Horizon Scanning Technology Briefing National Horizon Scanning Centre Prostate cancer gene 3 (Progensa PCA3) assay in the diagnosis of prostate cancer December 2006 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.
Prostate cancer gene 3 (Progensa PCA3) assay in the diagnosis of prostate cancer Target group Men with raised prostate specific antigen (PSA) but a negative prostate biopsy. Other indications in early development include: o men with a slightly raised PSA, and o men with signs and symptoms suggestive of prostate cancer. Technology description Prostate cancer gene 3 (PCA3) is one of the most prostate cancer specific genes identified, with over-expression in approxiamately 95% of cancers tested 1. The PCA3 assay (Progensa PCA3, previously known as the upm3 assay from DiagnoCure) is an amplified nucleic acid assay, which uses transcription-mediated amplification (TMA) to quantify PCA3 and PSA mrna in prostate cells found in whole urine samples. The PCA3 score is calculated as the ratio between PCA3 and PSA mrna. Innovation and/or advantages The PCA3 test is a new non-invasive diagnostic test for prostate cancer with a high specificity and positive predictive value compared to current PSA testing, in men scheduled for prostate biopsy or prostatectomy. Developer Gen-Probe. Place of use Home care e.g. home dialysis Secondary care e.g. general, non-specialist hospital General public e.g. over the counter Community or residential care e.g. district nurses, physio Tertiary care e.g. highly specialist services or hospital Other: Primary care e.g. used by GPs or practice nurses Emergency care e.g. paramedic services, trauma care Availability, launch or marketing dates, and licensing plans: The Progensa PCA3 assay was CE marked in November 2006. It is available in the UK from Medi-Lab and The Doctors Laboratory. NHS or Government priority area: Cancer Cardiovascular disease Children Diabetes Chronic conditions Mental health Older people Public health Renal disease Women s health None identified Other: Relevant guidance NICE. Improving outcomes in urological cancers. NICE cancer service guidance, September 2002. NICE guideline in progress. Prostate cancer: diagnosis and treatment. Expected November 2007. Dec 2006 2
Clinical need and burden of disease In 2002 there were 28,940 new cases of prostate cancer registered in England and Wales and in 2004 there were 9,166 deaths 2. An estimated 1,734,000 men with no prior diagnosis of prostate cancer have PSA tests in England and Wales per year 3. Existing comparators and treatments There are four main ways to investigate men with signs and symptoms suggestive of prostate cancer 4 : A Digital Rectal Examination (DRE) good for finding advanced cancers, but overall it can detect less than half of prostate cancers. The Prostate Specific Antigen (PSA) test this blood test measures the levels of PSA. Men with prostate cancer tend to have more PSA in their blood. The PSA test is not a foolproof test for prostate cancer. For every 100 men with a raised PSA level, only about 30 will have cancer cells in their prostate. Occasionally the PSA may read normal when cancer is present. Trans-Rectal Ultrasound Scan (TRUS) this type of scan is used to measure the size and density of the prostate. A Transrectal Needle Biopsy of the prostate this biopsy is usually done at the same time as an ultrasound. Efficacy and safety Trial name or code DD3PCA3 RNA Analysis in Urine 5 Prior to biopsy UPM3 6 Prior to biopsy Sponsor DiagnoCure DiagnoCure Status Published Published Participants in trial n=201 (158 analysed) undergoing transrectal ultrasound-guided biopsy. Urine sample collected after DRE but before biopsy. n=517 (443 analysed) undergoing transrectal ultrasound-guided biopsy. Urine sample collected after DRE but before biopsy. Primary outcome Analytic and clinical validity Analytic and clinical validity Key results 37% of men were positive for prostate cancer on biopsy. 79% of urine samples had sufficient PSA mrna (adequacy rate). 34% of men were positive for prostate cancer on biopsy. 86% of urine samples had sufficient PSA mrna (adequacy rate). PCA3 test sensitivity 82%, specificity 76%, positive predictive value(ppv) 67%, negative predictive value (NPV) 87%. Serum PSA test sensitivity 98%, specificity 5%, PPV 40%, and NPV 83%. The area under the ROC curve was 0.87 (95%CI 0.81 to 0.92). Likelihood ratio for positive test = 3.4. PCA3 test sensitivity 66% specificity 89%, PPV 75%, NPV 84%. Serum PSA test PPV 38%, NPV was 89% for a PSA cut-off of 2.5ng/mL and 80% for a PSA cut-off of 4.0ng/mL. The area under the ROC curve was 0.86 (95%CI 0.82 to 0.89). Likelihood ratio for positive test = 6. Trial name or code Ratio PCA3:PSA vs. PCA3 alone 7 APTIMA PCA3 Molecular Urine Test 1 PCA3 molecular urine assay 8 Sponsor Gen-Probe; DiagnoCure Gen-Probe Gen-Probe; DiagnoCure Status Poster Published Poster Dec 2006 3
