Risk of Developing Prostate Cancer in the Future: Overview of Prognostic Biomarkers

Risk of Developing Prostate Cancer in the Future: Overview of Prognostic Biomarkers Neil E. Fleshner and Nathan Lawrentschuk In many disease states, the use of biomarkers is a standard method of determining both the presence and the risk of the future development of disease. For several years, total prostate-specific antigen (PSA) levels have been the standard measure for the diagnosis of prostate cancer (PCa) and other prostatic diseases. However, recent data have indicated that PSA can also be used to determine the risk of developing PCa in the future. This evolving use of PSA is supported by clinical trial data from the Baltimore Longitudinal Study of Aging, the European Randomized Study of Screening for Prostate Cancer, and the Malmö Preventive Medicine Study. Data from the European Randomized Study of Screening for Prostate Cancer have demonstrated that men with a PSA level of ⱖ1.5 ng/mL are at a significantly elevated risk of developing PCa compared with patients with a PSA level ⬍1.5 ng/mL. The Malmö study showed that the PSA level could independently the predict cancer risk as far as 25-30 years into the future. Secondary nonserum risk factors (eg, age, family history, ethnicity) can also offer predictive value for determining the risk of developing future disease. Furthermore, recent investigations of novel biomarkers have yielded promising PCa prognostic candidates, including the PCa gene 3 and early PCa antigen 2. However, PSA remains the most reliable measure in assessing the risk of developing PCa. UROLOGY 73 (Suppl 5A): 21–27, 2009. © 2009 Published by Elsevier Inc.

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he number of new cases of prostate cancer (PCa) in the United States has been estimated at 186 320 in 2008. PCa is the second most common cause of cancer-related death in men in the United States.1 The burden of PCa in terms of both morbidity and economics is considerable. Moreover, once PCa has reached an advanced state, its treatment is associated with a variety of comorbidities that exert a deleterious effect on quality of life. Side effects related to sexual satisfaction, urinary incontinence and obstruction, and bowel function are common after prostatectomy, radiotherapy, and brachytherapy and are generally more common among patients with greater prostate-specific antigen (PSA) levels.2 In economic terms, the direct cost of treatment alone is high. The cumulative costs for PCa treatment during a 5.5-year period have been estimated at $42 570, with androgen deprivation and external beam radiotherapy the most expensive, followed by cryotherapy, radical prostatectomy (RP), and brachytherapy.3 Although no agents are yet available that will prevent PCa, pharmacologic strategies for the reduction in the risk of

From the Division of Urology, University Health Network; and Department of Surgery, Division of Urology, University of Toronto, Toronto, Ontario, Canada N. E. Fleshner serves as a consultant to AstraZeneca, GlaxoSmithKline, Merck, Sanofi-Aventis, Novartis, and Pfizer; he has received grant support for clinical trials from AstraZeneca, GlaxoSmithKline, and Sanofi-Aventis. N. Lawrentschuk has no conflicts to report. Reprint requests: Neil Fleshner, M.D., Division of Urology, University Health Network, 610 University Avenue, Room 3-130, Toronto, ON M5G 2M9 Canada. E-mail: [email protected] Submitted: February 2, 2009, accepted (with revisions): February 24, 2009

© 2009 Published by Elsevier Inc.

developing PCa are appealing, because they could alleviate the significant comorbidities and costs associated with the disease and its treatment. The use of biomarkers and screening programs to assess the risk of future disease has been well established across a spectrum of disease states. For example, in cardiovascular disease, elevations of low-density lipoprotein cholesterol (LDL-C) and blood pressure have been used to assess an individual’s risk of developing future disease. They serve as markers for the initiation of therapy intended to reduce the risk of future morbidity and mortality.4 Studies have shown that the coronary heart disease risk is strongly correlated with LDL-C levels: the higher the level, the greater the risk. This characteristic of LDL-C (obtained through lipid screening tests) has resulted in the establishment of threshold levels that indicate an individual’s risk for future coronary heart disease. Similarly, hypertension is strongly correlated with coronary heart disease, placing those with elevated blood pressure (ⱖ140/90 mm Hg or taking antihypertensive medication) at risk.5 Such a model of disease risk assessment using biomarkers could be similarly adapted for a disease such as PCa. Using clinical trial evidence, PSA levels (and other biomarkers) could be applied to assess an individual’s risk of developing PCa in the future and could then help physicians decide on a strategy that might help reduce that risk.6 This report reviews the current evidence for the utility of PSA and other secondary factors as biomarkers to identify the risk of developing PCa in the future. 0090-4295/09/$34.00 doi:10.1016/j.urology.2009.02.022

