Emerging PSA-Based Tests to Improve Screening




Key points







  • •

    Using prostate-specific antigen (PSA) derivatives and additional kallikrein markers for prostate cancer diagnosis can improve the current performance characteristics of the PSA test alone.


  • •

    An improved screening test may dramatically reduce the number of men undergoing an unnecessary biopsy while maintaining the ability to detect high-risk prostate cancer.


  • •

    The use of an improved screening test may reduce both overdiagnosis and overtreatment of prostate cancer.






Introduction


Prostate cancer is the most commonly diagnosed malignancy in men in the United States. It was estimated that during 2013 in the United States, some 238,590 new prostate cancer cases would be diagnosed and 29,720 men would die from this disease. Both early detection and treatment of clinically localized prostate cancer represent the most likely strategies that will enable clinicians to reduce the high rate of prostate cancer-related deaths. Prostate-specific antigen (PSA)-based testing has been widely used to aid prostate cancer detection since the late 1980s and prostate cancer-specific mortality has decreased because of PSA-based screening programs in recent years. However, there is a concern that this decline has come at the expense of overdiagnosis and overtreatment. This article provides an overview of emerging PSA-based biomarkers with the potential to improve the performance of prostate cancer screening programs.




Introduction


Prostate cancer is the most commonly diagnosed malignancy in men in the United States. It was estimated that during 2013 in the United States, some 238,590 new prostate cancer cases would be diagnosed and 29,720 men would die from this disease. Both early detection and treatment of clinically localized prostate cancer represent the most likely strategies that will enable clinicians to reduce the high rate of prostate cancer-related deaths. Prostate-specific antigen (PSA)-based testing has been widely used to aid prostate cancer detection since the late 1980s and prostate cancer-specific mortality has decreased because of PSA-based screening programs in recent years. However, there is a concern that this decline has come at the expense of overdiagnosis and overtreatment. This article provides an overview of emerging PSA-based biomarkers with the potential to improve the performance of prostate cancer screening programs.




PSA-based screening for prostate cancer


The term screening describes the diagnosis of preclinical cases of a disease at an early stage to improve the outcomes for that condition. PSA-based screening for prostate cancer has to justify several important requirements to be acceptable and thereby become widely adopted by health care providers. Several recent studies have demonstrated that clear survival benefits may occur because of population-based prostate cancer screening programs using PSA. Moreover, there is recent evidence that measuring a man’s PSA level in early midlife identifies a smaller subset of men who are at risk of developing metastatic prostate cancer several decades later. For example, men with a PSA level in the highest decile at age 45 to 55 years have a tenfold or higher risk of metastatic cancer 15 to 25 years later compared with men with a PSA level below the age-median. Similarly, a single PSA measurement at age 60 years may be very informative in predicting which men are at significant future risk of prostate cancer-specific death. However, despite the clear survival benefits that arise because of PSA-based prostate cancer screening, there are several disadvantages to the widespread adoption of this practice, including the potential for overdiagnosis and subsequent overtreatment of men.


Overdiagnosis and overtreatment of insignificant prostate cancers unlikely to become clinically apparent during a man’s lifetime are significant problems. The European Randomized Study of Screening for Prostate Cancer (ERSPC) showed that PSA-based screening can reduce prostate cancer-specific mortality by 20% within 9 years, but large numbers of men need to be screened for each life saved. Further follow-up to 11 years demonstrated a greater reduction in prostate cancer-specific mortality and an improvement in the numbers needed to screen and treat to save each life.


Unfortunately, PSA has several performance limitations when it is used for prostate cancer screening, including a lack of specificity. As the specificity of PSA alone is limited, a prostate biopsy is positive in only around 25% of men with a PSA between 2 and 10 ng/mL. Data reported using the control arm of participants in the Prostate Cancer Prevention Trial (PCPT) clearly demonstrated that there is no absolute lower limit of PSA below which there is no risk of detecting prostate cancer at biopsy among men aged 62 to 91. It is worthwhile noting, however, that there is a distinct difference between using the prostate biopsy endpoint of PCPT versus the prostate cancer metastasis or cancer death endpoints used in recent reports describing PSA-based testing. A further downside of using the PSA level alone in prostate cancer screening is that no single PSA cut-off threshold has particularly good test performance characteristics. Because PSA is an organ-specific, instead of a prostate cancer-specific biomarker, most men with an elevated level of PSA do not have prostate cancer. Men with a raised PSA may, therefore, be subjected to an unnecessary prostate biopsy and be exposed to the potential complications of this procedure along with considerable associated anxiety. Moreover, as explained above, some men with a low PSA result may actually have prostate cancer. Many screen-detected prostate cancers may not actually require treatment, hence there is a need for a marker that can help to identify high-risk prostate cancer at an early stage, thereby enabling clinicians to undertake radical treatment enabling cure of those patients with the greatest risk of developing morbidity or mortality because of this malignancy.


Given the clear limitations of PSA-based testing for prostate cancer, there are several concerns regarding the routine use of this test within the context of a national prostate cancer screening program. Currently, around half of all men in the United States undergo regular PSA testing and more than 1 million prostate biopsies are performed per annum in the United States alone. The US Preventative Services Task Force has recently recommended against PSA-based screening for prostate cancer. This announcement has caused considerable controversy in the United States and concerns have been raised regarding the methodology used to review the evidence base for screening, together with the interpretation of this evidence. One approach to improve the benefit to cost ratio of a prostate cancer screening program would be to focus more on those men with the highest risk of developing clinically significant malignancy. Another strategy would be to improve methods of detection, perhaps by identifying novel diagnostic tests with a greater positive predictive value than the currently used PSA test.




PSA


Prostate cancer is an example of a urological malignancy that has benefitted from the discovery and application of a tumor marker. PSA, or human kallikrein 3 (hK3, KLK3), was discovered in 1979 and first applied to clinical use in the late 1980s and early 1990s. The PSA-era has led to a greater detection of nonpalpable clinically localized disease and this has resulted in a subsequent reduction in prostate cancer-specific mortality.


