David Albala, MD

Screening helps to determine whether a full histopathological examination of prostate biopsy should be performed to diagnose prostate cancer. Although blood-based prostate-specific antigen (PSA) tests help clinicians to determine the need for this invasive tissue testing, PSA tests can give false-positive results that can result in unnecessary testing, treatment, and treatment complications.

 New liquid biomarker–based tests can provide additional information and help circumvent these unnecessary outcomes.

 program, 2 specialists discussed the need for risk assessment tools and the role of new liquid tests in early detection of prostate cancer: David Albala, MD, chief of urology at Crouse Hospital and medical director for Associated Medical Professionals in Syracuse, New York; and Judd W. Moul, MD, urological oncologist at the Duke Cancer Center in Durham, North Carolina. This article summarizes the key takeaways from that conversation.

US PREVALENCE OF PROSTATE CANCER AND PSA-TEST SCREENING

According to Moul, the US incidence of prostate cancer has dropped to about 200,000 cases per year compared with 330,000 cases annually over the past 15 to 20 years. Previously the US Preventive Services Task Force gave PSA-test screening a low rating, but Moul said that more primary care physicians are reembracing PSA-test screening.

Albala added that when PSA testing was first introduced, the US incidence of prostate cancer was about 1 in 6 or 7 men. “But we saw a drop in the [number of] patients [with metastatic disease] who we were seeing,” noted Albala. “I remember when I was at the [Veterans Health Administration], we’d see many of these [patients with meta-static disease] come in, and the PSA era really changed that.”

Although PSA-test screening does need to be refined, it should continue because it is an effective basic screening, Moul said, with secondary tests often used to “fine-tune” decisions before completing a biopsy. Albala added that urologists do recognize that the PSA test has limitations, as it is not cancer specific. The wide criticism of PSA-test screening may have been derived from how the medical field used the information generated by the test, Moul said. Indeed, PSA testing does not match the accuracy of tissue-based biopsy testing and is not recommended for diagnosis.

 However, as high PSA levels may indicate meta-static disease, PSA screening can help catch metastatic prostate cancer. Albala echoed Moul’s advocacy of PSA testing as a significant contributor to detecting prostate cancer; it has been used in various ways, he said, in testing free-to-total PSA ratios, PSA velocity, and PSA density in patients.

“Back when I [was] in training, 1 in 5 men [who presented with prostate cancer] typically presented with metastatic disease. And then in the PSA era, that dropped to 2% or 3%, meaning that only 2% to 3% of guys presenting with pros-tate cancer had [metastases],” Moul explained.

USE OF NOVEL LIQUID BIOMARKER TESTS IN PROSTATE CANCER SCREENING

Numerous next-generation tests to screen for pros-tate cancer have become commercially available, said Albala, including blood-based (eg, Prostate Health Index [PHI], 4Kscore) and urine-based tests (eg, Exosome, SelectMDx, PCA3).

When doing an Exosome test, practitioners do not need to complete a rectal exam, Moul explained, whereas with a PCA3 test, an attentive digital rectal exam must be done before the urine test. In completing the Exosome test, patients void urine through a special device; previously, this would be done in house, but as tests by mail have become available, patients are now able to collect the urine sample at home, return it through the mail, and receive results within a week. Regarding blood testing, Moul said that he has more experience with the PHI than other tests; the PHI predicts the likelihood of cancer in 4 risk groups: low, low-intermediate, intermediate, and high. Crucially, however, the Exosome test does not predict cancer or no cancer but rather the probability of Gleason 7 or higher. Moul believes that PHI and Exosome are somewhat complementary to one another.

Albala said that when most patients arrive at his clinic, they need to leave a urine sample, and it is often difficult to produce a second sample during the same visit. He has been using the Exosome test because patients can complete their second sample at home, but the Exosome and SelectMDx urine tests are comparable, Albala believes. With the SelectMDx test, a rectal massage is not necessary. Because urine tests predict prostate cancer slightly more accurately than do blood tests, Albala’s institution has pivoted more toward urine testing. “When a new test comes out, I look at the efficacy, cost, [adverse] effect profile, the ease of doing the test, and then the durability. I always think of those 5 things—whether it’s a new drug, a new procedure, or whatever—in the back of my head to try to put these tests in perspective because when new tests come out, there’s a lot of hype, a lot of excitement…You want to [come] back down to earth” and use tests when they are truly appropriate, Albala said.

