URINE GENETIC TEST FOR PROSTATE CANCER

An investigational urine test stratifies prostate cancer risk in men with elevated levels of prostate specific antigen (PSA), according to newly reported results from more than 1000 men.

Previous research has indicated that the urine test is 100% accurate in detecting a gene fusion directly linked to prostate cancer, say the authors.

However, the urine test, which detects the fusion of 2 genes (TMPRSS2 and ERG), has a weakness: this tell-tale gene fusion occurs in only about 50% of prostate cancers.

For this reason, in the new prospective study, the urine test was combined with another marker, prostate cancer antigen 3 (PCA3).

The study was published online August 3 in Science Translational Medicine.

All of the men in this study had elevated PSA levels and had undergone either biopsy or prostatectomy, report the researchers, headed by Scott Tomlins, MD, PhD, from the University of Michigan Health System in Ann Arbor.

The men in the study were also evaluated for TMPRSS2:ERG and PCA3, but some were tested with the initial version of the gene fusion test and others with the second-generation test. Hence, the researchers chose not to directly compare individual men; instead, they stratified patients into risk groups by score (low, intermediate, and high).

Of 1065 men who received biopsies, 363 (34%), 346 (32%), and 356 (33%) were in the lowest, intermediate, and highest TMPRSS2:ERG + PCA3 score groups, respectively.

These scores were then compared to biopsy results.

Biopsies indicated cancer in 21% of men in the low-score group, 43% in the intermediate-score group, and 69% in the high-score group. The difference between the low- and high-score groups was significant (P < .001).

"Testing for TMPRSS2:ERG and PCA3 significantly improves the ability to predict whether a man has prostate cancer," said Dr. Tomlins in a press statement. "We think this is going to be a tool to help men with elevated PSA decide if they need a biopsy, or if they can delay having a biopsy and follow their PSA and urine TMPRSS2:ERG and PCA3."

In effect, the test, if it reaches the clinic, would help improve the murky decision-making that plagues many men with elevated PSA levels as they consider a biopsy.

"Many more men have elevated PSA than actually have cancer, but it can be difficult to determine this without biopsy. This test will help in this regard. The hope is that this test will be an intermediate step before getting a biopsy," said senior study author Arul Chinnaiyan, MD, PhD, from the Michigan Center for Translational Pathology and University of Michigan Medical School in Ann Arbor.

In 2009 at the Genitourinary Cancers Symposium, when the first-ever clinical results of the urine test were presented, an expert not involved with the research praised the rapid development of the test.

"This is an amazingly short interval between the discovery [of the gene fusion] and [the emergence of a] possible clinical application in diagnosis," said Howard Sandler, MD, from the Samuel Oschin Comprehensive Cancer Institute, Cedars–Sinai Medical Center, in Los Angeles, California. The gene fusions quantified in the test were first reported in 2005, he said.

Scores Correlate with Aggressiveness

The men in the study were patients at 3 academic medical centers and 7 community-based hospitals, and had specimens collected from 2006 to 2009.

In addition to helping predict the likelihood of prostate cancer, the urine test scores correlated with aggressiveness, as indicated by Gleason score. Only 7% of men in the low-score group had an aggressive tumor (Gleason score above 6), compared with 20% in the intermediate-score group and 40% in the high-score group. The difference between the low- and high-score groups was significant (P < .001).

The researchers also found that, of the 966 men with enough information to determine the Epstein criteria for significance of cancer on biopsy, 15%, 33%, and 61% of men in the 3 groups, respectively, had Epstein-criteria-defined significant cancer.

The researchers also compared the TMPRSS2:ERG + PCA3 score with Prostate Cancer Prevention Trial (PCPT) risk calculator, a commonly used online tool.

"Calculated PCPT risks of cancer (or Gleason score >6 cancer) differed markedly from the actual risks observed in the lowest and highest TMPRSS2:ERG + PCA3 score groups of men," they write.

For instance, almost all of the men (90%) of PCPT-evaluable men in the highestTMPRSS2:ERG + PCA3 score group had PCPT risk scores less than their actual risk of cancer on biopsy, they say.

The combined TMPRSS2:ERG and PCA3 test is not yet available as a prostate cancer screening tool. The Michigan Center for Translational Pathology is working with Gen-Probe Inc., which has licensed the technology, to develop the testing strategy. The University of Michigan hopes to offer it to patients within the year, according to the press statement.

The study was funded by Gen-Probe Inc., the Early Detection Research Network, National Institutes of Health, Prostate Cancer Foundation, Burroughs Wellcome Fund, Doris Duke Foundation, and the Howard Hughes Medical Institute. Dr. Chinnaiyan reports serving as a consultant to Gen-Probe. Coauthor Yves Fradet, MD, from University of Laval Cancer Research Centre, in Québec City, Quebec, is cofounder of Diagnocure, which licensed diagnostic rights to the PCA3 gene to Gen-Probe.

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