PSA is a 33-kD glycoprotein and serine protease produced under androgen-regulation by the luminal cells of the prostate epithelium. PSA acts to liquefy semen after ejaculation and it is normally found in serum at low concentrations compared with the amount within the ejaculate. Several different molecular forms of PSA can be found within serum where around 70% of PSA is bound as complexed PSA (cPSA) in association with molecules such as α1-antichymotrypsin (ACT, SERPINA3 ) or macroglobulin (A2M). PSA bound to ACT, but not A2M, represents the largest proportion of bound PSA that remains detectable with immunologic assays and free inactive PSA (fPSA) is also detectable. The development of antibodies specific for fPSA and cPSA has enabled accurate assays for the particular forms of PSA to be developed so that the percentage of fPSA can be measured and used to try and improve the accuracy of prostate cancer detection.


PSA also exists as several different isoforms. Luminal prostate epithelial cells produce proPSA, an inactive precursor of PSA that has a 7-amino-acid leader sequence. This is cleaved by the protease action of human kallikrein 2 (hK2) and other kallikreins resulting in the 237-amino-acid mature form of PSA. Numerous truncated or clipped forms of proPSA may arise due to the incomplete removal of the 7-amino-acid leader sequence. These and other forms of PSA may be released more freely within the circulation of men with prostate cancer. It has recently been demonstrated that the levels of [-2] proPSA are higher in prostate cancer than the benign setting and that the use of this biomarker significantly improves the rate of cancer detection compared with using total PSA (tPSA) and the free-to-total PSA ratio. Intact PSA describes an intact and inactive form of proPSA that does not form a complex and which is released from prostate cancer cells. In fact, it is now known that prostate cancer cells actually produce less PSA than benign epithelial cells; however, changes in the architecture of the prostate epithelium arising from malignant progression result in the serum PSA level becoming elevated in many, though not all, of these men.


Because PSA is organ-specific and not prostate cancer-specific there is a considerable degree of overlap in PSA levels between patients with benign pathologies, such as prostatitis, benign prostate hyperplasia, or urinary retention, compared with patients with prostate cancer. A normal level of PSA was previously described as being below 4.0 ng/mL for men aged 50 to 80 years without prostate disease. However, recently, it has become clear that there is no such thing as a normal PSA in terms of prostate cancer risk. Moreover, there is no PSA cut-off threshold below which the risk of detecting a prostate cancer on biopsy is zero, so the choice of a PSA threshold at which a clinician might recommend a patient biopsy is controversial. If the PSA threshold is set too high, clinically significant prostate cancers might be missed. Conversely, if it is set too low then an unacceptably high number of men without prostate cancer would be subjected to an unnecessary biopsy and, thereby, be exposed to the inherent risks and anxieties associated with this invasive procedure. The use of several PSA derivatives, such as PSA density, PSA velocity, age-adjusted PSA, free-to-total PSA ratio, and different molecular derivatives of PSA has led to various refinements in the performance of the PSA test. Despite this, the limited sensitivity and specificity of PSA means that there remains an urgent need to identify prostate cancer biomarkers with better performance characteristics than PSA alone.




Additional human kallikreins as tumor markers


In addition to PSA, 14 other human kallikrein-related peptidases have now been identified and structurally characterized. Human kallikrein-related peptidase 2 (hK2, KLK2) is a protease with several similarities to PSA. For example there is 80% identity in primary structure between hK2 and PSA, the expression of both the KLK2 and KLK3 genes is regulated by the signaling activity of the androgen receptor ( AR ) stimulated by the supply of androgens, and both PSA and hK2 display a similar and highly extensive degree of prostate-specific expression pattern. hK2 is a trypsin-like serine protease responsible for cleaving proPSA into its enzymatically active form during a cascade reaction which regulates seminal clot liquefaction. Although the concentration of hK2 in serum is about two orders of magnitude lower than that of PSA, the development of reliable assays for hK2 suggests that this kallikrein may potentially be used as a prostate cancer biomarker. Interestingly, whereas PSA is strongly expressed in benign epithelium, hK2 becomes strongly expressed in malignant tissue, particularly in high-grade prostate cancer cases. Compared with individuals without prostate cancer, men with this malignancy have higher levels of hK2 in their serum and there is reasonable correlation between the serum level of hK2 and the aggressiveness of prostate cancer present in an individual.


Many of the kallikreins interact with each other within both normal physiologic pathways and during the development of prostate pathology. Several of the recently described kallikreins, including KLK4 , KLK5 , KLK6 , KLK8 , KLK10 , KLK11 , and KLK14 , have been tested as potential prostate cancer biomarkers in relatively small numbers of patients. To date, however, these additional kallikreins have not been proven clinically useful.


The kallikreins can be subject to degradation if samples undergo repeated freeze-thaw cycles, and the values of both free and intact PSA are lowered if samples are repeatedly frozen and thawed. In general, the plasma or serum should be separated from the cellular component of blood within around 1 hour of blood draw. fPSA in serum should be assayed within the same working day, whereas plasma-based assays should be undertaken within a day or two, given that there is evidence to suggest that kallikreins are more stable in plasma than in serum samples. Subsequently, the samples should be stored at −80°C and repeated freeze-thaw cycles should be avoided. In general, the performance characteristics of different PSA isoforms and novel kallikreins as prostate cancer biomarkers may be optimized by the correct handling and use of clinical samples.




The use of combinatorial panels of kallikrein biomarkers


In recent years, there has been interest in developing a prostate cancer screening test based on the use of assays for several kallikreins in combination. This is based on the principle that the use of a panel of biomarkers might outperform the use of PSA alone. As an example, a panel of four kallikrein markers measured in blood has been demonstrated to outperform the use of PSA alone in predicting the outcome of a prostate biopsy in several cohorts of men enrolled in randomized studies of screening. Specifically, these include fPSA, single-chain intact PSA (iPSA), tPSA, and hK2. Importantly, it has become apparent that predicting biopsy outcome based on this panel of four kallikrein markers may be better than using total PSA alone in both previously screened and hitherto unscreened men. Crucially, in terms of developing a test that might be applicable to a population-based screening program for prostate cancer, the four kallikrein marker panel has the potential to dramatically reduce the number of unnecessary biopsies conducted as part of the screening program. If the four kallikrein marker panel was used in a screening program along with a man’s age, regardless of whether a digital rectal examination (DRE) is incorporated, evidence suggests that the number of unnecessary biopsies can be greatly reduced without missing many high-grade cancers.


