Results. Conclusion. Keywords

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1 Prognostic value of urinary prostate cancer antigen 3 (PCA3) during active surveillance of patients with low-risk prostate cancer receiving 5a-reductase inhibitors Vincent Fradet, Paul Toren, Moliere Nguile-Makao, Michele Lodde, Jerome Levesque, Caroline Leger, Andre Caron, Alain Bergeron, Tal Ben-Zvi, Louis Lacombe, Frederic Pouliot, Rabi Tiguert, Thierry Dujardin and Yves Fradet Centre Hospitalier Universitaire de Quebec-Universite Laval, Quebec, QC, Canada Objectives To determine the clinical performance of the urinary prostate cancer antigen 3 (PCA3) test to predict the risk of Gleason grade re-classification amongst men receiving a 5a-reductase inhibitor (5ARI) during active surveillance (AS) for prostate cancer. Patients and Methods Patients with low-risk prostate cancer were enrolled in a prospective Phase II study of AS complemented with prescription of a 5ARI. A repeat biopsy was taken within the first year and annually according to physician and patient preference. In all, 90 patients had urine collected after digital rectal examination of the prostate before the first repeat biopsy. The PCA3 test was performed in a blinded manner at a central laboratory. Results Using a PCA3-test score threshold of 35, there was a significant difference (P < 0.001) in the risk of being diagnosed with Gleason 7 cancer during a median of 7 years of follow-up. Adjusted Cox regression and Kaplan Meier analyses also showed a significantly higher risk of upgrading to Gleason 7 during follow-up for those with a higher PCA3-test score. Conclusion The urinary PCA3 test predicted Gleason grade re-classification amongst patients receiving a 5ARI during AS for low-risk prostate cancer. Keywords 5a-reductase inhibitors, active surveillance, prostate cancer antigen 3, #PCSM, #ProstateCancer Introduction Prostate cancer is commonly diagnosed using PSA testing, DRE and TRUS-guided biopsy. However, this approach detects both indolent low-grade tumours and aggressive highgrade tumours. It is now well recognised that a significant proportion of prostate cancers do not require treatment. This knowledge has led to the widespread acceptance of active surveillance (AS) [1] as the preferred management strategy for low-grade tumours. The clinical protocols for AS include: regular follow-up with PSA testing, repeat biopsies, and more recently multi-parametric MRI in many jurisdictions [2,3]. About 30 35% of patients who meet criteria for AS eventually undergo treatment [4 6]. PSA testing has been shown to have limited utility to detect cancer upgrading during AS [7], and repeat biopsies are invasive, with attendant risks to patients [8] and increased healthcare costs [9]. Use of 5a-reductase inhibitors (5ARIs) and MRI may both play a role in diminishing these risks and costs [10 12]. Therefore, better quantifying of the risk of upgrading of low-risk prostate cancer continues to be a clear need for patients starting AS. The prostate cancer antigen 3 (PCA3) test is a USA Food and Drug Administration (FDA)-approved urine test used in assessing the risk of prostate cancer before prostate biopsy. The PCA3 test detects in the urine after DRE the expression of a long non-coding RNA (DD3) that is specifically overexpressed in cancerous relative to benign prostatic cells and is calculated as the ratio of the number of transcripts of DD3 over the number of transcripts of PSA RNA. Reviews of published studies report its utility in patients with previous negative biopsies by meta-analysis [13] or before initial biopsy [14,15]. Nonetheless, there exists some heterogeneity and controversy among published studies [15], and newer biomarkers now available, such as the Prostate Health Index (PHI) or BJU International 2017 BJU International doi: /bju BJU Int 2018; 121: Published by John Wiley & Sons Ltd. wileyonlinelibrary.com

