Urine Biomarker Test More Accurate in Detecting Prostate Cancer Than PSA

Roxanne Nelson

February 07, 2008

February 7, 2008 — Novel urine biomarker tests can detect prostate cancer more accurately than other currently available screening methods, researchers report. Results of a study published in the February 1 issue of Cancer Research show that combining biomarkers can improve testing characteristics. The novel, multiplexed, urine-based diagnostic test for prostate cancer had a positive predictive value of 79.8% and a negative predictive value of 60.8%.

The test outperformed serum prostate-specific antigen (PSA) and prostate cancer antigen 3 (PCA3), which is a prostate-cancer-specific gene and a promising marker for the early diagnosis of prostate cancer.

"These biomarkers help detect prostate cancer relative to benign enlargement or inflammation in the prostate, which is extremely common," explained lead author Arul M. Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology, University of Michigan, in Ann Arbor.

The PSA serum level is currently considered the standard of care for prostate cancer screening in the United States. However, although PSA screening has significantly increased the detection of prostate cancer, the test has many drawbacks. PSA levels are often elevated in men with benign conditions, and it has poor specificity for prostate malignancies. Therefore, there is a need for other biomarkers with better specificity and sensitivity.

"In the beginning, a urine biomarker combination test would be used to supplement PSA," Dr. Chinnaiyan told Medscape Oncology. "But in the future, we would expect that this test, or a test like it, will replace PSA."

Dr. Chinnaiyan and colleagues obtained urine samples from 276 patients with elevated PSA levels after a digital rectal exam and before undergoing either needle biopsy (n=216) or radical prostatectomy (n=60). Of this group, there were 111 biopsy-negative patients and 165 patients with prostate cancer (105 biopsy-positive patients and 60 prostatectomy patients).

In a final cohort of 138 patients with prostate cancer and 96 with negative needle biopsies, the researchers measured the expression of 7 putative prostate cancer biomarkers, including PCA3, in sedimented urine using quantitative polymerase chain reaction (qPCR). The goal was to develop a multiplexed qPCR-based test for prostate cancer.

Previously, Dr. Chinnaiyan and colleagues identified the prostate-specific gene called TMPRSS2, which fuses with either ERG or ETV1, 2 genes that are known to be involved in several other types of malignancies. Last year, another 5 genes were identified that also fuse to ERG or ETV1 to cause prostate cancer. In this study, the researchers added 6 more biomarkers to the PCA3 test, including TMPRSS2:ERG, along with other molecules known to be overexpressed in prostate cancer.

After univariate analysis, they found that, of the 7 biomarkers, increased GOLPH2, SPINK1, and PCA3 transcript expression and TMPRSS2:ERG fusion status were significant predictors of prostate cancer. Of the 7 markers initially selected for review, only PCA3 had been previously reported as a diagnostic biomarker.

The panel of 4 biomarkers (GOLPH2, SPINK1, and PCA3 transcript expression, and TMPRSS2:ERG) showed a sensitivity of 65.9% and a specificity of 76% in identifying men with prostate cancer. The positive and negative predictive values of the multiplexed model were 79.8% and 60.8%.

The authors also note that last year another study demonstrated that a combined test for PCA3 and TMPRSS2:ERG expression in urine, using alternative diagnostic assays, outperformed serum PSA and PCA3 alone for the detection of prostate cancer.

"This study represents a first-generation combination urine biomarker test for prostate cancer," said Dr. Chinnaiyan. "There is still room for improvement by adding additional markers."

Only PCA3 is currently available as a diagnostic test that physicians can order for their patients. "The other 3 markers in the test, including the gene fusions, have been licensed from the University of Michigan to the same company that developed the PCA3 test, and this should facilitate the introduction of these additional urine marker tests within a year or 2," he added.

However, Dr. Chinnaiyan cautioned that these studies are preliminary and need further confirmation on additional patients at other medical institutions.

The study was funded by the Early Detection Research Network, Department of Defense, the National Institutes of Health, the Prostate Cancer Foundation, and Gen-Probe Incorporated of San Diego. The gene-fusion technology has been patented by the University of Michigan and licensed to Gen-Probe Inc, which is also developing the PCA3 screening test. Dr. Chinnaiyan is a paid consultant to Gen-Probe.

Cancer Res. 2008; 68:645-649. Abstract

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