PSA Isoforms in Prostate Cancer Detection

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1 european urology supplements 5 (2006) available at journal homepage: PSA Isoforms in Prostate Cancer Detection Haluk Özen a, *, Sinan Sözen b a Department of Urology, Hacettepe School of Medicine, Ankara, Turkey b Gazi University School of Medicine, Ankara, Turkey Article info Keywords: Diagnosis Prostate cancer Prostate specific antigen Specificity Abstract Objectives: To give an overview on PSA isoforms that might help to improve specificity in Prostate Cancer (PCa) diagnosis. Methods: The authors review all the recent papers dealing with the effectiveness of PSA isoforms to improve the diagnosis potential of total PSA: percentage of free PSA (%fpsa) complexed PSA (cpsa), ProPSA, BPSA. Results: 10 to 30% of PSA is free in the serum and composed of various isoforms. It is composed of 3 distinct isoforms: ProPSA, BPSA and ipsa (for intact PSA which decreases with cancer). With the use of a single cut-off value of 25%, %fpsa specificity can be increased by 30% while maintaining 95% sensitivity. But free PSA measurement has limitations: namely specimen handling, assay variation and uncertainty about the appropriate reflex range. European and American multiinstitutional studies of cpsa have shown that this isoform has similar sensitivity and specificity values as %fpsa and that both perform better than total PSA in a PSA range of 2 10 ng/ml. The precursor form of PSA (pro-psa), especially its truncated (-2) form is significantly increased in PCa patients. However, so far no study has showed for low PSA range an advantage of (-5, -7) propsa over %fpsa. BPSA is still under investigation and reports on its clinical interest are still awaited. Conclusions: The performance of total serum PSA still needs to be improved. Several studies show potential clinical interest of PSA isoforms to improve specificity in PCa diagnosis. These preliminary results have to be confirmed especially with the most recently used isoforms: propsa and BPSA. # 2006 Published by Elsevier B.V. * Corresponding author. Kuleli Sokak 9/2, 06700, GOP/Ankara, Turkey. Tel ; Fax: address: ho02-k@tr.net (H. Özen). 1. Introduction Prostate cancer is the most common cancer in the United States in the male population excluding the skin cancers. Furthermore, it is the leading cause of /$ see front matter # 2006 Published by Elsevier B.V. doi: /j.eursup cancer death in American men who do not smoke. Prostate specific antigen (PSA) unquestionably has had a positive effect on the early detection of this very frequent health problem; however, problems with specificity remain.

2 496 european urology supplements 5 (2006) PSA became commercially available in 1987 and was used initially to detect recurrence of prostate cancer. Subsequent data demonstrating that PSA detects prostate cancer earlier than rectal examination and/or symptoms led to widespread PSA testing for early detection. Although no prospective randomized trials have tested the hypothesis that PSA reduces cancer-specific mortality, two studies from Quebec and Tyrol suggest that decreases in mortality probably are due to widespread PSA screening. Furthermore, age-adjusted cancer deaths attributable to prostate cancer have declined dramatically in the second part of the 1990s [1]. These findings, which might be at least partly due to PSA, screening were challenged by Stamey et al. [2], who stated that the PSA era is over in the USA. The authors have shown that, while serum PSA had an excellent correlation with the index tumor volume in the past, this correlation almost diminished after It was concluded that prostate weight was the single most important variable correlating with serum PSA in multivariate analysis. However, Catalona and Loeb [3] have replied to this manuscript stating that the PSA era is not over and emphasizing the successes of PSA screening. They pointed out that, according to SEER data, the relative 5-year survival rates in prostate cancer has reached almost 100% in 2000, while it was 67% and 75% during and , respectively [4]. Catalona and Loeb have shown elegantly that the relative decrease in the correlation between index tumor volume and PSA was due to the change in the patient population. The skepticism around serum PSA was amplified after publication of the Prostate Cancer Prevention Trial (PCPT) [5]. In this study, 2950 participants were randomized to the placebo group; they never had a serum PSA level >4 ng/ml or an abnormal digital rectal examination. Although all of these patients had serum PSA levels below the conventional cutoff value of 4 ng/ml, prostate cancer was detected in 6.6% to 26.9% of them. These results may be regarded as a severe blow to the usefulness of serum PSA in prostate cancer detection. However, the results may be viewed from a different perspective as well: In the PCPT, although there were a significant number of cancers below the conventional cut-off value, cancer detection rates actually increased as PSA level increased in this range. Prostate cancer was detected in 6.6%, 10.1%, 17.0%, 23.9% and 26.9% in the PSA ranges of <0.5, , , and ng/ ml, respectively. Catalona and Loeb have used these figures as a contrary argument to the famous comments of Stamey et al. by stating that, even with the most contemporary study, there was a striking relationship between serum PSA levels and cancer detection rates even in the low PSA levels. Therefore, instead of discarding PSA as a tumor marker, we have to use it more intelligently as Catalona has pointed out. We have to incorporate molecular forms in the decision-making process and should not concentrate on absolute cutoff values but rather view serum PSA as a continuum of risk assessment. 