2 Fradet et al. Mi-Prostate Score (MiPS) could potentially perform better in similar contexts [16,17]. Other studies have shown its utility in men receiving a 5ARI [18], and in predicting cancer risk before initial biopsy [19]. A positive association has also been shown between the PCA3-test score and tumour volume at radical prostatectomy [20], as well as to Gleason score [21]. Recent papers have now reported on the use of the PCA3 test in patients on AS or in those who would have been eligible for AS [22]. The largest prospective multi-centre study was in the Canary Prostate Active Surveillance Study (PASS) cohort and indicated that urinary PCA3 carries prognostic significance to identify men with high-grade and high-volume disease [23]. However, it remains unknown whether the PCA3 test retains similar predictive accuracy in men on AS receiving a 5ARI and if the predictive accuracy remains over time with longer follow-up. The goal of the present study was therefore to evaluate the PCA3 test performance in predicting upgrading in men on 5ARI therapy during AS for Gleason score 6 prostate cancers with a long follow-up. Patients and Methods A prospective phase II clinical trial of 5ARI use in men on AS was approved by our Institutional Review Board and informed consent was obtained from all patients. Patients were recruited when their prostate cancer was diagnosed. Included patients were diagnosed between March 2003 and December Inclusion criteria were: low-risk prostate cancer defined as a Gleason score 6 on four out of 12 biopsy cores, a serum PSA level of 10 ng/ml, and a willingness to undergo AS including treatment with a 5ARI. Patients were treated with either finasteride 5 mg/day or dutasteride 0.5 mg/day, according to the urologist s preference and patients tolerance. Follow-up biopsies were scheduled after 6 12 months and yearly thereafter, although practice patterns changed over time, with fewer repeat biopsies taken with longer follow-up. All prostate biopsies, initial and repeat, in the present study were taken at our institution under TRUS guidance. A standard 12-core template was used in all cases. Upgrading was defined as the presence of Gleason score 7 prostate cancer on a subsequent biopsy. Patients under 5ARI treatment before prostate cancer diagnosis or those who received prior definitive treatments for their cancer (e.g. radiotherapy) were excluded. Information on biopsy results, serum PSA levels and treatments received were recorded prospectively and verified from patient records. Pathology Assessment and PCA3 Testing A TRUS-guided 12-core biopsy was taken by an attending urologist in all cases. Histological analysis of the biopsy tissue was performed as per institutional protocol by qualified pathologists blinded to the clinical data and PCA3-test score of the patients. On the day of, and before their first follow-up biopsy, a post-dre urine specimen was collected using the company s kit. Briefly, as described by Groskopf et al. [24] after a DRE performed by an attending urologist, ml of first-catch urine was collected and kept at 4 C until processed. An aliquot of 2 ml urine was mixed with an equal volume of Hologic (previously Gen-Probe) RNA stabilisation buffer within 4 h of collection, and then frozen at 80 C until they were sent to Hologic for PCA3 analysis according to previously described protocols [24]. Hologic analyses were performed blinded to the clinical outcome. Briefly, a combination of target captures, transcription mediated amplification and hybridisation protection assays were used to quantify the RNA copy number of PCA3 and PSA. The PCA3 score was calculated as the number of RNA copies of PCA3/PSA Statistical Analysis For descriptive statistics, the Student s t-test and chi-squared test were used to compare groups. To compare the distribution of continuous and categorical variables we used the non-parametric Wilcoxon rank-sum test and Fisher s exact test, respectively. Logistic regression was used to estimate odds ratios (ORs) for the association between the PCA3-test score and prostate cancer upgrading observed at the first or subsequent repeat biopsies. Cox regression analysis was used to evaluate the hazard risk (HR) between the PCA3-test score and the prostate cancer upgrading observed on all biopsies during follow-up, adjusted for age, baseline PSA level, prostate volume at ultrasonography, and number of positive biopsy cores. To confirm