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Table 1. Summary of studies presenting evidence on PSA and its ability to assess risk of developing future PCa Trial

Patient Age (y)

n

Follow-up Duration (y)

PHS10

40-84

14 916

10

BLSA11

40-60

1054

ⱕ30

Rotterdam section of ERSPC12

55-70

5176

4

Malmö Preventive Medicine Study14

33-50

21 277

25

Malmö Preventive Medicine Study (advanced cancer risk substudy)18

33-50

161

25

PSA Level (ng/mL) Compared with men with PSA ⬍1.0: 2.0-3.0 Aged 40-49 y, compared with men with PSA ⬍0.6: ⱖ0.6 Aged 50-59 y, compared with men with PSA ⬍0.7: ⱖ0.7 Compared with men with PSA ⬍1.5: ⱖ1.5 Compared with men with tPSA ⱕ0.5: tPSA 1.01-2 Compared with men with tPSA ⱕ0.5: tPSA 2.01-3.00 Compared to men with tPSA ⱕ0.5: tPSA 1.01-2 tPSA 2.01-3.00

Risk of Future PCa RR 5.5 RR 3.6 RR 3.5 RR 7.466 OR ⬎7 OR ⬎19 OR 7* OR 22*

PSA, prostate-specific antigen; PCa, prostate cancer; PHS, Physicians Health Study; RR, relative risk; BLSA, Baltimore Longitudinal Study of Aging; ERSPC, European Randomized Study of Screening for Prostate Cancer; OR, odds ratio. * Probabilities determined for men aged 44-50 y at baseline.

PSA AS INDICATOR OF RISK OF DEVELOPING PCa PSA has been used for many years as a screening tool to detect the presence of PCa and to evaluate the treatment response.7 However, its role is evolving as a useful marker for assessing the risk of future PCa, although this concept has not yet been widely incorporated into clinical practice.8 A number of studies have evaluated PSA as an indicator of the risk of developing future PCa. The most important studies are summarized in Table 1 and described in the following sections in chronological order. Although the Prostate Cancer Prevention Trial had the important secondary finding of showing PSA as an effective predictor for the risk of future PCa, the protocol of the trial called for mandated biopsies, regardless of the PSA level, and the trial was not designed to test the effectiveness of PSA as an indicator of clinical risk.9 It was unlike the other trials listed in Table 1 in this regard and therefore was omitted. Initial Studies—Physicians Health Study and Baltimore Longitudinal Study of Aging The Physicians Health Study was an ongoing randomized trial that enrolled 22 071 men aged 40-84 years in 1982, from which 14 916 patient samples were analyzed for PSA level. The mean age at the baseline PSA measurement was 63 years. The patients participated in a 10-year follow-up, and by March 1992, 520 cases of PCa had been confirmed. One limitation of the study was that the reproducibility of the PSA measurements was impossible because only single frozen blood samples were available. The analysis nonetheless demonstrated that measuring a single PSA value and evaluating the patient if the level was ⬎4 ng/mL could have detected nearly 80% of all aggressive PCa case diagnosed within 5 years and approximately 50% of aggressive PCa cases diagnosed 9-10 years later. That study also showed that even at low levels, the 22

