cancer. J Clin Oncol 2009; 27:398–403.
33. Bryant RJ, Lilja H. Emerging PSA-based tests to improve screening. Urol Clin North Am 2014; 41:267–276.
34. Vedder MM, de Bekker-Grob EW, Lilja HG, et al. The added value of percentage of free to total prostate-specific antigen
, PCA3, and a kallikrein panel to the ERSPC risk calculator for prostate cancer in prescreened men. Eur Urol 2014; [Epub ahead of print].
35. Nordström T, Aly M, Eklund M, et al. A genetic score can identify men at high risk for prostate cancer among men with prostate-specific antigen
of 1–3 ng/ml. Eur Urol 2014; 65:1184–1190.
36. Knipe DW, Evans DM, Kemp JP, et al. Genetic variation in prostate-specific antigen
-detected prostate cancer and the effect of control selection on genetic association studies. Cancer Epidemiol Biomarkers
Prev 2014; 23:1356–1365.
37. Helfand BT, Loeb S, Hu Q, et al. Personalized prostate specific antigen testing using genetic variants may reduce unnecessary prostate biopsies. J Urol 2013; 189:1697–1701.
38. Donin NM, Loeb S, Cooper PR, et al. Genetically adjusted prostate-specific antigen
values may prevent delayed biopsies in African-American men. BJU Int 2014; [Epub ahead of print].
39. Liss MA, Chen H, Hemal S, et al. Impact of family history on prostate cancer mortality in Caucasian men undergoing PSA-based screening. J Urol 2014; [Epub ahead of print].
40. Loeb S, Catalona WJ. The prostate health index: a new test for the detection of prostate cancer. Ther Adv Urol 2014; 6:74–77.
41▪▪. Bruzzese D, Mazzarella C, Ferro M, et al. Prostate health index vs %free prostate-specific antigen
for prostate cancer detection in men with ‘gray’ prostate-specific antigen
levels at first biopsy: systematic review and meta-analysis. Transl Res 2014; [Epub ahead of print].
A systematic review and meta-analysis of the ability of PHI and %fPSA alone to discriminate men with PSA values of 2–10 ng/ml as having a low or high risk of prostate cancer.
42▪▪. Lazzeri M, Haese A, de la Taille A, et al. Serum isoform [-2]proPSA derivatives significantly improve prediction of prostate cancer at initial biopsy in a total PSA range of 2–10 ng/ml: a multicentric European study. Eur Urol 2013; 63:986–994.
This study shows that %p2PSA and PHI are better predictors of cancer at initial biopsy than the tPSA level and %fPSA among men with a tPSA of 2–10 ng/ml.
43▪▪. Fossati N, Lazzeri M, Haese A, et al. Clinical performance of serum isoform [-2]proPSA (p2PSA) and its derivatives, namely %p2PSA and PHI (prostate health index) in men younger than 60 years of age: results from a multicentric European study. BJU Int 2014; [Epub ahead of print].
The study reports on sensibility, specificity, and accuracy of serum pro2PSA, %pro2PSA, and PHI for detecting prostate cancer at first biopsy in 1000 men younger than 60 years.
44. Filella X, Foj L, Auge JM, et al. Clinical utility of %p2PSA and prostate health index in the detection of prostate cancer. Clin Chem Lab Med 2014; 52:1347–1355.
45. Ng CF, Chiu PK, Lam NY, et al. The prostate health index in predicting initial prostate biopsy outcomes in Asian men with prostate-specific antigen
levels of 4–10 ng/mL. Int Urol Nephrol 2014; 46:711–717.
46. Ferro M, Bruzzese D, Perdona S, et al. Prostate health index (Phi) and prostate cancer antigen 3 (PCA3) significantly improve prostate cancer detection at initial biopsy in a total PSA range of 2–10 ng/ml. PLoS One 2013; 8:e67687.
47. Mearini L, Ferri C, Lazzeri M, et al. Evaluation of prostate-specific antigen
isoform p2PSA and its derivates, %p2PSA, prostate health index and prostate dimension-adjusted related index in the detection of prostate cancer at first biopsy: an exploratory, prospective study. Urol Int 2014; 93:135–145.
48. Heidegger I, Klocker H, Steiner E, et al. [-2]proPSA is an early marker for prostate cancer aggressiveness. Prostate Cancer Prostatic Dis 2014; 17:70–74.
49. Tallon L, Luangphakdy D, Ruffion A, et al. Comparative evaluation of urinary PCA3 and TMPRSS2: ERG scores and serum PHI in predicting prostate cancer aggressiveness. Int J Mol Sci 2014; 15:13299–13316.
50▪. Fossati N, Buffi NM, Haese A, et al. Preoperative prostate-specific antigen
isoform p2PSA and its derivatives, %p2PSA and prostate health index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer: results from a multicentric European prospective study. Eur Urol 2014; [Epub ahead of print].
A multicenter study showing that PHI and [-2] proPSA alone both discriminate between high and low-grade cancer and between organ-confined and extraprostatic prostate cancer at radical prostatectomy.
51. Lughezzani G, Lazzeri M, Haese A, et al. Multicenter European external validation of a prostate health index-based nomogram for predicting prostate cancer at extended biopsy. Eur Urol 2013; [Epub ahead of print].
52. Lazzeri M, Abrate A, Lughezzani G, et al. Relationship of chronic histologic prostatic inflammation in biopsy specimens with serum isoform [-2]proPSA (p2PSA), %p2PSA, and prostate health index in men with a total prostate-specific antigen
of 4–10 ng/ml and normal digital rectal examination. Urology 2014; 83:606–612.
53. Stephan C, Jung K, Semjonow A, et al. Comparative assessment of urinary prostate cancer antigen 3 and TMPRSS2:ERG
gene fusion with the serum [-2]proprostate-specific antigen-based prostate health index for detection of prostate cancer. Clin Chem 2013; 59:280–288.
54. Scattoni V, Lazzeri M, Lughezzani G, et al. Head-to-head comparison of prostate health index and urinary PCA3 for predicting cancer at initial or repeat biopsy. J Urol 2013; 190:496–501.
55▪. Nordström T, Vickers A, Assel M, et al. Comparison between the four-kallikrein panel and prostate health index for predicting prostate cancer. Eur Urol 2014; [Epub ahead of print].
A comparison between the four kallikrein panel and PHI for men with PSA 3–15 ng/ml undergoing first-time prostate biopsy.
56. Carlsson S, Maschino A, Schroder F, et al. Predictive value of four kallikrein markers for pathologically insignificant compared with aggressive prostate cancer in radical prostatectomy specimens: results from the European Randomized Study of Screening for Prostate Cancer section Rotterdam. Eur Urol 2013; 64:693–699.
57. Garcia-Cruz E, Carrion Puig A, Garcia-Larrosa A, et al. Higher sex hormone-binding globulin and lower bioavailable testosterone are related to prostate cancer detection on prostate biopsy. Scand J Urol 2013; 47:282–289.
58▪. Friedersdorff F, Manus P, Miller K, et al. Serum testosterone improves the accuracy of prostate health index for the detection of prostate cancer. Clin Biochem 2014; 47:916–920.