It's also possible to measure the "complexed" PSA, or the amount bound to other proteins, but its ability to detect cancer is "very similar [to total PSA] in terms of sensitivity and specificity," says Robert Veltri, director of the Fisher Biomarker Biorepository Laboratory at Johns Hopkins University's Brady Urological Institute.
ProPSA. Catalona is involved with research into proPSA, one of three identified forms of free PSA. The more proPSA present as a percentage of free PSA, the more likely a man is to have cancer, he says. A study appearing in the April Journal of Urology found that a measure of proPSA (also called p2PSA) more accurately identified prostate cancer in 63 men than did total PSA or free PSA. And the combination of all three measures may be even more helpful. "It's not the proPSA value by itself, but it's an index of the proPSA over the free PSA, in relationship to the total PSA," says Veltri.
Daniel Chan, director of the clinical chemistry division and the Center for Biomarker Discovery at Hopkins, says proPSA has the potential to improve prostate cancer detection, particularly for men with a PSA between 2 and 10. It may also be able to improve detection of the aggressive cancers, which in some cases may be small and appear unthreatening under a microscope. Chan says results from a 566-person study that will be published in May are "promising" in two ways: ProPSA is better at distinguishing cancer from more benign problems than total or free PSA, and it also seems to correlate with aggressiveness—though using this to actually decide whether or not to treat a patient would require a much bigger study. (Beckman-Coulter Inc., which develops and makes lab and diagnostic equipment, has submitted a proPSA test to the FDA for consideration.)
Other markers. While the percentages of free PSA and proPSA are promising, "to be very honest, many of us are skeptical that the home-run breakthrough is going to be based on variant PSAs," says Ian Thompson, chairman of urology at the University of Texas Health Science Center–San Antonio and an author of the recently updated ACS guidelines. To really improve on our current assessments of risk, we need two things, he says: "A marker associated with prostate cancer but that is associated through a totally different mechanism" from what we have now and also a marker that picks up significant disease, not indolent cases.
One possible candidate: prostate-cancer gene 3 (PCA3). Research presented at an American Society of Clinical Oncology genitourinary tumors symposium earlier this month suggested that adding a PCA3 urine test to regular testing more accurately diagnoses prostate cancer and is also associated with more aggressive cancers. The test is undergoing other studies and is expected to be submitted to the FDA for consideration later this year, its manufacturer, Gen-Probe Inc., said at the meeting.
Researchers are also studying the usefulness of a test to detect the fusion of two genes—a precursor regulator gene called TMPRSS2 and a cancer-causing gene known as ERG. The fusion of the two seems to turn on the cancer cell and make it sensitive to hormones that can spur the growth of cancer. It may be present in as many as half of all prostate cancers, says John Wei, professor and associate chair for research at the University of Michigan urology department. Other cancers may involve a different gene variant. Combined with information such as PSA and family history, a urine test looking for the gene fusion seems to predict who will have cancer found in a subsequent biopsy. And it seems to be associated with the more aggressive forms of the disease.
It's important to know that none of these new measures are likely to replace PSA entirely, at least not in the near future. All of them need more research to figure out not only how well they detect cancer and especially aggressive cancer but also how, if at all, they would fit into any kind of general prostate cancer screening recommendations. (The goal of cancer screening, after all, is to save lives without causing much harm to healthy people, not just to find cancer.) The gold standard for use of a test in a screening program is a long-term, randomized clinical trial, though those trials are expensive and difficult to do. At this point, such trials have produced no clear guidance as to how to screen for prostate cancer.