What Comes After PSA?
When the U.S. Preventive Services Task Force issued new recommendations recently advising against routine use of prostate-specific antigen (PSA) testing to screen men aged 75 or older for prostate cancer, it caused some controversy. But at its core, the recommendation emphasized an important fact: Although the PSA test is one of the most commonly used cancer screening tests - approximately two out of every three men aged 50 to 74 have undergone PSA screening in the preceding 2 years - there is still no hard evidence that it actually saves lives.
In addition, explains Dr. Howard Parnes, chief of the Prostate and Urologic Cancer Research Group in NCI's Division of Cancer Prevention, the NCI-sponsored Prostate Cancer Prevention Trial has shown that "the true prevalence of prostate cancer is much higher than previously thought, and that the lower we set the PSA threshold for recommending biopsy, the more overdiagnosis there will be." Overdiagnosis refers to the detection of cancers that would never become clinically apparent during a man's lifetime, many of which will be treated, often with surgery, accompanied by potentially serious and lifelong side effects.
The overdiagnosis conundrum has been one of the factors driving the search for a new prostate cancer screening test. Progress on that front has been steady but slow. However, the research that has been done, some investigators caution, suggests that the PSA test will not be going away any time soon. But it may, eventually, be combined with some new tests.
Ideally, many prostate cancer researchers say, a new test will not only detect the disease at its earliest stages, but provide a window into a patient's prognosis: Is it an aggressive cancer that requires immediate treatment, or can it be monitored with active surveillance (or "watchful waiting") because it's unlikely to ever become life threatening?
The potential prostate cancer markers in the literature read like an alphabet soup of genes and RNA and proteins: PCA3, EPCA-1 and -2, B7-H3, and AMACR, among others. If there is a trend to be spooned out of the soup, it's that a single marker may not be sufficient to reliably detect cancer or provide insight into its likely clinical course.
"As we develop the next generation of biomarkers of prostate cancer detection," Dr. Parnes stresses, "it is important to keep in mind that accuracy and efficacy are not synonymous."
Several markers that were initially heralded for their potential as lone actors appear, in fact, to be more effective as the "anchor" of a test that includes a panel of markers. Among them is a novel gene-fusion product, TMPRSS2-ERG (novel, in part, because it was one of the first such gene fusions ever discovered in a solid tumor) and the silenced, or methylated, form of the gene GSTP1.
For both markers, investigators have favored developing tests based on screening urine samples. In February, for example, a team led by Dr. Arul M. Chinnaiyan from the University of Michigan, which discovered TMPRSS2-ERG, published a study showing that the presence of TMPRSS2-ERG and three other markers could correctly predict the presence of prostate cancer (sensitivity) two-thirds of the time and correctly rule it out (specificity) three-quarters of the time.
"The future is going to be panels of markers, because they will be able to achieve the sensitivity and specificity that you need, and also offer the security of monitoring more than one marker," Dr. Chinnaiyan says. "With the array-based technologies we have, we definitely should be able to do that."
Studies involving panels of markers anchored by hypermethylated GSTP1 have demonstrated modest results to date. One of the most rigorous studies conducted thus far with such a panel, for example, demonstrated sensitivity that ranged from 53 to 55 percent and specificity as high as 80 percent.
There are also data to suggest that these tests may give clinicians exactly what they're clamoring for: guidance on clinical decision making. Data from the GSTP1 study referenced above, for instance, suggest that the test results, when combined with other common clinical factors, could help clinicians determine which patients should undergo biopsy following an elevated PSA result. And a study presented in April at the American Association for Cancer Research annual meeting found that TMPRSS2-ERG-positive cancers represented a specific molecular subtype of prostate cancer that is more aggressive than other types.
Tests based on TMPRSS2-ERG and GSTP1 already have been licensed to large diagnostic companies. And that's a critical factor in getting a new test into the clinic, says Dr. Sudhir Srivastava, director of NCI's Early Detection Research Network (EDRN), which has supported studies of both biomarkers.
Part of EDRN's job is to help investigators establish the validity of these markers in rigorously designed studies. But ultimately, Dr. Srivastava adds, "The goal is to find an industrial partner who can help take it beyond these validation studies."
Dr. Chinnaiyan agrees. "To credibly bring a biomarker to market, that's the best way," he says. "If you do it all in an academic lab, things can move slowly and reagents aren't made at commercial-grade quality, which makes it hard to move forward to FDA approval."
Prospective, randomized clinical trials involving prostate cancer screening tests are difficult to conduct because of the long clinical course of many prostate cancers. However, such trials will be needed, Dr. Parnes says, to determine whether any novel prostate marker or panel of markers reduces prostate cancer mortality.
Because of the time and expense involved in such trials, Dr. Srivastava is hopeful that novel approaches or study designs can be developed that have a shorter time course and can move new screening tests for prostate cancer into clinical practice more quickly, particularly for men who are at high risk for the disease.