BBI

The same man who nearly two decades ago reported that serum prostate-specific antigen (PSA) was proportional to stages of prostate cancer that could be determined through digital rectal examination last month pronounced that, in the words of his study title, "The Prostate-Specific Antigen Era in the United States is Over for Prostate Cancer ..."

The PSA test, which men across the U.S know is a commonly used screening tool for detecting prostate cancer, is now all but useless, according to Thomas Stamey, MD, professor of urology at Stanford University (Palo Alto, California) and lead author of the study, published in the October issue of the Journal of Urology. "The PSA era is over in the U.S.," Stamey said in a statement released by Stanford University Medical Center. "Our study raises a very serious question of whether a man should even use the prostate cancer screening any more."

There are those who disagree with this statement, but the importance of the debate is undeniable, as prostate cancer is the most common cancer in men, although lung cancer is the leading cause of cancer-related deaths. The PSA test measures the level of prostate-specific antigen, a protein normally produced by the prostate gland. Stamey published his original findings in 1987 in The New England Journal of Medicine, which held that increased blood PSA levels could be used to indicate prostate cancer. According to the conclusions of the most recent study published in the Journal of Urology, "Serum PSA was related to prostate cancer 20 years ago. In the last 5 years serum PSA has only been related to benign prostatic hyperplasia. There is an urgent need for serum markers that reflect the size and grade of this ubiquitous cancer."

Benign prostatic hyperplasia, or BPH, is considered a harmless increase in prostate size, which occurs commonly with age. According to Stanford Medical Center, Stamey explained the change in correlation over the years by noting that the tumors encountered 20 years ago were typically so large they generated PSA levels high enough to provide a "reasonably good measure of cancer severity." Now that screening is more commonplace in this country, many cancers are being caught earlier and are usually smaller – not generating enough PSA to be a "good indicator of severity," he said.

Stamey, who declined being interviewed for this story, said prostate cancer is a disease "all men get if [they] live long enough. All you need is an excuse to biopsy the prostate and you are going to find cancer."

Another prominent urologist and researcher with definite opinions on PSA testing is William Catalona, MD, director of the Clinical Prostate Cancer Screening Program at Northwestern Memorial Hospital (Chicago). In fact, Catalona issued a response to Stamey's study on his web site, www.drcatalona.com, which stated: "A recent article by Dr. Thomas A. Stamey of Stanford University has caused men to question the use of PSA in screening for prostate cancer and to question the effectiveness of a radical prosatectomy for treatment of prostate cancer. My research, and the research of my colleagues, shows the most effective and acceptable treatments for prostate cancer get rid of the tumor at a very early stage before it has a chance to spread. The risk of unnecessary treatment is low when good clinical judgment is exercised." He said that "since advanced prostate cancer has no known cure and no means exist to prevent prostate cancer, the only hope for reducing suffering and death from prostate cancer is to detect it early and treat it effectively."

Catalona said Stamey's comments, "along with news stories about unnecessary biopsies, costs of screening and possible overtreatment or unnecessary treatment of prostate cancer have created more confusion and controversy than the information deserves."

From Stamey's research, he has concluded that "the basic dilemma" is that "men whose PSA levels are above 2 ng/ml frequently undergo biopsy, which will almost always find cancer, but this does not necessarily mean that prostate removal or radiation treatment is required."

Stephen Mikolajczyk, PhD, senior staff scientist and group manager of clinical discovery at Beckman Coulter (Fullerton, California), told BBI that while Stamey's remarks are "accurate," the findings are not a "startling discovery." Beckman Coulter has both the Hybritech PSA and Hybritech free PSA, and according to the company were the first such tests approved by the FDA.

"I think it's pretty well known and pretty evident in the field," Mikolajczyk said, noting that "certainly over the last 10 years ... PSA has been in the low ranges," or below 10 ng/ml. He said that "when you start getting high PSAs, you clearly have a problem, most likely, cancer." In the low ranges, he said, "clearly, there's a high probability that BPH and other prostate diseases are influencing that number." He said "the test continues to have value. It keeps getting used in different ways to improve the diagnosis."

Beckman Coulter and other companies are working on ways to further develop the PSA test to overcome weaknesses such as that of a high level of false positives, leading to what some say are too many biopsies that turn out to show there is no cancer and that are performed at a high cost to the healthcare system. In a study published in NEJM in July, Catalona and other researchers studied "1,095 men with localized prostate cancer to assess whether the rate of rise in the prostate-specific antigen level – the PSA velocity – during the year before diagnosis, the PSA level of diagnosis, the Gleason score, and the clinical tumor category could predict the time to death from prostate cancer and death from any cause after radical prostatectomy."

The authors stated in their conclusions that "men whose PSA level increases by more than 2.0 ng/ml during the year before the diagnosis of prostate cancer may have a relatively high risk of death from prostate cancer despite undergoing radical prostatectomy."

There also are new tests on the horizon that may offer higher specificity than PSA testing. DiagnoCure (Quebec City) reported last October that Bostwick Laboratories (Richmond, Virginia) would begin offering an in-house version of its investigational uPM3 assay for prostate cancer. In making that announcement, DiagnoCure noted that "patients with elevated PSA and negative biopsy are a significant dilemma for urologists, and it is difficult to decide when to re-biopsy the patient." At that time, David Bostwick, MD, chief executive officer and medical director of Bostwick Laboratories, said the uPM3 urine test is twice as capable of identifying patients at high risk of prostate cancer as the conventional PSA blood test.

Gen-Probe (San Diego) and DiagnoCure signed a license and collaboration agreement last November, under which they will develop, and Gen-Probe will market, the urine test to detect the gene called PCA3 that the companies said has been shown by studies to be over-expresssed only in malignant prostate tissue. DiagnoCure has uPM3, and "they are selling that currently as an ASR [analyte-specific reagent] to one lab in the U.S.," said Michael Watts, spokesman for Gen-Probe. "So we think there's a terrific opportunity there for us."

Gen-Probe CEO Henry Nordhoff said during an earnings conference call last month that the PCA3 project was "progressing nicely." He said, "We have successfully transferred DiagnoCure's first-generation assay onto our Aptama technology platform," which is based on transcription-mediated amplification, or TMA. "Based on the work we've done to date, we believe a quantitative assay format will optimize the sensitivity, specificity and value of our second-generation assay," Nordhoff said. "We continue to believe that from a technical standpoint we can introduce a quantitative ASR ... around the end of next year."

However, Watts noted that Gen-Probe "would not expect a PCA3 test to replace PSA, at least not initially," due to the fact that physicians can sometimes be cautious in adopting new tests or methods.

Last June, MediScience Technology (Cherry Hill, New Jersey) reported the formation of Proscreen as a wholly owned subsidiary to develop a new less-invasive clinical application for diagnosing prostate cancers without removing prostate tissues.

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