• Introduction
• PCA3 and its role in making better biopsy decisions
• PCA3 and its role in making better prognosis decisions
• In what subjects can PCA3 help make better decisions in the diagnosis and treatment of PCa?
• What will the PCA3 report look like?

Introduction

Currently the early detection of prostate cancer (PCa) relies primarily on

• digital rectal examination (DRE) of the prostate and
• the serum prostate specific antigen (PSA) concentration.

The outcome of both tests can result in a prostate biopsy to confirm the diagnosis of PCa. Each of these three measures has shortfalls that contribute to an increasing number of unnecessary biopsies. PCA3 (Prostate CAncer gene 3) is a new tool available in a simple urine test to help make better biopsy decisions in the diagnosis of PCa. It is CE-marked (November 2006) and available as the PROGENSA^TM PCA3 Assay in Europe.

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PCA3 and its role in making better biopsy decisions

Discovery of PCA3

• The PCA3 Assay (Prostate Cancer Gene 3; in the past referred to as DD3) is the first gene-based diagnostic test to help solve the current challenges associated with the diagnosis of PCa.
  
• The PCA3 gene was discovered by Dr. Marion Bussemakers while working with Dr. Jack Schalken at the University of Nijmegen in the Netherlands and in the laboratory of Dr. William Isaacs at Johns Hopkins University in Baltimore [1].
• They discovered that messenger RNA (mRNA) of the PCA3 gene is highly over-expressed (median 66-fold) in >95% of PCa tissue compared to normal or benign prostate tissue of the same patients [1,2].
• In contrast to serum PSA, PCA3 is not only prostate-specific, but also PCa-specific [1]. In contrast to serum PSA, prostate volume does not affect the PCA3 Assay result (Figure).

• The PROGENSA^TM PCA3 Assay from Gen-Probe Incorporated was CE-marked in November 2006 and is available in Europe.

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Usage of the PCA3 Assay in clinical practice

The PCA3 Assay [3] is a simple urine test and detects the presence of PCA3 messenger RNA (mRNA; Figure / click for animation):

1. Perform a DRE (3 strokes per lobe) to release a sufficient number of prostate cells into the urine
2. Post-DRE, collect 20-30 mL first-catch urine from the patient
3. Transfer 2.5 mL of urine to the transport tube and send it as soon as possible to the PCA3 testing laboratory.
   
4. Using transcription-mediated amplification (TMA) technology, PCA3 mRNA molecules are amplified and the PCA3 Score is calculated

Click figure to view the PCA3 collection procedure animation

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Interpreting the PCA3 Score for making better biopsy decisions

Several clinical studies have evaluated the use of the PCA3 Score in aiding the decision whether or not to biopsy. These studies included men who had their first biopsy and men scheduled for repeat biopsy.

US data, first biopsy [4]

• In 260 American men (mean serum PSA around 8 ng/mL) who were scheduled for a first biopsy, the PCA3 Score was determined and related to prostate biopsy outcome.
• In total, 111 men (43%) had a positive biopsy.
• The percentage of men with a positive biopsy increased with the PCA3 Score.
• A PCA3 Score cut-off of 35 provided the greatest diagnostic accuracy, i.e. balance between sensitivity (50%) and specificity (77%).
• Men with a PCA3 Score ≥ 35 had a 2-fold increased risk of a positive biopsy compared to those with a PCA3 Score < 35 (Figure).
• Men with a PCA3 Score ≥ 35 had a 62% probability of a positive biopsy;
• in other words about 2 in 3 men with a PCA3 score ≥ 35 had PCa (Figure).

