Toggle

Learn about PCA3

Breadcrumb

Introduction

Why is there a need for additional diagnostic tests in prostate cancer?

Currently the early detection of prostate cancer (PCa) relies primarily on serum prostate specific antigen (PSA) level and digital rectal examination (DRE). The outcome of both tests can result in a prostate biopsy to confirm the diagnosis of PCa. However, each of these measures has shortfalls that may lead to unnecessary biopsies and potentially overdetection and overtreatment of clinically insignificant cancer

PSA

Serum PSA is a standard tool used in the diagnosis of PCa, but is not PCa-specific. Elevated PSA levels can also be caused by other prostate conditions such as benign prostatic hyperplasia (BPH) and prostatitis. According to international guidelines PSA testing can be offered to well-informed men with a good performance status and a life expectancy of at least 10 years, to be started from 45-50 years of age [1,2].

DRE

DRE is another standard procedure, but has a low positive predictive value (PPV), a poor reproducibility and a high inter-examiner variability.

TRUS

A transrectal ultrasound (TRUS) of the prostate is also often performed during the diagnostic work-up. While it is useful for diagnostic volumetric and morphological assessments, its low resolution and inadequate reliability in detecting areas with PCa hamper its diagnostic performance [1,2].

Prostate biopsy

A prostate biopsy provides the diagnosis of PCa, and is indicated based on risk stratification, but due to the low PPVs of PSA and DRE approximately 75% of men will have an unnecessary negative initial biopsy [3]. The fear that cancer was missed often leads to repeat biopsies, most of which will also be negative [4]. The high number of negative initial and repeat biopsies will increase health care costs and diminish patients’ quality of life. Biopsies can induce anxiety because of the fear of having PCa and they may cause discomfort, pain and complications (e.g. hematuria, hematospermia, rectal bleeding and rarely septicemia) [5-7].

Over the years widespread PSA testing had led to overdetection and overtreatment of clinically insignificant cancer. One way to reduce overdiagnosis and overtreatment would be to supplement PSA testing with an additional diagnostic test that can differentiate between clinically insignificant and significant cancer.  

Considering all these factors there is obviously a need for additional diagnostic tests to make more informed biopsy decisions.

there is a need for additional diagnostic tests in prostate cancer

Currently several biomarkers are on the market or being investigated to help in PCa diagnosis, such as the PCA3 assay, the prostate health index (phi), the 4Kscore test, SelectMDx, a tissue-based epigenetic test (ConfirmMDx) and TMPRSS2:ERG [8,9]. Multiparametric magnetic resonance imaging (MRI) is another assessment for risk stratification prior to biopsy. The international guidelines discuss that multiparametric MRI may help to identify regions of cancer missed on prior biopsies. A multiparametric MRI should be considered in selected men with at least 1 prior negative biopsy and persistent suspicion of PCa [1,2].

What is the PCA3 assay?

The PCA3 assay is an additional test to help make better biopsy decisions in the diagnosis of PCa. It uses a simple urine specimen collected after a DRE. The PCA3 Assay detects the over-expression of the PCA3 gene, that is highly specific for PCa, in the urine sample. The information provided by the test (the PCA3 score) can be used in conjunction with other clinical information to decide whether a prostate biopsy is needed or can be delayed. The PCA3 assay is approved by the FDA, CE-marked and available as the PROGENSA® PCA3 assay worldwide.

Discovery of PCA3

PCA3 (Prostate Cancer Gene 3) was discovered by the research group of Dr. Jack Schalken in Nijmegen, the Netherlands, in co-operation with Dr. William Isaacs of Johns Hopkins in Baltimore, USA. When they published their findings in 1999 in Cancer Research, the gene was still referred to as DD3 [10].

They discovered that messenger RNA (mRNA) of the PCA3 gene is highly over-expressed in > 95% of PCa cells [10,11]. PCa cells express 60 to 100 times more PCA3 mRNA than normal prostate cells. PCA3 is thus highly PCa-specific.

This group of researchers was the first to develop a PCA3 test based on the measurement of PCA3 mRNA in urine [11]. The PROGENSA® PCA3 Assay measures the concentration of PCA3 mRNA and PSA mRNA in a urine sample. The PCA3 score is calculated as the ratio of the concentration of PCA3 mRNA to PSA mRNA x 1000.

