- Email: [email protected]
Editorial Comment on: Prostate Cancer Gene 3 (PCA3): Development and Internal Validation of a Novel Biopsy Nomogram
EUROPEAN UROLOGY 56 (2009) 659–668
[16] Nam RK, Toi A, Klotz LH, et al. Assessing individual risk for prostate cancer. J Clin Oncol 2007;25:3582–8. [17] Canto EI, Singh H, Shariat SF, et al. Effects of systematic 12-core biopsy on the performance of percent free prostate specific antigen for prostate cancer detection. J Urol 2004;172:900–4. [18] Shariat SF, Karam JA, Walz J, et al. Improved prediction of disease relapse after radical prostatectomy through a panel of preoperative blood-based biomarkers. Clin Cancer Res 2008;14: 3785–91. [19] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71–96. [20] Klotz L. Active surveillance for prostate cancer: for whom? J Clin Oncol 2005;23:8165–9.
Editorial Comment on: Prostate Cancer Gene 3 (PCA3): Development and Internal Validation of a Novel Biopsy Nomogram Alberto Briganti Department of Urology, Vita-Salute University San Raffaele, Milan, Italy [email protected] The introduction of prostate-specific antigen (PSA) into clinical practice has drastically changed the clinical approach and management of prostate cancer (PCa). Since the late 1990s, the utility of PSA in predicting the presence of PCa at biopsy has been corroborated by numerous studies [1–3]. But although PSA can be considered a reliable and useful marker in PCA diagnosis, it is limited by a (relatively) low specificity. This limitation results in the exposure of a certain number of patients to unnecessary prostate biopsies and urgently needs to be overcome in view of the upcoming results of PSA screening studies. Indeed, if an association between PCa screening and disease mortality is demonstrated, an increasing number of patients is expected to be referred for prostatic evaluation. Moreover, of those patients who are diagnosed with PCa, not all will be affected by life-threatening disease. Patient stratification with regard to PCa risk and aggressiveness is necessary in the clinical decision-making process. It is clear that such an important approach cannot be done on the basis of PSA alone. In the field of PCa diagnosis, other key variables such as digital rectal examination result, prostate volume, percent of free PSA, and familiarity of PCa are routinely considered in conjunction with PSA for determining the need for prostate biopsy [1–4]. Despite the combination of all of these parameters, the accuracy of multivariable models in predicting the presence of PCa has never reached 100% [5]. Therefore, something else is needed to improve our ability to detect PCa at biopsy. In this context, urinary PCa gene 3 (PCA3) has been shown to be an accurate predictor of PCa at biopsy [6–8]. Its sensitivity and specificity has been demonstrated to be superior even to PSA [7,8]. Moreover, Chun et al also demonstrated that inclusion of PCA3 in multivariable
667
[21] Chun FK, Haese A, Ahyai SA, et al. Critical assessment of tools to predict clinically insignificant prostate cancer at radical prostatectomy in contemporary men. Cancer 2008;113:701–9. [22] Nakanishi H, Groskopf J, Fritsche HA, et al. PCA3 molecular urine assay correlates with prostate cancer tumor volume: implication in selecting candidates for active surveillance. J Urol 2008;179:1804– 9, discussion 1809–10. [23] Thompson IM, Ankerst DP, Chi C, et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2006;98:529–34. [24] Briganti A, Chun FK, Suardi N, et al. Prostate volume and adverse prostate cancer features: fact not artifact. Eur J Cancer 2007; 43:2669–77.
models was able to improve significantly the predictive accuracy of models predicting presence of PCa at first or repeat biopsy [9]. The authors also developed and internally validated the first nomogram aimed at predicting the probability of PCa to include PCA3 as covariate. This tool showed a bootstrap-corrected 73% accuracy using a PCA3 cut-off threshold of 17, and it awaits external validation. Despite these very interesting results supporting the importance of PCA3 in PCa diagnosis, some key questions still need to be answered. First, despite a significant association between urinary PCA3 levels and PCa risk, the normal ranges of PCA3 in the population without PCa are still unknown. Hopefully, these data will be available soon from the results of an ongoing multicenter trial. Second, controversies exist with regard to the most significant cutoff value of PCA3 that should be considered as an indicator for prostate biopsy. Different PCA3 cut-offs have been proposed in different studies [6,8,9]. This issue must be fully addressed in future larger studies in which different cut-offs should be tested and given separately for patients submitted to either first or repeat biopsy. As for PSA, use of the same PCA3 cut-off (if any) is unlikely in clinical practice for patients who are considered for a first biopsy compared with patients who previously submitted to one or more negative biopsy sessions. Third, it would be interesting to test the role and the performance characteristics of PCA3 according to various PSA strata, such as patients with low and intermediate PSA levels, for whom the added value of a novel marker would be even more important. While waiting for these data, we can determine that PCA3 represents a novel and promising marker in the diagnosis and staging of PCa.
