Judd W. Moul, MD

Patient Case: A 64-Year-Old Man with Elevated PSA Levels

A 64-year-old-man underwent PSA testing during his annual physical with his primary care physician; PSA was 5.6 ng/mL and PSA density was 0.16.

He then saw a urologist, who ordered a multiparametric MRI; result was PI-RADS 4.

The patient was reluctant to undergo a prostate fusion biopsy, therefore the patient’s urologist recommended that he undergo exosome-based molecular testing to help determine risk of prostate cancer; his test score was 16.3.

The patient and urologist remained concerned about his PI-RADS 4 MRI score. The urologist also noted that the PSA density of 0.16 was slightly above the threshold of 0.1.

The patient elected to undergo TRUS-guided biopsy, which was negative for prostate cancer.

 The unmet needs in prostate cancer screening, since we’ve been talking mainly about screening and biomarkers, I think the biggest unmet need is trying to encourage the United States Preventive Services Task Force to change their recommendations on screening for prostate cancer. Currently, they have a guideline letter of C, which means that the primary care doctor should mention the PSA [prostate-specific antigen test], but not necessarily recommend the PSA and just talk about it, the pros, and cons, and let the patient ultimately decide if he wants to be screened. But we’ve seen the death rates from prostate cancer go up in light of the lack of screening. I would certainly like to see the guideline change to a B rating, I don’t think they’ll go to an A, but I would like them to change it to a B, where the benefit outweighs the harm.

Beyond that, we have to change men’s behavior. There are still too many men who just don’t go to the doctor no matter what the guideline is, or even if they have an elevated PSA, they don’t show up for their follow-up visit with their urologist or don’t show up for their biopsy. We see that a lot in our practice, sadly. Those are unmet needs. Then for the patient who’s compliant and comes in and gets his PSA test, we need to get more data to fine-tune how we use these secondary tests, where we employ the MRI, and which type of biopsy ultimately is the best type. Another final unmet need is the fact that even if we use MRI, the consistency around the country needs to be improved. The quality assurance continues to need to be improved because the quality of these MRIs does vary depending on whether it’s done in an academic institution or in a more private practice setting. It’s variable, so that needs to get better.

Obviously, MRI has had the biggest impact over the last several years, as far as imaging. I think there are going to be more biomarkers coming to market, potentially other blood markers and urine markers, which will be coming to fruition in the next decade. As far as imaging, there are 2 fields that might change the picture. One is, there are developments with regard to prostate ultrasound, a more accurate ultrasound, which could potentially replace the MRI fusion biopsy in the future, meaning as the prostate ultrasound gets better, it might eliminate the need for an MRI. That’s something that’s on the horizon. Then PET [positron emission tomography] scanning, using tracers to visualize prostate cancer using nuclear medicine technologies, that’s an exploding field. And it’s possible that over the next decade or the next 2 decades, as that technology improves, I could see a day where we can employ PET scanning specifically focused on the prostate, maybe combined with a more accurate ultrasound, or even a more accurate MRI, to further increase the accuracy of that initial prostate biopsy. It’s an exciting time, and we could see further advances that could change the field over the next 10 to 20 years.

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Judd W. Moul, MD, FACS, wraps up by discussing remaining unmet needs and potential future improvements in imaging modalities for prostate cancer screening. 

Remaining Unmet Needs and Future Directions in Prostate Cancer Screening

 It’s interesting, this particular patient, he did have a borderline exosomal test. And so, in general, I probably would’ve reassured him and probably would’ve not recommended a biopsy in that particular case. However, again, by the letter of the law, and if you follow the guidelines of the test the way it’s been published and the way it’s marketed, he did have an abnormal exosome test and did go on to receive a biopsy. In this case, he had a negative prostate biopsy.

His other numbers were very borderline. What I would do in practice is recommend I see him back for a repeat examination in 12 months. Now, that repeat examination would include a digital rectal exam and a repeat PSA [prostate-specific antigen test]. In my practice, I would honestly probably do a Prostate Health Index test instead of a repeat PSA because that Prostate Health Index would give me a total PSA, it would give me a free PSA, and it would give me a Prostate Health Index score. That’s solely because, at my institution, we do the Prostate Health Index blood test in house. It’s just as easy for me to get that test as a total PSA. However, if a practice doesn’t have access to that, then I think it would be very reasonable for this particular patient to simply have him come back in 12 months for a digital rectal exam and a total PSA.