How to apply and interpret the PCA3 assay

How to apply the PCA3 assay

The PCA3 assay is a simple urine test [12]: 

  1. Perform a DRE (3 strokes per lobe) to release a sufficient number of prostate cells into the urine
  2. After the DRE, collect 20-30 ml first-catch urine from the patient 
  3. Transfer 2.5 ml of urine to the transport tube/sample collection device and send it to the PCA3 testing laboratory within 5 days of collection. 
  4. The laboratory analyses the urine sample, determines the PCA3 score and reports back to the physician 

PCA3 collection

Watch the PCA3 collection procedure: 

How to interpret the PCA3 assay

The figure below illustrates how the PCA3 score should be interpreted. A low PCA3 score indicates a low probability of finding prostate cancer in the prostate biopsy and suggests that a biopsy can be delayed or avoided. A high PCA3 score indicates a high probability for a positive biopsy suggesting that a biopsy is needed.

An increasing PCA3 score corresponds with an increasing probability of a positive biopsy

The PCA3 score should be combined with other clinical and laboratory information, such as:

  • PSA level
  • outcome of DRE
  • prostate volume
  • family history of PCa

to decide whether a biopsy is needed or can be avoided/delayed. 

Interested in more information about how to apply and interpret the PCA3 assay?

Download the key data set!

How can the PCA3 assay help in making better repeat biopsy decisions?

The evidence from clinical studies

A negative prostate biopsy often presents a dilemma to the physician: repeat the biopsy or not?

A negative biopsy often presents a dilemma to the physician

The PCA3 score has been shown to be predictive of repeat biopsy outcome [13-17]. An increasing PCA3 score corresponds with an increasing risk of finding prostate cancer in the biopsy.

A higher PCA3 score was associated with a higher risk of a positive repeat biopsy

The PCA3 score predicts the outcome of a repeat biopsy more accurately than serum PSA [15]. Moreover, in contrast to serum PSA, the PCA3 score is not influenced by prostate volume [14].

A multicenter prospective study in 466 men with one or more prior negative biopsies showed that at a PCA3 score cut-off of 25 the negative predictive value (NPV) for detecting PCa on repeat biopsy was 90% [16]. This means that a PCA3 score cut-off 25 predicted a negative repeat biopsy 90% of the time, thereby optimally reducing the risk that men with a negative PCA3 score would still have PCa on biopsy. 

The negative predictive value for detecting cancer on repeat biopsy was 90% for a PCA3 score of 20

An independent study by the National Cancer Institute (NCI) Early Detection Research Network (EDRN) validated the role for PCA3 in the diagnosis of prostate cancer [17]. It showed that at a PCA3 score cut-off of 20 the NPV was 88%. A total of 46% of unnecessary repeat biopsies could be avoided while missing 3% of high-grade cancers.
When the PCA3 score was added as a variable to the Prostate Cancer Prevention Trial (PCPT) risk calculator, it performed better in predicting the outcome of a repeat biopsy than the PCPT risk calculator alone [17]. The PCPT risk calculator including PCA3 can be found at: http://deb.uthscsa.edu/URORiskCalc/Pages/calcs.jsp

Another study applied systematically analyzed expert recommendations for performing repeat prostate biopsies to the placebo cohort of the REDUCE study [18]. It confirmed that the combination of best clinical judgment and PCA3 can reduce the number of unnecessary repeat biopsies while maintaining the sensitivity to detect high-grade PCa. Best clinical judgment would have avoided 26% of repeat biopsies while 5% of high-grade cancers would be missed. When best clinical judgment was combined with PCA3, 64% of repeat biopsies could be avoided, while only 1% of high-grade cancers would be missed. Best clinical judgment combined with PCA3 demonstrated a very high NPV of 99%

A retrospective budget impact study in France showed that introducing systematic PCA3 testing to guide repeat biopsy decisions into the daily clinical practice reduced the number of unnecessary biopsies by 37% and also reduced costs incurred by the healthcare system [19]. The additional costs for PCA3 testing would be less than the reduction in costs for biopsy and managing associated complications.

Interested in more scientific information about the role of PCA3 in repeat biopsy decisions?

Download the key data set! 

What do the international guidelines say about the role of PCA3 in repeat biopsy decisions?

In the US, the PCA3 urine test is approved by the FDA for use in conjunction with other patient information to aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more previous negative prostate biopsies. A PCA3 score < 25 is associated with a decreased likelihood of a positive biopsy. In addition, the National Comprehensive Cancer Network (NCCN) guidelines recommend that PCA3 should be considered in men thought to be at higher risk of having PCa despite a negative biopsy [1]. In Europe, the European Association of Urology (EAU) guidelines state that the PCA3 test may provide additional information in the decision to perform a repeat biopsy in asymptomatic men with a normal DRE and a PSA level of 2-10 ng/mL [2].