PSA level stratified men for their risk of developing PCa. Compared with men with a PSA level of ⬍1.0 ng/mL, men with a PSA level of 2.0-3.0 ng /mL were 5-6 times as likely to be diagnosed with PCa in the subsequent 10 years.10 The analysis by Fang et al.11 of the Baltimore Longitudinal Study of Aging (BLSA) expanded the Physicians Health Study results by evaluating the PCa risk with lower PSA levels in men at younger baseline ages (40-60 years). In the BLSA, launched in 1958, patient serum samples were available from 1054 of 1665 male (primarily white) subjects for PSA analysis, and patients were stratified by baseline age into 2 groups covering 40-49 and 50-59 years. The use of frozen, archived serum samples to determine the PSA levels did present a limitation, because long-term storage can cause PSA degradation and, thus, partly inaccurate estimates. Nonetheless, the relative risks of developing PCa 2-3 decades into the future were estimated. Men 40-49 years old with a PSA ⱖ0.6 ng/mL had a relative risk of 3.6 (95% confidence interval 1.6-8.6, P ⬍ .01) compared with those whose PSA level was ⱕ0.6 ng/mL. Men 50-59 years old with a PSA level ⱖ0.7 ng/mL had a relative risk of 3.5 (95% confidence interval 2.0-6.2, P ⬍ .01) compared with men with a PSA level of ⱕ0.7 ng/mL. This interesting finding suggests that younger men are at a similar risk as older men for developing PCa 2-3 decades later. On the basis of their findings, the investigators suggested that interventions to prevent future disease or to alter the natural course of the disease should begin at a younger age.11 These studies provided the initial support for the role of PSA as a predictor of developing future PCa. European Randomized Study of Screening for Prostate Cancer Although the precise PSA level selected as the indicator of an increased risk of developing PCa in the future has UROLOGY 73 (Supplement 5A), May 2009

varied, recent data from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) have helped to identify a meaningful PSA level risk indicator. The ERSPC trial was initiated in 1993 and involved 8 countries. The Rotterdam study began with 5176 men (primarily white), aged 55-70 years, who underwent 2 PSA screenings 4 years apart and were offered biopsy if their PSA level was ⱖ3.0 ng/mL at the initial screening. Of those participants (n ⫽ 3501) who did not undergo biopsy during the first round of screening, or whose biopsy findings were negative, the incidence of PCa after 4 years was determined, and the mean PSA level of those patients with disease was calculated. The 4-year risk of PCa was 5.1% in men with a mean baseline PSA level of 1.5 ng/mL. Those men with a mean PSA value of ⱖ1.5 ng/mL at round 1 of screening were at a significantly greater risk of having a positive biopsy at round 2 than were men whose initial PSA level was ⬍1.5 ng/mL (odds ratio 7.466; P ⬍ .001).12 These data suggest that a relatively low PSA level can predict future PCa. These findings could be significant: they would allow for the identification of patients at greater risk of future PCa who would thus require more vigilant monitoring, as well as the identification of patients at a low risk of PCa who would require less surveillance. The role of PSA measurement in assessing the risk of developing PCa is also being studied in a large, randomized clinical trial in the United States (the Prostate, Lung, Colon, and Ovary trial). Both the ERSPC and Prostate, Lung, Colon, and Ovary trial aim to compare PCa mortality rates in men offered PCa screening against those of men not offered screening.13

Malmö Preventive Medicine Study Additional compelling data supporting the predictive value of PSA were provided by the Malmö Preventive Medicine Study, which from 1974 to 1986 analyzed PSA levels from 21 277 men in Sweden aged 33-50 years. In contrast to the BLSA study method, archived ethylenediaminetetraacetic acid-anticoagulated blood plasma, which is more stable in long-term storage than serum and less prone to degradation, was used to determine the PSA levels, resulting in greater accuracy and reproducibility of the PSA measurements. The analysis involved 462 patients ultimately diagnosed with cancer and 1222 matched controls. Of the 462 patients, 90% were 44-50 years old, and the median interval between the initial baseline PSA value and the diagnosis of PCa was 18 years. The total PSA (tPSA) level correlated strongly with PCa risk, with an odds ratio (OR) of 3.69 (95% confidence interval [CI] 2.99-4.56; P ⬍ .0005) within 25 years. Even small increases in tPSA markedly increased the risk of developing PCa: a tPSA level of 1.01-2 ng/mL increased the odds of developing future PCa by more than sevenfold compared with a tPSA level ⱕ0.5 ng/mL (OR 7.02, 95% CI 4.90-10.1).14 Considering that the recommended threshold PSA levels for treatment interUROLOGY 73 (Supplement 5A), May 2009

vention have fluctuated considerably during the past decade, data showing a nearly fourfold increase in the risk of future PCa with a PSA increase of 1 ng/mL underscores the importance of monitoring PSA levels carefully.15 A subsequent additional 5-year follow-up to the Malmö study included men ⬍40 years of age at PSA testing and confirmed the earlier results, determining that PSA was predictive of PCa as long as 30 years after the initial PSA value was attained.16 Vickers et al.17 also observed that tPSA can predict future PCa risk in younger patients (age 44-46 years) more effectively than in older patients (age 59-61 years), but they also observed that the interval to diagnosis had no significant effect on the predictive value of PSA (ie, the PSA level remained predictive of PCa many years before the cancer diagnosis).17 Together, these data emphasize the importance of PSA measurement in the early identification of patients at risk of developing PCa and suggest that PSA levels can effectively predict the risk of developing PCa as much as 25 years before the diagnosis. This could permit meaningful risk stratification among men in early middle age (according to the above study cohort) and pave the way for risk reduction measures that might significantly reduce the incidence of the disease.

