By: Dan Sperling, MD

Prostate cancer expert Dr. Stacy Loeb rejects what she calls a “one size fits all” approach to PSA testing. Dr. Loeb (Assistant Professor of Urology and Population Health, NYU) writes, “The days of using one PSA threshold to trigger a biopsy for all men are over…” Since the PSA blood test is not specific for prostate cancer (PCa) countless men with suspicion of PCa have been subjected to avoidable biopsies. Dr. Loeb notes that new approaches to prostate biopsy decisions are increasingly individualized, based on more detailed information from tests like the Prostate Health Index (phi).

A recently published article on the newest biomarkers and genomic tests (Falzarano et al., 2015) provides an in-depth description of the nature, merits and limitations of current tests that are far more specific for prostate cancer. Novel molecular tests and algorithms can provide a foundation for knowing when a biopsy is necessary, and for improved matching of treatment to disease. While preserving the value of early detection, these tests can reduce the risk of over-treating indolent (latent) prostate cancer or under-treating potentially deadly aggressive disease. The authors describe a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic [disease] processes, or pharmacologic responses to a therapeutic intervention.” The following are among the recent advances in PCa-specific biomarker identification.

Prostate Health Index (phi)

The phi analysis is based on a blood serum test, as is conventional PSA testing, and it is favored by Dr. Loeb. It was developed by Beckman Coulter, Inc. in collaboration with the National Cancer Institute, and approved by the FDA in 2012. It uses a combination of total PSA (tPSA), free PSA (fPSA) and an isoform of PSA called [-2]proPSA or simply p2PSA. (MedicineNet defines isoform as “a protein that has the same function as another protein but which is encoded by a different gene and may have small differences in its sequence.”) Greater amounts of pPSA have been shown to be present in men with PCa than those with benign prostate conditions. By including the isoform in combination with tPSA and fPSA, the phi test has demonstrated greatest utility in men ages 50 and older with PSA value 4-10 ng/mL. According to the Falzarano article, two studies by Lazzeri et al. reported phi improved detection of Gleason >7 PCa.

4K Score

Another promising blood test called the 4K Score consists of tPSA, fPSA, intact PSA and human kallikrein-related peptide 2 (hK2). The blood test results are used in calculating a probability algorithm of finding high grade PCa on biopsy; included in the algorithm are the history of prior biopsy (or not), age, and digital rectal exam (DRE) results. In clinical tests it has been shown to improve specificity for detection of aggressive PCa and its validity is independent of patient age and clinical factors. The 4K Score can help avoid unnecessary biopsies, contribute to better patient outcomes, and reduce the costs associated with needless biopsies, over treatment, and managing the side effects of invasive procedures. Although not yet FDA-approved, in June 2015 the National Comprehensive Cancer Network recommended the 4K Score for use before a first biopsy or in men with a previously negative biopsy but with other suspicious factors as a way to predict the presence of aggressive PCa.

PCA3 Score

This is an FDA-approved urine-based analysis involving giving a urine sample following a DRE. The physical stimulation of the prostate gland during the DRE causes the release of a type of protein called Prostate Cancer Antigen 3 (PCA3 or DD3) that is specific to prostate tissue, and which is overexpressed by abnormal growth within prostate tissue, usually cancer. PCA3 quickly concentrates in urine, where it can be measured. It is not recommended before a first biopsy, only before a repeat biopsy. A limitation of PCA3 is that men with a potentially precancerous condition called prostatic intraepithelial neoplasia (high grade PIN) tend have results similar to those with insignificant PCa. This may be a promising test for men considering active surveillance, but more studies are needed.

Mi-Prostate Score or MiPS

The same urine sample for PCA3 can be used for an additional analysis of the presence of a biomarker called TMPRSS2-ERG gene fusion. This test was developed at the University of Michigan and is available from their health system for predictive use prior to biopsy. This gene fusion has been detected in about half of PSA-screened PCa, and may be associated with worse clinical outcomes. Including TMPRSS2-ERG fusion with PCA3 Score appears to improve the specificity in predicting PCa diagnosis.

Tissue-based Genomic Tests

The article’s authors caution that while these tests are commercially available, as of this writing they are not FDA approved, possible due to lack of extensive validation. There is also a concern that different laboratories would generate different results.

Confirm MDx – This analysis of prostate tissue obtained by biopsy investigates the effect that cancer development has on neighboring normal cells (field effect). During the process of “cancerization” the DNA of adjacent healthy cells is affected in a specific way. Evidence of that effect in healthy cells may point to the existence of cancer even if a biopsy needle missed the tumor. It has a high negative value (if it says there’s no cancer, there’s probably no cancer) and can detect latent disease. It does not discriminate between aggressive and indolent cancer.

Oncotype DX® – Also based on biopsy tissue samples, this assay tests for 17 genes (12 cancer genes and 5 reference genes). The specific cancer genes have a distinct “fingerprint” associated with the onset, growth and proliferation of prostate tumors. Results are presented as a Genomic Prostate Score (GPS) ranging from 0 to 100, with higher scores indicating more dangerous cancer. While there have been some inconsistencies in terms of the genes identified, its merits lie in the fact that even very small tissue samples can provide enough information to distinguish significant from insignificant disease, thus helping determine treatment strategies.

Prolaris® – Using tissue from biopsy, Prolaris (also called CCP score) is an RNA expression-based assay of 46 genes (31 cell cycle progression and 15 housekeeping genes). It is designed to evaluate the aggressive potential of an individual’s PCa with the intent of matching treatment to the level of threat. Low-risk patients may decide on a strategy of surveillance and monitoring; when the test is performed on tissue from a post-prostatectomy specimen, it can help predict the risk of recurrence and whether a post-surgical course of radiation might be needed.

Research and development of other laboratory tests on blood, urine or tissue is ongoing. The challenge is to create a test that is noninvasive, inexpensive, highly specific for prostate cancer, and available for broad use. The tests described above have already changed the way information can be gathered to determine the need for a biopsy.

As an adjunct to biomarkers, multiparametric MRI (mpMRI) of the prostate is changing the landscape of PCa detection. Given the growing availability of powerful 3T (3 Tesla) magnets, and the number of experienced radiological readers, imaging is able to rule the need for a biopsy in or out because mpMRI has increasingly demonstrated the ability to detect the size, shape and location of significant cancer. If a biopsy proves necessary, mpMRI can guide a precise targeted biopsy to capture tissue for genomic analysis. Biomarkers, together with mpMRI, could prove to be the ideal diagnostic pathway, offering the richest aggregate of clinical information for decision-making.

Loeb S. Prostate Biopsy Decisions: One Size Fits All Approach with Total PSA is Out and a Multivariable Approach with the Prostate Health Index is In. BJU Int. 2015 Jun 5. doi: 10.1111/bju.13195. [Epub ahead of print]

Falzarano SM, Ferro M, Bollito C et al. Novel biomarkers and genomic tests in prostate cancer: a critical analysis. Minerva Urol Nefrol 2015;67:211-31.

Ibid., p. 212.

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