If that total PSA was “about the same,” in other words, there had been no significant rise, then I probably would not have ordered a repeat MRI, and I probably would not have ordered any other repeat molecular testing, such as exosome. However, if that 1-year follow-up, certainly if the PSA was greater than 2 points higher than it was when we did the initial biopsy, then I would be more concerned that we might have missed cancer or missed high-grade cancer. And then I would be more aggressive. His PSA was, looking back, it was 5.6 [ng/mL]. Let’s just say a year later, instead of 5.6 [ng/mL], it was 7.6 [ng/mL], 2 points higher. That would be a red flag that I might have missed cancer on the first biopsy. Then I would be more aggressive with repeating the MRI, or an exosomal test, or another repeat biopsy.

An expert urologic oncologist revisits a patient profile and discusses how he would have approached the patient’s prostate cancer screening process.

Recommended Management of the Profiled Patient

We are just coming out of a pandemic that lasted an excess of 2 years. COVID-19 has had a huge impact on all of us, including big changes in how we practice medicine. During the pandemic, patients were not able or not willing to necessarily come in for an in-person exam that would include a digital rectal exam. We did a lot of telehealth visits for patients who had an elevated PSA [prostate-specific antigen] and many times a borderline elevated PSA. Tests such as exosome [ExoDX] have really been helpful because No. 1, it could be done through mail order, and No. 2, it didn’t require a rectal exam. It was a secondary screening test or a biomarker test that I could employ for a patient who was having telehealth without having to have him come in for a rectal exam, and not even having to have him come in for a secondary blood test. What would happen is we would do the test. If the patient was fortunate to have a low value, then what I would typically do is reassure that patient and schedule him back for a follow-up in a year. Hopefully, now a year later, COVID-19 will be better, in-person visits will be safer and more doable. And that patient would be able to come in at that time and do his prostate exam, including a rectal exam.

The test is commercially marketed with an upper limit of normal of 15.6. I’m here to say that that is the gold standard, that’s what the validation studies used. However, in more simple practical terms, there are some clinicians who would keep it simpler and use a cut point of 20. That is, again, technically off-label because you’re changing the normal slightly. But if you increase it to 20, your negative predictive value is still about 90%. So you are sacrificing maybe a 1% or 2% risk of a Gleason 7 [score] if you increase the cut point to 20.

Judd W. Moul, MD, FACS, gives a real-world overview of how the exosome-based test is used in clinical practice.

Real-World Use of an Exosome-Based Urine Biomarker Test

 The ExoDx test has had a lot of validation and a lot of research done. It was validated in a large study that was published in 

, and then a number of subsequent validations including a large European study. When the company took those data to the FDA, the test was cleared and is commercially used for patients who have a total PSA [prostate-specific antigen] between 2 and 10 [ng/mL] in men who are 50 years of age or older. That is the labeled indication for the exosome test, men who have a total PSA between 2 and 10 [ng/mL] who are being screened for prostate cancer and are 50 years of age or older.

When we are talking about sensitivity and specificity, and negative predictive value and positive predictive value, it really becomes confusing, not only for us as clinicians, but for our patients and even for experienced clinicians and researchers.

In a general population in which you are using the exosome urine test, we expect about 20% to 25% of the patients to have a normal value, meaning they would have the exosome urine test come back less than 15.6, which is the upper limit of normal. Those men have a very low likelihood of having clinically important Gleason 7 [score] or higher prostate cancer. In fact, the negative predictive value was 92%, indicating that if you avoid a prostate biopsy in all those men who have a normal exosome test, you would only miss 8% who could have Gleason 7 or higher. Again, a 92% negative predictive value equates to an 8% risk of Gleason 7. That’s at least 20%, or pretty much of 1 out of 5 patients in your practice who would be referred to you with an elevated PSA where you could potentially avoid a biopsy. Or if you are not always using MRI, you could potentially avoid the MRI in those patients as well and reassure them, and perhaps see them back for a repeat test in 6 to 12 months as opposed to an immediate biopsy or immediate MRI.

An overview of the clinical validity and utility of a urine-based, exosomal molecular test for prostate cancer screening and risk assessment.

Judd W. Moul, MD

Articles

Remaining Unmet Needs and Future Directions in Prostate Cancer Screening

Recommended Management of the Profiled Patient

Real-World Use of an Exosome-Based Urine Biomarker Test

Clinical Validity and Utility of an Exosome-Based Urine Biomarker Test