Conclusions

The Progensa® PCA3 test can aid physicians and patients in the dilemma to repeat a prostate biopsy or not. It can help to avoid unnecessary repeat biopsies while maintaining the sensitivity to detect clinically significant cancer.

The pca3 test can help to decide whether a prostate biopsy should be repeated

 

How can the PCA3 assay help in making better initial biopsy decisions?

The evidence from clinical studies

An elevated PSA level can present a dilemma for the physician and patient: perform a biopsy or not?

an elevated psa level can present a dilemma: perform a biopsy or not

The PCA3 score has been shown to be predictive of initial biopsy outcome [17,20-22]. An increasing PCA3 score corresponds with an increasing risk of finding prostate cancer in the biopsy.

the pca3 score is predictive of initial biopsy outcome

PCA3 performed better than serum PSA, PSA doubling time and %free PSA in predicting the outcome of an initial biopsy [20,21]. 

A prospective European study in 516 men scheduled for initial biopsy showed that at a PCA3 score cut-off of 20, 40% of unnecessary biopsies could be avoided while 2% of high-grade PCa would be missed [20]. 

at a pca3 score of 20, 40% of unnecessary biopsy could be avoided

The independent study by the NCI EDRN validated the role for PCA3 in the initial diagnosis of prostate cancer [17]. It showed that at a PCA3 score cut-off of 60 the PPV for initial biopsy was 80%. This means that at a PCA3 score > 60 the PCA3 test predicted a positive initial biopsy 80% of the time. The NCI EDRN concluded that a PCA3 score > 60 increases the probability that cancer will be detected on initial biopsy, however, a PCA3 score < 20 is necessary to rule out a biopsy in the initial setting.

The PCA3 score has been added to several nomograms and risk calculators predicting initial biopsy outcome, and showed that it adds significant information and enables better risk-stratification of men prior to an initial biopsy [17,22]. For example, when the PCA3 score was added as a variable to the PCPT risk calculator, it performed better in predicting the outcome of an initial biopsy than the PCPT risk calculator alone [17]. The PCPT risk calculator including PCA3 can be found at: http://deb.uthscsa.edu/URORiskCalc/Pages/calcs.jsp

Interested in more scientific information about the role of PCA3 in initial biopsy decisions?

Download the key data set! 

What do the international guidelines say about the role of PCA3 in initial biopsy decisions?

In Europe, the EAU guidelines state that further risk-assessment should be offered to asymptomatic men with a PSA between 2-10 ng/mL prior to performing a prostate biopsy. A risk-calculator or an additional serum or urine-based test (e.g. PHI, 4Kscore or PCA3) or imaging can be used [2]. In the US, the NCCN guidelines do not recommend the PCA3 test for patients undergoing a first biopsy [1].

Conclusions

The PCA3 Assay can aid physicians and patients in the dilemma to perform an initial prostate biopsy in men with an elevated PSA level. It can help to help to avoid unnecessary biopsies while maintaining the sensitivity to detect clinically significant cancer.

the pca3 test can help in the dilemma to perform an intial biopsy

 

Can the PCA3 assay differentiate between clinically insignificant and significant prostate cancer?

The evidence from clinical studies

Several studies have evaluated the relationship between PCA3 and prostate cancer significance [23-29]. The PCA3 score was statistically significantly lower in men with low-volume vs. intermediate- to high-volume tumors in radical prostatectomy (RP) specimens [23-27].  

the pca3 score was lower in men with low-volume tumors

In addition, lower PCA3 scores were associated with Gleason sum ≤ 6 cancers [23,26], pathological stage < T3 [24], unifocal and unilateral cancer [25] and pathologically confirmed clinically insignificant PCa (organ-confined disease, tumor volume < 0.5 ml, no Gleason pattern 4 or 5) [26,27]. 

The pca3 score was lower in men with low grade tumors

These data suggest that the PCA3 score can be used as an additional marker to select patients with clinically insignificant PCa who would be candidates for active surveillance.  

Interested in more scientific information about the relationship between PCA3 and PCa significance?

Download the key data set! 

References

1. Carroll PR, Parsons JK, Andriole G, et al. National Comprehensive Cancer Network clinical practice guidelines in oncology: Prostate cancer early detection. Version 2.2016.