2. Biosynthesis of PSA Serum PSA is produced specifically by prostate epithelial cells [6]. Total serum PSA reflects normal and cancerous production rates as well as leak rates. PSA is a 34 kilo Dalton glycoprotein consisting of 237 amino acids. (-7) propsa is converted to mature PSA by human kalikrein-2. Seventy to ninety percent of serum PSA that leaks to the serum is complexed with serum protease inhibitors and is termed complexed PSA (cpsa). PSA is mostly bonded to alpha-1-antichymotripsin. At the same time, as a result of partial degradation of (-7) propsa, different forms of propsa such as (-2), (-4) and (-5) propsa are developed (Fig. 1). Although not all of these forms are available commercially at present, promising studies have been published. In contrast, 10% 30% of PSA is free in the serum and composed of various isoforms. Free PSA is produced preferentially in the transitional zone. Free PSA has three distinct isoforms: ProPSA, which comprises 33% of free PSA and increases with cancer, while BPSA, which is regarded as a nicked form of PSA, is secreted from the transitional zone and makes up 28% of free PSA (Fig. 1). The last isoform is termed inactive or intact PSA (ipsa), which decreases with cancer. 3. Percent free PSA Men with prostate cancer have been shown to harbor lower levels of free PSA levels, compared with men without prostate cancer. On the basis of this observation, interest in measurement of the percentage of free to total PSA (%fpsa) has increased dramatically during the last decade [7]. With the use of a single cutoff value of 25%, %fpsa specificity has been increased by 30% while maintaining 95% sensitivity. Capitalizing on these observations, we have attempted to incorporate %fpsa and PSA density (PSAD) to further augment the specificity and thus avoid unnecessary biopsies. [8] We have shown that %fpsa <0.21 and PSAD >0.18 yielded 55% specificity in 134 men with serum PSA ranging from 4 to 10 ng/ml. However, increased experience with free PSA measurements has delineated limitations of this

3 european urology supplements 5 (2006) Fig. 1 Biosynthesis of PSA. ACT = a 1 -antichymotrypsin; cpsa = complexed prostate specific antigen; ipsa = inactive/intact prostate specific antigen. approach, namely prostatic volume, specimen handling, assay variation and uncertainty about the appropriate reflex range. 4. Complexed PSA cpsa is the sum of immunodetectable forms of PSA complexed with protease inhibitors. Previous studies have shown that men with prostate cancer have higher levels of cpsa, compared with men without cancer. FDA approved the use of cpsa for monitoring patients with prostate cancer and, in 2000, approved its use for detection of prostate cancer. As shown in Table 1, almost all of the studies have shown that Table 1 Selected studies on complexed PSA Author N cpsa AUC tpsa AUC Brawer [9] Okegawa [10] Jung [11] Filella [12] Stamey [13] Miller [14] Mitchell [15] Tanguay [16] Sözen [17] AUC = area under curve; cpsa = complexed prostate specific antigen; tpsa = total prostate specific antigen. cpsa performed better than total PSA in patients with serum PSA levels >4 ng/ml [9 17]. Partin et al. [18] have reported a study on cpsa in 831 patients from seven referral centers in the United States. This study once again has shown that cpsa had better area under curve (AUC) values than total PSA in every total PSA range, albeit the difference was modest. In a multicenter study, we had investigated the role of cpsa and its derivatives in prostate cancer detection [17]. The cancer detection rate was 18.9% amongst 408 patients with total a PSA range of ng/ml who were included in this study. All participants had their first prostatic biopsy, which was performed as 10 cores. AUC analysis has revealed that cpsa was significantly better than total PSA. Contrary to some of the previous studies, we were not able to show the superiority of cpsa to %fpsa in this study. However, amongst cpsa derivatives, cpsa density (cpsad) was the best predictor of prostate cancer for all total PSA ranges regardless of digital rectal examination findings, except for a total PSA range of ng/ml. cpsa density of 0.06 at 90% sensitivity achieved 35% specificity, sparing 126 unnecessary biopsies. Although AUC for cpsad was greater than all other parameters, this difference was especially pronounced in patients with prostate volumes <45 cc. The performance of cpsad also was analyzed in quartile groups of transitional zone volumes; the best performance was detected in the smallest transitional zone (<26 cc).

