Eric Klein, MD, Chairman of Cleveland Clinic’s Glickman Urological & Kidney Institute joins the Cancer Advances podcast to discuss the IsoPSA Test, now being offered at Cleveland Clinic. The IsoPSA test is a novel prostate-specific antigen assay for patients with a PSA > 4ng/ml who are facing a decision on prostate biopsy. Listen as Dr. Klein discusses how the IsoPSA test differs from conventional PSA testing and how your patients can benefit.
Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Eric Klein. Eric is a urologist and Chairman of the Cleveland Clinic Glickman Urological and Kidney Institute. He's here today for our podcast again, this time to talk to me about the IsoPSA test. So, welcome Eric.
Eric Klein, MD: Thanks, Dale. Nice to be here.
Dale Shepard, MD, PhD: Well, maybe we could start out. What exactly is the IsoPSA test?
Eric Klein, MD: It is a new lab test, a new assay that measures PSA in the bloodstream of men at risk of prostate cancer in a novel way. All the current PSA assays that are out on the market are concentration based, that are monoclonal antibody based. And they measure the amount of the major PSA molecules in the bloodstream. IsoPSA takes us back to eighth grade aqueous chemistry class. It measures the PSA related proteins that are present in blood in a way that looks at their chemical structure rather than their concentration.
And the way it works is in a single tube there are two different aqueous phases, for example, dextran and ficoll in the same tube. It's like oil and water, they don't mix. And when you put a drop of blood, or several drops of blood that have proteins in them, the proteins segregate in the two phases, top and bottom, based on their physical structure. And the different ways that they interact with these two aqueous phases. And so, when you measure the ratio of how the PSA ISO forms segregate, you can predict the risk of cancer. That's probably the simplest way I can explain. It's a little complicated, but it's different than the current assays.
Dale Shepard, MD, PhD: And, I guess, when you think about this as a test. This, as I recall, is something that's done reflexively in people who already have an elevated PSA, is that correct?
Eric Klein, MD: Yes. The idea is, at least currently, to use this test to determine whether someone with an elevated PSA is at risk of high grade cancer. So, the problem with PSA, as you know well, is that it's prostate specific, but it's not prostate cancer specific. And, in fact, it's correct to say that most men in the world who have an elevated PSA actually don't have prostate cancer they have non-cancerous prostate enlargement or BPH.
And so, what happens if we use PSA alone as a reason to do a biopsy, we do way too many biopsies. That's bad for patients because it's a nuisance, it's uncomfortable, it's costly, there's a risk of infection. And we often get back benign tissue, or low grade cancer. And, in today's world, almost all low grade cancer gets managed by active surveillance. And the reality is we'd rather not even know that it's present because it's not like that it'd hurt anybody. So, PSA is far more accurate in finding high grade cancers, Gleason grade 7 or higher cancers that generally we treat than PSA is. That's what it's advantage is.
Dale Shepard, MD, PhD: So, clearly people are oftentimes concerned that they might have cancer. And you'll have patients, they'll say, "I just want to know. I have to know." Of people that have an elevated PSA. How many of them have cancer? And of the people who say, "I want a biopsy, how many might have complications?"
Eric Klein, MD: Yeah so PSA, in terms of predicting cancer, is almost a coin flip. It's a little better than 50%. but a lot of those cancers are low grade. And so, again, we'd rather not know about them. So, the more relevant question is what percentage of patients with a PSA over 4, or have a grade 7 or higher cancer that needs treatment. And it's less than 50%. IsoPSA is accurate with a readout of Gleason 7 or higher cancer at 80%.
So, if you have an IsoPSA below the cutoff, which is defined as 6, this ratio is defined a 6. Less than 6, you have a 92% chance of not having a high grade cancer. Let me say that again, a 92% chance of not having high grade prostate cancer. You might have low grade cancer, but we don't care about that. And if your IsoPSA is above 6, then you have about a 50% chance of having a high grade cancer. Not just any cancer, but a high grade cancer. And I think most urologists and probably most patients would recommend, and be willing to have a biopsy for a 50% risk of high grade cancer.
So, complications in the standard way biopsies are done transrectally, everybody got some rectal bleeding, and typically some urinary bleeding for a day or two because when the needle goes into the prostate it causes some bleeding into the ducts in the prostate for 6, or 8, or 10 weeks afterwards men will have blood in their ejaculate, in their semen, which is benign, but scary. And the main risk is of infection. So, about 3% of men overall, after a transrectal biopsy get an infection. And about half a percent actually get bacteremic and septic. There have been, in the distant past, reports of deaths after prostate biopsy. There haven't been any reported in many years now because we have better antibiotic regimens.
Along that line, let me just add as a tangent, we're starting to shift to transperineal prostate biopsy instead of transrectal, where the needle goes through the skin, rather than through the rectum. And that reduces the risk of infection to virtually zero.
