Featured Article
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Prostate cancer is the sixth most common cause of cancer death in men worldwide. In 2012, 242,000 new cases of prostate cancer and 28,170 prostate cancer deaths are expected in the United States. The mortality rates have been decreasing, although it is unclear whether this trend can be attributed to improvements in treatment, changes in the classification of cancer data, or to early detection of prostate cancer by prostate-specific antigen (PSA) testing.
The PSA Controversy
What is clear is that the long controversy over PSA-based screening flared when the U.S. Preventive Services Task Force (USPSTF) released its preliminary recommendation against PSA-based screening in late 2011. In May 2012, the USPSTF concluded that the harms of screening asymptomatic men substantially outweighed the benefits. The American Urological Association (AUA) issued a strenuous objection against the USPSTF’s “blanket” rejection of PSA-based screening. In addition, various investigators issued statements criticizing the USPSTF’s evaluations and conclusions, which were based on the results of two large screening trials from the United States and Europe.
Screening for Prostate Cancer: Informed Decision-Making
The American Cancer Society’s 2012 guidelines for the early detection of cancer reflect the general consensus of physicians who are uncomfortable with eliminating routine PSA testing in asymptomatic men: at age 50, men with average risk for prostate cancer who are expected to live at least ten years should be helped by their physician to make an informed decision on whether or not to be screened for prostate cancer, and this discussion should happen at an earlier age for men with increased risk, which is based on factors such as ethnicity, or having first-degree relatives who develop prostate cancer before age 65. Men choosing to be tested who are found to have a serum PSA lower than 2.5 ng/mL may only need retesting every 2 years, and men with a serum PSA higher than 2.5 ng/mL should be screened yearly. Currently, in the fall of 2012, Medicare is still providing coverage for an annual PSA test for all Medicare-eligible men aged 50 and older, and many private insurers also cover PSA screening.
Serum PSA: Testing Applications and Limitations
Therefore, measurement of serum PSA concentration is still being used for screening. It is also being used for active surveillance of untreated men with prostate cancer thought to be at low risk for progression, and for monitoring treated men for recurrence or progression—neither of these applications were addressed by the USPSTF.
As is true for many types of cancers, an unsolved problem is how to determine from a PSA screening result whether an individual has an aggressive cancer needing treatment or an indolent cancer needing surveillance. Early detection of the biochemical recurrence of prostate cancer after radical prostatectomy—that is, how to detect extremely low levels of PSA—is another concern. Investigations of methods that address these issues are ongoing. These include identifying new biomarkers and refining the testing parameters of PSA. PSA testing methods being evaluated include the PSA index (unbound [free] PSA level divided by total PSA level); PSA density of the transition zone (serum PSA level divided by the volume of the transition zone of the prostate); PSA velocity (rate of change in serum PSA levels); pro-PSA (inactive PSA precursors versus free and total serum PSA); and the PSA nucleic acid detection immunoassay (NADiA).
Centralized laboratory testing using multiassay automated instruments (contact company for status of regulatory approval):
- Siemens Healthcare Diagnostics (Tarrytown, NY) offers a range of immunoassay analyzers that measure a variety of PSA parameters, including total PSA, subsets of PSA, and other specialized PSA assays. The company’s ADVIA Centaur® XP Immunoassay System measures total PSA, with a reportable range of 0.01–100 ng/mL. The system employs chemiluminescence-based immunoassays and accommodates up to 240 tests per hour and 30 onboard reagents.
- Randox Laboratories US Limited (Kearneysville, WV) offers the Evidence Evolution Immunoassay Analyzer, which utilizes protein Biochip Array Technology, chemiluminescent detection, and competitive, sandwich, and antibody capture techniques. This is a high-throughput system for clinical, research, toxicology, and drug residue analytes that can process more than 1500 array-specific tests per hour. The tumor PSA array, which measures total PSA and free PSA, is included in its clinical array menu. The assay ranges are 0–100 ng/mL and 0–75 ng/mL for total and free PSA, respectively.
Point-of-care testing:
- Mediwatch USA (West Palm Beach, FL) offers the CE-marked (contact company for status of FDA approval) bioscanTM PSAwatchTM, which is a rapid point-of-care PSA test based on immunochromatography. A small sample of whole blood or plasma is placed into the test well of the PSAwatch cassette, which has been placed into the Bioscan reader (available separately from the company), and the quantitative result is available in 10 min. The test range for total PSA is 0.5–25 ng/mL, and the company says that the results are equimolar with the National Institute for Biological Standards and Control and with European standards.
Tests approved by the FDA in 2012:
- Beckman Coulter, Inc. (Brea, CA) offers the Access Hybritech p2PSA reagent pack, which allows determination of the Prostate Health Index (phi) by combining the results of three automated blood tests ([-2]proPSA, total PSA, and free PSA) performed on the company’s Access 2 and UniCel DxI immunoassay systems. The phi test is indicated for use in men with a PSA ranging from 4 to 10 ng/mL, a level at which physicians in the United States usually recommend biopsy. The company claims that the phi test has been proven to reduce the number of prostate biopsies. However, the clinical utility of the phi test has not been independently proven.
- Iris Personalized Medicine (Carlsbad, CA) offers NADiA® ProsVueTM, a prognostic test for identifying men with reduced risk for cancer after radical prostatectomy. The test determines the rate of change of total serum PSA (slope, pg/mL per month) in three samples collected from a patient between six weeks and 20 months after radical prostatectomy. The company reported that a ProsVue slope of ≤2.0 pg/mL was significantly associated with a reduced risk of clinical recurrence (HR 18.3, 95% CI, 10.6–31.8; P<0.0001), and a negative surgical margin was also significantly associated with reduced risk of recurrence, but to a lesser degree (HR 3.3, 95% CI, 2.0–5.4; P<0.0001). NADiA, or immuno-PCR, was developed to detect proteins or glycoproteins such as PSA that may be present in the plasma at extremely low levels. The test employs a reporter monoclonal antibody (MAb) targeted to an antigen (PSA) and labeled with an assay-specific double-stranded DNA sequence. There is a capture MAb specific for another site on the target antigen that is coated onto paramagnetic microparticles. The reporter MAb-DNA conjugate is reacted with sample to form the first immune complex with the target antigen. The immune complex is then captured by the paramagnetic particles, forming a sandwich immune complex. After several wash steps, the DNA of the bound immune complex is then subjected to real-time (quantitative) PCR, which amplifies the bound DNA. Therefore, the test allows highly sensitive quantification of PSA.
Conclusion
In 1986, the PSA test was first approved by the FDA for monitoring the progression of prostate cancer in men who had already been diagnosed. In 1994, the FDA also approved the use of the PSA test in conjunction with a digital rectal exam for screening. In 2012, the controversy over the use of PSA for screening heightened, and efforts are now underway to reassess the results of two large screening trials undertaken in the United States and Europe in the hopes of resolving the dispute. Meanwhile, many doctors are using an informed decision-making approach to individual patients, and efforts are also underway to refine PSA testing to identify patients with low-risk disease.
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