New biomarkers address key aspects of prostate Ca management

New biomarkers for prostate cancer are showing great promise for addressing the limitations of existing diagnostic and prognostic tools, according to opinion leaders who spoke on this topic at the Large Urology Group Practice Association annual meeting in Chicago.

The new laboratory tools can be divided into three categories according to whether their results can help guide decisions on who to biopsy, who to re-biopsy, or how to treat biopsy-confirmed disease. As such, they should reduce unnecessary biopsies and over-treatment while optimizing care for men with more aggressive disease.

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“The availability of these biomarkers that can help direct physician recommendations and patient choices has brought us into an exciting era of prostate cancer management, especially for localized disease,” said E. David Crawford, MD, of the University of Colorado, Denver.

Deciding when to biopsy

Dr. Crawford highlighted two new tests that can be used in deciding when to biopsy: the prostate health index (phi) and the 4Kscore test.

The FDA-approved phi test for prostate cancer (Beckman Coulter, Brea, CA) combines data from total PSA, free PSA, and [-2] proPSA in a mathematical formula that generates a score used to estimate the probability of finding prostate cancer on biopsy. For example, for men with a PSA between 2.0 and 10.0 ng/mL, the probability of prostate cancer is 11% if the phi score is <25 and 52% if it is ≥55.0. Higher phi score is also associated with more aggressive disease.

The 4Kscore test (OPKO Health, Miami) is on the horizon, although commercially available. It combines plasma levels of total PSA, intact PSA, free PSA, and hK2PSA with clinical data (age, DRE status, and prior biopsy status) in an algorithm that generates the patient’s risk of having high-grade prostate cancer across the range from <1% to 95%.

“This test is not perfect, but in the validation studies, the cancers that were missed were usually low grade and probably shouldn’t have been treated anyway,” said Dr. Crawford.

Next: Deciding when to re-biopsy

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Deciding when to re-biopsy

Alan W. Partin, MD, PhD, reviewed two new commercially available tests that may be useful for early prostate cancer detection in men with an initial negative biopsy: Prostate Cancer Antigen 3 (PCA3) and ConfirmMDx.

“An initial biopsy for prostate cancer is histologically negative in three out of four men who undergo the procedure in the United States. Population-wise, that translates into hundreds of thousands of men having to decide the next year whether to be checked again, and the numbers of men facing this situation will only be increasing because of population aging,” said Dr. Partin, of the Brady Urological Institute at Johns Hopkins Hospital, Baltimore. “Elevated PSA rarely resolves, but now there are additional options that should be helpful in making those decisions and reducing the number of unnecessary biopsies.”

PCA3 (Hologic, Bedford, MA) is an FDA-approved urinary assay for the mRNA of this noncoding gene that is highly overexpressed in prostate cancer. Results of a study conducted by Dr. Partin and colleagues in the Early Detection Research Network GU Group showed that when the test had a high value (>60), there was a high positive predictive value and when the test’s value was low (<20), there was a high negative predictive value.

“PCA3 may particularly be considered as an additional test to run when a patient returns for annual follow-up after an initial negative biopsy,” Dr. Partin said.

ConfirmMDx (MDxHealth, Irvine, CA) is a newer epigenetic test that is now widely available through CLIA testing. Addressing the possibility that sampling error underlies a false negative biopsy result, the test analyzes biopsy tissue for prostate cancer-associated DNA methylation changes in three genes. The first study assessing its ability to predict outcome of repeat biopsy after an initial negative result showed that it had a negative predictive value of 90% and outperformed standard clinical risk factors. A validation study yielded similar results.

Dr. Partin said that this test might be particularly appropriate for men with a previous negative biopsy, but clinical risk factors suggesting a high risk for undetected malignancy and being considered for repeat biopsy. Both the phi can be considered in this patient population as well.

Guiding treatment decisions

Peter Carroll, MD, MPH, summarized new genomic tests for determining risk in men with newly diagnosed prostate cancer. However, he prefaced his discussion with a plea for urologists to be considering the information already in hand before ordering any of these novel modalities.

“Existing risk calculators incorporating standard clinical and pathologic data do a pretty good job, but they are being underutilized,” said Dr. Carroll, of the University of California, San Francisco. “Genomic classifiers add information to what is known about risk; they don’t replace it.”

As of the end of October 2014, there are three commercially available genomic tests that can be used to guide management of men with prostate cancer: Prolaris (Myriad Genetics, Salt Lake City), Oncotype DX (Genomic Health, Redwood City, CA), and Decipher (Genome Dx, San Diego). Dr. Carroll said that there is a growing sense that both Prolaris and Oncotype DX are most appropriate as an additional test to reinforce decisions on active surveillance, particularly in men considered good candidates.

“Concern that the patient is harboring worse disease than was detected in the biopsy is a barrier to surveillance. The findings from either of those genomic classifiers may increase the confidence of both patients and providers about choosing or not choosing active surveillance,” Dr. Carroll said.

These same two tests may also be used to refine management decisions for men who appear to be good candidates for surveillance, albeit not perfect. Typically, these are patients for whom surveillance appears appropriate based on PSA, T stage, and cancer grade, but who have small-volume, secondary pattern Gleason 4 disease.

Dr. Carroll said there is also evidence that both Prolaris and Oncotype can predict recurrence after surgery. However, Decipher is being marketed and shows promise as a tool to guide decisions on adjuvant radiation therapy.

He also mentioned that more tests for risk stratification are on the horizon, including circulating DNA, microRNA, urinary exosomes, and multiparametric MRI, although their performance is yet to be validated.

“Ultimately, I think these genomic classifiers may all be telling us a lot about cancers in general and refining risk, although they may be utilized in different patient populations,” Dr. Carroll said.

Dr. Crawford is an adviser to and a speaker for Genomic Health, MDxHealth, and Myriad Genetics. Dr. Carroll has received grants or research support from Genomic Health.

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