 The PSA Gap
A little-known difference in PSA test standardization can leave clinicians with confusing information. Here’s what your lab needs to know.
Imagine this scenario: A doctor recommends a prostate-specific antigen (PSA) test for a 55-year old man. The blood sample drawn from this patient is tested using two different PSA tests. One test reports a PSA value of 4.1 ng/mL; the other test reports a 3.2 ng/mL.
Same blood. Two PSA tests. Different results. “That amount of difference is not due to biological variation or assay imprecision,” says Bernard Cook, lead scientific advisor for Beckman Coulter.
How can two PSA tests result in such significantly different readings? The problem stems from the way PSA tests have been standardized. “There are two different standards or ways to calibrate PSA tests,” explains Dr. Cook. “And it’s become evident that they don’t deliver equivalent results.”
In fact, one method consistently delivers results that are roughly 22 percent lower than another method.
“People are not very aware of this,” says Gerald L. Andriole, M.D., Professor and Chief of Urologic Surgery at Washington University School of Medicine and Director of the Prostate Study Center at Barnes-Jewish Hospital in St. Louis, MO. “But it’s concerning because in some cases physicians might unknowingly not be monitoring PSA in the optimal way.”
It’s imperative that clinical laboratories know about the difference. In addition, by understanding how the two PSA testing standards differ, labs can provide valuable information to healthcare providers who are unaware of the issue. This helps improve patient care—no matter which PSA calibration is used.
How Two Standards Emerged
Nearly every PSA assay on the market is aligned with one of two standards: The traditional Hybritech® standard or the World Health Organization (WHO) standard.
The Hybritech standard took root in 1986, when the Hybritech Tandem-R test became the first assay approved to monitor prostate cancer. Because the Hybritech test was well accepted and widely used, it served as the basis for the recognized PSA decision limits that are used today.
As other PSA assays followed on the heels of Hybritech Tandem-R, patient results with the new tests were fairly well aligned to Hybritech results. But not all early PSA tests were able to offer the same level of equimolarity as dual monoclonal antibody assays are designed to yield.
One of the assay’s strengths was its equimolarity—the ability to measure both “free” PSA (PSA floating freely in the bloodstream) and complexed PSA (PSA bound to other blood proteins). Together, these represent total PSA. The equimolar response of the Tandem-R assay is credited to Hybritech’s patented dual monoclonal antibody technology.
As more tests came on the market, skewed responses began to emerge; and by the mid-1990s the non-equimolar response of some PSA tests had clearly become a clinical challenge.
In response, a team of researchers began looking for ways to standardize PSA testing—and this was the beginning of a second PSA testing standard.
This group of researchers convened two scientific conferences to discuss standardization, and during one of the conferences—at Stanford University in 1994—they proposed a new PSA calibration material containing a 90:10 mixture of complexed PSA and free PSA, respectively.
This 90:10 calibration was an attempt to correct for the non-equimolar response of some PSA assays, and in 1999 the World Health Organization (WHO) adopted it as the First International Reference Preparation (IRP) for PSA. Over time, some European countries mandated that labs move to the WHO standardization—and some manufacturers shifted their standardization to align with the WHO preparation.
Initially, it seemed as though the Hybritech and WHO standards could co-exist. But the more the two standards were studied, the more it became evident that a serious problem existed.
The 22% Gap
Looking back, the pivotal moment occurred when researchers first created the 90:10 calibration method.
“The scientific team used newer ways to quantify PSA and calculate its molecular weight,” explains Dr. Cook. “The methods were state-of-the-industry, and they resulted in different molecular weight compared with the Hybritech standard.”
The result: The WHO standard contains more protein and can lead to results that are consistently lower than Hybritech results—by approximately 22 percent.
The clinical impact of this difference was not fully appreciated when the WHO standard was established. “Most of the big studies that look at PSA were standardized to Hybritech,” says Dr. Andriole. “The thresholds we use today are very ingrained. If we are going to use another standard, we need to ingrain a whole new set of numbers in physicians’ and patients’ minds.”
These important interpretive criteria include not just the recognized 4.0 ng/mL and more aggressive 2.5 ng/mL cutoffs, but PSA velocity indicators.