Studies of the four kallikrein markers have facilitated the development of mathematical laboratory models (based on assays of the four kallikrein-markers and a man’s age) and clinical models (using the four kallikreins, a man’s age, and the findings at DRE). A laboratory model is potentially very useful because men within a screening program do not have to undergo a DRE, and raises the concept of the use of a finger-prick blood test, which may be performed at home or in the office, instead of a visit to a particular screening center and a clinical examination. The adoption of a simpler and less intrusive test may raise compliance with the screening program. Fortunately, assays for tPSA and fPSA are now widely available and assays for iPSA and hK2 have now been developed; therefore, all four assays could be readily and conveniently incorporated into a single test with a relatively low cost.


The performance of fewer unnecessary prostate biopsies clearly has potential benefits such as a reduction in costs, a reduced risk of biopsy-associated complications such as bleeding and sepsis, and a reduction in the anxiety experienced by men who undergo screening. An additional potential benefit to undertaking fewer biopsies within a screening program might be that fewer clinically insignificant prostate cancers are detected, thereby reducing the associated problems of overdiagnosis and overtreatment of low-grade cancers that are otherwise considered overdiagnosed using current PSA-based detection methods. However, undertaking fewer prostate biopsies within a fixed population of screened men and thereby detecting fewer overall cancers, might be expected to result in the underdetection of clinically significant cancer cases. In fact, the available evidence from the studies performed thus far suggests that very few high-grade prostate cancers seem to be missed using the four kallikrein marker panel during an initial round of screening. In addition, it might be reasonable to assume that any high-grade cancers potentially missed by a round of screening using the four kallikrein panel could subsequently be detected during a further round of screening. This would still be within a “window of curability,” provided the screening rounds were sufficiently frequent to pick up any progressing malignancy before it had become incurable. All of the studies performed to date to evaluate the four kallikrein panel of biomarkers have been performed in European population cohorts using serum samples; however, plasma-EDTA anticoagulated samples may be more beneficial because they can be shipped to other centers for novel biomarkers to be evaluated in other laboratories. Moreover, validation studies performed using cohorts of men from the United States are needed to verify the applicability of this test in these populations. The four kallikrein marker assay is not yet readily available in the United States; however, it is likely to be introduced in the near future.


The use of different PSA isoforms and additional kallikreins as newer biomarkers within the context of a screening program has the potential to improve on the diagnostic performance of using PSA alone, resulting in fewer men needing to undergo a prostate biopsy procedure. Although the four kallikrein marker panel for example has shown particular promise in retrospective studies, many of the cohorts in the studies reported to date comprise serum, instead of plasma, samples, and many of the protocols within these screening studies included the use of sextant rather than extended core biopsies. It is now recognized that the use of extended core biopsies to detect prostate cancer is superior to sextant samples due to improved sampling of the gland. Moreover, many of the studies of PSA-based screening for prostate cancer have included men in the eighth decade of life, whereas it is now recognized that the men who are likely to benefit the most from prostate cancer screening are those in earlier midlife, perhaps between the ages of 40 and 60 years. A prospective study evaluating the contemporaneous use of a panel of PSA variants and additional kallikreins, focusing on early middle-aged men with the most to gain from a well-performing screening test, would be extremely helpful in clarifying the clinical usefulness of such a panel of kallikrein biomarkers.


A novel approach to improve the clinical performance of PSA is to combine the results of three automated blood tests (tPSA, fPSA, and [-2] proPSA) using a mathematical formula termed the Prostate Health Index (phi). The phi test specifically uses the formula ([-2] proPSA/fPSA × √tPSA) to calculate and report a phi result, which can improve the rate of prostate cancer detection compared with either tPSA or f/tPSA alone. Levels of phi have been demonstrated to differ significantly between men with and without prostate cancer in European cohorts. The phi had clinical specificities of 23% and 31% at a sensitivity of 95% and 90%, compared with specificities of 10% and 8% for tPSA alone. The phi has also been prospectively evaluated in a large cohort of men in the United States with PSA levels of 2 to 10 ng/mL. The performance of phi was compared with tPSA, fPSA, and [-2] proPSA. At a sensitivity of 80% to 95%, the specificity of phi to detect prostate cancer was higher than for tPSA and fPSA. The phi has also been shown to be a stronger predictor of prostate cancer at biopsy in men with PSA levels of 2 to 10 ng/mL in an Italian study.


Use of the phi may help to reduce the number of unnecessary prostate biopsies undertaken in men with moderately elevated levels of PSA and it may provide a useful tool in the discrimination of insignificant and aggressive prostate cancer. As an example, around three-quarters of prostate cancers detected with a phi value less than 25 have been found to be clinically insignificant at prostate biopsy. The phi has also been demonstrated to miss fewer prostate cancers with a Gleason score greater than 7 compared with tPSA or free-to-total PSA, whereas the risk of detecting a clinically aggressive cancer has been shown to be increased in men with higher phi readings. Studies have also shown an association between phi and [-2] proPSA levels and Gleason score, suggesting that these biomarkers may be useful in the prediction of aggressive disease. Whereas the level of PSA is known to correlate with prostate volume, the phi reading has been shown to correlate with tumor volume, providing further evidence that this tool may be helpful in the detection of clinically aggressive disease at prostate biopsy. By helping to reduce the number of unnecessary prostate biopsies, the use of phi not only provides a clinical benefit to men at lower levels of PSA but it can also facilitate substantial cost savings for health care systems. Taken together, the available evidence suggests that phi may play an important role in the identification of prostate cancer at biopsy, especially in men more than 50 years old with a negative DRE and a tPSA in the range of 2 to 10 ng/mL. Following a prospective multicenter Food and Drug Administration (FDA) registration study, which included men with contemporary and more extensive biopsy schemes, the phi has now been approved by the FDA in the United States.




