Test urinaire PCA3 et diagnostic du cancer prostatique : étude à partir de 1015 patients

25 décembre 2015

Auteurs : V. Vlaeminck-Guillem, M. Devonec, D. Champetier, M. Decaussin-Petrucci, P. Paparel, P. Perrin, A. Ruffion
Référence : Prog Urol, 2015, 16, 25, e1




 




Introduction


The first urine test for the quantitative assessment of prostate cancer gene 3 (PCA3 ) RNA transcripts in patients with suspected prostate cancer (PCa) was published more than 10 years ago [1]. The PCA3 RNA product is almost exclusively expressed in cancerous prostate tissue. It is not expressed in other tissues and only very weakly expressed in healthy prostate tissue or in non-malignant prostatic diseases [1, 2, 3]. The discovery and diagnostic use of PCA3 came about in response to the lack of specificity of serum prostate-specific antigen (PSA) testing for the diagnosis of PCa.


To date, approximately 100 studies, involving cumulatively close to 30,000 patients, have been conducted to evaluate urinary PCA3 RNA measurement (PCA3 test) in clinical practice [4, 5, 6]. The PCA3 test was approved for diagnostic purposes by the United States Food and Drug Administration in 2012, as a decisional aid for repeat prostate biopsy in patients aged at least 50 years who have had one or more previous negative biopsies. In France, as of this writing, the PCA3 test is only available for clinical research studies or in the setting of a voluntary, patient-payed diagnostic process. Published clinical studies, variable in scientific quality, tend to show that the urinary PCA3 test can be of significant value when deciding whether or not to perform prostate biopsy. In contrast to the serum PSA, which is affected by prostate volume, the PCA3 score does not increase in the presence of a non-malignant prostatic disease [7]. It does however correlate with the risk of positive biopsy and its use may reduce the number of ultimately-negative (and thus, a posteriori unnecessary) biopsies by half to two-third [4, 5, 6]. Correlations are assumed to exist between the PCA3 score and histoprognostic criteria identified on biopsy or prostatectomy specimens.


The purpose of the present work is to report our experience with the diagnostic and prognostic performance of the urinary PCA3 test in a large cohort of patients referred for prostate biopsy following a suspicion of prostate cancer.


Patients and methods


Patients


All patients referred to our urology department between 20 December 2007 and 5 May 2014 for prostate biopsy were consecutively included in this prospective, single-center study. Reasons for referral were serum PSA ≥ 4ng/mL and/or an abnormal digital rectal examination (DRE) and/or a family history of PCa. Patients with a personal history of PCa were excluded, but those with a history of one or more negative prostate biopsies were included. One hundred and sixty of the included patients had been included in an earlier study [8]. All patients provided written informed consent.


After the collection of urine samples for the PCA3 test, the patients underwent a prostate biopsy series in accordance with the recommendations of the European Association of Urology, i.e., at least six cores taken from each lobe under transrectal ultrasound guidance, this latter permitting also an evaluation of prostate volume. The following anatomopathological data were recorded: Gleason score, percentage of positive cores, percentage of tumorous prostatic tissue, unilateral or bilateral involvement, presence or absence of perineural invasion, presence or absence of extracapsular extension.


Urine samples and urinary PCA3 test


First-catch urine samples (25-30mL) were collected after standardized DRE [9]. The samples were immediately transferred to specific specimen tubes (Progensa Urine Specimen Transport Kit, Gen-Probe), and stored at −20°C until the test could be performed. The PCA3 test (Progensa PCA3 assay, DTS400 system, Hologic Gen-Probe) was performed at the hospital's biochemistry service as per the manufacturer's recommendations. The PCA3 score was calculated as the ratio of PCA3 to PSA RNA copies, multiplied by 1000. When less than 10,000 copies of PSA mRNA were detected, the urine sample was considered as non-informative.


Statistical analyses


The normal distribution of quantitative variables was verified to permit their comparison using the Student's t -test. Proportions for qualitative variables were compared using the Chi2 test. Correlations between quantitative variables were identified using linear regression.


ROC curve was established for PCA3 score to calculate the area under the curve (AUC). For a given threshold, test performance was evaluated in terms of sensitivity, specificity, positive and negative predictive values, and accuracy (rate of correctly-classified patients) by comparing PCA3 scores to biopsy histological results. The contribution of the PCA3 score in relation to existing clinical and biological data was evaluated in multivariate (nested logistic regression models) and decision curve analyses (DCA). Calculations were performed using Stata Statistical Software Release 11 (StataCorp, College Station, Texas, USA). A P -value < 0.05 was considered statistically significant.


