Since 1986, the prostate specific antigen (PSA) blood test has become a routine part of man's medical regimen. The test measures levels of a protein produced by the prostate and has enabled doctors to diagnose more than 80 percent of prostate cancers before they spread to lymph nodes, bones or other tissues. But even the strongest advocates of PSA testing admit that it has significant shortcomings. For one thing, PSA isn't specific for cancer. Although the likelihood of cancer increases with greater elevations in PSA, values considered abnormal—in the range of 4 to 10 nanograms per milliliter or even higher—occur in men with benign conditions, such as an enlarged prostate. Adding to the confusion: 15 percent of men with a PSA below 4 ng/ml who have a biopsy actually do have prostate cancer, according to a 2004 study. That's right: men with a "normal" PSA may have cancer, and most with an "abnormal" result do not.
PSA also falls short in its ability to distinguish potentially deadly cancers from insignificant ones. Some cancers spread rapidly, but many grow so slowly that they may never cause problems. For the slow-growing cancers, the side effects of treatment—which include impotence and incontinence—can be worse than the disease. "No one is entirely happy with PSA, including me," says Northwestern University's William Catalona, a prostate-cancer surgeon who helped pioneer PSA's role in prostate-cancer screening.
For the past several years, researchers have been combing through blood and tissue samples in the hopes of finding some sort of biological change, or biomarker, to more accurately diagnose prostate cancer and predict its behavior. Catalona has been studying a form of PSA called "free" PSA. (The other form is called "bound" PSA because it binds to proteins in the blood.) Today's PSA tests measure total PSA, the sum of free and bound PSA. Catalona's research has shown that a subcategory of free PSA called proPSA is superior to PSA in discriminating cancer from benign conditions. Its greater diagnostic accuracy, says Catalona, likely stems from the fact that proPSA is produced in the prostate's outer zone, the area where most cancers arise.
Subsequent studies of proPSA in 2,000 men confirmed Catalona's initial results, and a San Diego company has developed an automated method for detecting it. The company plans to seek FDA approval for the test, which Catalona estimates could be available in as little as three years. While it may one day supplant PSA, experts say it will initially be an adjunct to PSA, especially in cases where the total PSA reading might prompt a biopsy.
Another test that may soon be ready for market in the United States checks for the presence of a protein called PCA3. This cancer-associated protein can be detected in the urine. PCA3 levels don't rise if a man has an inflamed or enlarged prostate, so the test more closely correlates with cancer than PSA. Those with a slightly elevated PSA but low PCA3 could be spared a biopsy.
Perhaps the most promising biomarker is EPCA-2, discovered by researcher Robert Getzenberg and colleagues at Johns Hopkins Hospital. Examining biopsy tissue, the team found that EPCA-2 was present in prostate-cancer cells but not in normal tissue. Since biopsies are not a practical screening tool, the team tried to detect EPCA-2 in blood from 330 people. The results were striking: healthy men and women, those with other types of cancer and most men with benign prostate disorders had lower levels of EPCA-2 than men with prostate cancer. Only a few cases of noncancerous prostate enlargement had elevated EPCA-2 readings, meaning the test was highly specific for cancer. The test detected 94 percent of cancers—much better than the 65 percent detected with PSA in this same group of people.
While PSA testing remains the gold standard for predicting cancer risk, and the cancer's appearance under the microscope remains the best way to guess how it will behave, researchers are convinced that ongoing biomarker research and genetic analyses will lead to significant improvements in prostate-cancer detection and treatment. Each individual could have a panel of tests: one for diagnosing the cancer, a second to determine if the cancer needs to be treated and a third to determine the best treatment. That's what the hope of "personalized medicine" is all about.
Molecular studies designed to improve diagnosis and judge who needs treatment may also point to effective new therapies based on genetic studies. Massimo Loda at Harvard's Dana-Farber Cancer Institute has found that the fusion of two genes greatly increases the risk that prostate cancer will return and prove fatal. In other cancers, the discovery of such fused genes has led to powerful new treatments. Lewis Cantley and Pier Paolo Pandolfi at Harvard's Beth Israel Deaconess Medical Center are studying drugs that might enhance one gene that keeps cancers in check, as well as different drugs that inhibit a second, cancer-promoting gene. Whether or not this specific approach proves successful, most experts believe that today's molecular technologies will revolutionize the diagnosis, prognostication and treatment of prostate cancer. It's not a question of if, but when.