Summary


Although the use of PSA has revolutionized the detection and treatment of prostate cancer, there remains considerable scope for both improvements in the use of variations of the PSA test and the development of novel biomarkers. The use of PSA derivatives and additional kallikrein markers has the potential to improve the current performance characteristics of the PSA test alone. The use of PSA as part of a multivariable approach to early prostate cancer detection, including such tools as the phi test, has recently been supported by the Melbourne Consensus Statement on Prostate Cancer Testing. An improved screening test may dramatically reduce the number of men undergoing an unnecessary biopsy while maintaining the ability to detect high-risk cases of this common malignancy. Such an approach has the potential to reduce the overdiagnosis and overtreatment of prostate cancer while enabling clinicians to focus on high-risk cases of localized prostate cancer in a population of men likely to benefit from radical intervention.



References



  1. 1. Siegel R., Naishadham D., and Jemal A.: Cancer statistics, 2013. CA Cancer J Clin 2013; 63: pp. 11-30

  2. 2. Hugosson J., Carlsson S., Aus G., et al: Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 2010; 11: pp. 725-732

  3. 3. Schroder F.H., Hugosson J., Roobol M.J., et al: Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012; 366: pp. 981-990

  4. 4. Vickers A.J., Ulmert D., Sjoberg D.D., 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: pp. f2023

  5. 5. Vickers A.J., and Lilja H.: Predicting prostate cancer many years before diagnosis: how and why? World J Urol 2012; 30: pp. 131-135

  6. 6. Schroder F.H., Hugosson J., Roobol M.J., et al: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009; 360: pp. 1320-1328

  7. 7. Welch H.G., and Albertsen P.C.: Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: 1986-2005. J Natl Cancer Inst 2009; 101: pp. 1325-1329

  8. 8. Catalona W.J., Partin A.W., Slawin K.M., et al: Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998; 279: pp. 1542-1547

  9. 9. Thompson I.M., Pauler D.K., Goodman P.J., et al: Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med 2004; 350: pp. 2239-2246

  10. 10. Lilja H., Ulmert D., and Vickers A.J.: Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nat Rev Cancer 2008; 8: pp. 268-278

  11. 11. Thompson I.M., Ankerst D.P., Chi C., et al: Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA 2005; 294: pp. 66-70

  12. 12. Ulmert D., Serio A.M., O’Brien M.F., et al: Long-term prediction of prostate cancer: prostate-specific antigen (PSA) velocity is predictive but does not improve the predictive accuracy of a single PSA measurement 15 years or more before cancer diagnosis in a large, representative, unscreened population. J Clin Oncol 2008; 26: pp. 835-841

  13. 13. Drazer M.W., Huo D., Schonberg M.A., et al: Population-based patterns and predictors of prostate-specific antigen screening among older men in the United States. J Clin Oncol 2011; 29: pp. 1736-1743

  14. 14. Ross L.E., Taylor Y.J., Richardson L.C., et al: Patterns in prostate-specific antigen test use and digital rectal examinations in the Behavioral Risk Factor Surveillance System, 2002-2006. J Natl Med Assoc 2009; 101: pp. 316-324

  15. 15. Sirovich B.E., Schwartz L.M., and Woloshin S.: Screening men for prostate and colorectal cancer in the United States: does practice reflect the evidence? JAMA 2003; 289: pp. 1414-1420

  16. 16. Loeb S., Carter H.B., Berndt S.I., et al: Complications after prostate biopsy: data from SEER-Medicare. J Urol 2011; 186: pp. 1830-1834

  17. 17. Summaries for patients. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012; 157: pp. 1-44

  18. 18. Ablin R.J., Soanes W.A., Bronson P., et al: Precipitating antigens of the normal human prostate. J Reprod Fertil 1970; 22: pp. 573-574

  19. 19. Chan D.W., Bruzek D.J., Oesterling J.E., et al: Prostate-specific antigen as a marker for prostatic cancer: a monoclonal and a polyclonal immunoassay compared. Clin Chem 1987; 33: pp. 1916-1920

  20. 20. Kuriyama M., Wang M.C., Lee C.I., et al: Use of human prostate-specific antigen in monitoring prostate cancer. Cancer Res 1981; 41: pp. 3874-3876

  21. 21. Kuriyama M., Wang M.C., Papsidero L.D., et al: Quantitation of prostate-specific antigen in serum by a sensitive enzyme immunoassay. Cancer Res 1980; 40: pp. 4658-4662

  22. 22. Oesterling J.E., Chan D.W., Epstein J.I., et al: Prostate specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J Urol 1988; 139: pp. 766-772

  23. 23. Papsidero L.D., Wang M.C., Valenzuela L.A., et al: A prostate antigen in sera of prostatic cancer patients. Cancer Res 1980; 40: pp. 2428-2432

  24. 24. Seamonds B., Yang N., Anderson K., et al: Evaluation of prostate-specific antigen and prostatic acid phosphatase as prostate cancer markers. Urology 1986; 28: pp. 472-479

  25. 25. Sensabaugh G.F.: Isolation and characterization of a semen-specific protein from human seminal plasma: a potential new marker for semen identification. J Forensic Sci 1978; 23: pp. 106-115

  26. 26. Stamey T.A., Yang N., Hay A.R., et al: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987; 317: pp. 909-916

  27. 27. Wang M.C., Papsidero L.D., Kuriyama M., et al: Prostate antigen: a new potential marker for prostatic cancer. Prostate 1981; 2: pp. 89-96

  28. 28. Wang M.C., Valenzuela L.A., Murphy G.P., et al: Purification of a human prostate specific antigen. Invest Urol 1979; 17: pp. 159-163

