When laboratorians test a patient’s sample with two different brands of tumor marker assays, it’s not unusual to get two different results, which is why many organizations and regulatory bodies—including the Food and Drug Administration (FDA) and Clinical Laboratory Standards Institute (CLSI)—have developed international standards to align tumor marker assays to the same measurements. But standardizing prostate-specific antigen (PSA) assays has not produced a unified set of outcome values, even though that is the goal of developing standards. Currently, there are two calibration standards used by laboratorians to measure PSA levels: the “traditional” method based on Beckman Coulter’s Hybritech Tandem-R assay (Fullerton, Calif.)—one of the first commercially successful PSA assays; and the standard developed by the World Health Organization (WHO), which established the First International Reference Preparation (IRP) for PSA (WHO 96/670) in 1999. This month, Strategies looks at why having two standards can be problematic, and Beckman Coulter’s position on the WHO standards.
The utility of PSA testing continues to be debated. Even the field’s pioneering researcher, Thomas A. Stamey, MD, a Professor of Urology at the Stanford University School of Medicine (Palo Alto, Calif.), declared in September 2004 that the test is “all but useless” for assessing prostate cancer risk, after concluding a 20-year study of prostate biopsies. After studying these tissues, he concluded that because screening has become more common, cancers are usually caught earlier, but the PSA assay misses many tumors that are too small to produce enough of the protein.
While many clinicians continue to rely on this test to catch prostate cancer at an early stage, other problems haunt this assay. Because there are two calibration standards currently in use, a patient who is evaluated by an assay calibrated according to WHO standards—such as PSA assays on Bayer’s Centaur (Tarrytown, N.Y.) or Abbott AxSym (Abbott Park, Ill.) analyzers—may produce a different result when tested on a traditionally calibrated assay, such as Beckman Coulter’s Access. Since evaluating PSA levels over time is an important diagnostic strategy, it’s vital that the clinician monitoring the patient makes sure that he is repeatedly tested using the same brand of assay. Because laboratories usually do not indicate the type of assay used on the patient’s lab report or medical record, it’s important for the physicians and patients to be aware of the methodology used to determine PSA levels, particularly when the patient goes to a different physician or is tested using a different assay.
“Several manufacturers have calibrated their assays to the WHO standard, but we have adhered to the original Hybritech Tandem-R assay calibration,” explained Bernard Cook, PhD, DABCC, FACB, Manager, Scientific Professional Relations, Immunoassay Business Center, Beckman Coulter, Inc. (Chaska, Minn.). “If we were to change our calibration to the WHO standard, that could result in a change in patient values. There could be the potential for misdiagnosis of a patient’s medical condition if medical decision points are not adjusted simultaneously.”
It’s in the Proteins
The differences between the WHO and Hybritech standards go back to Stamey’s early work, said Cook, who insists that these differences might not have been fully appreciated by the clinical lab community until recently. In the early days of PSA screening, some assays failed to detect free and complexed forms of the antigen equally, and equimolar recognition of free and complexed PSA forms is critical to accurate PSA testing, especially at the cutoff used for biopsy recommendation. In the mid-1990s, Stamey proposed a PSA standard (90:10 ratio of complexed to free PSA) to mitigate the non-equimolar response of some PSA assays. This preparation then became the basis for the material adopted by WHO in 1999, with the intent to provide an "equimolarity-standard" as the “mass-standard” for PSA assays.
But since not every manufacturer has adopted the WHO standard, there is a potential risk that depending on what kind of analyzer a patient’s sample is run on, a doctor might not recommend a biopsy be performed when in fact, there might be cancer present. For instance, a study in the June 2004 issue of Journal of Urology compared results from assays run on Beckman Coulter’s Hybritech Access and Bayer’s Centaur systems. Using a cutoff of 4.0 ng/ml, 19% of the patients would have been biopsy candidates based on the Access, but not on the Centaur data (J Urol 2004; 171:2234-2238).
“Clinicians may be aware that PSA results differ from manufacturer to manufacturer, but they have not been informed that PSA assay restandardization has introduced a significant negative bias in mass units, compared to traditional PSA assays,” said Cook. “No one has really appreciated that if there’s a difference in the reference preparation, then there will be a difference in the final reported value in the assay after you’ve used that preparation to calibrate that assay.”
Pressure from the UK?
Beckman customers are not complaining about the standard differences to the manufacturer, according to Cook. “Right now, our customers are telling us not to change, that they are happy with our method,” he said. However, if the company does decide to provide the WHO option for its PSA assays in addition to the traditional standardization, it would mean undertaking a well-coordinated communication effort to all its customers. However, the company might not have a choice if it wants to maintain its position in the international marketplace, and there are forces outside the lab community that are driving PSA assay standardization. In the United Kingdom, for example, the country’s Department of Health is conducting a Prostate Cancer Risk Management Programme, which is requiring that all PSA assays be standardized to WHO.
“We’ve been talking about standardizing our assay to a WHO calibration and providing an option of traditional calibration for those customers who want it,” said Cook, who added that Beckman Coulter is not the only manufacturer whose assays show a positive bias in comparison to the WHO calibrated assays. “Our implementation strategy is still in the planning stages.”
For more information:
Visit Beckman Coulter’s PSA Web site: http://www.beckmancoulter.com/psa
Julie McDowell is the Editor of Strategies. She can be reached by email.