With the COVID-19 pandemic, the use of tele-health skyrocketed, allowing patients who did not want to come into the office to still meet with their physicians. A benefit of this trend, said Moul, is that it has helped him to develop a good therapeutic relationship with new patients, especially those with an elevated PSA level who would otherwise have been physically visiting the cancer center and been very uncomfortable and nervous. With telehealth, some first-time visits have been more relaxed and open. Exosome testing by mail has been especially convenient during this time, Moul stated.

SELECTING SECONDARY TESTS IN PROSTATE CANCER SCREENING

After a standard PSA test indicates that PSA level is elevated, borderline, or in the “gray zone,” many patients request more data before they undergo an invasive tissue biopsy, Moul explained. Those data can be generated by various secondary tests. A blood test (such as PHI) can be used to measure a patient’s risk of pros-tate cancer. Benefits of a PHI include fewer potential biopsies and more accurate detetion of prostate cancer, helping doctors not only see whether a more aggressive type of cancer is detected but also better target any necessary treatment. Urine tests can detect the overexpression of PCA3 and assess risk of prostate cancer.

 The PHI test is the first choice of secondary blood tests at Duke, said Moul, because it is done in house and can be performed right away. They have even begun to train primary care physicians to do this test.

When Moul first came to Duke, they were using the PCA3 urine test as a secondary test to standard PSA blood testing, but because it was a first-generation test, the data were not robust enough. Now, said Moul, they tend to use Exosome as their secondary urine test, and they have been satisfied with it. The Exosome diagnostics and SelectMDx tests are both widely used, said Moul, and his advice to new urologists is to become comfortable with at least 1 secondary blood test and 1 urine test to best be able to work with their patients.

Moul completes a rectal exam during a patient work-up to contextualize the PSA level based on prostate size, he explained. “Rectal exams are not perfect, and it’s hard to teach a primary care physician to do them—[plus] many of them are not that interested. But as urologists and as urology educators, we need to make sure that all residents who we train know how to do a good rectal exam, [including assessing the] size of the prostate,” Moul said.

If a patient is borderline on a rectal exam and has a borderline PSA level family history, a PHI is usually the next test Moul will order. Albala said that his institution uses PSA as its primary test, and for secondary tests, they previously used a blood test with 4K score but have started pivoting more toward urine tests.

Among the challenges presented by the use of MRI to screen for prostate cancer is that MRI quality can vary, depending on the institution.

“Sometimes patients will come in with an MRI [they’ve had done elsewhere], and they want a fusion biopsy based on that outside MRI. That’s problematic…because…we tell them, ‘Well, you have to repeat the MRI at our institution before we do a fusion,’” Moul said.

Also, said both Albala and Moul, insurance coverage presents another challenge. Moul said that in North Carolina, for instance, many insurance plans will not cover MRI in the setting of no previous biopsy, and the expensive out-of-pocket costs can run from $800 to $2500 at their institutions, Albala and Moul stated.

Several areas of unmet need exist in the prostate cancer screening space. Underserved populations is one, said Moul; many under-served patients who are at high risk for prostate cancer present with disease too late in the clinic. Also, patient adherence in following through with tests is less than ideal. Finally, both Moul and Albala emphasized the need for standardization in assessing the size of the prostate through rectal exam. Moul noted that if they could quickly capture the estimated size of the prostate, they could then more effectively contextualize the PSA level.

Albala echoed the need for a standardized way of assessing the size of the prostate. “I remember the days when Merck would give us the little models of the prostate. There was 30 g, 40 g, 50 g, and I remember trying to feel those. There was a disconnect with what you felt on the rectal exam and in the models, but that was the best that we had 20, 30 years ago. We are [getting] better, I think.”

In the urology community, Moul opined, more education is needed to better under-stand the use of secondary tests, including how to determine whether to use PHI or 4K, how to use a urine test, and when to order an MRI. Algorithms have been put in place at Duke, but much individual variation still exists.

“We’ve become more sophisticated. We’ve used these tools [and] put them together,” Albala concluded. “That’s the beauty of what we deal with [in] practice, that we’re assimilating different tests to try to decide. Because biopsy is a big commitment and complications [can happen—although] they’re relatively minor, they do exist for patients—and if we can be better clinicians, make diagnoses with [a higher] comfort level, I think that’s what our goal is. 