4 498 european urology supplements 5 (2006) Roddam et al. [19] have published a meta-analysis of 66 manuscripts on %fpsa and cpsa. The total PSA range was 2 10 ng/ml, and all of the patients underwent primary biopsies. A 6-, 8- or 10-core biopsy technique was used in different studies. Different assays for free PSA were utilized. All of the studies revealed that cpsa and %fpsa have similar sensitivity and specificity values and that both performed better than total PSA in a PSA range of 2 10 ng/ml. 5. ProPSA The precursor form of PSA propsa (ppsa)- is released into the lumen of the prostate and, since it contains a 7 amino acid pro-leader peptide, it is also referred to as (-7) ppsa. Immediately after its release into the lumen, the pro-leader part is removed and converted to its active form by the effect of hk-2 and hk-4. Partial removal of this leader sequence has led to the identification of other trunculated forms of ppsa such as (-2) ppsa, (-4) ppsa and (-5) ppsa. In a sample set of 157 men with total PSA between 4 to 10 ng/ml and biopsy-proven prostate cancer, free PSA represented 16% of the total PSA. BPSA represented 28% of the free PSA, and propsa (ppsa) comprised 33% of the free PSA. The rest was intact or inactive (ipsa). As mentioned before, ppsa increases in patients with prostatic carcinoma. ppsa is detectable in the serum as native (-7) or (-5) (-4) and (-2) forms [20]. Examination of serum from men with prostate cancer has revealed that these trunculated forms, especially the (-2) form, was elevated significantly. Sokoll et al. [21] have shown that specificities of %ppsa and %fpsa were 59% and 33%, respectively, and the difference was highly significant. Catalona et al. [22] also have shown that %ppsa performed better than cpsa and %fpsa throughout all PSA ranges from PSA 2 to 4, 2 to 6, 4 to 10 and 2 to 10 ng/ml. The clipped form of %ppsa, (-2) ppsa, had the highest specificity in detecting cancer in a total PSA range of 2 4 ng/ml. Lein et al. [23] also have confirmed that not all of the trunculated forms of ppsa had a beneficial effect in discriminating patients in a multicenter study with benign prostatic hyperplasia from those with cancer. This study has revealed that in the low PSA range neither (-5, -7) ppsa nor %(-5, -7) ppsa proved to be superior with regard to diagnostic accuracy, compared with total PSA and %fpsa. 6. BPSA (BPHA) As mentioned before, (-7) PSA is converted to active PSA by hk-2 and is complexed by protease inhibitors in the serum. At the same time, native PSA also may be converted to BPSA (BPHA) by nicking; this isoform may then be measured in the serum. Canto et al. [24] have shown that BPSA correlated significantly with transitional zone volume better than %f PSA and total PSA. Further studies on the relationship between BPHA and clinical parameters of BPH are underway. 7. Conclusion The use of serum PSA as a screening tool has resulted in a decrease in the incidence of metastatic disease and a possible fall in mortality. However, the performance of total serum PSA still needs to be improved. We were introduced to serum PSA in the 1980s, we witnessed the progress during the 1990s with complex and free PSA and we are looking forward to improvement of the PSA isoforms in this decade. References [1] American Cancer Society. Cancer Facts and Figures. Available at: Secured.pdf, [2] Stamey TA, Caldwell M, McNeal JE, et al. The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years? J Urol 2004;172: [3] Catalona WJ, Loeb A. The PSA era is not over for prostate cancer. Eur Urol 2005;48: [4] Ries LAG, Eisner MP, Kosary CL, et al., editors. SEER Cancer Statistics Review, Bethesda (MD): National Cancer Institute. Available at: November 2004 SEER data submission, posted to the SEER website [5] Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or = 4.0 ng per millilitre. N Engl J Med 2004;350: [6] Balk SP, Ko YJ, Bubley GJ. Biology of prostate specific antigen. J Clin Oncol 2003;21: [7] Catalona WJ, Partin AW, Slawin KM, 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: [8] Ozen H, Aygun C, Ergen A, Sozen S, Aki FT, Uygur MC. Combined use of prostate specific antigen derivatives decreases the number of unnecessary biopsies to detect prostate cancer. Am J Clin Oncol 2001;24: [9] Brawer MK, Cheli CD, Neaman IE, et al. Complexed prostate specific antigen provides significant enhancement of specificity compared with total prostate specific antigen for detecting prostate cancer. J Urol 2000;163:

5 european urology supplements 5 (2006) [10] Okegawa T, Noda H, Nutahara K, Higashihara E. Comparisons of the various combinations of free, complexed, and total prostate specific antigen for the detection of prostate cancer. Eur Urol 2000;38: [11] Jung K, Elgeti U, Lein M, Brux B, et al. Ratio of free or complexed prostate specific antigen (PSA) to total PSA: which ratio improves differentiation between benign prostatic hyperplasia and prostate cancer? Clin Chem 2000;46: [12] Filella X, Alcover J, Molina R, Corral JM, Carreto P, Ballesta A. Measurement of complexed PSA in the differential diagnosis between prostate cancer and benign prostatic hyperplasia. Prostate 2000;42: [13] Stamey TA, Yemoto CE. Examination of the 3 molecular forms of serum prostate specific antigen for distinguishing negative from positive biopsy: relationship to transition zone volume. J Urol 2000;163: [14] Miller MC, O Dowd GJ, Partin AW, Veltri RW. Contemporary use of complexed PSA and calculated percent free PSA for early detection of prostate cancer: impact of changing disease demographics. Urology 2001;57: [15] Mitchell IDC, Croal BL, Dickie A, Cohen NP, Ross I. A prospective study to evaluate the role of complexed prostate specific antigen and free/total prostate specific antigen ratio for the diagnosis of prostate cancer. J Urol 2001;165: [16] Tanguay S, Begin LR, Elhilali MM, Behlouli H, Karakiewicz PI, Aprikian AG. Comparative evaluation of total PSA, free/ total PSA, and complexed PSA in prostate cancer detection. Urology 2002;59: [17] Sözen S, Eskicorapci S, Kupeli B, Irkilata L, et al. Complexed prostate specific antigen density is better than the other PSA derivatives for detection of prostate cancer in men with total PSA between 2.5 and 20 ng/ml: results of a prospective multicenter study. Eur Urol 2005;47: [18] Partin AW, Brawer MK, Bartsch G, et al. Complexed prostate specific antigen improves specificity for prostate cancer detection: results of a prospective multicenter clinical trial. J Urology 2003;170: [19] Roddam AW, Duffy MJ, Hamdy FC, et al. Use of prostate specific 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: [20] Mikolajczyk SD, Rittenhouse HG. Pro PSA: a more cancer specific form of prostate specific antigen for the early detection of prostate cancer. Keio J Med 2003;52: [21] Sokoll LJ, Chan DW, Mikolajczyk SD, et al. Proenzyme PSA for the early detection of prostate cancer in the ng/ ml total PSA range: preliminary analysis. Urology 2003;61: [22] Catalona WJ, Bartsch G, Rittenhouse HG, et al. Serum 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: [23] 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: [24] Canto EI, Singh H, Shariat SF, et al. Serum BPSA outperforms both total PSA and free PSA as a predictor of prostatic enlargement in men without prostate cancer. Urology 2004;63: