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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

Hans Lilja, David Ulmert, Thomas Björk, Charlotte Becker, Angel M. Serio, Jan-Åke Nilsson, Per-Anders Abrahamsson, Andrew J. Vickers, Göran Berglund

From the Departments of Laboratory Medicine, Urology, and Medicine, Lund University, University Hospital UMAS, Malmö, Sweden; and Departments of Clinical Laboratories, Urology, Medicine, and Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY

Address reprint requests to Hans Lilja, MD, PhD, Departments of Clinical Laboratories, Urology, and Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA; e-mail: liljah{at}mskcc.org

	ABSTRACT

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Purpose: We examined whether prostate-specific antigen (PSA) forms and human kallikrein 2 (hK2) measured at age 44 to 50 years predict long-term risk of incident prostate cancer.

Methods: From 1974 to 1986, 21,277 men age 50 years in Malmö, Sweden, enrolled onto a cardiovascular study (74% participation). The rate of PSA screening in this population is low. According to the Swedish Cancer Registry, 498 were later diagnosed with prostate cancer. We measured hK2, free PSA, and total PSA (tPSA) in archived blood plasma from 462 participants later diagnosed with prostate cancer and from 1,222 matched controls. Conditional logistic regression was used to test for association of prostate cancer with hK2 and PSA forms measured at baseline.

Results: Median delay between venipuncture and prostate cancer diagnosis was 18 years. hK2 and all PSA forms were strongly associated with prostate cancer (all P < .0005). None of the 90 anthropometric, lifestyle, biochemical, and medical history variables measured at baseline was importantly predictive. A tPSA increase of 1 ng/mL was associated with an increase in odds of cancer of 3.69 (95% CI, 2.99 to 4.56); addition of other PSA forms or hK2 did not add to the predictive value of tPSA. tPSA remained predictive for men diagnosed 20 years after venipuncture, and the predictive value remained unchanged in an analysis restricted to palpable disease.

Conclusion: A single PSA test at age 44 to 50 years predicts subsequent clinically diagnosed prostate cancer. This raises the possibility of risk stratification for prostate cancer screening programs.

	INTRODUCTION

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Prostate-specific antigen (PSA) and human kallikrein 2 (hK2), members of the kallikrein-type serine protease family, are abundantly produced and secreted by both normal and malignant prostate epithelial cells. Their concentration in blood is normally very low,^1-3 but PSA in serum can increase up to 10⁴-fold during advanced stages of prostate cancer. Nearly all immunoreactive PSA in blood is of two types: free PSA (fPSA), a heterogeneous group of noncomplexed forms, and complex PSA (cPSA), predominantly a covalently linked complex between PSA and the protease inhibitor 1-antichymotrypsin.^1-3 Total PSA (tPSA) is the form most commonly measured.

Several guidelines in the United States recommend annual serum PSA measurements and digital rectal examination for men age 50 years or older, and a prostate biopsy if PSA is 4.0 ng/mL.^4-7 However, the value of PSA screening is controversial, given that PSA may be affected by many factors other than prostate cancer, particularly benign prostate conditions.^8-11 Studies have questioned both the specificity¹² and sensitivity of PSA testing.^13,14

Several reports have indicated that PSA levels may predict prostate cancer some years before the diagnosis. Stenman et al¹⁵ identified 44 cases of prostate cancer among 21,172 Finnish men. Baseline PSA was 2.5 ng/mL in 95% of men diagnosed with cancer within the first 5 years and 52% diagnosed within 6 to 10 years. Gann et al,¹³ analyzing 366 Physicians' Health Study participants diagnosed with prostate cancer, reported that serum PSA was elevated 5 to 6 years before the identification of a palpable tumor. Among participants in the prospective Baltimore Longitudinal Study of Aging, more rapid increases in PSA indicated higher risk of cancer during long-term follow-up.^16,17

All of these long-term studies analyzed archived serum. However, long-term storage and flawed procedures for preanalytic workup can cause significant degradation of PSA, particularly fPSA.¹¹ Stenman et al¹⁵ estimated that 38% of tPSA was lost from their archival serum samples due to suboptimal preanalytic workup and storage at –20°C, and they introduced a correction factor to compensate. However, the influence of potential degradation has not been addressed fully in most studies of PSA in archival samples.

