Medical Articles New Markers for Prostate Cancer Screening - pro PSA
New Markers for Prostate Cancer Screening - pro PSA
New Prostate Blood Test May Be the Answer to the USPSTF’s Negative Outlook on PSA Screening
USPSTF’s recent downgrade of PSA screening
The USPSTF’s recent downgrade of PSA screening in healthy men to a D rating has generated a firestorm of controversy from both screening foes and advocates about the merits of this decision, which could affect the health and well being of men who are confused by the mixed messages surrounding this emotionally charged debate.
The best performed studies have shown that PSA-based screening reduces the risk of dying from prostate cancer by 20%-50% when the men studied are observed for at least 10 years or more1. Since PSA screening was introduced in this country, the risk of dying of prostate cancer has fallen 35% from its peak in the late 1980’s, a testament to the beneficial effects of PSA based prostate cancer screening in this country. However, prostate cancer remains a significant public health concern, with over 32,000 men dying each year from the disease, making it the second leading cause of men dying from cancer in this country.
Problems with our current method of screening
Despite the benefits seen since PSA was introduced widely, PSA is not an ideal prostate cancer screening test. Using just PSA, with DRE, as the screening method, up to 50% of men screened will have a “false positive” test that leads them to undergo what ultimately turns out to be an unnecessary biopsy. Unnecessary biopsies carry their own risk of infection, sometimes severe, along with the cost and worry associated with them. Furthermore, because prostate cancers vary widely in their potential to progress and spread, a significant portion of the men diagnosed with screen-detected prostate cancer may be treated for a cancer that may never have posed a risk to their life, left undiagnosed and/or untreated. One way to quantify this phenomenon is to determine the number of people who would need to be diagnosed and treated with a cancer in order to prevent one death. Depending the on quality and length of study observation period, for prostate cancer this number is somewhere between ~10 – 49, an indication that there is significant over diagnosis and over treatment of the disease. While this “number needed to treat (NNT)” seems high, it is similar to the NNT for breast and colon cancer screening programs.
Improved methods of testing
One clear way to reduce the risks of unnecessary biopsies and prostate cancer overtreatment, and thus tilt the risk to benefit equation more firmly in the direction of prostate cancer screening would be to develop a better screening test than PSA. Such an improved test would have a lower false positive rate, reducing the number of biopsies done in men without cancer. Such an improved test would also be associated with higher grade, more aggressive prostate cancer, so that its use would lead to the preferential detection of potentially lethal prostate cancers over those less aggressive cancers more likely to add to the problem of prostate cancer overtreatment if detected.
Thankfully, such a test is not just a wish but has been developed and is already widely used in Europe, where it is approved2. The test, called the ‘Prostate Health Index (phi)” (Beckman Coulter, Inc.) is based on a novel clipped form of the precursor form of PSA, called -2proPSA, first co-discovered and reported by Dr. Kevin Slawin, M.D. in a publication co-authored by him in 20003. The -2proPSA is a component of a mixture of different forms of unbound PSA, called “free PSA”, whose collective measurement was the basis of the last FDA approved diagnostic marker for prostate cancer after it was approved by FDA in 1998.
“The PSA test has evolved in the same way measuring cholesterol has,” says Kevin Slawin, M.D., director of the Vanguard Urologic Institute and Texas Prostate Center at Memorial Hermann-Texas Medical Center. “We used to evaluate cholesterol as a single level but now we look at the ratio of LDL to HDL to predict the risk of heart disease. In a similar way, the free to total PSA ratio could predict the risk of prostate cancer. This is important in light of the USPSTF recent position against PSA based prostate cancer screening, prompted to some extent by the negative impact of a falsely high PSA test due to factors other than prostate cancer.” Dr. Slawin was instrumental in performing the pivotal studies that led to FDA approval of the free PSA test4. Now, over a decade later, the free PSA test performance has waned, largely a victim of its own success, and the time is ripe for advancement in the field.
After more than a decade of research on the -2 pro PSA molecule by Dr. Slawin and others, using a blood test developed by Beckman Coulter, who exclusively licensed the technology from Dr. Slawin/Baylor College of Medicine, that could specifically measure it in the blood, the new “Prostate Health Index” (phi) was developed, incorporating the total PSA, free PSA and the new -2proPSA into a new mathematical ratio and evaluated in a large, multicenter screening study of 892 men with no history of prostate cancer and a PSA level between 2 and 10 ng/mL. Dr. Slawin was one of a group of investigators who recently reported positive results of this trial using this new blood test in screening for prostate cancer in the July issue of the Journal of Urology5. Importantly, the use of the phi reduced the risk of unnecessary biopsies due to “false positive” elevations, and was better at identifying high risk, potentially lethal prostate cancers, than the standard PSA test or the percent free PSA alone. “The phi improves upon the performance of the PSA test in key areas identified by the USPS Task Force as a concern, the risk of false positive test results and risk of overdiagnosis of non-lethal prostate cancer.” says Dr. Slawin. “Once this test is available in the United States, its use should help strengthen the rationale in support of prostate cancer screening”
Conclusion - Don't throw out the baby with the bathwater
The history of PSA testing is one of significant breakthroughs and advancement in our understanding of the molecular biology of the PSA molecule, which has led directly to the development of novel blood tests based on these discoveries. In 1998, this process led to the approval of the Free PSA test, which significantly improved upon the clinical performance of the PSA test in detecting prostate cancer. Now, 13 years later, once again we are on the cusp of FDA approval for the -2 pro PSA test and the phi, based on all three molecular forms of PSA (total PSA, free PSA and -2 pro PSA). Dr. Slawin has been a leader in this process since the early days of PSA, and has been responsible for some of the key discoveries and studies that have enabled advancement in the field. The lesson learned is that continuous study and improvement of PSA-based screening, rather than abandonment as recommended by the USPSTF, is the road to improved health and reduced morbidity and mortality from prostate cancer.
1. Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 2010;11:725-32.
2. Guazzoni G, Nava L, Lazzeri M, et al. Prostate-specific antigen (PSA) isoform p2PSA significantly improves the prediction of prostate cancer at initial extended prostate biopsies in patients with total PSA between 2.0 and 10 ng/ml: results of a prospective study in a clinical setting. Eur Urol 2011;60:214-22.
3. Mikolajczyk SD, Millar LS, Wang TJ, Rittenhouse HG, Marks LS, Song W, Wheeler TM, and Slawin KM. A precursor form of prostate-specific antigen is more highly elevated in prostate cancer compared with benign transition zone prostate tissue. Cancer Res 2000;60:756-9.
4. Catalona WJ, Partin AW, Slawin KM, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998;279:1542-7.
5. Catalona WJ, Partin AW, Sanda MG, Wei JT, Klee G,Bangma CH, Slawin KM, Marks LS, Loeb S, Broyles DL, Shin SS, Cruz AB, Chan DW, Sokoll LJ, Roberts WL,van Schaik RHN and Mizrahi IA. A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. J Urol 2011;185:1650-5.