Malmö Preventive Medicine Study—Secondary Analysis in Advanced Cancer A recent analysis of the original Malmö data sought to establish whether the predictive value originally observed for PSA could be applied to the prediction of more advanced cancer (defined as clinical stage T3 or greater or skeletal metastases at cancer diagnosis). In this analysis of 161 patients with advanced cancer and 436 matched controls, the median total baseline PSA level was 1.22 ng/mL for the advanced cancer patients and 0.54 ng/mL for the matched controls, and the median interval from the baseline PSA test to PCa diagnosis was 17 years. The PSA level was a significant (P ⬍ .0005) predictor of advanced PCa in patients aged 44-50 years ⱕ25 years before the PCa diagnosis. A multivariate model examined tPSA, free PSA, free-to-total PSA ratio, and human glandular kallikrein 2. The analysis showed that the combined model had an area under the curve of 0.785, and the predictive accuracy of tPSA alone had an area under the curve of 0.791, highlighting that PSA itself is a sufficient marker for assessing the risk of developing PCa (Fig. 1). Patients with a PSA level of 1.012.00 ng /mL were ⬎7 times as likely to have advanced PCa as those with a PSA level of ⱕ0.5 ng/mL, and patients with a PSA level of 2.01-3.00 ng/mL had a ⬎21-fold increased risk during the 25-year period. It is worth noting that 66% of the advanced cancer cases occurred in patients with the greatest 20% of PSA levels (ie, baseline PSA level of ⱖ0.9 ng/mL).18 These studies put into perspective the evolving utility of PSA determination. PSA can be used not only as a 23

diagnostic marker in patients with PCa but also as a measurement with predictive ability for patients at risk of future PCa. Although a consensus has been reached that PSA values ⬎2.5 but ⱕ4.0 ng/mL (and/or an abnormal DRE findings) warrant the recommendation of a biopsy to determine whether PCa is present,19 it is evident from the above-mentioned studies that PSA values ⬎2.5-4.0 ng/mL may be used to assess the risk of developing future disease. The ERSPC set the PSA threshold at 1.5 ng/mL, which was the average baseline value for the patient population in that study12; thus, values considerably lower than 4 ng/mL might ultimately be used to predict the risk of future PCa. This evolving role of PSA may allow clinicians to determine the risk of future disease.15,20

ADDITIONAL PROGNOSTIC RISK FACTORS SECONDARY TO PSA Age The relationship between age and the risk of PCa is very strong, with increasing age being predictive of a greater risk of developing the disease. Fewer than 10% of PCa cases occur in patients ⬍54 years old, and 64% of PCa cases are diagnosed within the 19 years between the ages of 55 and 74 years.21 Data from the Olmsted County, Minnesota, study have shown that PSA levels are associated with age, with men aged 50-59 years having a median PSA level of 1.0 ng/mL, those aged 60-69 years, a median PSA of 1.4 ng/mL, and those aged 70-79 years, a median PSA level of 2.0 ng/mL. With advancing age, an increase in prostate volume and other nonspecific factors will result in an increased serum PSA concentration even in the absence of clinically identifiable PCa. Therefore, greater agespecific reference ranges than those that define normal PSA parameters were proposed by the study investigators. This would increase the specificity of PSA in older men and potentially enhance the accuracy of the early detection of PCa.22

Race and Ethnicity The variability among racial and ethnic groups in the risk of the development of PCa is large. The incidence of PCa in the United States from 2000 to 2004 was 161.4/ 100 000 among white men, but for black men, it was considerably greater, 255.5/100 000 (ie, 58% more). The rates of PCa among Hispanics and Asian Americans/Pacific Islanders were lower than those for white men (140.8/ 100 000 and 96.5/100 000, respectively). The differential in mortality rates has been even more substantial. Between 2000 and 2004, the PCa mortality rate among black men was 62.3/100 000 vs 25.6/100 000 for white men, a difference of 143%.1 Because of the greater risk of PCa in black men, it is recommended that black men should be screened at a younger age than white men.23 24

