Tested last year for prostate cancer, John Lenahan was found to have high levels of a potential telltale substance called prostate specific antigen, or PSA.
Although a subsequent biopsy didn't show any evidence of cancer, Lenahan, 64, was left wondering. "I worry," said the semiretired lawyer from Woodbridge, Va. "I'd be lying if I said I wasn't."
Every year, almost 2 million American men have prostate cancer biopsies, almost all because of a high PSA reading. But about 75 percent of these men don't have cancer.
The problem, experts say, is that the PSA test is not very accurate. Many men with high levels of PSA don't have prostate cancer, and some with low PSA do have a tumor.
To help men like Lenahan, researchers are looking for more accurate ways to detect prostate cancer - and to pinpoint the most aggressive tumors.
"There are much more specific markers for prostate cancer than PSA," said Johns Hopkins University urologist Dr. Angelo De Marzo, one of dozens of scientists around the world who are working in this area.
De Marzo and his colleague, cancer specialist Dr. William G. Nelson, are studying a gene called GSTP1, which seems to protect cells against carcinogens. In prostate and other cancers, this gene is abnormally switched off by a process called methylation.
Researchers have found that cancerous prostate tissue has much lower levels of GSTP1. De Marzo and Nelson suspect that this decrease may be an early sign of disease; they are trying to figure out how to detect GSTP1 in the blood.
Another Hopkins researcher, Robert Getzenberg, has focused on a protein called early prostate cancer antigen, or EPCA. In a small study published this month, he showed that a blood test for EPCA predicted prostate cancer with 94 percent accuracy. PSA, by comparison, has 25 percent to 30 percent accuracy.
Getzenberg is beginning a much larger trial, with 600 patients, to verify the results. A Seattle biotech company, Tessera, has licensed the test and hopes to win approval from the U.S. Food and Drug Administration by next year.
"Assuming that the data holds up, this will really help us," Getzenberg said of the test.
Another intriguing possibility is an enzyme known as alpha-methylacyl-coenzyme A racemase, or AMACR. Identified three years ago, this substance helps metabolize phytanic acid, which is found in red meat and dairy products.
Some research indicates that these foods can raise the risk of prostate cancer. Scientists hypothesize that AMACR helps certain kinds of cancer cells grow, which could explain this link. In any case, researchers have found a clear connection between high levels of AMACR and prostate cancer.
Many experts say this marker is the most promising; some top cancer treatment centers are using AMACR to confirm difficult-to-diagnose cases.
De Marzo and others at Hopkins are refining a method to detect AMACR in urine. And at Harvard University, surgical pathologist Dr. Mark Rubin is studying AMACR as a way to predict how quickly a given cancer will spread. Paradoxically, he has found that the nastier a tumor is, the less AMACR it contains. He is not sure why.
"The main issue is trying to distinguish slow-growing from aggressive prostate cancer," Rubin said. "PSA doesn't do that."
Most of the 230,000 cases diagnosed every year are relatively benign. But a significant percentage are deadly: The disease kills 30,000 people annually.
Without a reliable way to gauge a given cancer's risk, many patients undergo unnecessary treatment, while others are not treated as intensively as they should be.
Getzenberg is also working on another marker - a gene called D-2, which seems to show up more often in more aggressive prostate tumors. His lab is developing a D-2 blood test.
Of course, not all of these possibilities will pan out. Dr. William Catalona, a urology professor at Northwestern University, says he knows of more than a dozen promising prostate cancer markers being investigated.
"All of these things sound good. But they have to be tested in real-world situations," he said. Catalona is working on one, a gene called MLH1.
And many doctors argue that the PSA test is useful. Several recent studies have shown that PSA velocity - the rate at which the level rises over time - more accurately predicts prostate cancer than a single PSA measurement.
"We don't need another marker at this point," said Dr. Anthony D'Amico, a prostate cancer specialist at Harvard Medical School. "We just need to use PSA more wisely."
PSA may even be able to predict prostate cancer more than a decade before a tumor appears.
At the annual meeting of the American Urological Association, held last week in San Antonio, Hopkins researcher Dr. Ballentine Carter presented evidence that men whose PSA rises faster than .2 per year are four times as likely to get prostate cancer over the next 20 years as men with a slower rate of increase.