Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And today, our discussion focuses on how a recent blood test may reduce unnecessary prostate cancer biopsies, revolutionizing prostate cancer detection, a blood test breakthrough. Joining me is Dr. Adam Murphy. He's a distinguished Professor of Population Health Research in Urology and an associate Professor of Urology and Preventive Medicine at Northwestern Medicine.

Dr. Murphy, I'm so glad that we have you with us today. This is a really great topic and it's fascinating actually. But before we get into it, I'd like you to tell us just a little bit about yourself and your role at Northwestern Medicine.

Dr. Adam Murphy: Okay. Thank you for the introduction and also for having me. I am a Population Health researcher focused on biomarker and risk prediction tools, and prostate cancer. And so, I've really been focused on how these risk prediction tools can be used to enhance detection of prostate cancer, biopsy decision-making. And then, also for people who are newly diagnosed with prostate cancer, I would like to know if these risk prediction tools are accurate across different racial and ethnic groups.

So, that's been something that's been really born out of my work in Chicago and also being a native Chicagoan. It's a very cool, diverse city that we get to live in with very different neighborhoods that have rich cultural history and also ethnic and racial diversity. And because of that, I thought it was important to have the people who come to Northwestern when we are talking to them about their prostate cancer risk, then we were very very accurate about giving them personalized answers to help them make really informed decisions for their prostate biopsy decisions and also what they're going to choose for their prostate cancer treatment.

Melanie Cole, MS: Yeah, this is a very, very important topic, Dr. Murphy. And as you say, our city is so diverse, and it really is necessary, and it's a great initiative to reach out to underserved communities, but really to all men that are looking at their risks. So, provide us a little bit of an overview of your recent study on Stockholm3 and its role in prostate cancer detection. Can you discuss for us how the study methodology, recruitment influenced the outcomes of the study? Tell us about it.

Dr. Adam Murphy: So, this was a really cool project. I was approached now five years ago by a mentee actually at University of Illinois at Chicago, before he went into his lab year as a Urology resident named Hari Vigneswaran, and he asked me to be his mentor on this research project he was starting with Karolinska Institute in Sweden.

And they were interested in asking me to help them validate their fairly new biomarker called the Stockholm3 assay. And the  Stockholm3 assay is like PSA but better. It helps people predict a person's risk of having a clinically significant prostate cancer. Remember, we don't want to detect all prostate cancers, so we're trying to detect the ones that are potentially lethal and can metastasize.

So, they had this assay that they had validated in Swedish men and then in European men. And they wanted to bring it to the United States population. And they were really focused on African Americans and Blacks in this country, and that's what I was initially known for. And I told them that it wouldn't be fair just to focus it in on Black men, and we had to do a better job of representing the people in the United States, who at least represented 5-10% of the population. And so, they agreed with me. And they ended up using my samples that we had, which were rich in Black men and in White men. But they made it so that they could recruit in other centers. So, they ended up recruiting at 17 different sites across the United States, most of them are academic medical centers, but some private practice groups like Europartners here in Chicago. And so, they basically got this 17 clinical sites recruited based off of their ability to recruit ethnic diversity. So, we wanted to make sure there was enough White males, enough Hispanics, enough Blacks, and enough Asians to basically represent the major ethnic groups in the United States. And that's what they did.

So, over four years, they recruited enough men so that you could do an analysis of this biomarker called  Stockholm3 across the four different ethnic groups. So, they had 46% White male, this is non-Hispanic White men. But they also had 14% Hispanics for 305 men. They had 16% Asian recruitment, and that was 350 men. And then, there was 24% of the population that were black, and so that was 505 men. That meant that they were powered. They had enough statistical power to show how this assay worked in each of those racial and ethnic subgroups, which is what I was most excited about.

So, the methodology was we had people that we had already recruited, and then we also went about recruiting new participants from all these sites and combine this population. So, we got 2,129 men overall for the study. And we were able to just really prove that this test was non-inferior, not worse than the accuracy of the normally used PSA greater than 4 threshold for making biopsy decisions to see if it was going to be as sensitive or nearly as sensitive in detecting clinically significant prostate cancer.

