Screening for cancer: are biomarkers of value?

– February/March 2011 16 Tumour markers
and 10% fPSA, similar to the distribution
found in the circulation of PCa patients [28].
This 90:10 PSA preparation was established
as the World Health Organisation standard
(WHO 96/670) [29]. PSA assays using the
WHO 96/670 standard yield 20-25% lower
PSA values than those using the Hybritech
standards [30].
In 2004 Link et al compared the Beckman
Coulter Access and Bayer Centaur system
as well as the third generation DCP Immulite
System, and found higher PSA values
measured with Access than Centaur and
similar results with the Centaur and Immulite
systems [31]. Blijenberg et al compared
the Hybritech Tandem E, Beckman Coulter
Access, DCP Immulite, Roche Diagnositcs
Elecsys and Defia Prostatus systems and
showed similar measurements for total
PSA but not for fPSA [32].
These findings were confirmed by two
recent studies comparing equimolar assays
calibrated to WHO standards. Kort et al
compared tPSa, fPSa and cPSA in 70 samples
in 6 different assays (Beckman Coulter
Access, Abbott ARCHITECTS and Abbott
AxSYM, Bayer Centaur, DPC Immulite
2000, Roche Modular Analytics E170).
Results showed variation in values for tPSA
from 0.5 to 1.0µg/L and for fPSA from 0.12
to 0.40µg/L. Overall results showed less
diversity for tPSA than fPSA, but tPSA
assays were still not interchangeable [33].
Stephan et al investigated the interchangeability
of tPSA, fPSA and %fPSA between
Beckman Coulter Access, DPC Immulite
2000, Abbott AxSYM, Bayer Centaur and
Roche Diagnositcs Elecsys assays and still
found significant interassay variability.
This may be due to the different epitope
specificity of the antibodies used [34].
Figure 1. Design of immunoassay for simultaneous
measurement of free, uncomplexed forms of PSA
and total PSA. Monoclonal antibodies coated on
plate as capture antibody for free and complexed
forms in equimolar fashion (Mab1). Monoclonal
antibodies to detect PSA-ACT and free PSA (Mab2)
and monoclonal antibodies accessible for fPSA
epitope only (Mab3), both measureable
with fluorescence (27).
Conclusion
Since the introduction of WHO 96/670
Standards and development of tPSA-assays
designed to detect free PSA and PSA-ACT
on an equimolar basis, inter-assay variability
has decreased – in particular regarding
tPSA values. Nevertheless results of commercially
available tPSA assays are not yet
interchangeable, not uniformly standardised,
and with no widely accepted conversion
factor to correct the accuracy. Large
discrepancies in fPSA values may result in
clinical misinterpretation as the decision to
consider a prostate biopsy may be based on
the ratio of fPSA to tPSA.
Persisting discrepancies between assays
result from a combination of the overall
design, epitope specificity and affinity
of capture and detector antibodies, use
of monoclonal or polyclonal antibodies,
cross-reactivity and non-specific interferences,
as well as standardisation. Physicians
should therefore be aware of which assay
and standards have been used and note
whether the same test is also being used for
longitudinal monitoring of their patients.
Acknowledgements
Grant support: Swedish Cancer Society, Swedish
Research Council (Medicine), The Tegger Foundation,
Lund University Medical Faculty ALF grants,
the National Cancer Institute [P50-CA92629], the
Sidney Kimmel Center for Prostate and Urologic
Cancers, David H. Koch through the Prostate
Cancer Foundation, Fundación Federico SA, and
German Association of Urology (DGU), Ferdinand
Eisenberger research grant Competing interest
declaration: Dr Hans Lilja holds patents for free
PSA and hK2 assays.