Prostate cancer screening guidelines. Memorial Sloan Kettering Cancer Center. Accessed May 26, 2021. https://www.mskcc.org/cancer-care/types/prostate/screening/screening-guidelines-prostate

American Cancer Society recommendations for prostate cancer early detection. American Cancer Society. Updated April 23, 2021. Accessed May 26, 2021. https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/acs-recommendations. html

US Preventive Services Task Force; Grossman DC, Curry SJ, Owens DK, et al. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. 

. 2018;319(18):1901-1903. doi:10.1001/jama.2018.3710.

Boerrigter E, Groen LN, Van Erp NP, et al. Clinical utility of emerging biomarkers in prostate cancer liquid biopsies. 

. 2020;20(2):219-230. doi:10.1080/14737159.2019.1675515

Prostate cancer: advancements in screenings. Accessed June 11, 2021. https://www.hopkinsmedicine. org/health/conditions-and-diseases/prostate-cancer/prostate-cancer-advancements-in-screenings

Articles

This article features insights from David Albala, MD, and Judd W. Moul, MD, on using liquid biomarker-based testing for the early detection of prostate cancer.

UroView: The Role of Liquid Biomarkers for Early Detection of Prostate Cancer

 do you see any unmet needs in early detection for prostate cancer? We have what we have now, do you think we can be better and what do you see in your crystal ball as you look forward? Your contributions in this area have been significant. You are a prolific writer, you've seen the changes much like I have, we saw the PLACO and the European studies for screening, we saw the task force recommendations. There has been a lot of changes that have happened over the years. First is, what do you see the unmet needs and what are your predictions for the future?

 Just unmet needs. I can speak locally, I'm not sure if this would apply to everyone, but we still have unmet needs in our underserved population. We have a lot of underserved patients who are at high risk for prostate cancer and sadly, we still see those patients presenting too late. I do not have all the answers for that but that is clearly an unmet need. We have an unmet need in having patients be more compliant to following through on some of these tests. We have an unmet need in assessing the rectal exam. I know that sounds weird, but I wish there were a simple, very easy way, almost like a bladder scanner where one could measure prostate size a little more accurately but make it so easy where even it could be done in a primary care office. And I think that even in urology offices, if you could quickly get a prostate size estimate you could contextualize the PSA more effectively. PSA [prostate cancer antigen] density is a great task. We as urologists do these ultrasounds and do a pretty good job – we are not perfect; PSA density is powerful but it is not practical. What we talked about earlier, the prostate health index, the secondary blood test or the urine test, a lot easier to deploy than other things, but PSA density is useful if you can get it. Finally, I would say that we as a urologic community and our physician extenders, just to get more education in having a better understanding of how to use these secondary tests. How to decide when to use a pHi or 4K, how to use the urine test, and then when to apply MRI. We have tried to put algorithms in place at Duke and they work to some extent but there's still a lot of individual variation.

 I agree. If we could standardize how to assess the size of the prostate. I remember the days when Merck would give us the little models of the prostate, there was 30 grams, 40 grams, 50 grams, and I remember trying to feel those. There was a disconnect with what you felt on the rectal exam and in the models but that was the best that we had back 20, 30 years ago. We are better, I think. We have become more sophisticated, we have used these tools, put them together. That is the beauty of what we deal with practice, that we are assimilating different tasks to try to decide. Because biopsy is a big commitment and there are complications, thank God they are relatively minor, but they do exist for patients and if we can be better clinicians, make diagnosis with a much more comfort level, I think that is what our goal is. Well, listen, this has been terrific. Judd, thank you. It is always great to work with you and I enjoyed my years with you. I just want to thank our viewing audience. We hope that you found these Uroview videos discussion today to be rich and informative. I look forward to working with you again and thank you for listening.

 Thanks, David. It was a sincere pleasure. Really enjoyed it.

Videos

Expert urologists remark on unmet needs in prostate cancer by emphasizing the importance of reaching under-served communities, addressing patient discomfort, increasing education about liquid biopsy testing, and standardizing prostate size assessment.

Unmet Needs in the Early Detection of Prostate Cancer

 I am trying to get a practical little algorithm developed for the audience. Obviously, almost everybody around the country does PSA [prostate cancer antigen] testing in some form, maybe regular to total PSA or free to total PSA or looks at PSA velocity. Then would you go to the blood test, or would you go to the urine-based test? I am curious on how you put that together and then I will tell you what my algorithm is, and we'll see if we're similar.

 Sure. There may be patients who only get a PSA and a rectal exam. For example, a patient with a PSA more than 20 and an abnormal digital rectal exam.

