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PSA: There's More to Your Score

Two Types of PSA Tests: Changes in Some PSA Tests May Require Changes in How Results are Interpreted

The PSA (prostate specific antigen) test is one of our best weapons in the battle against prostate cancer, but in recent years, changes to some PSA tests mean some test results may have to be interpreted differently than doctors have become accustomed to. For many years, 4.0 was the cutoff many physicians and medical professionals used for a "normal" test result. But today, a 4.0 isn't always a 4.0 on all tests. Physicians and patients who do not know which type of test was used may not interpret the results appropriately, potentially leading to a delay in care for men with prostate cancer.

It has always been important for men to know their PSA test results and to discuss results with their doctors; now they also need to identify which test they had to ensure that the appropriate interpretation is made.

PSA: Two Types of Tests

PSA is a protein made in the prostate gland and, normally, very little should be found in the blood in men without disease. In the mid-1980s, researchers discovered that PSA may indicate prostate cancer in men when elevated levels are detected in the blood. Until then, a digital rectal exam (DRE) was the primary method of prostate cancer detection. Within several years, clinical studies established the role of PSA in prostate cancer screening.

Measuring the concentration of PSA in a man's blood proved to be a major advance in the fight against prostate cancer. Along with the digital rectal exam (DRE), physical exam and risk factors, PSA testing has helped identify which men are at sufficient risk for cancer that a biopsy is warranted. PSA testing has led to a more than 30 percent decline in prostate cancer death rates since it began to become widely used, according to the American Cancer Society.

The first PSA test approved by the U.S. Food and Drug Administration (FDA) for use in prostate cancer screening (in conjunction with DRE) was developed by Hybritech. Based on its own clinical studies of more than 6,600 men, Hybritech established 4.0 ng/mL as the cutoff for a normal test. This means men with a score above 4.0 should be referred for further testing, such as a biopsy. Men with a result lower than 4.0 may not be referred for biopsy, depending on their physician's instructions. As other manufactures developed PSA tests, they aligned their tests to the same standard, which became known as the "Hybritech standard," and other manufacturers used the same recommended cutoff of 4.0.

By the mid-1990s, some researchers began to recognize that test results from different test manufacturers could be slightly different. Some researchers joined together to create a common calibration standard, to better align results from different PSA tests. This standard was accepted by the World Health Organization (WHO). This soon became known in the medical community as the "WHO standard" PSA test.

Different Tests Require Different Cutoff Points

In establishing the new standard, the WHO scientists used a different scientific process in measuring the molecular weight of PSA. They determined the weight of PSA is about 20% higher than had been determined by Hybritech scientists, who used a scientific process that was widely used at the time the Hybritech test was developed.

Since the weight of the sample is used to determine the concentration of PSA and since the WHO test uses a higher weight measure for PSA, it follows that the WHO test would show a proportionately lower PSA concentration level than would a Hybritech test for the same sample. As a result, the cutoff point at which men are referred for further testing would more appropriately have been set about 20 percent lower than the 4.0 used for the Hybritech test.

But unfortunately, many still use 4.0 as the cutoff for both tests.

Many manufactures rushed to incorporate the new standardization in their PSA assays. Patient results determined from the WHO standardized assay began to be reported in 2000.

Scientific studies noted this difference in results between the two tests soon after the introduction of the WHO standard.¹ A study published in the Journal of Urology in 2004 concluded that "the potential clinical impact of this variability on cancer detection is significant."² A comparable study, which confirmed a 22 percent gap between the tests, was presented earlier this earlier this year at the American Urological Association's annual meeting.³

This approximately 20 percent gap means that a man who received a 4.0 result on the Hybritech test should receive a 3.1 on the WHO test. Unfortunately, many in the medical community continue to use a strict 4.0 as the cutoff, unaware that the cutoff is not the same for all tests. Consequently, men who receive a score between 3.1 and 4.0 on a WHO test may not be referred on to further testing as quickly as they might have.

The issue at hand is not which test is better, but that changes in the test require changes in the interpretation -- a different cutoff score. It's not unlike the difference between kilometers per hour and miles per hour when driving a car. If you don' know how the speed limit is measured, you could end up with a speeding ticket.

But the consequences of not knowing what scale you are using are much more serious than a speeding ticket when it comes to prostate cancer. Just as drivers are cautioned to know the correct speed limit on the road, so should doctors be cautioned in how they interpret the results for the Hybritech and WHO tests. If the cutoffs for screening are not adjusted accordingly, the conclusions doctors draw about their patients may be flawed.

Impact on Patient Care

No one knows exactly how many men with prostate cancer have been missed due to this issue. But given the number of tests that are conducted each year and the prevalence of prostate cancer, the implications could be staggering.

Of the approximately 18 million PSA tests conducted each year in the United States for screening purposes, about 12 million are based on the WHO standard and the remaining on the Hybritech standard.⁴ Studies have shown that about five percent of men who are tested with a WHO test likely would not be referred for a biopsy using the 4.0 cutoff, when they would have if they had received a Hybritech test. As a result, about 600,000 men per year may not be referred for biopsy due to differences between results on WHO test compared to the Hybritech test. Among these men are an estimated 180,000 per year who likely have prostate cancer, including 50,000 who have an aggressive form of prostate cancer (these numbers are based on cancer rates reported in the Prostate Cancer Prevention Trial⁵).

Some men are referred for biopsy even though their value may not have reached 4.0 because their PSA value has increased rapidly over a short period of time. The measure of change in PSA level over time, which may be PSA velocity or doubling time, may be used to determine if further testing is warranted. For instance, even if the PSA score is below 4.0, an increase of 50 percent or more in one year may indicate prostate cancer. But this change may be not be detected as rapidly in a patient being tested with a WHO test.

In addition, if a patient's results are a mix of WHO and Hybritech tests, the doctor may not detect a change, or he may believe a change has occurred when nothing has changed. For instance, the scores of a patient who goes from the Hybritech test to the WHO test would understate the change, while the change in condition would be overstated for the patient who goes from the WHO test to the Hybritech test. In the first case, the patient was missed; in the second, he may have received an unnecessary biopsy.

• For additional information on the two types of PSA tests, click here to see an article in CAP TODAY (October 2009).

Accurately Interpreting PSA Results

The medical community is only beginning to become aware of this issue. Many labs do not know that cutoff level may differ depending on the test they provide. Many health providers continue to use the 4.0 cutoff for all tests. Until now, at least, most health care providers do not know if their test is based on WHO or Hybritech standards.

Until manufacturers and the medical community agree on how to resolve this issue, it is important for everyone involved, from the laboratories to the physician to the patient, to know what type of test was administered and how that might affect the interpretation of the resulting value.

Men who have been screened with the PSA test in the past five years may want to speak with their doctor or other health provider about what type of test you were given.

The PSA test is one of the best tools we have to catch prostate cancer early and help save lives. But it is vital for the health of patients that we interpret the tests accurately.

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