New Urine Test ID’s Prostate Cancer (PCA3)

ICIM Medics has acquired another diagnostic tool to help in the battle against prostate cancer.

The ICIM Medics Prostate assessment is already the best prostate assessment in Ireland and now the centre went one step further by offering a means to avoid unnecessary and painful biopsies. A national campaign should be implemented where consequently it will save government money, decrease referrals for unnecessary biopsies therefore doctors will have more time per biopsy made so accuracy will increase.

This PCA3 is valued in two mainly currently problematic areas; It will help men with a [relatively] low PSA who need reassurance but don’t want an invasive test. And it will help men with a negative biopsy but a rising PSA decide whether they need a second set of biopsies.

The advent of molecular diagnostics has brought the promise of a specific test for prostate cancer (CaP), the urinary PCA3 gene test. Widespread testing with prostate-specific antigen (PSA) has increased the numbers of prostate biopsies to perhaps one million annually in the U.S. However, serum PSA levels are not specific for CaP. Thus, approximately four men with elevated PSA levels undergo prostate biopsies to find one with cancer, and some cancerous men with “normal” PSA levels escape detection with this measurement. Early studies of the urinary PCA3 gene test indicate this new marker has a much greater degree of CaP specificity than PSA testing.

Limitations of PSA Testing for Prostate Cancer

Within the prostate gland, benign prostatic hyperplasia (BPH) cells contain a concentration of PSA several fold higher than adjacent cancer cells1, which seriously undermines the theoretical basis of CaP testing with PSA. Thompson, in data from the Prostate Cancer Prevention Trial, where biopsies were obtained irrespective of PSA levels, has shown

“There is no cut point of PSA with simultaneous high sensitivity and high specificity for monitoring healthy men for prostate cancer, but rather a continuum of prostate cancer risk at all values of PSA” .

And Stamey, an early advocate of PSA testing, has declared, “Serum PSA levels are no longer related to prostate cancer, but only to the volume of BPH present3.” Why? Because the disease has changed! Nowadays, instead of finding large primary cancers in the prostate as seen 20 years ago, the usual findings are multiple small lesions, where the serum PSA coming from the cancer is overwhelmed by the BPH contribution. Despite these changes, nearly 30,000 men will still die of CaP this year, and an accurate test for the disease is an urgent priority.

Current Use and Availability of PCA3 Testing

In presentations at the 2006 American Urological Association meeting (J.Urol., 175: 174-6 (S), 2006), in recent data gathered on approximately 1000 men, the Gen-Probe PCA3 test was shown to exhibit a high degree of sensitivity and specificity for prostate cancer. For cancer vs non-cancer, a specificity of 76% at 50% sensitivity (PCA3 cutoff = 35 copies/copy of PSA mRNA), with an area under the ROC curve (AUC) of 0.680, was reported by Fradet’s group. By comparison, serum tPSA specificity was only 22% for the same men. In addition, the quantitative PCA3 Score correlated with the probability of positive biopsy in this population: at low PCA3 Scores (< 5) the biopsy positive rate was only 20%, while at PCA3 Scores > 100 the risk of positive biopsy was 67%. A suggestion was presented in Schalken’s recent data that some correlation with Gleason grade and cancer volume may also be present. In data from USRF, almost no overlap was seen in PCA3 Scores from men with cancer and men with only BPH, confirming the specificity of the test. PCA3 RNA is uniformly undetectable in urine from post-radical prostatectomy patients, even following attentive DRE.

A particularly important role of the new marker appears to be in men with persistently elevated serum PSA levels, but a negative initial biopsy. In such men, who constitute a large problematic group, the odds ratio for the PCA3 test to predict cancer upon re-biopsy is 3.6, compared to only 1.2 for serum PSA testing11.

PCA3 testing is highly dependent on the cutoff Score used to determine a “positive” or “negative” test, because sensitivity and specificity vary reciprocally with the Score. The higher the cutoff, the greater the specificity and the lower the sensitivity; the lower the cutoff, the greater the sensitivity and the lower the specificity. Thus, although the test is now available commercially, physicians must be cautious in interpreting the lab report and should know the performance characteristics of the assay, before decisions are based on a “positive” or “negative” test result.

PCA3 Score vs PSA Testing

In comparison with serum levels of PSA, the urinary PCA3 Score appears to be highly specific for prostate cancer. While serum PSA levels are known to be influenced by volume of BPH tissue, age, inflammation, trauma, and use of 5 alpha-reductase inhibitors (finasteride, dutasteride), preliminary data indicate that these factors do not appear to influence PCA3 Scores. For example, standard teaching is to draw blood for PSA levels before rectal exam, for fear the exam might cause spurious elevations in serum PSA. However, an attentive DRE actually increases the “informative” rate of PCA3 determinations and is, in fact, recommended.