  29. 29. Polascik T.J., Oesterling J.E., and Partin A.W.: Prostate specific antigen: a decade of discovery–what we have learned and where we are going. J Urol 1999; 162: pp. 293-306

  30. 30. Pound C.R., Partin A.W., Eisenberger M.A., et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281: pp. 1591-1597

  31. 31. Pound C.R., Walsh P.C., Epstein J.I., et al: Radical prostatectomy as treatment for prostate-specific antigen-detected stage T1c prostate cancer. World J Urol 1997; 15: pp. 373-377

  32. 32. Stephenson R.A., and Stanford J.L.: Population-based prostate cancer trends in the United States: patterns of change in the era of prostate-specific antigen. World J Urol 1997; 15: pp. 331-335

  33. 33. Henttu P., Liao S.S., and Vihko P.: Androgens up-regulate the human prostate-specific antigen messenger ribonucleic acid (mRNA), but down-regulate the prostatic acid phosphatase mRNA in the LNCaP cell line. Endocrinology 1992; 130: pp. 766-772

  34. 34. Young C.Y., Montgomery B.T., Andrews P.E., et al: Hormonal regulation of prostate-specific antigen messenger RNA in human prostatic adenocarcinoma cell line LNCaP. Cancer Res 1991; 51: pp. 3748-3752

  35. 35. Diamandis E.P., and Yousef G.M.: Human tissue kallikrein gene family: a rich source of novel disease biomarkers. Expert Rev Mol Diagn 2001; 1: pp. 182-190

  36. 36. Diamandis E.P., Yousef G.M., Luo L.Y., et al: The new human kallikrein gene family: implications in carcinogenesis. Trends Endocrinol Metab 2000; 11: pp. 54-60

  37. 37. Levesque M., Hu H., D’Costa M., et al: Prostate-specific antigen expression by various tumors. J Clin Lab Anal 1995; 9: pp. 123-128

  38. 38. Christensson A., Laurell C.B., and Lilja H.: Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine proteinase inhibitors. Eur J Biochem 1990; 194: pp. 755-763

  39. 39. Lilja H.: A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal vesicle protein. J Clin Invest 1985; 76: pp. 1899-1903

  40. 40. Lilja H., and Laurell C.B.: Liquefaction of coagulated human semen. Scand J Clin Lab Invest 1984; 44: pp. 447-452

  41. 41. Lilja H., Oldbring J., Rannevik G., et al: Seminal vesicle-secreted proteins and their reactions during gelation and liquefaction of human semen. J Clin Invest 1987; 80: pp. 281-285

  42. 42. McGee R.S., and Herr J.C.: Human seminal vesicle-specific antigen is a substrate for prostate-specific antigen (or P-30). Biol Reprod 1988; 39: pp. 499-510

  43. 43. Christensson A., Bjork T., Nilsson O., et al: Serum prostate specific antigen complexed to alpha 1-antichymotrypsin as an indicator of prostate cancer. J Urol 1993; 150: pp. 100-105

  44. 44. Christensson A., and Lilja H.: Complex formation between protein C inhibitor and prostate-specific antigen in vitro and in human semen. Eur J Biochem 1994; 220: pp. 45-53

  45. 45. Lilja H.: Prostate-specific antigen: molecular forms and the human kallikrein gene family. Br J Urol 1997; 79: pp. 44-48

  46. 46. Lilja H., Christensson A., Dahlen U., et al: Prostate-specific antigen in serum occurs predominantly in complex with alpha 1-antichymotrypsin. Clin Chem 1991; 37: pp. 1618-1625

  47. 47. McCormack R.T., Rittenhouse H.G., Finlay J.A., et al: Molecular forms of prostate-specific antigen and the human kallikrein gene family: a new era. Urology 1995; 45: pp. 729-744

  48. 48. Stenman U.H., Leinonen J., Alfthan H., et al: A complex between prostate-specific antigen and alpha 1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer. Cancer Res 1991; 51: pp. 222-226

  49. 49. Brawer M.K.: Prostate-specific antigen: current status. CA Cancer J Clin 1999; 49: pp. 264-281

  50. 50. Partin A.W., Brawer M.K., Bartsch G., et al: Complexed prostate specific antigen improves specificity for prostate cancer detection: results of a prospective multicenter clinical trial. J Urol 2003; 170: pp. 1787-1791

  51. 51. Lee R., Localio A.R., Armstrong K., et al: A meta-analysis of the performance characteristics of the free prostate-specific antigen test. Urology 2006; 67: pp. 762-768

  52. 52. Partin A.W., Brawer M.K., Subong E.N., et al: Prospective evaluation of percent free-PSA and complexed-PSA for early detection of prostate cancer. Prostate Cancer Prostatic Dis 1998; 1: pp. 197-203

  53. 53. Roddam A.W., Duffy M.J., Hamdy F.C., et al: Use of prostate-specific antigen (PSA) isoforms for the detection of prostate cancer in men with a PSA level of 2-10 ng/ml: systematic review and meta-analysis. Eur Urol 2005; 48: pp. 386-399

  54. 54. Stephan C., Jung K., Diamandis E.P., et al: Prostate-specific antigen, its molecular forms, and other kallikrein markers for detection of prostate cancer. Urology 2002; 59: pp. 2-8

  55. 55. Veltri R.W., and Miller M.C.: Free/total PSA ratio improves differentiation of benign and malignant disease of the prostate: critical analysis of two different test populations. Urology 1999; 53: pp. 736-745

  56. 56. Vessella R.L., Lange P.H., Partin A.W., et al: Probability of prostate cancer detection based on results of a multicenter study using the AxSYM free PSA and total PSA assays. Urology 2000; 55: pp. 909-914

  57. 57. Kumar A., Mikolajczyk S.D., Goel A.S., et al: Expression of pro form of prostate-specific antigen by mammalian cells and its conversion to mature, active form by human kallikrein 2. Cancer Res 1997; 57: pp. 3111-3114

