A brief commentary on how clinical validity (CV) and clinical utility (CU) are measured for pre-biopsy biomarker tests in patients suspected of having prostate cancer, followed by a focused discussion on the available tests in the space.
Dr. Gerald Andriole: I think the 4Kscore is, I think, the best of the available biomarkers, and I say that just because I think it has a lot of informative data points inserted in the process of deriving the score. So, in addition to PSA, there's three other kallikrein markers, and that's why it's referred to as the 4Kscore. One also inputs the patient age, one also inputs the findings of the digital rectal exam, one also inputs the presence of a previous negative biopsy into the algorithm that helps generate the score. And to me for that biomarker, it utilizes a lot of clinically meaningful information to derive the estimate of that individual man's risk for prostate cancer. Now some of these other markers rely on just one or two [00:12:00] genes, gene products or other analytes and it just seems from a conceptual point of view that the more information you put into your model, the more accurate and the better your outcome will be. So, I tend to reflex to the 4Kscore, unless a patient isn't eligible for it, either because of age, or because of the magnitude of PSA elevation, or because of the use of bivalve reductase inhibitors. And also, I think blood tests are for most patients, or more patients, preferable than urinary-based tests, especially urinary-based tests that require a digital rectal exam. Patients really don't like having repeated digital rectal exams of the prostate. So, for all of those reasons, that's why the 4Kscore has become my first choice among the biomarkers. But having said that, the urinary markers and the other blood-based markers also have pretty reasonable performance characteristics; sensitivities and negative predictive value, as we were discussing before. And it's important to point out that these family of biomarkers have never been adequately compared one against the other. So, my preference is based on my analysis and view of the data; other people could look at it another way and choose a different marker.
On the blood testing side, there is the PHI, the Prostate Health Index, that looks at three markers in the blood. And there's also IsoPSA, which looks at, if I'm phrasing it properly, the geometric shape of PSA in the blood. And these perform better than PSA alone and are approved, or at least recommended, in the NCCN guidelines. I know PHI is, actually, IsoPSA may not be at this point because of data. The urinary tests, the ExoDX and the urinary SelectMDX test, as well as the PCA3 version of the test can also be useful, but most of them require a prior digital rectal exam.
Among all of the biomarkers that are available, some have been studied, usually in patients who had a previous negative biopsy; some have only been studied in biopsy naive patients; some have been studied in both populations of patients; and that would be the most useful markers are those that, in which we have data both in the biopsy naive population as well as the previous negative biopsy population. So there's a certain preference based on that. The patients who take bivalve reductase inhibitors, we’ll all the PSA-based markers would be perturbed by the use of a bivalve reductase inhibitor, such as finasteride or dutasteride; Another important thing from my point of view that I mentioned earlier, is the number of data inputs, to me, relying on multiple sources of data, which suggests to me that an assay that uses more data points is going to be better in the end than an assay that relies on just one or two or three analytes. And so that's one of the reasons that I like the 4Kscore because it inputs four biomarkers, the age of the patient, the rectal exam finding, and the clinical history of a prior or not previous negative biopsies. Other considerations are the preference for urinary versus blood. I think most American men are happiest to have a blood test that can be added to other annual blood tests that they may be having. The urinary tests are a little less desirable for many men, particularly those that require a digital rectal exam prior to providing the specimen. So those are the considerations that generally I have used and many practitioners use in selecting the optimum biomarker.