Results


Baseline characteristics


In the study period, 1029 patients had a urinary PCA3 test before undergoing prostate biopsy for suspicion of PCa. Urine samples were informative for 1015 (98.6%) of them. The characteristics of the 14 patients with non-informative samples did not differ from those of the other patients except for a higher rate of 5α-reductase inhibitor use: 21% vs 2% (P =0.003). Further analyses were thus performed in the 1015 patients with informative samples (Table 1). Significant differences between the 480 (47%) patients with positive biopsies and the 535 (53%) with negative biopsies were, for the former: older age, higher serum PSA levels, lower prostate volume, less frequent history of negative biopsies, DRE more frequently suspicious (Table 1).


Diagnostic performance of the urinary PCA3 test


The median PCA3 score was significantly higher in patients with positive biopsies, i.e., 53 vs 20 (P <0.0001) in patients with negative biopsies (Table 1), and the risk of positive biopsy increased with the PCA3 score (Figure 1). The AUC of the PCA3 score was significantly higher than that of the serum PSA, respectively 0.76 (95% CI: 0.73-0.79) and 0.55 (0.51-0.58) (Figure 2). The cutoff of 35, usually used in the literature, was indeed a good compromise between sensitivity (68%) and specificity (71%) for an accuracy of 69% (Figure 2). The risk of positive biopsy (67%) in the 482 (47%) patients with PCA3 score ≥ 35 was more than twice that of the 533 patients with PCA3 score < 35 (P <0.001).


Figure 1
Figure 1. 

Increasing risk of positive biopsies with the urinary PCA3 score.




Figure 2
Figure 2. 

Diagnostic performances of the urinary PCA3 score and comparison with serum PSA. AUC: area under curve ROC; 95% CI: 95% confidence interval; Se: sensitivity; Spe: specificity; PPV: positive predictive value; NPV: negative predictive value; Acc: accuracy (proportion of correctly-classified patients).




The diagnostic performance of the PCA3 test was similar in patients with or without a history of negative biopsies, i.e., AUCs of 0.74 (0.67-0.82) and 0.76 (0.73-0.79) respectively, P =0.643. It differed however as a function of PSA values. Whether the PSA values were between 2.5 and 4, between 4 and 10, or greater than 10ng/mL, the diagnostic performance of the PCA3 test was homogenous, with AUCs between 0.73 and 0.76. However, in the group of patients with PSA < 2.5ng/mL, performance was particularly high with an AUC of 0.95 (0.85-1.00).


Integration of the PCA3 score in a nomogram


Age, DRE findings (suspicious vs non suspicious), history of negative prostate biopsies (no history vs at least one negative biopsy series), prostate volume, history of physical treatment for benign prostate hyperplasia (BPH), serum PSA and PCA3 score were all predictive factors of biopsy results in univariate analysis (Table 2). They were all independently predictive in multivariate analysis also, except for physical treatment for BPH. All the clinical and biological variables predictive of biopsy results in multivariate analysis (except the PCA3 score) were integrated into a base predictive model, the AUC of which was 0.75 (0.72-0.78) (Table 2). When the PCA3 score was added to the base model, the AUC increased significantly to 0.80 (0.77-0.83) (P <0.001) (Table 2). To compare the net predictive benefit of the PCA3 test, a decision curve analysis (DCA) was performed. The model incorporating the PCA3 score produced a predictive benefit greater than that of the base model (Figure 3).


Figure 3
Figure 3. 

Evaluation of the ability of the PCA3 score to predict positive biopsies (net benefit) using decision curve analysis (DCA); base model: age, digital rectal examination, previous negative biopsies, prostate volume, serum PSA. DCA examined the theoretical relationship between the threshold probability of the outcome of positive prostate biopsies and the relative value of false-positive and false-negative results. Here, we estimated the magnitude of benefit resulting from altering clinical management in patients with different threshold probabilities of positive biopsies.




Prediction of prostate cancer aggressiveness


In the 480 patients with positive biopsies, the median PCA3 score did not differ significantly between the 225 (47%) patients with Gleason 6 score and the 255 (53%) patients with Gleason score ≥ 7 (Table 3). Equally, there were no differences according to the presence or absence of perineural invasion or extracapsular extension (Table 3). Conversely, PCA3 score was significantly higher when lesions were bilateral, when ≥ 33% of cores were positive or when ≥ 10% of prostate tissue was tumorous (Table 3).