  58. 58. Kumar A., Mikolajczyk S.D., Hill T.M., et al: Different proportions of various prostate-specific antigen (PSA) and human kallikrein 2 (hK2) forms are present in noninduced and androgen-induced LNCaP cells. Prostate 2000; 44: pp. 248-254

  59. 59. Mikolajczyk S.D., Grauer L.S., Millar L.S., et al: A precursor form of PSA (pPSA) is a component of the free PSA in prostate cancer serum. Urology 1997; 50: pp. 710-714

  60. 60. Mikolajczyk S.D., Marker K.M., Millar L.S., et al: A truncated precursor form of prostate-specific antigen is a more specific serum marker of prostate cancer. Cancer Res 2001; 61: pp. 6958-6963

  61. 61. Mikolajczyk S.D., Marks L.S., Partin A.W., et al: Free prostate-specific antigen in serum is becoming more complex. Urology 2002; 59: pp. 797-802

  62. 62. Peter J., Unverzagt C., Krogh T.N., et al: Identification of precursor forms of free prostate-specific antigen in serum of prostate cancer patients by immunosorption and mass spectrometry. Cancer Res 2001; 61: pp. 957-962

  63. 63. Zhang W.M., Leinonen J., Kalkkinen N., et al: Purification and characterization of different molecular forms of prostate-specific antigen in human seminal fluid. Clin Chem 1995; 41: pp. 1567-1573

  64. 64. Bangma C.H., Wildhagen M.F., Yurdakul G., et al: The value of (-7, -5)pro-prostate-specific antigen and human kallikrein-2 as serum markers for grading prostate cancer. BJU Int 2004; 93: pp. 720-724

  65. 65. Lein M., Semjonow A., Graefen M., et al: A multicenter clinical trial on the use of (-5, -7) pro prostate specific antigen. J Urol 2005; 174: pp. 2150-2153

  66. 66. Martin B.J., Finlay J.A., Sterling K., et al: Early detection of prostate cancer in African-American men through use of multiple biomarkers: human kallikrein 2 (hK2), prostate-specific antigen (PSA), and free PSA (fPSA). Prostate Cancer Prostatic Dis 2004; 7: pp. 132-137

  67. 67. Mikolajczyk S.D., Catalona W.J., Evans C.L., et al: Proenzyme forms of prostate-specific antigen in serum improve the detection of prostate cancer. Clin Chem 2004; 50: pp. 1017-1025

  68. 68. Mikolajczyk S.D., Millar L.S., Wang T.J., et al: A precursor form of prostate-specific antigen is more highly elevated in prostate cancer compared with benign transition zone prostate tissue. Cancer Res 2000; 60: pp. 756-759

  69. 69. Mikolajczyk S.D., and Rittenhouse H.G.: Tumor-associated forms of prostate specific antigen improve the discrimination of prostate cancer from benign disease. Rinsho Byori 2004; 52: pp. 223-230

  70. 70. Mikolajczyk S.D., Song Y., Wong J.R., et al: Are multiple markers the future of prostate cancer diagnostics? Clin Biochem 2004; 37: pp. 519-528

  71. 71. Nurmikko P., Pettersson K., Piironen T., et al: Discrimination of prostate cancer from benign disease by plasma measurement of intact, free prostate-specific antigen lacking an internal cleavage site at Lys145-Lys146. Clin Chem 2001; 47: pp. 1415-1423

  72. 72. Sokoll L.J., Chan D.W., Mikolajczyk S.D., et al: Proenzyme psa for the early detection of prostate cancer in the 2.5-4.0 ng/ml total psa range: preliminary analysis. Urology 2003; 61: pp. 274-276

  73. 73. Steuber T., Nurmikko P., Haese A., et al: Discrimination of benign from malignant prostatic disease by selective measurements of single chain, intact free prostate specific antigen. J Urol 2002; 168: pp. 1917-1922

  74. 74. Catalona W.J., Bartsch G., Rittenhouse H.G., et al: Serum pro prostate specific antigen improves cancer detection compared to free and complexed prostate specific antigen in men with prostate specific antigen 2 to 4 ng/ml. J Urol 2003; 170: pp. 2181-2185

  75. 75. Catalona W.J., Partin A.W., Sanda M.G., et al: A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. J Urol 2011; 185: pp. 1650-1655

  76. 76. de Vries S.H., Raaijmakers R., Blijenberg B.G., et al: Additional use of [-2] precursor prostate-specific antigen and “benign” PSA at diagnosis in screen-detected prostate cancer. Urology 2005; 65: pp. 926-930

  77. 77. Filella X., and Gimenez N.: Evaluation of [-2] proPSA and Prostate Health Index (phi) for the detection of prostate cancer: a systematic review and meta-analysis. Clin Chem Lab Med 2013; 51: pp. 729-739

  78. 78. Guazzoni G., Lazzeri M., Nava L., 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. Eur Urol 2012; 61: pp. 455-466

  79. 79. Guazzoni G., Nava L., Lazzeri M., et al: Prostate-specific antigen (PSA) isoform p2PSA significantly improves the prediction of prostate cancer at initial extended prostate biopsies in patients with total PSA between 2.0 and 10 ng/ml: results of a prospective study in a clinical setting. Eur Urol 2011; 60: pp. 214-222

  80. 80. Houlgatte A., Vincendeau S., Desfemmes F., et al: Use of [-2] pro PSA and phi index for early detection of prostate cancer: a prospective of 452 patients. Prog Urol 2011; 22: pp. 279-283

  81. 81. Isharwal S., Makarov D.V., Sokoll L.J., et al: ProPSA and diagnostic biopsy tissue DNA content combination improves accuracy to predict need for prostate cancer treatment among men enrolled in an active surveillance program. Urology 2011; 77(3): pp. e1-e6

  82. 82. Jansen F.H., van Schaik R.H., Kurstjens J., et al: Prostate-specific antigen (PSA) isoform p2PSA in combination with total PSA and free PSA improves diagnostic accuracy in prostate cancer detection. Eur Urol 2010; 57: pp. 921-927