Figure 1. Predicted probability of advanced prostate cancer using total prostate-specific antigen (PSA) level in anticoagulated plasma measured at age 44-50 years. Dashed lines indicate 95% confidence intervals. Reprinted, with permission, from Ulmert et al.18

The Prostate Cancer Prevention Trial found that black race was a statistically significant predictive risk factor for high-grade disease (Gleason score ⱖ7; OR 2.6, P ⬍ .001) compared with other ethnicities in the study.9 A study by Morgan et al.24 determined that the use of age-specific reference ranges for the detection of PCa determined from a white population’s PSA levels (at 95% specificity, taken from the Olmsted study) would exclude 41% of PCa cases among black men. For the PSA level to have a high sensitivity among black men, the normal reference range for black men in their 40s should be 0-2.0 ng/mL.24 Prostate Volume The role of prostate volume in predicting PCa risk is an emerging, and still controversial, topic. Studies have correlated smaller prostate volumes with unfavorable pathologic characteristics.25-27 A study by Briganti et al.26 examined the hypothesis that smaller prostate glands might be predisposed to higher grade or metastatic PCa. In their study, 3412 men with localized PCa who had never been exposed to hormonal manipulation underwent RP, and their prostates were histologically evaluated. The study results suggested that smaller prostate glands were associated with more aggressive PCa. An increasing gland size was associated with more favorable pathologic grade and stage, including a lower rate of high-grade PCa at biopsy and at RP, a lower rate of extracapsular extension, a lower rate of seminal vesicle invasion, and a lower tumor volume (⬎3.4 cm3) at RP. This protective effect was most obvious for very large glands (prostate volume ⬎44 cm3).26 In study by Sajadi et al.,27 the prostate gland volume was negatively associated with a diagnosis of PCa when sampled with saturation prostate biopsy (OR 0.965, 95% CI .932-.999, P ⫽ .041). A prostate volume ⬍37 cm3 was the optimal cutoff as a predictor of PCa diagnosis at the saturation prostate biopsy (OR 30.7, 95% CI 5.9-158, P ⬍ .0001). Rounding the cutoff to 40 cm3 maintained the association with UROLOGY 73 (Supplement 5A), May 2009

cancer detection (OR 10.9, 95% CI 2.4-48.9, P ⫽ .002).27 A smaller prostate volume might ay serve as another measure to be factored into the assessment of the risk of developing future PCa. PSA Velocity Although the PSA velocity (PSAV) does not appear to improve the long-term prediction of PCa compared with PSA measurement alone, its assessment might offer some prognostic value in identifying men at risk of developing life-threatening PCa.8,28 An analysis of data from the BLSA demonstrated that men with a PSAV ⬎0.35 ng/ mL/y 10-15 years before the diagnosis of PCa or their last visit (when most men had a PSA level ⬍4.0 ng/mL), were significantly more likely to have died of PCa at 25 years than men with a PSAV of ⱕ0.35 ng/mL/y (92% vs 54%, P ⬍ .001).8 PSAV remains an active area of investigation, and additional work is needed to elucidate its prognostic value. Family History and Genetics The contribution of family history to an increased risk of PCa was recently addressed by a study evaluating a subcohort of the Health Professional Follow-Up Study, which followed up 3695 patients with PCa (family history was assessed at the beginning of the study and at intervals throughout the study) from 1986 to 2004. The results pointed to a strong association between family history and the incidence of PCa: patients with both a father and ⱖ1 brother with PCa had a 2.3-fold increased risk of the disease (95% CI 1.76-3.12). When a father or brother had been diagnosed with the disease before 60 years of age, the relative risk was 2.16 (95% CI 1.702.73); if either the father or a brother was diagnosed at ⱖ60 years, the relative risk was 1.95 (95% CI 1.77-2.15). An increased risk of early-onset PCa (age ⬍65 years) was 2.25 times more likely (95% CI 1.95-2.60) in men with a family history of the disease.29 The influence of genetics on familial associations was also addressed in a Scandinavian study of twins from Swedish, Danish, and Finnish twin registries (n ⫽ 44 788). These combined data showed that the contribution of heritability—in this case, the contribution of genetic defects—to the occurrence of PCa was an estimated 42%. It was also observed that the interval between the diagnosis of PCa among monozygotic twins was significantly shorter than that among dizygotic twins (P ⫽ .04).30 Five individual single-nucleotide polymorphisms have been identified that possess a moderate association with PCa.31 Taken together, the cumulative effect of the 5 single-nucleotide polymorphisms significantly correlated with disease risk and further indicated that a genetic component exists.31,32 The deCODE ProstateCancer test is a noninvasive, novel, DNA-based reference laboratory test used to identify the first genetic risk factors found to increase the risk UROLOGY 73 (Supplement 5A), May 2009

of PCa in the general population. The test identifies 8 known genetic variants; together, these 8 seem to be responsible for roughly one half of all PCa cases. The deCODE ProstateCancer test results are reported as a combined genetic risk associated with the genotype combination of the individual. Likely other genes exist that have yet to be discovered; other risk factors, such as family history and ethnicity, need to be applied to this genetic risk to fine tune the evaluation of an individual’s risk. Tests such as the deCODE ProstateCancer test might soon be used in physicians’ offices to add weight to the analysis of an individual’s risk of PCa. The use of genetic testing could help the physician to decide on future monitoring, prevention, and/or specific treatments.33 Prostatic Intraepithelial Neoplasia Prostatic intraepithelial neoplasia (PIN) is a proliferation within the prostate that is often associated with subsequent PCa. Long-term, large-scale studies to evaluate the incidence of PCa relative to a positive biopsy for PIN have not been conducted. Nevertheless, a number of shorter term studies have found that 25.8%-51% of patients with high-grade PIN develop PCa.34,35 Of the patients with high-grade PIN on sextant needle biopsy, 33%-100% will have PCa on a repeat evaluation.35

NEW BIOMARKERS WITH POTENTIAL USE FOR ASSESSING PCa RISK A number of potential biomarkers have been identified that might provide additional predictive value in determining the risk of future PCa. Transforming growth factor-␤1, interleukin-6, the urokinase plasminogen activation system, chromogranin A, and prostate-specific membrane antigen have all demonstrated some degree of predictive value in PCa, but all are unproved to date.36 In the case of transforming growth factor-␤1, the data from some studies have shown it to be valuable in predicting tumor progression, metastasis, and biochemical progression, but other studies failed to confirm these data.37-39 Some limited data have also pointed to the value of interleukin-6 as a predictor of disease progression and patient survival.40,41 Few of these newer biomarker candidates are likely to eventually play an important role in future PCa prediction. From the data from several recent studies, only PCa gene 3 (PCA3), BRCA, and early PCa antigen 2 (EPCA-2) show considerable promise. In a study evaluating the utility of PCA3 in 96 men (one half of whom were scheduled for RP, with the remainder scheduled for biopsy), the PCA3 scores differed significantly between those with positive and negative biopsy results (P ⫽ .029). PCA3 was also significantly effective in discriminating the tumor volume in RP (P ⫽ .001) and the prostatectomy Gleason score (P ⫽ .005 for 6 vs ⱖ7) and demonstrated utility in predicting which patients would have low-volume/low-grade disease.42 Another study evaluated the prognostic utility of PCA3 in repeat biopsies in 463 men. A positive biopsy rate of 28% among the study subjects was observed, and 25