US data, repeat biopsy [5]

• Another study involved 233 American men (mean serum PSA 7.4 ng/mL) who had had at least 1 negative previous biopsy and were scheduled for repeat biopsy.
• The PCA3 Score was also determined and related to prostate biopsy outcome.
• In total, 60 men (27%) had a positive biopsy.
• The percentage of men with a positive biopsy increased with the PCA3 Score.
• A PCA3 Score cut-off of 35 provided the greatest diagnostic accuracy, i.e. balance between sensitivity (58%) and specificity (72%).
• Men with a PCA3 Score ≥ 35 had a 2.5-fold increased risk of a positive biopsy compared to those with a PCA3 Score < 35 (Figure).
• Men with a PCA3 Score ≥ 35 had a 43% probability of a positive biopsy;
  in other words almost 1 in 2 men with a PCA3 Score ≥ 35 had PCa (Figure).

European data, repeat biopsy [6]

• In a preliminary analysis, 199 European men (mean serum PSA 8.2 ng/mL) had had 1-2 previous negative biopsies and were scheduled for repeat biopsy. In these men, the PCA3 Score was also determined and related to prostate biopsy outcome.
• The results were very consistent with the US data.
• In total, 49 men (25%) had a positive biopsy.
• The percentage of men with a positive biopsy increased with the PCA3 Score.
• A PCA3 Score cut-off of 35 provided the greatest diagnostic accuracy, i.e. balance between sensitivity (57%) and specificity (73%).
• Men with a PCA3 Score ≥ 35 had a 2.5-fold increased risk of a positive biopsy compared to those with a PCA3 Score < 35 (Figure).
• Men with a PCA3 Score ≥ 35 had a 41% probability of a positive biopsy;
• in other words almost 1 in 2 men with a PCA3 Score ≥ 35 had PCa (Figure).

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PCA3 and its role in making better prognosis decisions

So far, one study has evaluated if the PCA3 Score could be used as an additional test for predicting the prognosis of men diagnosed with PCa [7].

• In this study, 83 men with prostate cancer scheduled for radical prostatectomy also had their PCA3 Score measured.
• The PCA3 Score correlated with total tumour volume and tumour grade in prostatectomy specimens.
• The mean PCA3 Score in men with low volume tumours (< 0.5 mL) was significantly lower than in men with intermediate volume (0.5-2.0 mL; P = 0.004) or high volume (≥ 2.0 mL; P = 0.002) tumours.
• The mean PCA3 Score in men with low volume (< 0.5 mL) and low grade (Gleason score ≤ 6) was significantly lower than in men with significant cancers (P = 0.004) (Figure).
• A high PCA3 Score seems to be helpful in predicting which men with PCa have a high probability of significant PCa.
  

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In what subjects can PCA3 help make better decisions in the diagnosis and treating of PCa?

There are 4 scenarios in which PCA3 could help in making better decisions in diagnosing and treating PCa:

1. which men with ≥ 1 negative biopsy have a high probability of a positive repeat biopsy
2. which men with an elevated PSA level (between 2.5 and 10 ng/mL) or a low PSA level but a suspicious DRE have a high probability of a positive first biopsy
3. which men with PCa have a high probability of significant PCa
4. which men with PCa have a high probability of disease progression on watchful waiting

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What will the PCA3 report look like?

This figure shows how the laboratory will provide feedback on the PROGENSA^TM PCA3 Assay and how you should interpret the PCA3 Score.

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Reference List

[1] 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.

[2] Hessels D, Klein Gunnewiek JM, van Oort I et al. DD3^PCA3-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol 2003;44: 8-16.

[3] Groskopf J, Aubin SM, Deras IL et al. APTIMA PCA3 molecular urine test: development of a method to aid in the diagnosis of prostate cancer. Clin Chem 2006;52: 1089-95.

[4] Gen-Probe Incorporated data on file. 2007

[5] 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.

[6] Haese A, Van Poppel H, Marberger M et al. The value of the PCA3 assay in guiding decision which men with a negative prostate biopsy need immediate repeat biopsy: preliminary European data. Eur Urol Suppl 2007;6: 48 (abs. 101).

[7] Nakanishi H, Groskopf J, Bhadkamkar V et al. The relationship between PCA3 score and tumor volume in prostatectomy samples. J Clin Oncol 2007 abs. 354.