The effect of prostate volume is shown on both PSA and PCA3 in the same group of adult men. Clearly, PSA is directly related to prostate volume, while PCA3 is not. Unpublished data from USRF indicate that the same is likely to be true for age and use of 5ARI drugs. Thus, with the caveat that data are limited, the urinary PCA3 Score appears to offer a great specificity advantage over serum PSA levels in the early diagnosis of prostate cancer.

Conclusion and Future Directions

The PCA3 gene, a noncoding segment of mRNA located on chromosome 9, is over-expressed by prostate cancer cells in comparison with all other cells studied. The differential expression is great, permitting detection of the gene in nuclear material from cancer cells shed into urine after attentive digital rectal exam. Thus, urinary PCA3 appears useful as a highly specific marker for prostate cancer. While the early data look promising, the PCA3 test must still be regarded as a ‘work in progress,” from several perspectives. PCA3 expression is denoted against a background of prostate-specific genetic material, a PCA3 Score, ie, a ratio of PCA3 to PSA mRNA, and normative values have only been defined in a preliminary fashion. Factors regulating PCA3 gene expression are not yet clearly defined, but the great confounds of serum PSA levels (prostate volume, age, trauma) appear to affect PCA3 to a much lesser degree than PSA. Additional clinical research trials, now in an organizational phase, should provide further guidelines for widespread application of the urinary PCA3 Score.

The ICIM Medics Prostate Assessment can prevent and save lives. It is private and appointments only are accepted.

The ICIM Prostate assessment cost €380 – the PCA3 test costs €457.

Contact +353 (0)45 844 819 to make your appointment or e-mail: info@icim.ie

References

1. Magklara A, Scorilas A, Stephan C, Kristiansen GO, Hauptmann S, Jung K and Diamandis EP: Decreased concentrations of prostate-specific antigen and human glandular kallikrein 2 in malignant versus nonmalignant prostatic tissue. Urology. 56: 527-32, 2000.
2. Thompson IM, Ankerst DP, Chi C, Lucia MS, Goodman PJ, Crowley JJ, Parnes HL and Coltman CA, Jr.: Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. Jama. 294: 66-70, 2005.
3. Stamey TA, Caldwell M, McNeal JE, Nolley R, Hemenez M and Downs J: The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years? J Urol. 172: 1297-301, 2004.
4. Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA, Debruyne FM, Ru N and Isaacs WB: DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 59: 5975-9, 1999.
5. de Kok JB, Verhaegh GW, Roelofs RW, Hessels D, Kiemeney LA, Aalders TW, Swinkels DW and Schalken JA: DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res. 62: 2695-8, 2002.
6. Schalken JA, Hessels D and Verhaegh G: New targets for therapy in prostate cancer: differential display code 3 (DD3(PCA3)), a highly prostate cancer-specific gene. Urology. 62: 34-43, 2003.
7. Hessels D, Klein Gunnewiek JM, van Oort I, Karthaus HF, van Leenders GJ, van Balken B, Kiemeney LA, Witjes JA and Schalken JA: DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol. 44: 8-15; discussion 15-6, 2003.
8. Fradet Y, Saad F, Aprikian A, Dessureault J, Elhilali M, Trudel C, Masse B, Piche L and Chypre C: uPM3, a new molecular urine test for the detection of prostate cancer. Urology. 64: 311-5; discussion 315-6, 2004.
9. Tinzl M, Marberger M, Horvath S and Chypre C: DD3PCA3 RNA analysis in urine–a new perspective for detecting prostate cancer. Eur Urol. 46: 182-6; discussion 187, 2004.
10. Groskopf J, Aubin SM, Deras IL, Blase A, Bodrug S, Clark C, Brentano S, Mathis J, Pham J, Meyer T et al.: APTIMA PCA3 molecular urine test: development of a method to aid in the diagnosis of prostate cancer. Clin Chem. 52: 1089-95, 2006.
11. Marks LS, Fradet Y, Deras IL, Blase A, Mathis J, Aubin SMJ, Cancio AT, Desaulniers M, Ellis WJ, Rittenhouse HG, Groskopf J: Prostate cancer specificity of PCA3 Urinary Gene Test. In Press, Urology, 2006.

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Tags: Prostate, Prostate Cancer