2. Mottet N, Bellmunt J, Briers E, et al. Guidelines on Prostate Cancer. European Association of Urology 2016.

3. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009;360:1320-8.

4. Campos-Fernandes JL, Bastien L, Nicolaiew N, et al. Prostate cancer detection rate in patients with repeated extended 21-sample needle biopsy. Eur Urol 2009;55:600-6.

5. Loeb S, Vellekoop A, Ahmed HU, et al. Systematic review of complications of prostate biopsy. Eur Urol 2013;64:876-92.

6. Wade J, Rosario DJ, Macefield RC, et al. Psychological impact of prostate biopsy: physical symptoms, anxiety, and depression. J Clin Oncol 2013;31:4235-41.

7. Nam RK, Saskin R, Lee Y, et al. Increasing hospital admission rates for urological complications after transrectal ultrasound guided prostate biopsy. J Urol 2010;183:963-8.

8. Tosoian JJ, Ross AE, Sokoll LJ, et al. Urinary biomarkers for prostate cancer. Urol Clin North Am 2016;43:17-38.

9. Leapman MS, Carroll PR. New genetic markers for prostate cancer. Urol Clin North Am 2016;43:7-15.

10. Bussemakers MJ, van Bokhoven A, Verhaegh GW, et al. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res 1999;59:5975-9.

11. Hessels D, Klein Gunnewiek JM, van Oort I, et al. DD3PCA3-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol 2003;44:8-16.

12. Hologic

13. 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.

14. 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.

15. Aubin SMJ, Reid J, Sarno MJ, et al. PCA3 molecular urine test for predicting repeat prostate biopsy outcome in populations at risk: validation in the placebo arm of the dutasteride REDUCE trial. J Urol 2010;184:1947-52.

16. Gittelman M, Hertzman B, Bailen J, et al. PROGENSA®PCA3 molecular urine test as a predictor of repeat prostate biopsy outcome in men with previous negative biopsies: a prospective multicenter clinical study. J Urol 2013;190:64-9.

17. Wei JT, Feng Z, Partin AW, et al. Can urinary PCA3 supplement PSA in the early detection of prostate cancer? J Clin Oncol 2014;32:4066-72.

18. Tombal B, Andriole GL, de la Taille A, et al. Clinical judgment versus biomarker Prostate Cancer Gene 3: which is best when determining the need for repeat prostate biopsy? Urology 2013;81:998-1004.

19. Malavaud B, Cussenot O, Mottet N, et al. Impact of adoption of a decision algorithm including PCA3 for repeat biopsy on the costs for prostate cancer diagnosis in France. J Med Econ 2013;16:358-63.

20. de la Taille A, Irani J, Graefen M, et al. Clinical evaluation of the PCA3 assay in guiding initial biopsy decisions. J Urol 2011;185:2119-25.

21. Chevli KK, Duff M, Walter P, et al. Urinary PCA3 as a predictor of prostate cancer in a cohort of 3,073 men undergoing initial prostate biopsy. J Urol 2014;191:1743-8.

22. Hansen J, Auprich M, Ahyai SA, et al. Initial prostate biopsy: development and internal validation of a biopsy-specific nomogram based on the prostate cancer antigen 3 assay. Eur Urol 2013;63:201-9.

23. 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.

24. Whitman EJ, Groskopf J, Ali A, et al. PCA3 score before radical prostatectomy predicts extracapsular extension and tumor volume. J Urol 2008;180:1975-8.

25. Vlaeminck-Guillem V, Devonec M, Colombel M, et al. Urinary PCA3 score predicts prostate cancer multifocality. J Urol 2011;185:1234-9.

26. Ploussard G, Durand X, Xylinas E, et al. Prostate cancer antigen 3 score accurately predicts tumour volume and might help in selecting prostate cancer patients for active surveillance. Eur Urol 2011;59:422-9.

27. Auprich M, Chun FKH, Ward JF, et al. Critical assessment of preoperative urinary prostate cancer antigen 3 on the accuracy of prostate cancer staging. Eur Urol 2011;59:96-105.

28. Durand X, Xylinas E, Radulescu C, et al. The value of urinary prostate cancer gene 3 (PCA3) scores in predicting pathological features at radical prostatectomy. BJU Int 2012;110:43-9.

29. Lin DW, Newcomb LF, Brown EC, et al. Urinary TMPRSS2:ERG and PCA3 in an active surveillance cohort: results from a baseline analysis in the Canary Prostate Active Surveillance Study. Clin Cancer Res 2013;19:2442-50.