with current practice, a PCA3- test score threshold value of 35 was used for all binary analyses [13]. The predictive accuracy of the logistic and Cox regression models was validated with the area under the curve (AUC) analysis and the C-index, respectively [25]. The log-rank test was used to compare the probability of pathological upgrading on AS between PCA3-test score groups. Results We enrolled in this study 90 consecutive patients who had an initial diagnosis of Gleason score 6 prostate cancer and for whom post-dre urine could be collected before the first repeat biopsy performed after at least 6 months of 5ARI treatment. Details of the baseline characteristics of this cohort are described in Table 1. At initial diagnosis, the mean (SD) age was 64 (7.0) years, the mean (SD) serum PSA level was 5.7 (3.0) ng/ml, the mean (SD) prostate volume was 43 (20.0) ml, and 78 patients (87%) had a normal DRE, whilst 12 (13%) had a suspicious prostate nodule. After a mean (SD) follow-up to last PSA measurement of 6.9 (2.5) years, repeat biopsies re-classified 36 patients to Gleason 400 BJU International 2017 BJU International

3 PCA3 test during active surveillance of low-risk prostate cancer Table 1 Baseline characteristics of patients enrolled in study. Patient characteristic All patients PCA3-test score <35 PCA3-test score 35 P Number of patients Age, years, mean (SD) 64.7 (7.0) 64.5 (6.7) 65.7 (8.3) 0.42 PSA level, ng/ml, mean (SD) 5.7 (3.00) 5.6 (2.9) 6.2 (3.4) 0.55 Prostate TRUS volume, ml, mean (SD) 42.9 (20.03) 43.9 (20.4) 38.3 (18.3) 0.28 Clinical stage, n (%) T1c 77 (86) 63 (85) 14 (88) 0.8 T2a 11 (12) 9 (12) 2 (12) T2b 2 (2) 2 (3) 0 Follow-up, months, mean (SD) 45.6 (30.07) 47.7 (30.06) 35.6 (28.9) ARI treatment, n (%) Dutasteride 52 (60) 43 (59) 9 (56) 0.99 Finasteride 38 (40) 31 (42) 7 (44) Time on 5ARI prior to PCA3 test, months, mean (SD) 14.6 (10) 14.6 (10) 14.7 (11) 0.59 Initial biopsy positive cores, n, mean (SD) 1.66 (0.89) 1.58 (0.78) 2.0 (1.26) 0.08 PSA density, ng/ml/ml, mean (SD) 0.19 (0.12) 0.18 (0.12) 0.21 (0.09) 0.49 score 7 prostate cancer (four patients had two positive biopsies with Gleason score 7; Table 2). This upgrading did not appear to occur more frequently at the first repeat biopsy as others have reported [26]. The median 5ARI treatment duration before the first repeat biopsy was 10.8 months. This treatment decreased the median PSA level to 2.7 ng/ml and the median prostate volume to 31 ml. Predictive Power of the PCA3 Test The PCA3-test score was determined at study entry immediately before the first repeat biopsy: 16 of 90 patients (17.7%) had a PCA3-test score of 35. Compared to patients with a PCA3-test score of <35, these patients had a similar age, PSA level, prostate volume, number of positive cores, number of previous biopsies, and duration of 5ARI treatment (Table 1). Both unadjusted and adjusted logistic regression models showed that men with a PCA3-test score of 35 had a significantly higher probability (P < 0.001) of cancer upgrading at that first repeat biopsy than those with a PCA3- test score of 35 (unadjusted OR 11.3, 95% CI ). Adjusting for age, prostate volume and PSA level at the first biopsy yielded similar results, with an OR of 12.4 (95% CI , P < 0.001). The Cox regression analysis also showed a significant risk of cancer upgrading at all repeat biopsies for those with a PCA3-test score of 35, with an unadjusted HR of 3.48 (95% CI ) and adjusted HR of 3.82 (95% CI Table 2 Prostate biopsy results following commencement of AS. Biopsy No cancer, n (%) Gleason score 6, n (%) Gleason score 7, n (%) First 49 (54) 27 (30) 14 (16) Second 40 (60) 13 (20) 13 (20) Third 17 (47) 9 (25) 10 (28) Fourth 5 (50) 4 (40) 1 (10) Fifth 0 1 (33) 2 (67) ) (Table 3). The Kaplan Meier curve depicted in Fig. 1 shows that the rate of cancer upgrading was significantly greater (P < 0.001) in patients with a PCA3-test score of 35. Figure 2 shows the performance of the PCA3 test in discriminating cancer upgrading at the first repeat biopsy (AUC 0.91). The global performance in predicting cancer upgrading over time based on the baseline PCA3 measurement was very good (mean C-index = 0.68) and constant