Dale Shepard, MD, PhD: But still, with those kinds of numbers, it is really, really important to minimize biopsy. So, it makes this even more important.
Eric Klein, MD: Yeah. When you do the big cost-benefit analysis, when you look at what the benefits are, it's really interesting. IsoPSA has been available exclusively at the Cleveland Clinic about five months now. That's changing as we speak, and will disappear soon. But in our first 200 patients who had IsoPSA across 25 clinicians, we did 60% fewer biopsies, which is tremendous. So, we have avoided biopsying 60% of patients who were likely to have either benign biopsies or only low grade cancer. And that saves on the cost and inconvenience for the patient and the risk.
Dale Shepard, MD, PhD: And in our current era with COVID minimizing procedures, and interactions, and things is important as well.
Eric Klein, MD: Yes, all of those things. But even absent COVID, there's real benefit. And we've published one cost-benefit analysis of how this would work out. And not only, most importantly, do the right thing for the patients, but save the system money.
Dale Shepard, MD, PhD: When we think about people and getting diagnosed with cancer, or concerned about diagnosis for cancer, of course, there's a lot of anxiety. What kind of timeframe is this? So, patients get a PSA, it's elevated. They go to get this test, how much longer do they have to wait to get an idea if they have cancer or not?
Eric Klein, MD: Yeah, right now it's about a five day turnaround time. And that's because it's a new test. The lab is just scaling up, and it does have to be sent out to a central lab that's here in Cleveland. And, eventually, that turnaround time, I hope, it will be even a little bit.
Dale Shepard, MD, PhD: You mentioned available here at Cleveland Clinic, you mentioned that that might be changing. Can you elaborate on that at this point?
Eric Klein, MD: Yes. For the first three months, I think it was available only exclusively at the Glickman Institute. The company has started to make it available in select markets as a lab developed test for an out-of-pocket cost. And that's going to continue to expand. And the company is preparing an application for FDA approval that will get submitted, I think, in the first quarter of next year. And they have already engaged major insurers to educate them about the test, and get them interested in understanding what the potential insurance savings are, and so forth. So, it does have breakthrough designation by FDA, which means that once the application's submitted that a decision on approval or not approval will come relatively quickly. And if FDA approves it, then usually Medicare coverage follows. And when Medicare pays for something, usually, private insurers follow after that.
Dale Shepard, MD, PhD: When we think about physicians that might be listening in, how would they go about getting this test for their patients at this point?
Eric Klein, MD: Well, for the moment in Cleveland, the patient needs to be seen at the Cleveland Clinic, and at the Glickman Institute. And I'm not actually certain as to when the company is going to make the test more widely available in the local community here. Soon though, I think, soon. And we'll publicize that on our website when it happens.
Dale Shepard, MD, PhD: All right. How does this compare to some other tests that are either available, or being developed? How does this fit into the market of looking for prostate cancer in patients?
Eric Klein, MD: Yeah, so it's a great question. So, there are two other reflex tests on the market. Meaning tests intended to be used in a similar way. Elevated PSA, do I need a biopsy or not, that sort of thing. One of them is called the 4Kscore, which is a monoclonal antibody based test that measures a precursor to PSA and some other related proteins. And the other one is called Prostate Health Index, which measures PSA, free PSA and a precursor and so forth. There have been head-to-head studies of those two tests in the reflux setting, and they perform identical to each other. We have not done any head-to-head tests with IsoPSA. My guess is that they're going to be in the same ballpark of about 80% accuracy. If you combine IsoPSA with MRI guided imaging and so forth, we can push the accuracy of the area under the curve to around 0.83 or 0.84. So, IsoPSA may be marginally better but, honestly, there haven't been head-to-head tests yet in the same population.
In terms of practice, the days of biopsying everybody who have a PSA above 4 or over and a reflex test, any three of these would serve the purpose of avoiding some unnecessary biopsies. IsoPSA is very easy to use. It is designed for those who work in an Epic EMR environment to be easy to order in Epic, and then have the result returned to your Epic inbox. And that's not always the case with the other tests that are available. So, this will be a little easier. And theoretically, because it measures all the ISO forms of PSA in the bloodstream, not just the ones that you need to know about because the monoclonal antibody, it may have slightly broader sensitivity and specificity. We haven't proven that, but it may be so.
Dale Shepard, MD, PhD: So, far we've been discussing patients come in, they get a PSA that's elevated. We're trying to decide on that initial biopsy. Is there a thought that this could ultimately have a benefit for patients who are on active surveillance to see if their tumor has become high grade?
Eric Klein, MD: Yeah. There is that thought, and not much data on that yet, but that is another area that we'll be looking at once the lab scales up, and can handle more samples. I mean, there's a critical need to figure out in patients on surveillance, whether their next surveillance biopsy will show high grade cancer, or something else that would change management, and push you towards treatment. There are a lot of markers out there that have been looked at it in that space, for example, 4K and Prostate Health Index, and they're not predictive for that.