References [1] Carlson GD, Calvanese CB, Partin AW. An algorithm combining age, total prostate-specific antigen (PSA), and percent free PSA to predict prostate cancer: results on 4298 cases. Urology 1998; 52:455–61. [2] Chun FK-H, Briganti A, Graefen M, et al. Development and external validation of an extended 10-core biopsy nomogram. Eur Urol 2007;52:436–45.
668
EUROPEAN UROLOGY 56 (2009) 659–668
[3] Karakiewicz PI, Benayoun S, Kattan MW, et al. Development and
[7] Deras IL, Aubin SM, Blase A, et al. PCA3: a molecular urine assay
validation of a nomogram predicting the outcome of prostate
for predicting prostate biopsy outcome. J Urol 2008;179:1587–
biopsy based on patient age, digital rectal examination and serum prostate specific antigen. J Urol 2005;173:1930–4. [4] Walz J, Haese A, Scattoni V, Steuber T. Percent free prostatespecific antigen (PSA) is an accurate predictor of prostate cancer risk in men with serum PSA 2.5 ng/mL and lower. Cancer 2008;113:2695–703. [5] Chun FK-H, Graefen M, Briganti A, et al. Initial biopsy outcome
92. [8] Marks LS, Fradet Y, Deras IL, et al. PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. Urology 2007;69:532–5. [9] Chun FK, de la Taille A, van Poppel H, et al. Prostate cancer gene 3 (PCA3): development and internal validation of a novel biopsy nomogram. Eur Urol 2009;56:659–68.
prediction—head-to-head comparison of a logistic regressionbased nomogram versus artificial neural network. Eur Urol 2007;51:1236–43. [6] Haese A, de la Taille A, van Poppel H, et al. Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. Eur Urol 2008;54:1081–8.
DOI: 10.1016/j.eururo.2009.03.030 DOI of original article: 10.1016/j.eururo.2009.03.029
[16] Nam RK, Toi A, Klotz LH, et al. Assessing individual risk for prostate cancer. J Clin Oncol 2007;25:3582–8. [17] Canto EI, Singh H, Shariat SF, et al. Effects of systematic 12-core biopsy on the performance of percent free prostate specific antigen for prostate cancer detection. J Urol 2004;172:900–4. [18] Shariat SF, Karam JA, Walz J, et al. Improved prediction of disease relapse after radical prostatectomy through a panel of preoperative blood-based biomarkers. Clin Cancer Res 2008;14: 3785–91. [19] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71–96. [20] Klotz L. Active surveillance for prostate cancer: for whom? J Clin Oncol 2005;23:8165–9.
Editorial Comment on: Prostate Cancer Gene 3 (PCA3): Development and Internal Validation of a Novel Biopsy Nomogram Alberto Briganti Department of Urology, Vita-Salute University San Raffaele, Milan, Italy [email protected] The introduction of prostate-specific antigen (PSA) into clinical practice has drastically changed the clinical approach and management of prostate cancer (PCa). Since the late 1990s, the utility of PSA in predicting the presence of PCa at biopsy has been corroborated by numerous studies [1–3]. But although PSA can be considered a reliable and useful marker in PCA diagnosis, it is limited by a (relatively) low specificity. This limitation results in the exposure of a certain number of patients to unnecessary prostate biopsies and urgently needs to be overcome in view of the upcoming results of PSA screening studies. Indeed, if an association between PCa screening and disease mortality is demonstrated, an increasing number of patients is expected to be referred for prostatic evaluation. Moreover, of those patients who are diagnosed with PCa, not all will be affected by life-threatening disease. Patient stratification with regard to PCa risk and aggressiveness is necessary in the clinical decision-making process. It is clear that such an important approach cannot be done on the basis of PSA alone. In the field of PCa diagnosis, other key variables such as digital rectal examination result, prostate volume, percent of free PSA, and familiarity of PCa are routinely considered in conjunction with PSA for determining the need for prostate biopsy [1–4]. Despite the combination of all of these parameters, the accuracy of multivariable models in predicting the presence of PCa has never reached 100% [5]. Therefore, something else is needed to improve our ability to detect PCa at biopsy. In this context, urinary PCa gene 3 (PCA3) has been shown to be an accurate predictor of PCa at biopsy [6–8]. Its sensitivity and specificity has been demonstrated to be superior even to PSA [7,8]. Moreover, Chun et al also demonstrated that inclusion of PCA3 in multivariable
667
[21] Chun FK, Haese A, Ahyai SA, et al. Critical assessment of tools to predict clinically insignificant prostate cancer at radical prostatectomy in contemporary men. Cancer 2008;113:701–9. [22] Nakanishi H, Groskopf J, Fritsche HA, et al. PCA3 molecular urine assay correlates with prostate cancer tumor volume: implication in selecting candidates for active surveillance. J Urol 2008;179:1804– 9, discussion 1809–10. [23] Thompson IM, Ankerst DP, Chi C, et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2006;98:529–34. [24] Briganti A, Chun FK, Suardi N, et al. Prostate volume and adverse prostate cancer features: fact not artifact. Eur J Cancer 2007; 43:2669–77.