throughout the whole follow-up duration as repeat prostate biopsy sessions were undertaken. Use of the PCA3- test score as a continuous variable showed a significant ability to predict the reclassification to Gleason score 7 in both univariate and multivariate models (Table 4). Discussion In this homogeneous cohort with a long follow-up (median 7 years) of men under AS for low-risk prostate cancer treated with a 5ARI, a PCA3-test score of 35 before the first repeat biopsy after >6 months of treatment was a strong predictor of later upgrading to Gleason score 7 prostate cancer. In patients with a PCA3-test score of 35, the median time to pathological upgrading was 30 months (verifier) and >80% had progressed at 5 years, compared to a median time to Table 3 Cox regression analysis of risk of developing Gleason score 7 prostate cancer during AS modelling the PCA3 test as a dichotomous variable. Covariate Univariate model Multivariate model HR (95% CI) P HR (95% CI) P PCA3-test score ( ) < ( ) Age (years) 1.01 ( ) ( ) Prostate volume 0.99 ( ) ( ) (ml) PSA (ng/ml) 1.00 ( ) ( ) Number of positive cores 1.76 ( ) ( ) BJU International 2017 BJU International 401

4 Fradet et al. Fig. 1 Kaplan Meier analysis of the risk of upgrading to Gleason score 7 prostate cancer during AS of Gleason score 6 prostate cancer, stratified by PCA3-test score. Progression to Gleason PCA3<35 PCA3 35 PCA3 35 PCA3< Number at risk Time, Months Time, Months Fig. 2 Receiver operating characteristic (ROC) curve for the PCA3-test score modelled continuously in predicting upgrading to Gleason score 7 prostate cancer on the first repeat surveillance biopsy. True positive rate ROC curve AUC = upgrading of 90 months and <35% upgrading at 5 years for those with a PCA3-test score of <35. The PCA3 test has previously been shown to have predictive utility in men on False positive rate Table 4 Cox regression analysis of upgrading to Gleason score 7 prostate cancer during AS modelling the PCA3 test as a continuous variable. Covariate Univariate model Multivariate model HR (95% CI) P HR (95% CI) P PCA3-test score* 1.15 ( ) ( ) Age (years) 1.01 ( ) ( ) Prostate volume (ml) 0.99 ( ) ( ) PSA level (ng/ml) 1.00 ( ) ( ) *Continuous covariate. AS, and the present study suggests even better performance in men on AS who are receiving 5ARI therapy. The prognostic potential of the PCA3 test in AS was first evaluated by Tosoian et al. [27]. Their study included 294 men diagnosed with low-risk prostate cancer, as defined by a clinical stage T1c, Gleason score 6 and a PSA density of <0.15 ng/ml/ml. They defined upgrading as a Gleason pattern of 4 or 5 on more than two positive biopsy cores or >50% involvement of any biopsy core with cancer. They reported a low level of upgrading (12.9%) and thus were not able to show a statistical difference between the mean PCA3-test score of those with and without upgrading (60.0 vs 50.8). The median follow-up was 3.7 years. In a recent similar study based on a similar cohort of 260 patients under AS at John s Hopkins with a longer follow-up (median 6 years), the PCA3-test score was associated with upgrading. Similarly, another large-scale study [28], in which 1072 patients with a previous negative biopsy were enrolled and followed over 4 years, reported that the PCA3 test at 2 years was a significant predictor of the biopsy outcome at 4 years, results that have been confirmed by Auprich et al. [29]. This last group has also shown the superiority of the PCA3 test over the serum PSA test to predict upgrading at a first repeat biopsy session in this population at risk of prostate cancer but who did not necessarily have a confirmed case of prostate cancer at study entry [14]. Finally, the analysis of the baseline data of the Canary PASS [23] showed that the PCA3 test appears to stratify men on AS for the risk of harbouring aggressive cancer. Although convincing, none of these studies examined the ability of the PCA3 test to determine upgrading in a cohort of patients with confirmed low-risk prostate cancer receiving an intervention with 5ARI. Two 5ARIs, finasteride and dutasteride, have been tested for the prevention of prostate cancer and prevention of prostate cancer upgrading in large phase III clinical trials [10,30,31]. The results show a reduction in the size of the prostate and the finding of low-grade prostate cancer on subsequent biopsy in all cases. An increased risk of highgrade tumours after treatment with these drugs has led to 402 BJU International 2017 BJU International

