Urine Biomarker Tests for Prostate Cancer: Part 2

In Part I of this article, I looked at the need for non-invasive biomarker testing to reduce unnecessary, invasive biopsies, as well as overdiagnosis and overtreatment. In addition, I looked at a couple of urinary marker tests (PCA3 and TMPRSS2:ERG), which offer increased diagnostic capabilities over the PSA test alone.

In this part I will examine one additional diagnostic test that even further refines prostate cancer (PCa) prediction and urinary tests that go beyond the diagnostic, to include the prognostic ability to stratify risk. Finally, I will look at why these biomarker tests are underutilized and what can be done to bring these useful tools into the standard of care for PCa.

MiPS

Some of the most successful urine tests for both identifying PCa and severity utilize combinations of markers. The first major test along these lines is the Michigan Prostate Score or MiPS, developed in 2013. The announcement for the test states it “[I]ncorporates blood PSA levels and two molecular RNA markers specific for prostate cancer in one final score that provides men and their doctors with a personalized prostate-cancer risk assessment.”1 MiPS combines PCA3 and TMPRSS2:ERG, along with the PSA to improve the ability to assess PCa risk pre-biopsy.

Research has found it to be better at predicting the existence of PCa than PCA3+PSA or TMPRSS2:ERG+PSA and that MiPS substantially reduced unnecessary biopsies, “while only delaying the diagnosis of 1–2.3% of clinically significant PCa.”2

SchLAP1

SchLAP1 is a long noncoding RNA (just means that it is a type of RNA—you really don’t want the full explanation) “that is overexpressed in a subset of prostate cancers. SChLAP1 levels independently predict poor outcomes, including metastasis and prostate cancer-specific mortality.”3 Researchers focused specifically on aggressive cancers, seeking the RNA associated with it and discovered two particular outliers. Of the two, they found one, in particular, expressed in higher levels in prostate cell lines and called the gene Second Chromosome Locus Associated with Prostate-1 or SChLAP1.4 Additional research found that high levels of SchLAP1 were associated with increasing Gleason score and to be useful in predicting metastasis would occur within 10 years.5

So now, instead of the urinary biomarker test simply indicating the existence of cancer, it is prognosticating more aggressive disease. All of this is extremely useful information for guiding decisions not only on biopsies but also on overall treatment. Yet, in spite of SchLAP1 being discovered in 2013, there is no commercial test currently available.

ExoDX

ExoDX Prostate Intelliscore or EPI is a urinary test that combines biomarkers, like MiPS, but moves into the realm of prognosticating cancer severity. It combines TMPRSS2:ERG, PCA3, and SPDEF (known to express in men with a Gleason score of 7 or above6).

It was granted FDA Breakthrough Device Designation in June 2019. One study found that 27% of biopsies could be avoided and a 92% sensitivity at finding PCa grade 7 or above.7 Another randomized, blinded, two-armed clinical utility study (in layperson's terms -- looking at how it would operate in the real world) found a 30% jump in detecting high-grade PCa and that 68% of urologists report that the test influenced their decision on recommending a biopsy.8

Clearly, this test can make a difference in avoiding unnecessary biopsies and overtreatment, while guiding treatment for potentially aggressive PCa. Hopefully, Breakthrough Designation and studies showing the utility to urologists in the real world will lead to increased utilization.

PUR

Finally, the Prostate Urine Risk or PUR test is one of the newest urinary biomarker tests. Developed by researchers at the University of East Anglia and the Norfolk and Norwich University Hospital (both in England), PUR utilizes a combination of 35 different genes to produce risk signatures. According to their announcing press release “this new test uses four PUR signatures to provide a simultaneous assessment of non-cancerous tissue and risk groups (low, intermediate, and high-risk) to show how aggressive the cancer is.” They also claim that it can predict who will require treatment up to five years earlier than current standard methods. The test not only predicts high-grade cancer but also whether those on active surveillance would require treatment.9

One of the interesting things about the PUR test is that it can be done at home. In fact, the researchers discovered that testing with the first urine of the day yields better results than a sample taken after a DRE in the doctor’s office and without the problems that can be associated with this method I discussed with the PCA3 test in Part 1. PUR was originally done post-DRE, but one of the lead researchers, Dr. Jeremy Clark states: “We found that the urine samples taken at home showed the biomarkers for prostate cancer much more clearly than after a rectal examination,” explains Dr. Clark, “And feedback from the participants showed that the at-home test was preferable.”10

One of the lead researchers on PUR notes that there are other urine tests for diagnosing prostate cancer, but that none are widely used.11 This brings us to the question of why urinary biomarker testing is not more widely implemented and becoming part of the standard of care. I want to stress that these articles are not a complete listing of urinary biomarker tests (I can think of another right off, SelectMDx, which can help with diagnosis and shows promise for predicting aggressive cancer, however, I found conflicting research and didn’t want to misstate capabilities), but rather an exposition of some of the best researched and showing the most promise at this point.

The gap between biomarker discovery and validation

The research is important. As one recent article on the utility of liquid biomarker tests states: “In our opinion, the most critical step before implementing novel liquid biomarkers in routine patient care is the validation of the assays. Quality management and reproducibility must be determined prior to clinical use.”12 They note the gap between biomarker discovery and validation.

This raises an interesting problem -- urinary tests are designed to be less invasive and, perhaps more importantly, less expensive. The authors write “the use of biomarkers aims to categorize patients, steer clinical decision making, and prevent overtreatment. This brings forth the question: will the infrastructure used for drug marketing be accessible for liquid biomarker validation?”13

Will urinary biomarkers get a fair chance?

This isn’t me being this skeptical. This is other scientists wondering if urinary biomarkers will get a fair shake since they do not look to be big moneymakers. The problem with the research on the efficacy of taking the PUR test at home is that it only involved 14 subjects. Hopefully, the resources will be available to do the extensive validation necessary for a marketable product.

There is a bit of a catch-22. Urinary biomarkers display great promise for reducing unnecessary biopsies, overdiagnosis, and overtreatment, yet often lack extensive validation studies. Doctors are, thus, reluctant to recommend a test they see as unproven when the price of recommending no biopsy or treatment could be a patient’s life. That said, considering the non-invasive nature of the tests and low expense, it would seem combining them with existing protocols would give patient’s valuable additional information to guide decision making.

We must look ahead to new opportunities

To end on a high note, I’ll give the last word to the researchers: “Nonetheless, we must emphasize the opportunities and promising outlook for clinical use of liquid biomarkers in PCa...platforms have demonstrated the potency to outperform sPSA in diagnostic and prognostic settings. Hence it is time to implement the next generation of liquid biomarkers in clinical practice.”14

Read Urine Biomarker Tests for Prostate Cancer: Part 1.

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