models was able to improve significantly the predictive accuracy of models predicting presence of PCa at first or repeat biopsy [9]. The authors also developed and internally validated the first nomogram aimed at predicting the probability of PCa to include PCA3 as covariate. This tool showed a bootstrap-corrected 73% accuracy using a PCA3 cut-off threshold of 17, and it awaits external validation. Despite these very interesting results supporting the importance of PCA3 in PCa diagnosis, some key questions still need to be answered. First, despite a significant association between urinary PCA3 levels and PCa risk, the normal ranges of PCA3 in the population without PCa are still unknown. Hopefully, these data will be available soon from the results of an ongoing multicenter trial. Second, controversies exist with regard to the most significant cutoff value of PCA3 that should be considered as an indicator for prostate biopsy. Different PCA3 cut-offs have been proposed in different studies [6,8,9]. This issue must be fully addressed in future larger studies in which different cut-offs should be tested and given separately for patients submitted to either first or repeat biopsy. As for PSA, use of the same PCA3 cut-off (if any) is unlikely in clinical practice for patients who are considered for a first biopsy compared with patients who previously submitted to one or more negative biopsy sessions. Third, it would be interesting to test the role and the performance characteristics of PCA3 according to various PSA strata, such as patients with low and intermediate PSA levels, for whom the added value of a novel marker would be even more important. While waiting for these data, we can determine that PCA3 represents a novel and promising marker in the diagnosis and staging of PCa.
References [1] Carlson GD, Calvanese CB, Partin AW. An algorithm combining age, total prostate-specific antigen (PSA), and percent free PSA to predict prostate cancer: results on 4298 cases. Urology 1998; 52:455–61. [2] Chun FK-H, Briganti A, Graefen M, et al. Development and external validation of an extended 10-core biopsy nomogram. Eur Urol 2007;52:436–45.
668
EUROPEAN UROLOGY 56 (2009) 659–668
[3] Karakiewicz PI, Benayoun S, Kattan MW, et al. Development and
[7] Deras IL, Aubin SM, Blase A, et al. PCA3: a molecular urine assay
validation of a nomogram predicting the outcome of prostate
for predicting prostate biopsy outcome. J Urol 2008;179:1587–
biopsy based on patient age, digital rectal examination and serum prostate specific antigen. J Urol 2005;173:1930–4. [4] Walz J, Haese A, Scattoni V, Steuber T. Percent free prostatespecific antigen (PSA) is an accurate predictor of prostate cancer risk in men with serum PSA 2.5 ng/mL and lower. Cancer 2008;113:2695–703. [5] Chun FK-H, Graefen M, Briganti A, et al. Initial biopsy outcome
92. [8] Marks LS, Fradet Y, Deras IL, et al. PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. Urology 2007;69:532–5. [9] Chun FK, de la Taille A, van Poppel H, et al. Prostate cancer gene 3 (PCA3): development and internal validation of a novel biopsy nomogram. Eur Urol 2009;56:659–68.
prediction—head-to-head comparison of a logistic regressionbased nomogram versus artificial neural network. Eur Urol 2007;51:1236–43. [6] Haese A, de la Taille A, van Poppel H, et al. Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. Eur Urol 2008;54:1081–8.
DOI: 10.1016/j.eururo.2009.03.030 DOI of original article: 10.1016/j.eururo.2009.03.029