Participants in trial Primary outcome Key results n=150: scheduled for biopsy (n=93) or radical prostatectomy (n=26). Control group (n=31) radical prostatectomy 1 or more years earlier. Urine sample collected after DRE. n=143: scheduled for prostate biopsy (n=70), healthy men (n=52), or men who have undergone radical prostatectomy (n=21). Urine sample collected after DRE. National Horizon Scanning Centre n=564: scheduled for prostate biopsy (n=465), or scheduled for prostatectomy (n=26). Controls: men with no known prostate cancer risk (n=52) and men who had undergone radical prostatectomy (n=21). Urine sample collected after DRE. Analytic validity Analytic validity Analytic validity 45% of men were positive for prostate cancer on biopsy. Best correlation with biopsy from PCA3: PSA mrna ratio. PCA3 test sensitivity 66%, specificity 75%. Area under ROC curve 0.72. Serum PSA sensitivity 89%, specificity 19%. 98% of urine samples had sufficient PSA mrna (adequacy rate). PCA3 test pre-biopsy - sensitivity 69%, specificity 79%. Area under ROC curve 0.75 (95% CI 0.57 to 0.92). Serum PSA specificity 28%. PCA3 test postprostatectomy men - negative except 1 with recurrence. 96% of urine samples had sufficient PSA mrna (adequacy rate). Mean PCA3:PSA ratios for normal (presumed disease free), biopsy negative, prostatic intraepithelial neoplasia (PIN), atypical small acinar proliferation (ASAP) and biopsy positive groups were significantly different (p<0.01). Higher PCA3/PSA ratios correlated with a higher probability of positive biopsy. Trial name or code PCA3 in 1 st or 1 or more prior negative biopsies 9 APTIMA PCA3 Molecular Urine Test 10 Sponsor Gen-probe; DiagnoCure GenProbe; Diagnocure Status Poster Poster Participants in trial n=448: scheduled for prostate biopsy, (n=430) or prostatectomy (n=18). 223 men were having their 1 st biopsy; 225 had had at least 1 prior negative biopsy. Urine sample collected after DRE. n=488: men scheduled for biopsy (n=426), scheduled for radical prostatectomy (n=62). Urine sample collected after DRE. Primary outcome Analytic and clinical validity Analytic validity Key results Pre 1 st biopsy group - PCA3 test sensitivity 53%; specificity 72%. The area under ROC curve 0.68. Serum PSA assay AUC 0.60. Prior negative biopsy group PCA3 sensitivity 58%; specificity 74%. Odds Ratio 3.9; area under ROC curve 0.68. Serum PSA assay Odds Ratio 1.2; area under ROC curve 0.504. Difference between PCA3 and serum PSA assay AUC significantly different p=0.002. 44% of men were positive for prostate cancer on biopsy. Centre 1 PCA3 test specificity 76%; sensitivity 50%; area under ROC curve 0.680 (95% CI 0.63 to 0.73). Serum PSA test specificity 22%. Centre 2 PCA3 specificity 91%, sensitivity 60%. Area under ROC curve 0.757. Serum PSA test specificity 50%. Dec 2006 4
Estimated cost and cost impact The tests currently offered by MediLab and the Doctor s Laboratory cost between 280-350 per test including administration costs. Serum PSA testing costs up to 28. 11 Potential or intended impact speculative Patients Reduced morbidity Quicker or more accurate diagnosis Reduced mortality or increased survival Earlier identification of disease Improved quality of life for patients and/or carers Other: Potential reduction of repeat biopsies. Services Increased use e.g. length of stay, Service reorganisation required out-patient visits Decreased use: reduction in biopsies or second Other: negative biopsies Staff or training required Costs Increased unit cost compared to alternative New costs: Increased costs: more patients coming for treatment Savings: Potential reduction in prostate biopsies and repeat PSA testing. Increased costs: capital investment needed Other: References 1 Groskopf et al. APTIMA PCA3 Molecular Urine Test: Development of a Method to Aid in the Diagnosis of Prostate Cancer. Clinical Chemistry 2006; 52 (6): 1089-1095. 2 Cancer Research UK. Cancer Stats Prostate Cancer UK. 3 Cancer Screening Programmes. Prostate specific antigen (PSA) tests. http://www.cancerscreening.nhs.uk/prostate/psa-tests.html accessed 03/10/06. 4 CancerBACUP website www.cancerbacup.org.uk accessed 23/2/05. 5 Tinzl M, Marberger M, Horvarth S, Chypre C. DD3 PCA3 RNA Analysis in Urine- A New Perspective for Detecting Prostate Cancer. European Urology 2004; 46:182-187. 6 Fradet Y et al. upm3, a New Molecular Urine Test for the Detection of Prostate Cancer. Urology 2004; 64:311-316. 7 Brentano S. et al. The Ratio of PCA3 to PSA mrnas in Urine is a Better Predictor of Prostate Biopsy Results than the Absolute Copy Level of PCA3 mrna Alone. American Association for Cancer Research Conference, 2005 Poster 3156. 8 Groskopf et al. PCA3 Molecular Urine Assay: Characterization of a Method to Aid in the Diagnosis of Prostate Cancer, European Association of Urology, 2006 Poster. 9 Fradet Y et al. Performance of the PCA3 Urine Test on Subjects with Previous Negative Prostate Biopsies. European Association of Urology, 2006 Poster. 10 Groskopf et al. APTIMA PCA3 Molecular Urine Test: Development of a method to aid in the diagnosis of prostate cancer. 6 th International Congress on New Developments in Prostate Cancer and Prostate Disease, 2005 Poster. 11 Ryan A, Wilson S, Greenfield S et al. Range of self-tests available to buy in the United Kingdom: an Internet survey. Journal of Public Health 2006;28(4):370-374. Dec 2006 5
The National Horizon Scanning Centre is funded by the Research and Development Division of the Department of Health, England The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.pcpoh.bham.ac.uk/publichealth/horizon Dec 2006 6