We've looked at serial MRIs and most serial MRI is also not predictive. So, we're looking for a biomarker that can help us avoid repeat biopsy, and [inaudible 00:11:56] surveillance. And I don't know if IsoPSA will be that biomarker or not, but it is planned for study.
I would say one other important thing about IsoPSA, I just saw the data for that this morning, it performs equally well in the African-American population as it does in non African-Americans. And I think that's important. It'll be a useful tool across the spectrum of everybody who gets prostate cancer.
Dale Shepard, MD, PhD: That's outstanding because, certainly, there are differences in risk. When we think about something you've talked about frequently is this whole nature of not treating people that don't need treated and the number of patients with prostate cancer. And how we over treat often in the past. Just broadly speaking in terms, again, of scope about 190,000 cases a year. How many of those cases do you think really need treated? Where do you, where do you think we can settle with a test like this to really making sure the right people get treated?
Eric Klein, MD: It depends on your biopsy strategy. The percentages can be misleading. So, if you use current biopsy strategy, which is biopsy everybody with a PSA over 4 probably 60% of those patients have low grade prostate cancer and don't need to be treated. If we stop biopsying those patients, and we only biopsy patients who have high grade cancers, or are likely to have high grade cancer the percentage who actually need treatment is going to go up, but that's an artifact of doing fewer biopsies, but it's a substantial portion. Only about 60% of men with low grade cancer across the US actually go on surveillance even though probably 90% of them are really good candidates for it.
Dale Shepard, MD, PhD: So, ultimately, we're talking about screening and strategies to figure out who has a prostate cancer. This test seems like it's going to be very, very good at sorting out who actually needs treated. But while we have you here, views on screening. There's a lot of confusion in terms of who gets screened, when they get screened, how that process works. Can you share some thoughts on how you've used screen, and where we are now, and what this would ideally look like?
Eric Klein, MD: Let me say, first, that there's solid evidence that screening saves lives. It prevents men from dying of prostate cancer. And I say that based on my own personal experience. When I started in urology, PSA didn't exist, more than half the men that we saw with newly diagnosed prostate cancer had metastatic disease. And the commonest and the only treatment for that then was castration, bilateral orchiectomy. Five years after PSA was introduced in the late 1980s, we saw the huge stage shift, so that 90 to 95% of newly diagnosed men had early stage disease and not metastatic disease. And I am absolutely convinced, based on that experience alone, that PSA screening works.
But, beyond that, we have actual data. There was a large trial done in Europe that we have a 16 year follow-up on now that shows a marked reduction in the risk of dying of prostate cancer on the order of 27% reduction in the risk of dying of prostate cancer in patients aged 55 to 69, which is really the target population for screening. And more important than that, and really overlooked and not appreciated is that not only was the death rate markedly lower, but there was a 35% reduction in the need for palliative therapy for metastatic disease.
Metastatic disease is painful and costly to treat, and that needs to be added into the denominator of the benefit of screening. And if you look at the number needed to screen to save one life based on that data, and then some projected data out to 25 years from that trial, the results are better than comparable numbers of screening for breast cancer and so forth. So, then the question becomes who to screen? So, we rarely see prostate cancer in men under 50. So, the current recommendation is generally a baseline PSA at age 50. And then, how often someone gets screened after that depends on what that PSA is at 50. If your PSA is below the population average, which is about 0.7, you probably only need to be screened once every two to three years. And if your PSA is below 2, when you're 60, the likelihood of you getting metastatic, or lethal prostate cancer is under 2%. And so, you can probably be screened even less frequently after that.
On the other hand, if you have risk factors, if you're African-American, if you have a strong family history, and particularly in first degree relatives, brothers and fathers, we know that those individuals are higher risk. If you're a BRCA carrier, we know that you're at three to five times higher risk of getting prostate cancer. Those people ought to be screened, certainly, at age 50. And some would argue even starting at age 40 or 45 to be followed closely and to be screened yearly for life.
Dale Shepard, MD, PhD: Excellent. So, just to reiterate back on this IsoPSA tests, can you just remind us, as we're wrapping up here, who's best suited for this test? I know that there's certain PSA limits that might be in play. Who should we be thinking about?
Eric Klein, MD: Yeah so, the FDA label requests is going to be for men over 50, 50 or over who have a PSA above 4. And who are being considered for prostate biopsy based on those characteristics. Of course, you would never order a test unless it's going to change your management so, if you have someone who's 50, who's got three brothers who got prostate cancer when they were in their 50s and their PSA is 4 1/2 that's probably someone you're going to do an MRI on and biopsy. But for the average patient who doesn't have those risk factors, and PSA above 4, IsoPSA is a great choice to decide whether or not they need be biopsied.
Dale Shepard, MD, PhD: Well, thank you very much for being with us today.
Eric Klein, MD: All right, pleasure. Thanks for having me.
Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget you can access real-time updates from Cleveland Clinic's cancer center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.