One Score, Many Implications
Complicating matters further, the PSA score is much more than a stand-alone data point. Physicians monitor PSA levels over several visits to track PSA doubling time, PSA density and PSA velocity (change over time).
“More doctors are beginning to look at how PSA levels change over time, and use that to guide diagnosis and treatment,” explains Stacy Loeb, M.D., Urologist at Johns Hopkins and co-author of several articles in the Journal of Urology. “But if PSA levels are tested using one method the first year, then a different method the following year, this can confound the results.”
For example, a patient could be tested using the Hybritech method and receive a PSA score of 3.2 ng/mL. One year later, the patient returns and receives another PSA test. But this time the laboratory is using a WHO-calibrated test. Once again the score is 3.2 ng/mL.
It appears as though the level has remained steady, but that’s not the case. If the patient had been tested using a Hybritech assay, as he was the first time, the score would have been higher—around 4.1 ng/mL. That significant PSA velocity within a one-year period would be a red flag. But the healthcare provider misses the warning sign because different testing standards were used.
Conversely, a patient could see his PSA levels artificially increase if his results are based on a WHO-calibrated test one year, then a Hybritech test the following year.
“Whenever you talk about PSA velocity, you have to make sure the patient is tested using the same assay on an annual basis,” says Dr. Loeb. “Otherwise, you might see pseudo-acceleration or pseudo-deceleration of PSA levels—and this creates false alarm or false security.
“You can easily imagine that if there is a string of three or four PSA tests switching between methods, you won’t be able accurately calculate the change in PSA levels over time,” adds Dr. Andriole. “As a result, these men may not be appropriately evaluated.”
What Should Labs Do?
“All laboratories need to understand there are two ways to standardize PSA testing,” says Dr. Cook. “No matter which method you use, it’s important to be aware of the difference and appropriately inform physicians of the assay calibration and the appropriately matched clinical decision points.”
Laboratories that currently use the Hybritech method can continue reporting results as normal. But laboratories that use the WHO standard—or are considering a move to this standard—need to understand the impact as well as communicate with physicians.
“If you replace the Hybritech calibration with the WHO calibration, prostate cancer detection rates may shift unacceptably,” says Dr. Cook. “Labs need to proactively manage this by issuing lower cutoff values and explaining the rationale behind the change.”
“Whether physicians are using an absolute PSA threshold or looking at PSA change over time, they need to be aware of this issue,” emphasizes Dr. Loeb.
Indeed, while clinicians are aware that PSA assays can differ significantly among manufacturers, many still remain unaware of the potential for under-reporting with the WHO method. By communicating about the issue, laboratories can help doctors and patients make the best decisions possible when treating prostate cancer.
For more information, visit www.beckmancoulter.com/PSAvalue.
References
1. Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA. 1992; 267:2215–20.
2. Carter HB, Ferrucci L, Kettermann A, et al. Detection of life-threatening prostate cancer with prostate-specific antigen velocity during a window of curability. J Natl Cancer Inst. 2006; 98:1521–7.
3. Punglia RS, D’Amico AV, Catalona WJ, et al. Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen. N Eng J Med. 2003; 349:335–342.
4. Catalona WJ, Smith BS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostatic examination: Enhancement of specificity with free PSA measurements. JAMA. 1997; 277:1452–1455.
5. Babaian RJ, Johnston DA, Naccarato W, et al. The incidence of prostate cancer in a screening population with a serum prostate specific antigen between 2.5 and 4.0 ng/mL: Relationship to biopsy strategy. J Urol. 2001; 165:757–760.
6. Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, deKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL, Waters WB, MacFarlane MT, Southwick PC. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: Results of a multicenter clinical trial of 6,630 men. J Urol 1994; 151:1283-1290.
7. Armitage TG, Cooper EH, Newling DW, Robinson MR, Appleyard, I. The value of the measurement of serum prostate specific antigen in patients with benign prostatic hyperplasia and untreated prostate cancer. Br J Urol. 1988 Dec; 62(6):584–9.
8. D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 280; 969, 1998.
|