An issue in PCa diagnosis is to only identify significant cancers. Using a cut-off of 20 for the PCA3 score to perform a biopsy, 332 (33%) of the patients in this study would have not undergone the biopsy. A third of the ultimately unnecessary biopsies would have been avoided, but 67 of the 480 cancers (14%) would have missed. Among those 67 cancers with PCA3 score < 20, 17 were Gleason 7 and 2 were Gleason 8. Among the 48 unidentified Gleason 6 cases, only one had a rate of positive cores ≥ 33%. Among the 67 missed cancer cases, 14 had abnormal DRE and/or PSA level ≥ 10ng/mL.


Discussion


In the present study, we evaluated the ability of the PCA3 urine test to predict prostate biopsy results in more than 1000 patients. To our knowledge, this is the largest study of its kind ever performed in France. Our results confirm previously published data concerning the urinary PCA3 test, particularly its function as a predictor of biopsy outcome, independent of other clinical and biological variables routinely used in clinical practice to decide whether or not to perform a biopsy. We demonstrated here, both in multivariate logistic regression and in DCA, that the addition of the PCA3 score to the usual clinical and biological variables provides a significant diagnostic gain. The main limit of our study is its single-center nature; all of the patients used in this study were treated in the same urology department. We do emphasize however that the referrals for the 1015 patients were made by 20 different urologists with different practices. For example, the rate of positive biopsy for the six physicians who referred at least 75 patients each ranged from 36 to 65%. We think therefore that our cohort was sufficiently diverse and representative of a large range of sensibilities in urology.


The overall diagnostic performance of the PCA3 test that we report here, with an AUC of 0.76, is perfectly coherent with that reported in the literature [4, 5, 6]. In our experience, the cut-off of 35 has indeed proven to be a good compromise between sensitivity (68%) and specificity (71%). Two-thirds of our patients with PCA3 score ≥ 35 had positive biopsies compared to less than a third for those with score < 35. However, our findings also clearly indicate that a high PCA3 score is not necessarily synonymous with cancer (false positives) and that low or even very low scores are not necessarily synonymous with the absence of cancer (false negatives). It underlines the importance to use the PCA3 score in conjunction with the usual clinical and biological findings, and even consider its use as part of a specific nomogram [10, 11]. Five to ten percent of PCa do not express the PCA3 RNA product [2, 12], which explains a certain number of false negatives. In contrast, there is currently no clearly identified mechanism to explain false positives, but patients should be closely monitored [13, 14, 15]. We also confirmed that the risk of positive biopsies increases as the PCA3 score increases (Figure 1). The use of a threshold is thus an arbitrary approach that must find a balance between two contradictory imperatives: avoiding unnecessary biopsies whenever possible (to reduce public healthcare costs, morbidity, psychological impacts for the patient) and not missing too many cancers, particularly those that are life-threatening. The PCA3 threshold of 20 may be a better compromise than 35; with its a-third of our biopsies (i.e., half of the ultimately unnecessary biopsies) could have been avoided. However, the absence of correlation between the PCA3 score and the Gleason score on biopsied tissue, at least in our study (see infra), is an obstacle to improve the ratio of avoided biopsies to missed significant cancers. Cost effectiveness studies are needed to determine if the generalized use of the PCA3 test can effectively reduce healthcare costs by lowering the number of unnecessary biopsies and their associated complications.


In our large cohort, the PCA3 test was robust, particularly with more than 98% of informative samples. This high rate is usual with this commercial kit, which includes a target RNA selection step before amplification [9]. In our study, only the use of 5α-reductase inhibitors appeared to reduce the rate of informative samples, which is logical since these agents induce a reduction in the expression of PSA RNA. However, when informative samples are retrieved from patients taking 5α-reductase inhibitors, the diagnostic performance of the PCA3 test does not appear to be affected, as was demonstrated in the REDUCE trial on dutasteride for PCa prevention [16].