 We need a biopsy. We have been seeing quite a number of those guys seem more as we have gone through COVID. I do not know if it is just more or the fact that this primary care initiative that we have has just been bringing these guys out of the woodworks.

 Or maybe the after-effects as well of the task force were stuck. Several papers have shown that when prostate screening and PSA testing got a de-rating, we started to see an uptake in metastatic disease then they reduced it to a C rating a couple of years later. I do not think we have caught up completely. You are exactly right. I think that patient that has a PSA of 20 or you find an abnormality on the rectal exam, that is a no-brainer. We are going to biopsy those guys and that's the standard of care. Let us take a guy that comes in, his PSA is abnormal, maybe it's between 4 and 10, you don't feel anything which is many of the patients that we examine. How do you work that patient up and what do you do? Do you do the urine-based test first or do you do the blood test?

 First, as a urologist, I do the rectal exam. That is my first step when I'm seeing a patient because I really want to contextualize the PSA based on the size of the prostate. Rectal exams, we all know, are not perfect, and it is hard to teach a primary care physician to do a rectal exam and many of them are not that interested. But we as urologists and as urology educators, we need to make sure all our residents who we train know how to do a good rectal exam and size of prostate. If I have a gentleman who has a very robust prostate, significant BPH on DRE, and it's a smooth DRE with no nodules, sometimes I may just only do the PSA test and reassure that gentleman and schedule him back in a year. Just important to point out that the basics of what we do as urology is still there. However, if it is a borderline on rectal exam, if the patient has a borderline PSA family history, our next test usually is going to be a prostate health index and those are going to be binned in four groups. Generally, if the patient is low risk on pHi then they're going to be reassured and maybe come back in six to 12 months. If it is a high-risk pHi with a 50% greater probability of prostate cancer most of the time, we will recommend a biopsy without necessarily going to the exosome. However, as you said, sophisticated patients, many patients are reluctant, and they want more data. In those patients who want more data we will get the exosome and then if they have a combination of high-risk pHi and exosome greater than 15.6, we are going to really push for a biopsy. If the patient still does not want a biopsy and insists on an MRI, we will order the MRI counseling the patient that he might have to pay out of pocket. Where the exosome has helped me, the most is in patients who have that intermediate prostate health index – the gray zone. There is a gray zone there too. Then I like to get the exosome. Or the patient who is just reluctant and just has a no show and I am the third urologist telling him he needs a biopsy. Sometimes I am using the exosome test to try to convince him that he has a condition that needs to be taken seriously. I use it to try to increase compliance as much as anything. Also, finally I will say, our practice is employing more physician extenders, APPs. We train them the best we can, but they are not urologists, they have not been in practice 30 years like I have. Sometimes our younger APPs are using these tests because they are not quite as confident with a rectal exam. Is that right or wrong? It is a reality of needing some of those tests in our current workforce.

 I think that is terrific. We up here have adopted obviously using PSA as our primary test, much like what I did when I was at Duke. We did go to a blood test with the 4K score and then we pivoted a little bit to the urine studies. It started with SelectMDx and now, I think, with exosome, having the home kit – a couple of things. One is, for exosomes they must be over the age of 50 to do the test. Most of our patients, when they come into the urology clinic leave a urine specimen so it is hard to get them to urinate again. Then I just say, "We're going to mail this to you," and it works out well. That has been my test. When they get the exosome test, as you say, if they are hesitant about a biopsy, that is where the MRI, to me, fits in place. If the patients are concerned, then we go directly to a biopsy. I think the algorithms can be massaged depending on the area where you are and the tests that are readily available. We don't have pHi up here, so we relied on the K, which is commercially available, and it was a good starter test.

 Dave, I do not have a lot of experience or any experience with the Select urine test. What is the difference or what has been your experience when you look at those two?

 They're very comparable tests. With the Select test, you do need to do a rectal massage, so it is almost like a PCA 3 test. Maybe it is a PCA 3 on steroids, so to speak, because you do have to do a rectal exam in these patients. But when you looked at the areas under the curve and the accuracy of the test it appeared to be a little bit better than some of the blood tests and so that's why we initially pivoted a little bit to the urine test and then when exosome came out, just the ease for the physician made it a little bit easier to do. When a new test comes out, I look at the efficacy, I look at the cost, I look at the side effect profile, I look at the ease of doing the test and then the durability. Those five things, whether it's a new drug, a new procedure, or whatever, I always think of those five things in the back of my head to try to put these tests in perspective. Because when they come out, there is a lot of hype, there's a lot of excitement about these new tests, you want to bring them back down to earth and put them in their place on where they really have a place. That is how I've used things and it's served me pretty well.