The Preventive Project in Malmö, Sweden, is a prospective study of a representative cohort of 21,277 men with a baseline evaluation, including a questionnaire, physical examination, and venipuncture.¹⁸ We investigated the usefulness of different PSA forms and hK2 measured at age 50 years to predict the risk of being diagnosed with prostate cancer up to 25 years later. Archived EDTA-anticoagulated blood plasma, rather than serum, was assayed because fPSA is more stable during long-term storage in plasma.¹¹ We have previously shown that our fPSA and tPSA measurements on the Malmö cohort samples are reproducible and accurate.¹⁹ As a secondary analysis, we examined whether any of 90 other variables measured at baseline predicted prostate cancer.

	METHODS

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Patient Enrollment
Between 1974 and 1986, the Malmö Preventive Project invited all men born between 1926 and 1949 (except men born in 1943, 1945, or 1947) who were living in Malmö, Sweden, to receive a baseline evaluation and venipuncture.²⁰ In total, 21,277 men age 33 to 50 years participated, representing 74% of the eligible population. One EDTA-anticoagulated blood sample was collected, rapidly centrifuged, and stored at –20°C until analysis. Participants had no additional medical checkups organized by the project unless they were identified with hypertension, hyperlipidemia, or diabetes. They were not given any recommendations to undergo early screening for prostate cancer. According to the Swedish Cancer Registry, 498 participants (2.3%) were diagnosed with prostate cancer up to December 31, 1999.

We performed a case-control study nested within the Malmö Preventive Project cohort. For each patient, we identified matching participants without a prostate cancer diagnosis whose age and date of venipuncture were within 3 months. Three controls were then randomly selected from matches. If three matching controls could not be identified, we searched for matches within 6 months and then 2 years. The study was approved by the ethics committee of Lund University.

PSA Measurements
PSA was measured in archived anticoagulated blood plasma from 462 of 498 men subsequently diagnosed with prostate cancer and from 1,222 controls. Plasma samples were not thawed previously. Although archived plasma was stored at a suboptimal temperature (–20°C), we previously found that archived plasma from the Malmö Preventive Project had no significant decrease in tPSA, fPSA, or cPSA.²⁰

fPSA and tPSA were measured according to Mitrunen et al²¹ using the Prostatus Free/Total PSA assay (Perkin-Elmer Life Sciences, Turku, Finland). Results of this assay differ by 13% from WHO calibration standards.²² Percent free to total PSA (%fPSA) corresponds to fPSA/tPSA, and cPSA corresponds to tPSA – fPSA. In samples from 248 cancer patients and 738 controls, we also tested cPSA using an assay from Bayer Diagnostics (Tarrytown, NY).²³ Values from the Bayer assay closely corresponded to those calculated from the Prostatus Free/Total PSA assay across all levels of cPSA (correlation coefficient, 0.99); therefore, we used only the calculated cPSA values in the analysis.

Total hK2 was measured by a research assay with a functional detection limit of 0.005 ng/mL and 0.01% cross-reaction with PSA.²⁴

Statistical Analysis
We conducted conditional logistic regression to determine associations between prostate-specific kallikreins and cancer. As a secondary aim, we repeated this analysis for 90 lifestyle, anthropometric, biochemical, and medical history variables. Although we did not formally adjust for multiple testing in this secondary analysis, we planned to evaluate any findings in the context of the large number of secondary hypotheses tested. To calculate the predicted probability of cancer for a given PSA level, we entered PSA in a logistic model using restricted cubic splines with knots at the tertiles. Due to the 3:1 matched case-control design, the incidence of cancer in our study is close to 25%. To correct the incidence of prostate cancer to 10%, the estimated incidence by age 75 years in this cohort,²⁵ we adjusted probabilities from the model by adding a constant (a Bayes factor) to the linear prediction. All analyses were conducted using Stata version 8.2 (Stata Corp, College Station, TX).