References
1. Lilja H. J Clin Invest 1985;76:1899-1903
2. Schedlich LJ, Bennetts BH, Morris BJ. DNA 1987;6:429-437
3. Hara M, Koyanagi Y, Inoue T, Fukuyama T. Nihon Hoigaku
Zasshi 1971;25:322-324
4. Graves HC, Kamarei M, Stamey TA. J Urol 1990;
144:1510-1515
5. Papsidero LD, Wang MC, Valenzuela LA, Murphy GP, Chu
TM. Cancer Res 1980;40:2428-2432
6. Kuriyama M, Wang MC, Lee CI, et al. Cancer Res 1981;
41:3874-3876
7. Lundwall A, Clauss A, Olsson AY. Biol Chem 2006;
387:243-249
8. Lilja H, Cronin AM, Dahlin A, et al. Cancer 2010
9. Crawford ED, Grubb R, 3rd, Black A, et al. J Clin Oncol 2011;
29:355-361
10. Christensson A, Laurell CB, Lilja H. Eur J Biochem 1990;
194:755-763
11. Lilja H, Christensson A, Dahlen U, et al. PClin Chem 1991;
37:1618-1625
12. Lilja H, Ulmert D, Bjork T, et al. J Clin Oncol 2007;25:431-436
13. Christensson A, Bjork T, Nilsson O, et al. J Urol 1993;
150:100-105
14. Roddam AW, Duffy MJ, Hamdy FC, et al. Eur Urol 2005;
48:386-399; discussion 398-389
15. Mikolajczyk SD, Millar LS, Wang TJ, et al. Urology 2000;
55:41-45
16. Nurmikko P, Pettersson K, Piironen T, Hugosson J, Lilja H.
Clin Chem 2001 ;47:1415-1423
17. Stenman UH, Paus E, Allard WJ, et al. Tumour Biol 1999;20
Suppl 1:1-12
28. Nurmikko P, Vaisanen V, Piironen T, et al. Clin Chem 2000;
46:1610-1618
18. Black MH, Grass CL, Leinonen J, Stenman UH, Diamandis
EP. Clin Chem 1999; 45:347-354
19. Zhu L, Leinonen J, Zhang WM, Finne P, Stenman UH. Clin
Chem 2003; 49:97-103
20. Bjork T, Piironen T, Pettersson K, et al. Urology 1996;
48:882-888
21. Piironen T, Lovgren J, Karp M, et al. Clin Chem 1996;
42:1034-1041
22. Lilja H, Haese A, Bjork T, et al. J Urol 1999;162:2029-2034;
discussion 2034-2025
23. Baumgart Y, Otto A, Schafer A, et al. Clin Chem 2005;
51:84-92
24. Graves HC, Wehner N, Stamey TA. J Urol 1990;
144:1516-1522
25. Semjonow A, Brandt B, Oberpenning F, Roth S, Hertle L.
Prostate Suppl 1996; 7:3-16
26. Roehrborn CG, Gregory A, McConnell JD, Sagalowsky AI,
Wians FH, Jr. Urology 1996; 48:23-32
27. Leewansangtong S, Goktas S, Lepoff R, Holthaus K, Crawford
ED. Urology 1998; 52:467-469
28. Prestigiacomo AF, Chen Z, Stamey TA. Scand J Clin Lab
Invest Suppl 1995; 221:57-59
29. Rafferty B, Rigsby P, Rose M, Stamey T, Gaines Das R. Clin
Chem 2000; 46:1310-1317
30. Stamey TA. Urol Clin North Am 1997;24:269-273
31.Link RE, Shariat SF, Nguyen CV, et al. J Urol 2004;171:
2234-2238
32. Blijenberg BG, Yurdakul G, Van Zelst BD, et al. BJU Int 2001;
88:545-550
33. Kort SAR, Martens F, Vanpoucke H, van Duijnhoven HL,
Blankenstein MA. Clinical Chemistry 2006;52:1568-1574
34. Stephan C, Klaas M, Muller C, et al. Clin Chem
2006;52:59-64
The authors
Katharina Braun 1,5 , David Ulmert 1,3,4 and
Hans Lilja 1,2,3
Departments of 1 Surgery (Urology), 2 Clinical
Laboratories, and Medicine, Memorial Sloan-
Kettering Cancer Center, New York, USA
Departments of 3 Laboratory Medicine, and
4
Urology, Lund University, Skåne University
Hospital, Malmö, Sweden
5
Department of Urology, Marienhospital
Herne, University Bochum, Herne, Germany
Corresponding author:
Hans Lilja, MD, PhD.
Memorial Sloan-Kettering Cancer Center
Department of Clinical Laboratories, Urology,
1275 York Avenue, Box 213, New York, NY
10065, USA
e-mail: liljah@mskcc.org