a greater PCA3 score correlated with a greater likelihood of positive repeat biopsy findings. PCA3 was determined to be superior to the percent free PSA in predicting positive biopsy findings, and it was also seen to be independently predictive of tPSA, number of previous biopsies, age, and prostate volume. Data from the study by Haese et al.43 also showed that PCA3 could distinguish men with high-grade PIN from those without it and provided specificity regarding the clinical stage. The Prostate Cancer Risk Assessment Program was a 10-year longitudinal screening program for men at high risk and included 609 men aged 35-69 years with a family history of PCa, any black man regardless of family history, and any patient with a known mutation in the BRCA 1 gene.44 Prostate biopsies were performed on 19% of the subjects; the incidence of PCa was 9.0%. More than 90% of the PCa cases were Gleason score ⱖ6, 22% were Gleason score ⱖ7, and most were organ confined. Of those diagnosed with PCa, 20% had a PSA level ⬍2.5 ng/mL and a free PSA level ⬍25%. These results support aggressive screening measures for men at high risk of PCa, including those with the BRCA 1 mutation. Most PCa cases detected had a PSA level ⬍4.0 ng/mL, with a fifth diagnosed at a PSA level ⬍2.5 ng/mL. These cancers were intermediate to high grade and organ confined, indicating a greater likelihood of cure after local therapy for these men.44 In a systematic review of ⬎30 epidemiologic studies on the incidence of cancer other than breast or ovarian in BRCA mutation carriers, men with mutations in the BRCA gene had an increased risk of developing PCa (relative risk 1.62, 95% CI 1.31-2.00).45 In a large case-control study of 251 unselected men, after adjusting for age, the presence of a BRCA 1 or BRCA 2 mutation was associated with the development of PCa (OR 3.41, 95% CI 1.64-7.06, P ⫽ .001).46 When the results were stratified by gene, BRCA 2 mutation carriers showed an increased risk of PCa (OR 4.78, 95% CI 1.87-12.25, P ⫽ .001); however, the risk in BRCA 1 mutation carriers was not significantly increased, supporting the hypothesis that mutations in BRCA are associated with increased PCa risk. Another promising biomarker, EPCA-2, has shown a high degree of specificity in distinguishing patients with PCa, not only from men who are healthy, but also from men with benign prostatic hyperplasia. EPCA-2 was also able to distinguish localized from extracapsular disease with a high degree of accuracy (area under the curve 0.89, P ⬍ .0001).44 The use of an alternative epitope from the EPCA-2 protein in serum tests showed potential utility in distinguishing men with PCa from those without.47,48 Although the data from these studies are preliminary and, indeed, neither of these markers, EPCA-2 or PCA3, has been subjected to the kind of longitudinal study required to ascertain future risk, additional planned clinical trials will determine whether PCA3 and EPCA-2 will be useful as PCa biomarkers. Until validation of EPCA-2, PCA3, and other potential biomarkers is 26

achieved, PSA will remain the most effective biomarker in predicting risk of developing PCa.

CONCLUSIONS Therapy-related comorbidities and the high treatment costs associated with advanced PCa treatment argue a need for early detection and strategies to prevent disease progression. Future disease risk assessment paradigms using biomarkers (eg, LDL-C in cardiovascular disease) provide a model for the use of biomarkers in assessing the risk of PCa. PSA has been firmly established as the primary diagnostic marker for PCa, and recent clinical data support a new role for PSA in the determination of the risk of future PCa. Data have shown that men with a PSA level ⱖ1.5 ng/mL are at a significantly elevated risk of future PCa compared with men with a PSA level ⬍1.5 ng/mL and that PSA might predict the development of PCa ⱕ3 decades into the future. Although a number of biomarkers have shown promise across a variety of PCa studies, PSA remains the most reliable biomarker for predicting the risk of future PCa. References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71-96. 2. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 2008;358:1250-1261. 3. Wilson LS, Tesoro R, Elkin EP, et al. Cumulative cost pattern comparison of prostate cancer treatments. Cancer. 2007;109:518527. 4. Grover SA, Dorais M, Paradis G, et al. Lipid screening to prevent coronary artery disease: a quantitative evaluation of evolving guidelines. Can Med Assoc J. 2000;163:1263-1269. 5. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421. 6. Rosario DJ, Lane JA, Metcalfe C, et al. Contribution of a single repeat PSA test to prostate cancer risk assessment: experience from the ProtecT Study. Eur Urol. 2008;53:777-784. 7. Canby-Hagino E, Hernandez J, Brand TC, et al. Prostate cancer risk with positive family history, normal prostate examination findings, and PSA less than 4.0 ng/mL. Urology. 2007;70:748-752. 8. Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA. 1992;267:2215-2220. 9. Thompson IM, Ankerst DP, Chi C, et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst. 2006;98:529-534. 10. Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. JAMA. 1995;273:289-294. 11. Fang J, Metter EJ, Landis P, et al. Low levels of prostate-specific antigen predict long-term risk of prostate cancer: results from the Baltimore Longitudinal Study of Aging. Urology. 2001;58:411-416. 12. Schröder FH, Roobol MJ, Andriole GL, et al. Defining increased future risk for prostate cancer: evidence from a population based screening cohort. J Urol. 2009;181:69-74. 13. Grubb RL III, Pinsky PF, Greenlee RT, et al. Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian cancer screening trial:

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