	RESULTS

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Characteristics of Patients and Controls
Blood samples were missing or could not be analyzed for 36 of the 498 cancer patients (7%), leaving 462 patients in the study. Most patients (69%) had three matched controls, but 124 (27%), 17 (4%), and two (0.4%) patients, respectively, had two, one, or no controls, either because matching controls could not be found (n = 3) or because controls were not followed until diagnosis of the matched patient, usually due to early death of the control. Both age and date of venipuncture were ± 3 months of the matched case for approximately 95% of controls; dates varied by more than 6 months for only six controls. Almost all patients (414; 90%) were age 44 to 50 years at venipuncture; the rest were approximately equally split between age 40 to 43 years (20 patients) and 33 to 39 (26 patients). Age was a matching criterion, so the age distribution in controls was similar. There were few obese participants: only 6% had a body mass index of 30. Hence, obesity is unlikely to influence our findings.²⁶

Median delay between baseline venipuncture and prostate cancer diagnosis was 18 years (interquartile range, 15 to 20). Patient records were reviewed from 344 patients (75%). Fine needle biopsy showed that 128 patients (37%) were WHO grade 1, 129 patients (38%) were grade 2, and 87 patients (25%) were grade 3; 83 patients (24%) were clinically judged to be T1, 130 patients (38%) were T2, 129 patients (38%) were T3-4, with two patients lacking stage data.

Levels of PSA forms and hK2 are listed in Table 1. Median tPSA, cPSA, fPSA, and hK2 were higher, and median %fPSA was somewhat lower in plasma collected at baseline from men who later were diagnosed with prostate cancer, compared with men with no registered prostate cancer diagnosis.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Predicted probability of a prostate cancer diagnosis before age 75 years by total prostate-specific antigen (PSA) measured at age 44 to 50 years, with 95% CIs.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Predicted probability of a prostate cancer diagnosis before age 75 years by population-based centiles of prostate-specific antigen (PSA) measured at age 44 to 50 years, with 95% CIs.

	DISCUSSION

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We found that PSA measured in middle age predicts a diagnosis of prostate cancer up to 25 years later. We have shown that these are likely to reflect true fPSA and tPSA levels had they been measured contemporaneously.¹⁹ This collection of samples was highly representative, given that 74% of men of the invited age groups in a medium-sized city participated, and archived plasma was retrieved from 93% of the men who were diagnosed subsequently with prostate cancer. Assignment of patients was based on the Swedish Cancer Registry, which in 1978 included an estimated 95.4% of prostate cancers²⁷; more recent studies on breast cancer have found that the accuracy of the registry has improved and its estimated completeness is 99%.^28,29 Consistent with current national guidelines, the study cohort has not received recommendations to participate in early detection programs for prostate cancer. Hence, the incident cancer occurrences are likely to be representative for the combination of genetic and environmental pressures among middle-age white men in Malmö, Sweden. PSA was a strong predictor for clinically palpable disease, suggesting that our findings are not an artifact of screening. Our results are also robust after correction by cross validation.

Cancer risk was markedly lower (1% to 7.5%) for the men with tPSA 0.5 ng/mL (corresponding to about half the control population) than the average 10.5% cumulative risk for this population by age 75 years.²⁵ Compared with individuals with tPSA 0.5 ng/mL, men with PSA 0.51 to 1.0 ng/mL had a 2.5-fold increase in the odds for incident prostate cancer, corresponding to a long-term risk close to the population mean.²⁵ PSA levels of 2 to 3 ng/mL, which frequently are cited as within the normal range, were associated with an increase in odds for prostate cancer of more than 19-fold. Although the tPSA assay used in this study does not conform to WHO calibration standards, the difference (13%) does not affect the interpretation of our results importantly.

A previous report from Baltimore Longitudinal Study of Aging including 60 cancer patients in a cohort of 549 men¹⁷ found the risk for prostate cancer to be four-fold higher when serum PSA at age 40 to 50 years was more than 0.60 ng/mL (the median level) compared with results below this level. Similar results were also reported by Antenor et al.³⁰

The utility of PSA in prostate cancer diagnosis has engendered increasing skepticism.^12,31 Stamey et al¹² described a trend toward decreased association of PSA level with prostate cancer size and grade in the current US population, and concluded that PSA is only tenuously related to prostate cancer, especially for PSA values less than 10 ng/mL. This observation, however, likely applies most to older men in a population subject to widespread PSA screening for a number of years. Although our study does not address the utility of PSA measurements in that context, we emphasize that it does demonstrate that PSA in middle age is a highly powerful predictor of long-term prostate cancer risk.