  83. 83. Le B.V., Griffin C.R., Loeb S., et al: [-2]Proenzyme prostate specific antigen is more accurate than total and free prostate specific antigen in differentiating prostate cancer from benign disease in a prospective prostate cancer screening study. J Urol 2010; 183: pp. 1355-1359

  84. 84. Makarov D.V., Isharwal S., Sokoll L.J., et al: Pro-prostate-specific antigen measurements in serum and tissue are associated with treatment necessity among men enrolled in expectant management for prostate cancer. Clin Cancer Res 2009; 15: pp. 7316-7321

  85. 85. Sokoll L.J., Sanda M.G., Feng Z., et al: A prospective, multicenter, National Cancer Institute Early Detection Research Network study of [-2]proPSA: improving prostate cancer detection and correlating with cancer aggressiveness. Cancer Epidemiol Biomarkers Prev 2010; 19: pp. 1193-1200

  86. 86. Sokoll L.J., Wang Y., Feng Z., et al: [-2]proenzyme prostate specific antigen for prostate cancer detection: a national cancer institute early detection research network validation study. J Urol 2008; 180: pp. 539-543

  87. 87. Stephan C., Kahrs A.M., Cammann H., et al: A [-2]proPSA-based artificial neural network significantly improves differentiation between prostate cancer and benign prostatic diseases. Prostate 2009; 69: pp. 198-207

  88. 88. Nurmikko P., Vaisanen V., Piironen T., et al: Production and characterization of novel anti-prostate-specific antigen (PSA) monoclonal antibodies that do not detect internally cleaved Lys145-Lys146 inactive PSA. Clin Chem 2000; 46: pp. 1610-1618

  89. 89. Pinzani P., Lind K., Malentacchi F., et al: Prostate-specific antigen mRNA and protein levels in laser microdissected cells of human prostate measured by real-time reverse transcriptase-quantitative polymerase chain reaction and immuno-quantitative polymerase chain reaction. Hum Pathol 2008; 39: pp. 1474-1482

  90. 90. Armitage T.G., Cooper E.H., Newling D.W., et al: The value of the measurement of serum prostate specific antigen in patients with benign prostatic hyperplasia and untreated prostate cancer. Br J Urol 1988; 62: pp. 584-589

  91. 91. Dalton D.L.: Elevated serum prostate-specific antigen due to acute bacterial prostatitis. Urology 1989; 33: pp. 465

  92. 92. Ercole C.J., Lange P.H., Mathisen M., et al: Prostatic specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostatic cancer. J Urol 1987; 138: pp. 1181-1184

  93. 93. Nadler R.B., Humphrey P.A., Smith D.S., et al: Effect of inflammation and benign prostatic hyperplasia on elevated serum prostate specific antigen levels. J Urol 1995; 154: pp. 407-413

  94. 94. Partin A.W., Carter H.B., Chan D.W., et al: Prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. J Urol 1990; 143: pp. 747-752

  95. 95. Catalona W.J., Smith D.S., Ratliff T.L., et al: Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991; 324: pp. 1156-1161

  96. 96. Carter H.B.: A PSA threshold of 4.0 ng/mL for early detection of prostate cancer: the only rational approach for men 50 years old and older. Urology 2000; 55: pp. 796-799

  97. 97. Catalona W.J., Ramos C.G., Carvalhal G.F., et al: Lowering PSA cutoffs to enhance detection of curable prostate cancer. Urology 2000; 55: pp. 791-795

  98. 98. Catalona W.J., Southwick P.C., Slawin K.M., et al: Comparison of percent free PSA, PSA density, and age-specific PSA cutoffs for prostate cancer detection and staging. Urology 2000; 56: pp. 255-260

  99. 99. Becker C., Piironen T., Kiviniemi J., et al: Sensitive and specific immunodetection of human glandular kallikrein 2 in serum. Clin Chem 2000; 46: pp. 198-206

  100. 100. Darson M.F., Pacelli A., Roche P., et al: Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker. Urology 1997; 49: pp. 857-862

  101. 101. Finlay J.A., Evans C.L., Day J.R., et al: Development of monoclonal antibodies specific for human glandular kallikrein (hK2): development of a dual antibody immunoassay for hK2 with negligible prostate-specific antigen cross-reactivity. Urology 1998; 51: pp. 804-809

  102. 102. Klee G.G., Goodmanson M.K., Jacobsen S.J., et al: Highly sensitive automated chemiluminometric assay for measuring free human glandular kallikrein-2. Clin Chem 1999; 45: pp. 800-806

  103. 103. Lovgren J., Valtonen-Andre C., Marsal K., et al: Measurement of prostate-specific antigen and human glandular kallikrein 2 in different body fluids. J Androl 1999; 20: pp. 348-355

  104. 104. Martin B.J., Cheli C.D., Sterling K., et al: Prostate specific antigen isoforms and human glandular kallikrein 2–which offers the best screening performance in a predominantly black population? J Urol 2006; 175: pp. 104-107

  105. 105. Nam R.K., Diamandis E.P., Toi A., et al: Serum human glandular kallikrein-2 protease levels predict the presence of prostate cancer among men with elevated prostate-specific antigen. J Clin Oncol 2000; 18: pp. 1036-1042

  106. 106. Piironen T., Pettersson K., Suonpaa M., et al: In vitro stability of free prostate-specific antigen (PSA) and prostate-specific antigen (PSA) complexed to alpha 1-antichymotrypsin in blood samples. Urology 1996; 48: pp. 81-87

  107. 107. Rittenhouse H.G., Finlay J.A., Mikolajczyk S.D., et al: Human Kallikrein 2 (hK2) and prostate-specific antigen (PSA): two closely related, but distinct, kallikreins in the prostate. Crit Rev Clin Lab Sci 1998; 35: pp. 275-368

  108. 108. Stephan C., Jung K., Lein M., et al: Molecular forms of prostate-specific antigen and human kallikrein 2 as promising tools for early diagnosis of prostate cancer. Cancer Epidemiol Biomarkers Prev 2000; 9: pp. 1133-1147

