Screening for prostate cancer is controversial and very likely will be for the foreseeable future, or at least until better tools are available to suss out which cases of cancer need aggressive treatment and which are unlikely to cause harm and thus can be monitored or left alone. Plenty of researchers are working hard in pursuit of that goal; some are using so-called variants on or derivatives of the prostate-specific antigen test, and others are going in different directions entirely. Here's a rundown:
Using PSA differently. Right now the American Cancer Society recommends that physicians discuss the pros and cons of screening with the PSA test with male patients age 50 and up, if they're at average risk (and at a younger age if they're at higher risk). For those who opt for screening, the society says that men whose PSA levels are less than 2.5 ng/mL can be screened every other year rather than annually. But there is another way to use the test, says Andrew Vickers, an associate attending research methodologist at Memorial Sloan-Kettering Cancer Center in New York. Research conducted in Sweden suggests that a reading taken at a young age, between 45 and 50, "is an extremely good predictor of whether you're [at] a long-term risk of having a 'bad' prostate cancer," says Vickers. In fact, after tracking the Swedish men for years, he and other researchers found that about 80 percent of subsequent advanced cancers occurred in men who had higher-than-usual PSA levels at a young age. In other words, the PSA test can help determine not only who might have prostate cancer now but who might get it in the future and therefore should receive the test regularly.
[To explore two sides of the PSA debate, read Benefits of PSA Test Are Exaggerated and PSA Cancer Screening, Much Like a Seat Belt, Is a Wise Choice for Men]
PSA velocity. This is the rate of increase in the PSA value from year to year, and as the ACS noted in its updated guidelines, a PSA velocity of more than 0.75 ng/mL per year "was associated with a higher risk of prostate cancer" even if the PSA value itself was within normal ranges. But still, the ACS said it "does not recommend routinely incorporating PSA velocity into prostate cancer screening strategies." Why? Mostly, it said PSA velocity, when considered with the PSA value and other risk factors such as race, earlier biopsy results, and family history, doesn't add much to the ability to predict whether a given man is at risk of developing either aggressive prostate cancer or the disease in any form. So measuring the PSA velocity isn't going to do much to solve the essential dilemma of prostate screening: figuring out which men should be sent for a biopsy and treated aggressively for whatever cancer is there and which might be observed, either before getting that biopsy or after learning there is some cancer present.
Of course, much like the PSA test, PSA velocity has stirred controversy. William Catalona, a urologist who initially showed that the PSA test can be used as a first-line screening tool, is now director of the clinical prostate cancer program of Northwestern University's Robert H. Lurie Comprehensive Cancer Center. He says PSA velocity can help rule out inflammation, a common cause of PSA false alarms. If there's a significant spike in PSA, a physician could either treat the patient with an antibiotic and repeat the test (something Catalona doesn't recommend lightly given concerns over antibiotic resistance) or simply wait six weeks and check the level again. "When you have a parameter of PSA velocity shown by many investigators to be associated with an ultimate risk of dying, it's a very valuable thing to use," he says.
Free PSA. PSA exists in two forms: unbound to other proteins ("free") or bound to other proteins. The higher the percentage of free PSA as a part of total PSA, the less likely it is that cancer is present and the more likely the PSA is instead elevated owing to benign prostate hyperplasia, or BPH, says Catalona. If the figure is greater than 25 percent, there's only about a 1 in 10 chance that a biopsy would show cancer, says Catalona. (The American Cancer Society says physicians disagree on where to draw the line using free PSA but that it generally ranges between 10 percent and 25 percent; any lower than that, and you're sent for biopsy.)
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.
[See a slide show of 11 screening tests you should (or shouldn't) consider.]