And really, the goal was to help men avoid unnecessary biopsies. And so, we were trying to measure that through what's called specificity. And specificity is a true negative rate. If you have a negative test, how often is it actually truly a person that does not have disease? So, the true negative rate allows men to avoid biopsies when they don't have cancer, essentially.

And so, we found that this assay was on average 2.9 or approximately three times more specific for saying when you do not have clinically significant prostate cancer. And that allows a lot more men across all the four ethnic groups we talked about in the U.S. to avoid unnecessary biopsy.

Melanie Cole, MS: What important work you're doing, Dr. Murphy. So, how do you foresee the  Stockholm3 test fitting into everyday Urology practice? Speak a little bit about patient selection that other urologists should consider when deciding to use it.

Dr. Adam Murphy: The main finding of the study was that the threshold that they used, which is this greater than 15 number, the threshold that they used to say what a positive test is defined by. That worked pretty well across all populations, but it did miss some cancers in Blacks. And so, they decided to lower the threshold to greater than 11 in Black men to give them similar sensitivity to American Whites and Hispanics and Asians. So, that was the only thing that was, I think, worth mentioning about, the thresholds not being exactly the same across all the populations. And that aligns with the fact that Black men have a 70% higher risk of cancer and twice the mortality rate. And so, the thresholds were slightly lower because it was just more common to have clinically significant prostate cancer in Black men. And so, that's one thing that I think is a little Important caveat to add in about why this study was important to do across the four ethnic groups we chose. And then, for the average urologist, how they should they use this test.

For the average urologist right now, we tend to use whatever tests we like on the biomarker space. Some folks may still be using free PSA. And now, that there's MRI out, they may be using MRI with PSA density. PSA densities, prostate volume is in the denominator and the PSA is in the numerator of that formula. So, it basically is, is this PSA level appropriate for the amount of prostate tissue this patient has? So, people are using that because it's readily available if you already have an MRI and you know the patient's PSA from before.

I think this one is a little bit better in the sense that it does have better specificity than PSA, and it's very similar in its sensitivity to PSA. So, I think it's one of the tools that we can use like a 4Kscore or like prostate health index. There are others in this space as well. The urine test called ExoDx. There's Confirm MDx, Select MDx. So, there are other tests that are like this, like the MyProstateScore. This one's good in that it's very thoroughly validated across ethnic racial groups, and you can use it almost the same across each group. And most of the other assets, you can't exactly say that. So if you have this test, you can use it in Hispanics comfortably and Asians comfortably and Whites comfortably, non-Hispanic Whites and in Black men. But you just may lower the threshold in Black men to 11 to be safe to determine who to biopsy if you are not going to use MRI in your decision-making.

And, as far as cost, it's similar in cost to a lot of its competitors. Prostate health index is still the cheapest. And if you don't account for the MRI cost, PSA density, if you have an MRI, becomes the cheapest with an MRI. So, I think it's fair to use this if you don't have an MRI by itself. I think if you do have an MRI, you could use this test before MRI and say if they have a threshold greater than 11 if they're Black or greater than 15 if they're non-Black to then order an MRI if you choose to, and then make your decision based off of the MRI findings, whether or not you biopsy somebody. And so, I think it's just a good way to help more men avoid unnecessary biopsy by using these tools one after the other or in series.

Melanie Cole, MS: Just so many tools in your toolbox these days, Dr. Murphy. It just seems like every day, something new. So if this is being used along with PSMA, if we're looking at these advanced MRIs, take us from bench to bedside, do you see this being used in the future, even in someone with non-clinically significant prostate cancer? As you've said, you're looking for something very specific. So, look to the future for us and tell us what that looks like.

Dr. Adam Murphy: So, PSMA, PET scans, whether it's by CT or MRI, are really pretty sensitive in detecting prostate cancers within a prostate. But this is a very expensive test, about $5,000 on the cheaper end of that, just for the PSMA tracer that they use. That PSMA tracer is basically kind of like an antibody that has a radioisotope tag to the end of it, and it can bind to prostate cancer cells or blood vessels that supply blood to prostate cancer cells because they all have the PSMA molecule on their cell surface or cell membrane. And so, it's very specific and fairly sensitive too for detecting prostate cancer wherever it is in the body.