5 PCA3 test during active surveillance of low-risk prostate cancer the rejection of their use as chemopreventive agents for prostate cancer, although this remains controversial [32,33]. Nonetheless, these agents are widely used for BPH, and are commonly given to men on AS for prostate cancer [10,34]. In Quebec, a study revealed that GPs prescribe 5ARIs to more than one-third of patients presenting with BPH [35], and our experience is that these treatments are not discontinued upon prostate cancer diagnosis. Given that 5ARIs are involved in the conversion of testosterone into dihydrotestosterone (DHT), the active form of this hormone, and that DHT is a transcriptional activator of both the PSA and PCA3 genes [36,37], it was important to determine the effects of 5ARI on the ability of the PCA3 test to detect prostate cancer upgrading. Indeed, as the PCA3-test score is calculated by dividing the number of PCA3 mrna copies by the number of PSA mrna copies, any treatment that would affect the transcriptional activation of either of these genes may have consequences on the results of this test. On the other hand, given that both genes are regulated by that same molecule, the ratio of the expression of these two genes should remain unchanged and thus the sensitivity and specificity of the test should be preserved. This is indeed what we and others have found [18]. Our present study has some limitations worth mentioning. The number of patients assessed during the course of the present study is relatively small. This limits the ability to evaluate subgroups, such as intermediate- or high-grade cancer being detected during follow-up. Nonetheless, our treatment follow-up is reasonably long, at close to a median of 7 years, which is amongst the studies evaluating PCA3 with the longest follow-up. What is more, the predictive accuracy of the baseline PCA3 test was stable throughout the whole study follow-up. Further validation in other cohorts is needed to strengthen the results. Another limitation is that the evaluation was based on one PCA3 measurement before the first repeat biopsy. Notably, the predictive power of the PCA3-test score was highest in the biopsy subsequent to the test, suggesting that repeated PCA3 testing may yield better results, something which we were unable to evaluate. In conclusion, our present findings show that, the urinary PCA3 test is an early prognostic biomarker of upgrading to high-grade disease for low-grade prostate cancer during AS complemented with 5ARI treatment. With further validation in users of 5ARIs, the PCA3 test may be useful to help distinguish early on patients on AS who require definitive treatment. Acknowledgements The authors thank Jack Groskopf at Hologic for his help in performing the PCA3 tests. Conflict of Interest Dr V. Fradet reports personal fees from Abbvie, grants and personal fees from Amgen, grants and personal fees from Astra Zeneca, grants and personal fees from Astellas, personal fees from Bayer, personal fees from Ferring, grants and personal fees from Janssen, grants and personal fees from Sanofi, all outside the submitted work. Dr Toren reports grants from Innocrin Pharmaceuticals, personal fees from Ferring, Sanofi Canada, and Astellas outside the submitted work. Dr Dujardin reports personal fees from Ferring, and Sanofi outside the submitted work. Dr Y. Fradet reports grants from GSK Biologicals Inc., non-financial support from DiagnoCure Inc. during the conduct of the study; personal fees from DiagnoCure Inc. outside the submitted work. In addition, Dr Y. Fradet holds multiple pending and issued patents related to the PCA3 test. Dr Nguile-Makao, Dr Lodde, Mr Levesque, Dr Leger, Dr Caron, Dr Bergeron, Dr Ben-Zvi, Dr Lacombe, Dr Pouliot and Dr Tiguert have nothing to disclose. 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