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Learn about PCA3

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).1 The outcome of both tests can result in a prostate biopsy to confirm the diagnosis of PCa.1 However, each of these measures has shortfalls that may lead to unnecessary biopsies and potentially overdetection and overtreatment of clinically insignificant cancer.1 

PSA

Serum PSA is a standard tool used in the diagnosis of PCa, but is not PCa specific.1 Elevated PSA levels can also be caused by other prostate conditions such as benign prostatic hyperplasia (BPH) and prostatitis.1 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 10-15 years.1,2

DRE

DRE is another standard procedure that has a poor positive predictive value (PPV), fair reproducibility and a high inter-examiner variability.1,3-4

TRUS

A transrectal ultrasound (TRUS) of the prostate is sometimes used to guide a biopsy procedure, or to establish prostate volume and PSA density.2 It is no more accurate at predicting organ-confined disease than DRE.2 It is not recommended for the detection of early-stage prostate cancer.3

Prostate biopsy

A prostate biopsy provides the diagnosis of PCa and is indicated based on risk stratification. However, due to the low PPVs of PSA and DRE, approximately 75% of men will have an unnecessary negative initial biopsy.5 The fear that cancer was missed often leads to repeat biopsies, most of which will also be negative.6 The high number of negative initial and repeat biopsies may increase healthcare costs and diminish patients’ quality of life.7-9 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).7-9

Addressing Overdiagnosis and Overtreatment

Over the years, widespread PSA testing has led to overdetection and overtreatment of clinically insignificant cancer.1 Because PSA does not reliably distinguish between clinically insignificant and significant cancers, there is a demand for novel biomarkers to address clinical need.10

Need for additional diagnostic tests

What is the Progensa® PCA3 assay?

The Progensa PCA3 assay detects PCA3, a prostate-specific mRNA biomarker.11 It uses a simple urine specimen collected after a DRE.11 The Progensa PCA3 assay detects the overexpression of the PCA3 gene, which is highly specific for PCa, urine samples.11 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.11 The Progensa PCA3 assay is FDA approved and CE marked.

Intended Use for FDA approved assay11

The Progensa PCA3 assay is an in vitro nucleic acid amplification test.11 The assay measures the concentration of prostate cancer gene 3 (PCA3) and prostate-specific antigen (PSA) RNA molecules and calculates the ratio of PCA3 RNA molecules to PSA RNA molecules (PCA3 score) in post-DRE, first-catch male urine specimens.11 The Progensa PCA3 assay is indicated 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 and for whom a repeat biopsy would be recommended by a urologist based on current standard of care, before consideration of Progensa PCA3 assay results.11 A PCA3 score < 25 is associated with a decreased likelihood of a positive biopsy.11 Prostatic biopsy is required for diagnosis of cancer.

Warning: The Progensa PCA3 Assay should not be used for men with atypical small acinar proliferation (ASAP) on their most recent biopsy. Men with ASAP on their most recent biopsy should be treated in accordance with current medical guidelines .11

Warning: The Clinical Study only included men who were recommended by urologists for repeat biopsy. Therefore, the performance of the Progensa PCA3 Assay has not been established in men for whom a repeat biopsy was not already recommended.11

 

How to apply and interpret the Progensa PCA3 assay

The Progensa PCA3 assay is a simple urine test.12 Below are basic collection and processing steps.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. Within 4 hours of collection, 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. If not immediately processed, the urine specimen must be maintained at 2-8°C or kept on ice.
  4. The laboratory analyzes the urine sample, determines the PCA3 score and reports back to the physician. 

Progensa PCA3 assay demonstration

For more information on urine collection and processing, please consult the Progensa PCA3 assay physician’s instructions.

Watch the PCA3 collection procedure: 

 

How to interpret the Progensa PCA3 assay

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.12 A high PCA3 score indicates a high probability for a positive biopsy suggesting that a biopsy is needed.12

The PCA3 score should be combined with other clinical and laboratory information, such as11

  • PSA level
  • Outcome of DRE
  • Age
  • Race
  • Number of previous negative biopsies
  • Family history of PCa

These standard of care factors can be used to decide whether a biopsy is needed or can be avoided/delayed.1

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

Evidence from clinical data

The PCA3 score predicts the outcome of a repeat biopsy more accurately than serum PSA.13 Moreover, in contrast to serum PSA, the PCA3 score is not influenced by prostate volume.11

A multicenter prospective study in 466 men with 1 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%.11 This means that a PCA3 score cut-off value of 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.11

In the US, the Progensa PCA3 assay 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 1 or more previous negative prostate biopsies.11 A PCA3 score < 25 is associated with a decreased likelihood of a positive biopsy11. 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

Evidence from published data

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

What to do after a negative prostrate biopsy

The PCA3 score has been shown to be predictive of repeat biopsy outcome.14-18 An increasing PCA3 score corresponds with an increasing risk of finding prostate cancer in the biopsy.

