Researchers make strides toward more effective screening
Prostate cancer is the most common cancer in American men, with more than 234,000 new cases diagnosed each year, according to some estimates. However, screening for the disease remains controversial because scientists have yet to prove that current screening methods—which primarily rely on the prostate specific antigen (PSA) test and a digital rectal exam—actually save lives.
Although there is no question that these tests detect cases of prostate cancer, neither test offers a 100% accuracy rate. As a result, prostate cancer is not identified in some men who undergo screening, and others undergo invasive follow-up testing procedures even though they do not have the disease.
Recognizing the clear need for more accurate screening procedures, a number of researchers are looking into alternative approaches that show promise for offering improved results.
For example, investigators at Johns Hopkins University School of Medicine in Baltimore believe they have identified a better marker for prostate cancer that not only offers a higher degree of accuracy than PSA levels, but also enables clinicians to differentiate between cancers that have spread beyond the prostate from cancers that are confined to the single organ. In addition, evidence is mounting that by looking at PSA velocity (PSAV) in addition to PSA levels over time, clinicians can more accurately gauge whether a patient should be further evaluated for prostate cancer.
Reliability is the issue
Investigators at the Johns Hopkins Division of Adult Urology decided to look more closely at PSAV because data from the Prostate Cancer Prevention Trial1 made it clear that although a high PSA level can be a marker for prostate cancer, there really is no PSA level at which the clinician can reassure a patient that he does not have prostate cancer, according to H. Ballentine Carter, MD, the lead investigator of the study. In other words, the lack of specificity in the PSA test makes it difficult to determine when a patient should undergo further testing, such as a biopsy.
“No matter what cutoff you choose, and no matter how low you go, you could miss significant cancers,” explains Carter. Conversely, many men who do not have cancer may be targeted for a biopsy, which comes with certain risks and costs. “We were looking for a measure that would more reliably predict the presence of prostate cancer,” adds Carter.
To examine whether PSAV could help clinicians make better decisions regarding screening, Carter and colleagues looked at serum samples that were taken and frozen from participants as long ago as 1958 as part of an ongoing study of men’s health. What they found was that PSAV, determined at a time when PSA levels would not have triggered a biopsy, was predictive of death from prostate cancer 20–30 years later.
The researchers found that men who had a lower PSAV had a 92% chance of not dying from prostate cancer 25 years later, whereas those who had a higher PSAV had a 54% chance of not dying from the disease. Put in other terms, the rates of prostate cancer death were 1,240 in 100,000 for men with a high PSAV, and 140 in 100,000 for those with lower PSAV levels. The findings suggest that by looking at PSAV, clinicians can potentially identify men with aggressive prostate cancers at a time when the disease is curable.
In order to take advantage of these new findings, Carter is recommending that men undergo baseline PSA/PSAV testing at age 40 so that they will have a measurement with which to compare later PSA test results. Carter emphasizes that he is not suggesting that men should begin regular screening for prostate cancer at age 40.
“What I am recommending is a baseline PSA at age 40, and then perhaps another one at age 45, so that by the time a man is 50, and he begins regular screening, you already have a lot of information to compare to PSA levels that will be accumulated,” says Carter.
In determining what PSAV levels should prompt a cause for some concern, Carter says that just as men with bigger prostates tend to have higher PSA levels, they also tend to have faster rates of rising PSA levels. Consequently, a patient with a low PSA, in the two to three range, should not have a rapid rise in their PSA level.
“We have shown that if [the person] has a PSAV greater than 0.3 or 0.4, he may not have a life-threatening cancer right then, but he is statistically more likely to die of prostate cancer over the next two to three decades,” says Carter. “So the person whose PSA is increasing at that rate should be watched more carefully, if not biopsied.”
Alternatively, researchers identified a different cutoff point for men whose early PSA readings tended to be higher, in the four to 10 range. “The velocity cutoff that we found was important was 0.75 nanograms per milliliter,” says Carter. “That should trigger concern about the presence of cancer [in these men].”
Although some guidelines already take into account the predictive value of PSAV, Carter points out that expert panels are in the process of revising their recommendations to reflect his and other findings from the past year. He expects new guidelines to emphasize baseline PSA testing at a younger age, as well as the importance of paying attention to changes in PSA levels rather than absolute PSA levels. Adds Carter, “Rather than prompting a biopsy on everyone who reaches a certain point, I think there is going to be more emphasis on how fast the person got to that point.”
Down the road, it is possible that PSAV may be used as a way to rule out the need for further screening in some men. “Let’s say a person reaches a certain age, and he maintains a particular PSA that is below a certain level,” explains Carter. “We are looking at the safety of telling an older person that he doesn’t really need to have any further PSA testing because he is not at risk of ever developing anything life-threatening. We are looking carefully at that right now.”
New test shows promise
Although Carter’s work suggests the accuracy of PSA testing can be improved, other research suggests that a different blood test could ultimately prove to be a better tool for prostate cancer screening. Another group of researchers at Johns Hopkins has published work suggesting that a blood test based on the protein EPCA-2 (early prostate antigen-2) is not only considerably more accurate than the PSA test in identifying patients at risk for prostate cancer, but it can also distinguish between cancers that are confined to the prostate and cancers that have spread to other organs.2
“That is probably the biggest [advantage], because right now what we have is a tool that can identify men with prostate cancer, but a large number of men with prostate cancer don’t die from their disease, so we need better tools that separate the men with prostate cancer that is never going to kill them in their lifetime from the group of men with prostate cancer that will, indeed, give them problems,” says Robert Getzenberg, PhD, the director of research at the James Buchanan Brady Urological Institute at Johns Hopkins and the lead author of the study. “And I think that the distinction that we found with EPCA-2 has the potential to do that.”
In the study, researchers measured EPCA-2 levels in blood samples from 330 patients. Patients were separated into several groups, ranging from men with normal PSA levels and no evidence of disease to men with normal PSA levels that did have prostate cancer. Patients with an EPCA-2 cutoff level of 30 nanograms per milliliter or higher were considered to be at risk for prostate cancer. Overall, the test identified 94% of the men with prostate cancer. In addition, the results showed that men with cancers that had spread beyond the prostate had significantly higher EPCA-2 levels than the men whose cancers were confined to the prostate.2
The results thus far are preliminary. However, several clinical trials involving EPCA-2 are currently under way, and if they validate these early findings, Getzenberg suggests that the new blood test could be FDA-approved and available for use in 2009. “I think the first step will be to see if we can use the EPCA-2 test together with the PSA test,” he says. “But assuming that all of these values hold up over time, I would envision that with a marker with these characteristics, you wouldn’t need to run [the PSA test] anymore. We have to do some more work, and it is going to take some time to get that done.”
If the test is ultimately approved for use, Getzenberg says that labs across the country should have no trouble implementing the EPCA-2 test because it is a simple antibody test that should be easy to standardize. Further, with large-scale use, Getzenberg is hopeful that the new test will enable physicians to do a much better job of distinguishing between the men who need to undergo prostate biopsies from the men who have elevated PSA levels but do not have prostate cancer. “With the doubling of the population of older men that is going to happen in the next 10 years, we think this test is going to be critical,” adds Getzenberg.
1. The Prostate Cancer Prevention Trial is an intergroup study implemented at 219 sites in the United States and Canada. The study was activated in October of 1993 and enrolled its last participant in May 1997.
2. Getzenberg, et al. “EPCA-2: A Highly Specific Serum Marker for Prostate Cancer.” Urology 2007; 69: 714–720.