The predictive power of cPSA was very similar to that of tPSA. In addition, increased fPSA and hK2 and decreased %fPSA were all significant predictors of incident diagnosis of prostate cancer more than 20 years later. None of the 90 lifestyle, anthropometric, biochemical, and medical history variables assessed at baseline was an important predictor. Hence, measurements of any PSA form or hK2 constitute extraordinarily sensitive means to detect very early signs of malignant transformation in the prostate gland. The current data surpass any previous reports, given that earlier retrospective data have estimated an average interval of 7 to 10 years from increased serum PSA to clinical diagnosis of prostate cancer,^15,32,33 and a screening study suggested an interval of 11.2 years.^34,35 The predictive power of tPSA or cPSA alone was sufficiently robust that none of the other PSA or hK2 measures added important predictive value in this specific context. For older men closer to diagnosis, in contrast, cPSA, fPSA, %fPSA, and hK2 have been shown to add to the predictive value of tPSA.^36-38

The current data suggest that early biochemical changes (ie, slightly increased release of PSA and hK2 into blood) indicate a predisposition to prostate cancer that may be detectable two decades before the disease is diagnosed clinically. This result raises the question of whether the increased release of PSA and hK2 into blood is merely an early sign of prostate cancer, or whether it also plays a causal role. One possibility is that protease-antiprotease imbalances associated with the increased extracellular PSA or hK2 may trigger processes that promote the progression and invasion of prostate cancer. This possibility has become more relevant in light of the recent demonstration that functional genes coding for PSA and hK2 may be present only in dogs and old-world primates,^39,40 and spontaneous development of prostate cancer has been described only in dog and man.⁴¹

Whatever mechanism underlies the effect, the strong association of PSA and hK2 with cancer many years later suggests that screening men at age 44 to 50 years for these biomarkers may have clinical utility. The primary goal for such testing would not be detection of cancer, but risk stratification for subsequent intervention. Such a strategy may largely eliminate the poor specificity of these biomarkers associated with benign prostate hyperplasia, which also increases levels of every PSA form and hK2.⁴² However, any recommendations to undergo biopsy on the basis of our findings would be premature, given that biopsies performed 15 to 25 years before the cancer would otherwise be diagnosed may not be informative. Hence, additional data are needed before any changes in early detection strategies can be recommended. Nonetheless, it appears attractive to suggest more frequent and elaborate cancer risk evaluation for the small percentage of 44- to 50-year-old men with tPSA 2 ng/mL, who are most likely to benefit. Conversely, it may be safe for men whose PSA level before age 50 years is below the median to undergo less frequent follow-up. Such stratification of screening strategies by PSA level in middle age has the obvious potential to increase the cost-benefit of prostate cancer screening. Moreover, if risk stratification identified as high-risk men who would otherwise have had insufficient motivation to attend regular prostate cancer screening, this might also increase the effectiveness of screening programs.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: Hans Lilja, Arctic Partners Oy Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Hans Lilja, Thomas Björk, Charlotte Becker, Jan-Åke Nilsson, Göran Berglund

Financial support: Hans Lilja, Charlotte Becker, Jan-Åke Nilsson, Göran Berglund

Administrative support: Göran Berglund

Provision of study materials or patients: Göran Berglund

Collection and assembly of data: David Ulmert, Thomas Björk, Charlotte Becker, Jan-Åke Nilsson, Per-Anders Abrahamsson

Data analysis and interpretation: Hans Lilja, David Ulmert, Thomas Björk, Angel M. Serio, Jan-Åke Nilsson, Per-Anders Abrahamsson, Andrew J. Vickers, Göran Berglund

Manuscript writing: Hans Lilja, David Ulmert, Thomas Björk, Angel M. Serio, Jan-Åke Nilsson, Per-Anders Abrahamsson, Andrew J. Vickers, Göran Berglund

Final approval of manuscript: Hans Lilja, David Ulmert, Thomas Björk, Charlotte Becker, Angel M. Serio, Jan-Åke Nilsson, Andrew J. Vickers, Göran Berglund

	Appendix

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	ACKNOWLEDGMENTS

 
We thank Gun-Britt Eriksson and Kerstin Håkansson for expert assistance with immunoassays.

	NOTES

 
Supported by grants from the Swedish Cancer Society (projects No. 3555 and 4715), European Union Contract #LSHC-CT-2004-503011 (P-Mark), and the National Cancer Institute No. P50-CA92629 - SPORE Pilot Project 7.

Parts of this work were presented at a meeting of the American Urological Association, and an abstract appeared in a 2002 supplement to the Journal of Urology. None of the material in this article has been otherwise published.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted April 13, 2006; accepted October 5, 2006.

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