Urine Biomarker Tests for Prostate Cancer: Part 1
The need for better markers and testing pre-biopsy for indicating the existence of prostate cancer and also (perhaps more importantly) clinically-significant prostate cancer has been evident for some time. For well over 30 years the prostate-specific antigen (PSA) test along with the digital rectal exam (DRE) has been the first-line screening for potential prostate cancer (PCa) and the primary determinant in a recommendation to move on to a biopsy.
The realities of the PSA test
Make no mistake, PSA testing absolutely revolutionized PCa screening and treatment, but pretty much anyone reading this is aware of the controversies surrounding the PSA. I’m not going to rehash all of them in detail here, but a majority of the problems revolve around the fact that PSA is specific to prostate tissue, not cancer. It shows up regardless of the existence of cancer and can become elevated from other conditions, such as prostatitis and benign prostate hyperplasia. In addition, it does absolutely nothing in relation to determining the grade of any existing cancer.
The PSA test, thus, draws a lot of heat for potentially leading to overdiagnosis, overtreatment, and unnecessary procedures. Roughly 70% of biopsies do not detect prostate cancer and, in addition, biopsies may detect indolent (when scientists use this they mean slow growing -- I know, it would be too easy just to say slow-growing or just plain lazy) tumors leading to unnecessary treatment of low-grade cancer.1
Promising urine-based tests offer possible solutions
To avoid these problems, while still enabling men with significant prostate cancer to get an accurate diagnosis and the early treatment needed for the best possible results, it is necessary for the development and utilization of new biomarker tests for better detection of high-grade PCa.
The goal over these next couple of articles is to look at existing and promising urine-based tests designed with these goals in mind. There are other biomarker tests, such as serum (when experts say this, they mean blood) and tissue, but I’m focusing on urine-based tests here due to the fact that they are non-invasive, easy to repeat, tend to be less expensive, and because, frankly, I can’t cover every potential type of test at once.
Role of biomarkers found in urine
Over the last decade, there has been a lot of research developing PCa risk-assessment tests derived from biomarkers found in urine. The biomarkers have their strengths and weaknesses, which we shall examine. In addition, there are tests that combine biomarkers in an attempt to further refine the prediction of clinically significant disease. These tests could and should be useful tools in evaluating men for PCa and guiding treatment.
The reality, however, is that to this point urinary biomarker testing is not widespread, with many patients having no idea this is an option or that these tests even exist. I’ll also offer some thoughts on what needs to change to bring these tests more into the fore of PCa evaluation.
The first urine test for a specific prostate cancer gene and possibly still the best known is for the prostate cancer antigen or PCA3 gene. It was developed all the way back in 2008. At the time research stated that “[A] specific marker for early prostate cancer would fill an important void” and went on with praise that [I]n initial evaluations of the prostate cancer antigen 3 (PCA3) gene vis-à-vis serum prostate-specific antigen (PSA) levels, the gene offers great promise.”2
So, what exactly is the PCA3 test, and what has kept it from widespread use? The test received FDA approval in 2012 and was originally for use on men who had a negative biopsy, but a high PSA and were considering getting retested.3 PCA3 is prostate-specific and is useful in detecting PCa because it is highly overexpressed in the cancer relative to normal prostate tissue and is present in up to 95% of PCa -- translation: you find this in the urine it is very likely there is cancer.4
There are limitations and problems with the PCA3 test. First, it is diagnostic and not prognostic. It can help with determining the existence of cancer, but not the grade. In addition, there is controversy surrounding at exactly what level the cutoff should be for ruling out a repeat biopsy. A PCA3 score is determined using found levels of PCA3 and PSA, but different experts disagree on what score justifies another invasive biopsy or put another way, who wants to risk their life that the score is low enough to rule it out. Another problem is that once treatment has begun PCA3 levels can be affected by androgen deprivation therapy, making it fairly useless in monitoring the clinical course of the disease.5 Finally, the PCA3 test must be done in conjunction with a DRE. Besides introducing an invasive element, without a DRE results are valid at only 80%, but it is thought that number can jump up to 98% with the DRE.6 Of course, this assumes the proper level of additional prostate massage, which is another source of uncertainty.
Another stand alone/single purpose urine test (like PCA3) for PCA is the TMPRSS2:ERG. The fusion of these two genes is a highly-specific PCa biomarker found in at least 50% of PCa cases. Originally testing for it was expensive, required specialized equipment, and had a long processing time, however, a rapid, low-cost, naked-eye detectable urine test was developed. At the time of its development it was considered the most specific PCa biomarker because it is associated with premalignant PCa, but not benign conditions.7
One of the prime drawbacks of TMPRSS2:ERG is pretty self-evident in the above paragraph -- 50% presence of the biomarker isn’t all that impressive (how many men are going to bet their life on that number). For this reason, it is sometimes combined with the PCA3. The TMPRSS2:ERG is highly specific and the PCA3 is highly sensitive. However, it suffers from some of the same problems as the PCA3 test. Like PCA3, it does not determine grade. Some studies have found evidence that the presence of TMPRSS2:ERG in PCa corresponded with a worse diagnosis, but other studies failed to find clinical significance. In addition, the presence of TMPRSS2:ERG varies widely by ethnicity -- as high as 50% in the western nations and as low as 11% in China. Finally, it seems to suffer from the same issue as PCA3 in regards to androgen deprivation therapy, leaving it ineffective for use once treatment has begun.8
Where does this leave urine-based tests?
Even with these drawbacks, both of these tests offer better diagnostic potential than the PSA test alone. So, it remains unclear as to why they have not been utilized to a greater degree to give better indications for when a biopsy is necessary.
O.K., this article is long -- hope you are still with me and see you in Part 2. In Part 2 I will look at a further refinement of diagnostics and urine biomarker tests that have demonstrated prognostic ability to determine the severity or lack thereof for PCa. This ability further enables the elimination of unnecessary, invasive procedures and overtreatment, while allowing for the focus on high-grade PCa.
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