PCA3 score in relation to percentage of men with a positive repeat biopsy

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.18 It showed that at a PCA3 score cut-off of 20 the NPV was 88%.18 A total of 46% of unnecessary repeat biopsies could be avoided while missing 3% of high-grade cancers.18 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.18 The PCPT risk calculator including PCA3 can be found at: myprostatecancerrisk.com.

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

Evidence from published data

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

What to do after an elevated PSA

The PCA3 score has been shown to be predictive of initial biopsy outcome.18-21 An increasing PCA3 score corresponds with an increasing risk of finding prostate cancer in the biopsy.18-21

The higher the PCA3 score, the greater the probability of a positive initial biopsy

PCA3 performed better than serum PSA, PSA doubling time and percent free PSA in predicting the outcome of an initial biopsy.19-20 

The independent study by the NCI EDRN validated the role for PCA3 in the initial diagnosis of prostate cancer.18 It showed that at a PCA3 score cut-off of 60 the PPV for initial biopsy was 80%.18 This means that at a PCA3 score > 60 the PCA3 test predicted a positive initial biopsy 80% of the time.18 The NCI EDRN concluded that a PCA3 score > 60 increases the probability that cancer will be detected on Initial biopsy. A PCA3 score of < 20, however, is necessary to rule out a biopsy in the initial setting.18

Conclusions

The Progensa PCA3 assay can aid physicians and patients in the dilemma to perform an initial prostate biopsy in men with an elevated PSA level.11 It can help to avoid unnecessary biopsies while maintaining the sensitivity to detect clinically significant cancer.11

The PCA3 aids physicians and patients on what to do next

 

References: 1. Carroll PR, et al. NCCN Guidelines Insights: Prostate Cancer Early Detection, Version 2.2016. J Natl Compr Canc Netw. 2016;14(5):509-19. doi:10.6004/jnccn.2016.0060. 2. Mottet N, et al. European Association of Urology. EAU – ESTRO – SIOG Guidelines on Prostate Cancer. European Association of Urology. https://uroweb.org/wp-content/uploads/EAU-Guidelines-Prostate-Cancer-20…. Updated March 2016. Accessed April 19, 2017. 3. Borley N, et al. Prostate cancer: diagnosis and staging. Asian J Androl. 2009;11(1):74-80. doi:10.1038/aja.2008.19. 4. Smith DS, et al. Interexaminer variability of digital rectal examination in detecting prostate cancer. Urology. 1995;45:70-74. doi:10.1016/S0090-4295(95)96812-1. 5. Schröder FH, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320-8. doi: 10.1056/NEJMoa0810084. 6. Campos-Fernandes JL, et al. Prostate cancer detection rate in patients with repeated extended 21-sample needle biopsy. Eur Urol. 2009;55:600-6. doi:10.1016/j.eururo.2008.06.043. 7. Loeb S, et al. Systematic review of complications of prostate biopsy. Eur Urol. 2013;64:876-92. doi:10.1016/j.eururo.2013.05.049. 8. Wade J, et al. Psychological impact of prostate biopsy: physical symptoms, anxiety, and depression. J Clin Oncol. 2013;31:4235-41. doi:10.1200/JCO.2012.45.4801. 9. Nam RK, et al. Increasing hospital admission rates for urological complications after transrectal ultrasound guided prostate biopsy. J Urol. 2010;183:963-8. doi:10.1016/j.juro.2009.11.043. 10. Jakobsen NA, et al. Novel biomarkers for the detection of prostate cancer. J Clin Urol. 2016;2 Suppl):3-10. doi:10.1177/2051415816656121. 11. Progensa PCA3 Assay [package insert]. 502083-IFU-PI, Rev. 001. San Diego, CA: Hologic, Inc.; 2015. 12. Progensa PCA3 Assay [physician instructions]. L693-MKT, Rev. A. San Diego, CA: Hologic, Inc; 2013. 13. Aubin SMJ, 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. doi:10.1016/j.juro.2010.06.098. 14. Marks LS, et al. PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. Urology. 2007;69:532-5. doi:10.1016/j.urology.2006.12.014. 15. Haese A, 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.2008.06.071. 16. Aubin SMJ, 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. doi:10.1016/j.juro.2010.06.098. 17. Gittelman M, 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. doi:10.1016/j.juro.2013.02.018. 18. Wei JT, et al. Can urinary PCA3 supplement PSA in the early detection of prostate cancer? J Clin Oncol. 2014;32:4066-72. doi:10.1200/JCO.2013.52.8505. 19. de la Taille A, et al. Clinical evaluation of the PCA3 assay in guiding initial biopsy decisions. J Urol. 2011;185:2119-25. doi:10.1016/j.juro.2011.01.075. 20. Chevli KK, 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. doi:10.1016/j.juro.2013.12.005. 21. Hansen J, 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. doi:10.1016/j.eururo.2012.07.030.