And so, right now, it's really used mostly for staging purposes and for detecting where cancer is if it's come back after a primary treatment. But for detection, which is where this space is, you know, you're using it as a screening tool, pSMA is a fairly expensive screening tool, so it doesn't work there very often now, but prices probably will drop over time.

Right now, they have to make these PSMA radiotracers, and they have a very short half life. And so, if hospitals don't have their own facility for making PSMA molecule, it's an expensive molecule if you let it go to waste. So if someone misses an appointment, it's a costly endeavor. So, it's not really in the PSMA space very often for screening. Right now, it's being used in the screening spaces, PSA-related markers like this one, this is also PSA-related. Prostate health index assay, those are awesome. Those other tests I mentioned, like MyProstateScore and ExoDx and 4Kscore. Those are the kind of urine or blood-based biomarkers that are similar to this. We're mostly pairing it with prostate MRI at this point, which has become pretty standard of care because of two large clinical trials that kind of validated its accuracy.

So, many people are using both biomarkers like Stockholm3 and MRI. And I would say the way that this is best positioned is that there's good validation data across four different ethnic groups in the U.S., which makes up 90% of the U.S. population. So, if you're worried about validation, that's where it is.

What's new and exciting in this space, I think  Stockholm3 is actually putting in more genetic markers into their tests. And often incorporating more genetic ancestry markers into their tests to make it more robust and predicting risk in a more race-based individualized manner. So, that's exciting.

I do think that PSMA PET scan will get more utilization in the future as prices come down. And as you can find ways to do similar work without a hospital having to have their own cyclotron to generate these radioisotopes, it's only going to be in major academic medical centers right now, is my belief.

Melanie Cole, MS: Yeah. This is so interesting. Dr. Murphy, as we wrap up, I'd like you to speak to other providers, the key takeaways, what you think, and what you see is how this might shape future guidelines in prostate cancer care and the long-term outcomes that you anticipate seeing as the Stockholm3 test is implemented in clinical practice.

Dr. Adam Murphy: For the takeaways for the urologists, I would say that, if you deal with a racially or ethically diverse population,  Stockholm3 has really good validation data across race. It compares favorably to some of the other biomarker tests. And if you're using it by itself as a one-time test, it's pretty good to use. You can feel confident across most patients in your population that you get a good answer. If it's negative, it would be negative. If it's above the threshold, you could go ahead and order an MRI or receive the biopsy if that's not available in your center. That's my take-home for the actual  Stockholm3, kind of how you use it. It's available in the U.S. Market now. Insurances are covering it. I think Medicare and Medicaid already cover it. So, most patients should be safe to try it.

So, how I think that the  Stockholm3 will be changing in the near future as it gets more implemented, one, I'd love to see this being used alongside MRI. And so, people will do some comparisons of these biomarkers to show that it works well with prostate MRI. And it will develop algorithms like they do for prostate health index assay and MRI, how they can be used together to inform biopsy decision-making. So, I think that is the next step. I think they're already working on that, those publications now in fact. And then, validating it in other populations.

I mean, I think we did a very good job with the 17 sites in 2000 men. What we've seen is that the negative predictive value of these tests vary by different populations. And so, we have special populations here, like in the VA. Veterans are exposed to Agent Orange, and so they may have a different risk profile. And so, that would be a group that it would be nice to have validation data in. There are other ethnic minorities that we did not get large numbers of. Obviously, Native American indigenous populations for one. And so, I think just getting more data about how they work as a standalone marker in these more high-risk or less studied populations will be good. And then, these companies are usually trying to push for inclusion into the NCCN and the AUA and the EAU prostate cancer screening early detection guidelines. And so, I think we'll just have to keep looking out for the updates for how they work over time.

So, just looking forward to more insurance coverage, more validation data and how it works with MRI and eventually with PSMA PET scan.

Melanie Cole, MS: Thank you so much, Dr. Murphy, for joining us today and sharing your study and your incredible expertise. What an interesting conversation. To refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/urology to get connected with one of our providers.

That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. Thanks so much for joining us today.