Key opinion leaders in urology review factors to consider when selecting screening and risk-assessment tests for the diagnosis of prostate cancer including insurance coverage, commercial availability, and patient preference.  

Algorithms for Diagnostic Testing in Prostate Cancer

 COVID, I think, hit our whole country, and really turned the way we practice medicine. We saw an explosion happen in telehealth, and these patients did not want to come into the office, but they still wanted to see their physicians. And the beauty of the Exosome test, which really is just a – It's a urine test that I kind of think of like little tweets. The exosomes are tweets of RNA and DNA and proteins that give us some insight on, what is that risk of cancer, of prostate cancer, and of high-grade prostate cancer 7 and above? And the urine test was quite nice. I think that really kind of changed the playing field a little bit. You did not have to do the massage. You could do a tele visit. If the patient had an elevated PSA you would say, "Well, you're in perhaps a gray zone. Let us do a test that may give us a little more insight." You mail them the kit, you get the results back in seven to ten days and then you can say, "I think you should get a biopsy," or "No, I think we're fine. Let us continue to monitor yourself." And bringing them in. Obviously, you did not need to do a rectal exam. I think that that really was a significant boon for us because it allowed us to still diagnose prostate cancer with patients that had elevated PSA's [prostate-specific antigen].

 I just want to make a comment about telehealth and just your experience. COVID [coronavirus disease of 2019] has been a terrible situation for the world and our country, so I do not want to downplay, it's been overall very bad time for us. But out of badness comes some good things and we really forced our profession to really embrace telehealth and so the advances that we had just at our hospital in the technical ability to make telehealth work was amazing. What I have found is it's pretty easy for me to develop a good therapeutic relationship with a patient. My clinic is primarily in a cancer center. It is intimidating. And I have these guys coming in with an elevated PSA into the cancer center, they are uncomfortable, many of them are out of their element and they are nervous, their blood pressure's up. I found that telehealth for an elevated PSA, at least a first-time visit, they are at home, they are more relaxed. They can open to me more; they are not as freaked out. And, as you said, they do not like the rectal exam anyway so they can do potentially a lab. We have set up lab and leave so patients can even go to a remote location – four sites in our health system – and do not even need an appointment. They just call from their car when they are in the parking lot and the lab just go ahead and do it. But with exosome, the mail-order test has been really, nice and we can get those results back. And compliance. It blew me away when we started this initiative with Duke Primary Care, really embracing working with primary care on getting these younger guys in, how non-compliant patients are. Sometimes the patients who had the highest PSA's or seem to be at the highest risk are the ones that were most likely to no show. Not only for their PSA appointment but no show for their biopsy. I guess you do not get that that much in private practice. You used to work at Duke Cancer Center, and you know you might have a CEO in one exam room and someone who is low socioeconomic status or low health literacy in the next exam room. The point is that tests like exosome and/or pHi, more data increases the patient's compliance. Some of my embrace of these tests was to try to convince some of these guys that they need to come in for the procedure and that they should not no-show. I do not know if you have seen that in Syracuse.

 I agree completely with you. Again, we are talking about more sophisticated patients that know a lot about prostate cancer. I am sure many of them have had relatives or family members that have had it so they are really keen on these tests and they know these tests now, which is really a change. The educational level of patients is significantly higher I think than it was 10 years ago. When I was at Duke Cancer Center, I think my active surveillance rate was around 10%. It is now close to 40%. As clinicians, we are seeing, once we diagnose prostate cancer, if they have a Gleason 6, we may do some genomic testing on these individuals. And if they have an Oncotype or a Polaris or a Decipher score that's low risk we are going to follow those patients. Those patients for the most part do quite well, and that is another significant contribution that we've learned over the years to change the way we practice.

David Albala, MD and Judd W. Moul, MD consider the impact that COVID-19 has had on the clinical experience of patients with prostate cancer and share personal insights regarding telehealth and patient compliance.

David Albala, MD

Articles

UroView: The Role of Liquid Biomarkers for Early Detection of Prostate Cancer

Unmet Needs in the Early Detection of Prostate Cancer

Algorithms for Diagnostic Testing in Prostate Cancer

COVID-19: Telehealth and Compliance in Prostate Cancer