Also illustrating the robustness of the PCA3 test was the lack of influence of the usual clinical variables on its performance, which remained good regardless of age, prostate volume, DRE results, or the presence or absence of a history of negative biopsies. Considering these findings, it appears to us that restricting the availability of the PCA3 test to only those patients with a history of negative biopsies is not justified; this position is additionally strengthened by the results of recent studies on patients undergoing an initial prostate biopsy [11, 17]. In contrast to PSA levels, the PCA3 score does not increase with prostate volume. Furthermore, in our study, we detected an inverse correlation wherein the PCA3 score increases as prostate volume decreases. This reflects essentially the higher frequency of cancer in patients with low prostate volume (PCA3 being a cancer marker) in opposition to the higher frequency of BPH in patients with high prostate volume. The only factor that had an influence on PCA3 test performance in our study was the PSA level itself. More precisely, the diagnostic performance of the PCA3 test was stable across all PSA levels greater than 2.5ng/mL (AUCs between 0.73 and 0.76), but under that threshold, it improved (AUC of 0.95). These patients with PSA < 2.5ng/mL were mainly referred for biopsy based solely on a confirmed family history of prostate cancer. Thus, the PCA3 test appears to be particularly advantageous in this specific population, where its accuracy has the potential to limit repeated and unnecessary biopsies in frequently young patients.


The diagnostic performance of the PCA3 test prompted the clinicians to assess its interest for prognosis. Correlations between the PCA3 score and the Gleason score on biopsies have been suggested [4], but the literature remains contradictory on this question. In the present study, we found no correlations between the PCA3 score and the Gleason score; our negative result can be explained neither by a lack of statistical power nor by differences in studied populations (similar proportions of patients with Gleason scores<or ≥ 7). We note as well that in an earlier work, our team found no correlations between PCA3 scores and Gleason scores calculated on radical prostatectomy specimens (study on 154 patients from the same source cohort as here) [18]. Additionally, early histological studies did not demonstrate any links between PCA3 gene expression and cancer differentiation [2, 3, 19]. In contrast, studies on prostatectomy specimens have demonstrated associations between the PCA3 score and tumor volume [18, 20], as have biopsy studies such as the present via the proportions of positive cores and tumorous prostatic tissue.


Conclusion


The present study involving more than 1000 patients confirmed performance data on the urinary PCA3 test for the prediction of prostate biopsy results. The classic clinical and biological variables such as age, DRE findings, history of negative biopsies, prostate volume or serum PSA level did not influence the performance of the test. Additional studies are needed to evaluate the interest of pairing (simultaneously or sequentially) the PCA3 test with MRI of the prostate, which is increasingly used for the diagnosis of PCa and the assessment of its aggressiveness. The benefits of avoiding unnecessary biopsies is a major issue. When evaluated as a part of decisional models for repeat biopsies on a history of negative biopsies, the introduction of the PCA3 test in clinical practice could save between €1.7 and 5 million according to the costs related to biopsy complications [21]. The cost of cancers that may escape detection when the PCA3 test is used to decide on a biopsy should be integrated into these calculations. Finally, the impact of the test in the diagnostic process overall remains to be determined. Toward this, an evaluation is underway as part of a support program for costly innovative technologies funded by the French National Cancer Institute (INCa).


Disclosure of interest


The authors declare that they have no competing interest.



Acknowledgments


We thank Doctors M. Vinet, E. Briant, N. Gobeaux, J.L. Campos-Fernandez, E. Adam, S. Genevoix, C. De Vendin, R. Lardon, G. Pic, F.X. Buttin, F. Lalloue, M. Goris and X. Borgnat for their aid in enrolling patients, Ms. M. Cottancin and Ms. B. Grangier for their technical assistance, and Ms. M. Dupuis for her assistance with data collection.