  109. 109. Young C.Y., Andrews P.E., Montgomery B.T., et al: Tissue-specific and hormonal regulation of human prostate-specific glandular kallikrein. Biochemistry 1992; 31: pp. 818-824

  110. 110. Yousef G.M., Kyriakopoulou L.G., Scorilas A., et al: Quantitative expression of the human kallikrein gene 9 (KLK9) in ovarian cancer: a new independent and favorable prognostic marker. Cancer Res 2001; 61: pp. 7811-7818

  111. 111. Darson M.F., Pacelli A., Roche P., et al: Human glandular kallikrein 2 expression in prostate adenocarcinoma and lymph node metastases. Urology 1999; 53: pp. 939-944

  112. 112. Kwiatkowski M.K., Recker F., Piironen T., et al: In prostatism patients the ratio of human glandular kallikrein to free PSA improves the discrimination between prostate cancer and benign hyperplasia within the diagnostic “gray zone” of total PSA 4 to 10 ng/mL. Urology 1998; 52: pp. 360-365

  113. 113. Tremblay R.R., Deperthes D., Tetu B., et al: Immunohistochemical study suggesting a complementary role of kallikreins hK2 and hK3 (prostate-specific antigen) in the functional analysis of human prostate tumors. Am J Pathol 1997; 150: pp. 455-459

  114. 114. Nakamura T., Mitsui S., Okui A., et al: Molecular cloning and expression of a variant form of hippostasin/KLK11 in prostate. Prostate 2003; 54: pp. 299-305

  115. 115. Nakamura T., Stephan C., Scorilas A., et al: Quantitative analysis of hippostasin/KLK11 gene expression in cancerous and noncancerous prostatic tissues. Urology 2003; 61: pp. 1042-1046

  116. 116. Obiezu C.V., Soosaipillai A., Jung K., et al: Detection of human kallikrein 4 in healthy and cancerous prostatic tissues by immunofluorometry and immunohistochemistry. Clin Chem 2002; 48: pp. 1232-1240

  117. 117. Parekh D.J., Ankerst D.P., Baillargeon J., et al: Assessment of 54 biomarkers for biopsy-detectable prostate cancer. Cancer Epidemiol Biomarkers Prev 2007; 16: pp. 1966-1972

  118. 118. Sardana G., Marshall J., and Diamandis E.P.: Discovery of candidate tumor markers for prostate cancer via proteomic analysis of cell culture-conditioned medium. Clin Chem 2007; 53: pp. 429-437

  119. 119. Xi Z., Klokk T.I., Korkmaz K., et al: Kallikrein 4 is a predominantly nuclear protein and is overexpressed in prostate cancer. Cancer Res 2004; 64: pp. 2365-2370

  120. 120. Yousef G.M., Stephan C., Scorilas A., et al: Differential expression of the human kallikrein gene 14 (KLK14) in normal and cancerous prostatic tissues. Prostate 2003; 56: pp. 287-292

  121. 121. Vickers A.J., Cronin A.M., Aus G., et al: A panel of kallikrein markers can reduce unnecessary biopsy for prostate cancer: data from the European Randomized Study of Prostate Cancer Screening in Goteborg, Sweden. BMC Med 2008; 6: pp. 19

  122. 122. Ulmert D., Becker C., Nilsson J.A., et al: Reproducibility and accuracy of measurements of free and total prostate-specific antigen in serum vs plasma after long-term storage at -20 degrees C. Clin Chem 2006; 52: pp. 235-239

  123. 123. Benchikh A., Savage C., Cronin A., et al: A panel of kallikrein markers can predict outcome of prostate biopsy following clinical work-up: an independent validation study from the European Randomized Study of Prostate Cancer screening, France. BMC Cancer 2010; 10: pp. 635

  124. 124. Gupta A., Roobol M.J., Savage C.J., et al: A four-kallikrein panel for the prediction of repeat prostate biopsy: data from the European Randomized Study of Prostate Cancer screening in Rotterdam, Netherlands. Br J Cancer 2010; 103: pp. 708-714

  125. 125. Vickers A., Cronin A., Roobol M., et al: Reducing unnecessary biopsy during prostate cancer screening using a four-kallikrein panel: an independent replication. J Clin Oncol 2010; 28: pp. 2493-2498

  126. 126. Vickers A.J., Cronin A.M., Aus G., et al: Impact of recent screening on predicting the outcome of prostate cancer biopsy in men with elevated prostate-specific antigen: data from the European Randomized Study of Prostate Cancer Screening in Gothenburg, Sweden. Cancer 2010; 116: pp. 2612-2620

  127. 127. Vickers A.J., Cronin A.M., Roobol M.J., et al: A four-kallikrein panel predicts prostate cancer in men with recent screening: data from the European Randomized Study of Screening for Prostate Cancer, Rotterdam. Clin Cancer Res 2010; 16: pp. 3232-3239

  128. 128. Vickers A.J., Gupta A., Savage C.J., et al: A panel of kallikrein marker predicts prostate cancer in a large, population-based cohort followed for 15 years without screening. Cancer Epidemiol Biomarkers Prev 2011; 20: pp. 255-261

  129. 129. European Association of Urology. Prostate cancer. Full guidelines. 2012 [cited 7th May 2013]. Available at: http://www.uroweb.org/guidelines/online-guidelines/. Accessed May 7, 2013.

  130. 130. Nichol M.B., Wu J., An J.J., et al: Budget impact analysis of a new prostate cancer risk index for prostate cancer detection. Prostate Cancer Prostatic Dis 2011; 14: pp. 253-261

  131. 131. Murphy D. The Melbourne Consensus Statement on Prostate Cancer Testing. 2013 [cited 24th November 2013]. Available at: http://www.bjuinternational.com/bjui-blog/the-melbourne-consensus-statement-on-prostate-cancer-testing/. Accessed November 24, 2013.

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Mar 3, 2017 | Posted by in UROLOGY | Comments Off on Emerging PSA-Based Tests to Improve Screening

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