Table 1 - Baseline characteristics of the 1015 patients with informative urine samples, and correlations with presence of cancer on biopsies. For quantitative variables, median, IQR (interquartile range), mean and standard deviation are indicated.
  Whole cohort  Patients with negative biopsies  Patients with positive biopsies  Significativity (P
Number of patients   n =1015  n =535 (53%)  n =480 (47%)   
Median age
( n= 1015)  
64 years (59-69)
(mean: 64±7) 
63 years (58-67)
(mean: 63±6) 
66 years (61-70)
(mean: 66±7) 
<0.0001 
Prior negative biopsies  
n =825 (81%)  n =406 (76%)  n =419 (87%)  <0.001 
n =144 (14%)  n =95 (18%)  n =49 (10%) 
n =31 (3%)  n =22 (4%)  n =9 (2%) 
≥ 3  n =15 (1%)  n =12 (2%)  n =3 (1%) 
Previous administration of 5α-reductase inhibitors  
Yes  n =20 (2%)  n =11 (2%)  n =9 (2%)  =0.836 
No  n =995 (98%)  n =524 (98%)  n =471 (98%) 
Digital rectal examination  
Suspicious  n =145 (14%)  n =41 (8%)  n =104 (22%)  <0.001 
Not suspicious  n =870 (86%)  n =494 (92%)  n =376 (78%) 
Median prostate volume
(n =1003) 
40mL (29-54)
(mean: 44±21) 
45mL (32-60)
(mean: 49±23) 
35mL (26-48)
(mean: 38±17) 
<0.0001 
Median number of biopsy cores  12 (12-12)
(mean: 12±1) 
12 (12-12)
(mean: 12±1) 
12 (12-12)
(mean: 12±1) 
=1.000 
Total serum PSA 
Median  6.6ng/mL (5-9.4)
(mean 6.2±4.3) 
6.4ng/mL (4.9-9)
(mean: 7.6±4.8) 
6.8ng/mL (5.1-10)
(mean: 16.4±57.2) 
=0.0004 
< 2.5ng/mL  n =25 (2%)  n =17 (8%)  n =8 (2%)  =0.018 
2.5-3.99ng/mL  n =67 (7%)  n =36 (7%)  n =376 (6%) 
4-9.99ng/mL  n =697 (69%)  n =382 (71%)  n =315 (66%) 
≥ 10ng/mL  n =226 (22%)  n =100 (19%)  n =126 (26%) 
Median urinary PCA3 score  32 (16-66)
(mean: 57±67) 
20 (11-41)
(mean: 35±47) 
53 (28-100)
(mean: 81±78) 
<0.0001 





Table 2 - Multivariate analyses evaluating the ability of clinicobiological variables to predict prostate biopsy outcome and comparison with the addition of urinary PCA3 score (n = 1015 patients).
  Univariate analysis 
Multivariate analysis 
        Base model 
Base model
+ PCA3 score 
  OR
(IC 95%) 
P   AUC  OR
(IC 95%) 
P   OR
(IC 95%) 
P  
Age  1.06
(1.04-1.08) 
< 0.001  61.6%
(58-65) 
1.07
(1.05-1.10) 
< 0.001  1.05
(1.02-1.07) 
< 0.001 
Previous biopsies  0.46
(0.33-0.64) 
< 0.001  55.7%
(53-58) 
0.45
(0.30-0.67) 
< 0.001  0.48
(0.31-0.75) 
0.001 
Prostate volume  0.97
(0.96-0.98) 
< 0.001  65.5%
(62-69) 
0.97
(0.96-0.97) 
< 0.001  0.97
(0.96-0.97) 
< 0.001 
Digital rectal examination  3.33
(2.27-4.90) 
< 0.001  57.0%
(55-59) 
2.15
(1.39-3.34) 
0.001  2.03
(1.31-3.15) 
0.002 
Serum PSA  1.04
(1.02-1.06) 
< 0.001  54.9%
(51-58) 
1.07
(1.02-1.12) 
0.005  1.07
(1.02-1.12) 
0.006 
PCA3 score  1.02
(1.01-1.02) 
< 0.001  75.8%
(73-79) 
1.01
(1.01-1.02) 
< 0.001 
Prediction accuracya        74.6%
(72-78) 
80.1%
(77-82) 
Increase in performances        +5.5%
P < 0.001 



Légende :
OR: odds ratio.

[a] 
Estimation using the AUC (%).


Table 3 - Pathological characteristics of the prostate biopsies and correlations with the urinary PCA3 score.
Pathological criteria      PCA3 Score
Median (IQR) (P
Gleason score         =0.674 
n =225 (47%)  n =225 (47%)  48 (26-96)   
n =208 (43%)  n =255 (53%)  60 (32-108)   
n =35 (7%)       
n =12 (3%)       
Proportion of invaded cores         =0.0001 
Median (IQR)  25% (14-48)       
< 33%  n =264 (55%)    45 (23-85)   
≥ 33%  n =216 (45%)    68 (39-132)   
Proportion of invaded tissue         =0.002 
Median (IQR)  6% (2-14)       
< 10%  n =307 (64%)    49 (24-93)   
≥ 10%  n =171 (36%)    65 (36-129)   
Laterality         <0.0001 
Unilateral  n =263 (55%)    42 (23-82)   
Bilateral  n =217 (45%)    72 (42-132)   
Perineural involvement         =0.863 
No  n =389 (81%)    51 (28-97)   
Yes  n =91 (19%)    61 (29-110)   
Extracapsular extension         =0.200 
No  n =464 (97%)    52 (28-99)   
Yes  n =16 (3%)    80 (25-141)   



Légende :
IQR: interquartile range.


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